Applied Evidence

What’s it like to be the caregiver for an Alzheimer’s patient? In my case, it was like being both married and widowed at the same time. Or as a person in my support group once put it: It’s a life filled with grief on the installment plan.

My wife, Clare, struggled for nearly 10 years with Alzheimer’s disease before passing away in April 2016—just one month shy of her 70th birthday and 2 months shy of our 49th wedding anniversary.

Our experience was gut-wrenching, but not unique for families coping with Alzheimer’s disease. Life as a caregiver is one of non-stop daily stress, with much sadness and anxiety, often accompanied by periods of mild or serious depression. Doubt, guilt, frustration, and many other emotions lead many caregivers to take anti-anxiety or antidepressant medication, meet regularly with therapists, take sleeping pills, or experience significant weight gain or loss. Stress drove me to my comfort foods, and I gained nearly 100 pounds while caring for Clare. Only in the last few months have I been able to start taking off that weight.

Helping a loved one who has Alzheimer’s with even the basic activities of daily living—hygiene, dressing, eating—becomes progressively difficult. Caring for a loved one who is confused, no longer remembers your name or who you are, or can occasionally become aggressive, is emotionally painful.

After being Clare’s 24/7 caregiver for 6 years, I agreed that placement in an assisted living facility was in her best interest. My role morphed from primary caregiver to primary care advocate, but the stress did not lessen. I met regularly with facility staff to ensure proper care because many staff members were not sufficiently motivated, educated, or trained to consistently provide proper care for individuals with Alzheimer’s disease.

Financial stress weighs heavily on caregivers. Unless one qualifies for Medicaid, is very wealthy, or is lucky enough to have outstanding long-term health care insurance and prescription drug coverage, caregiving costs can be astronomical. For someone with Alzheimer’s in a community such as Long Island, NY, assisted living facilities charge between $7000 and $10,000 per month, and nursing homes between $15,000 and $18,000 per month. Home health aides working 24/7 also cost around $15,000 per month. Caregiving costs can drain not just the patient’s bank account, but can wipe out the retirement life savings of the surviving caregiver.

Once Clare went into assisted living, I dealt with the daily loneliness and the enormous lifestyle changes. Being alone in my bed those first few nights after placement was painful beyond words, and learning to live alone for the first time after many years of marriage brought incredible sadness. It is no surprise to me that research points to caregiver stress as an independent risk factor for elderly caregiver mortality.¹

My experience navigating the health care system with my wife included numerous challenges and instances of unnecessary frustration. My hope in providing the following suggestions is that they will help you help other families like mine.

1. Listen carefully to caregivers

When Clare first exhibited symptoms suggestive of Alzheimer’s, I started logging them and presented written summaries to doctors at each visit. But unless Clare exhibited those same symptoms in the presence of her doctors, my observations were routinely ignored. I’d try to discuss concerns—eg, Clare getting lost while driving to familiar locations, experiencing increased aphasia—but the doctors didn’t read my logs or listen carefully to what I was trying to tell them. The January/February 2017 AARP Bulletin² noted studies showing that doctors listen for about 23 seconds before interrupting patients, but it also cited a 2001 South Carolina study³ that found patients spoke, uninterrupted, for an average of 12 seconds before being interrupted by a resident.

I eventually did learn that early Alzheimer’s symptoms can be easily misinterpreted as signs of stress, anxiety, or depression. But that underscores the need for doctors to listen carefully to caregivers, especially spouse caregivers who observe behaviors 24/7 that may not be present in a quick office visit or revealed on a brief cognitive screening test.

2. Stay up to date on screening tools that detect Alzheimer’s

The Mini-Mental State Examination, or MMSE, is the most frequently used cognitive screening tool, in part because it can be administered in less than 10 minutes. Although unquestionably valuable, a Cochrane review “did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI [mild-cognitive impairment] patients who could develop dementia.”⁴

Time-pressured doctors might consider using the AD8 screening interview, an informant questionnaire that takes only 2 to 3 minutes to administer, but has demonstrated superior sensitivity in detecting early dementia compared with the MMSE.⁵ In addition, a study in the December 2016 issue of the Journal of Alzheimer’s Disease  ⁶ confirmed the usefulness of the Sniffin’ Sticks Odor Identification Test whereby patients try to identify 16 different odors. I can attest to Clare’s rapidly deteriorating senses of taste and smell as her disease progressed.

A simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer's.

“Results suggest that a simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer’s, and even for identifying people who are at the highest risk of worsening,” according to principal investigator, David R. Roalf, PhD.⁷

Prompted by prior studies that have linked a weakening sense of smell to Alzheimer’s, doctors in a few larger dementia clinics have already begun using smell tests in their assessments. One possible reason the practice has not yet become common, however, is that the tests take about 5 to 8 minutes to administer. Roalf and his colleagues are hoping to develop a shorter test that will work as well as the longer ones. “We’re hoping to shorten the Sniffin’ Sticks test … down to 3 minutes or so … We think that will encourage more neurology clinics to do this type of screening.”⁷

Is 5 minutes too much time to take to administer a valuable screening test?

3. Be candid when speaking with patients and their caregivers

A survey reported in Time magazine on March 24, 2015, found that as many as 64% of doctors do not share a diagnosis of Alzheimer’s with their patients because of “fear of causing emotional distress in their patients” due to a lack of effective treatment or cure, and because of a “lack of time and resources to fully explain what the diagnosis means.”⁸

But Alzheimer’s patients and their caregivers need as much time as possible to plan accordingly, especially if they have not already discussed and finalized end-of-life planning (will, living will, health care proxy, durable power of attorney), preferences for staying at home with aides or being placed in a facility, or wishes to take final trips or enjoy final activities together before cognitive impairment worsens. Withholding a diagnosis can rob patients and caregivers of that valuable planning time.

4. Connect caregivers to resources and support groups

If caregivers have already observed issues with their loved one's driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer.

Information on the stages of the disease, available local support groups, and online resources are extremely helpful. Of the 15 people in my spouse support group, only one or 2 were referred there by a doctor. Become familiar with local support groups because that is where caregivers discuss common needs, learn and share helpful caregiving strategies and techniques, and find emotional support from others walking in similar shoes.

5. Help caregivers take away the car keys

When to take away the car keys is an extremely difficult emotional decision that often leads to heated arguments. People with Alzheimer’s rightfully fear losing their independence and only reluctantly accept they can no longer drive safely. But their caregivers worry about them getting lost or causing an accident or, worse, a death. Even though some people with Alzheimer’s can continue to drive safely for a while, the ever-worsening cognitive decline with the disease sooner or later leads to impaired judgment and the inability to drive safely.

If caregivers have already observed issues with their loved one’s driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer. And please do not routinely refer people with Alzheimer’s to driving test facilities. A person with Alzheimer’s may do very well at the particular moment of the test, yet might fail that same test if it was given an hour earlier or later.

6. Manage expectations of what medications can do

None of the current FDA-approved medications have proven to have any long-term positive effects on Alzheimer’s. Clinical trial data show that these meds may be able to slow the rate of disease progression for some people who take them, but even then the benefit is short-lived. Yet many doctors, year after year, renew these “expensive bottles of hope,” as I call them, when the thousands of dollars needed to buy them could be much better spent on day-care programs or personal aides. A candid disclosure to patients and caregivers would enable better decision-making.

What’s it like to be the caregiver for an Alzheimer’s patient? In my case, it was like being both married and widowed at the same time. Or as a person in my support group once put it: It’s a life filled with grief on the installment plan.

My wife, Clare, struggled for nearly 10 years with Alzheimer’s disease before passing away in April 2016—just one month shy of her 70th birthday and 2 months shy of our 49th wedding anniversary.

Our experience was gut-wrenching, but not unique for families coping with Alzheimer’s disease. Life as a caregiver is one of non-stop daily stress, with much sadness and anxiety, often accompanied by periods of mild or serious depression. Doubt, guilt, frustration, and many other emotions lead many caregivers to take anti-anxiety or antidepressant medication, meet regularly with therapists, take sleeping pills, or experience significant weight gain or loss. Stress drove me to my comfort foods, and I gained nearly 100 pounds while caring for Clare. Only in the last few months have I been able to start taking off that weight.

Helping a loved one who has Alzheimer’s with even the basic activities of daily living—hygiene, dressing, eating—becomes progressively difficult. Caring for a loved one who is confused, no longer remembers your name or who you are, or can occasionally become aggressive, is emotionally painful.

After being Clare’s 24/7 caregiver for 6 years, I agreed that placement in an assisted living facility was in her best interest. My role morphed from primary caregiver to primary care advocate, but the stress did not lessen. I met regularly with facility staff to ensure proper care because many staff members were not sufficiently motivated, educated, or trained to consistently provide proper care for individuals with Alzheimer’s disease.

Financial stress weighs heavily on caregivers. Unless one qualifies for Medicaid, is very wealthy, or is lucky enough to have outstanding long-term health care insurance and prescription drug coverage, caregiving costs can be astronomical. For someone with Alzheimer’s in a community such as Long Island, NY, assisted living facilities charge between $7000 and $10,000 per month, and nursing homes between $15,000 and $18,000 per month. Home health aides working 24/7 also cost around $15,000 per month. Caregiving costs can drain not just the patient’s bank account, but can wipe out the retirement life savings of the surviving caregiver.

Once Clare went into assisted living, I dealt with the daily loneliness and the enormous lifestyle changes. Being alone in my bed those first few nights after placement was painful beyond words, and learning to live alone for the first time after many years of marriage brought incredible sadness. It is no surprise to me that research points to caregiver stress as an independent risk factor for elderly caregiver mortality.¹

My experience navigating the health care system with my wife included numerous challenges and instances of unnecessary frustration. My hope in providing the following suggestions is that they will help you help other families like mine.

1. Listen carefully to caregivers

When Clare first exhibited symptoms suggestive of Alzheimer’s, I started logging them and presented written summaries to doctors at each visit. But unless Clare exhibited those same symptoms in the presence of her doctors, my observations were routinely ignored. I’d try to discuss concerns—eg, Clare getting lost while driving to familiar locations, experiencing increased aphasia—but the doctors didn’t read my logs or listen carefully to what I was trying to tell them. The January/February 2017 AARP Bulletin² noted studies showing that doctors listen for about 23 seconds before interrupting patients, but it also cited a 2001 South Carolina study³ that found patients spoke, uninterrupted, for an average of 12 seconds before being interrupted by a resident.

I eventually did learn that early Alzheimer’s symptoms can be easily misinterpreted as signs of stress, anxiety, or depression. But that underscores the need for doctors to listen carefully to caregivers, especially spouse caregivers who observe behaviors 24/7 that may not be present in a quick office visit or revealed on a brief cognitive screening test.

2. Stay up to date on screening tools that detect Alzheimer’s

The Mini-Mental State Examination, or MMSE, is the most frequently used cognitive screening tool, in part because it can be administered in less than 10 minutes. Although unquestionably valuable, a Cochrane review “did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI [mild-cognitive impairment] patients who could develop dementia.”⁴

Time-pressured doctors might consider using the AD8 screening interview, an informant questionnaire that takes only 2 to 3 minutes to administer, but has demonstrated superior sensitivity in detecting early dementia compared with the MMSE.⁵ In addition, a study in the December 2016 issue of the Journal of Alzheimer’s Disease  ⁶ confirmed the usefulness of the Sniffin’ Sticks Odor Identification Test whereby patients try to identify 16 different odors. I can attest to Clare’s rapidly deteriorating senses of taste and smell as her disease progressed.

A simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer's.

“Results suggest that a simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer’s, and even for identifying people who are at the highest risk of worsening,” according to principal investigator, David R. Roalf, PhD.⁷

Prompted by prior studies that have linked a weakening sense of smell to Alzheimer’s, doctors in a few larger dementia clinics have already begun using smell tests in their assessments. One possible reason the practice has not yet become common, however, is that the tests take about 5 to 8 minutes to administer. Roalf and his colleagues are hoping to develop a shorter test that will work as well as the longer ones. “We’re hoping to shorten the Sniffin’ Sticks test … down to 3 minutes or so … We think that will encourage more neurology clinics to do this type of screening.”⁷

Is 5 minutes too much time to take to administer a valuable screening test?

3. Be candid when speaking with patients and their caregivers

A survey reported in Time magazine on March 24, 2015, found that as many as 64% of doctors do not share a diagnosis of Alzheimer’s with their patients because of “fear of causing emotional distress in their patients” due to a lack of effective treatment or cure, and because of a “lack of time and resources to fully explain what the diagnosis means.”⁸

But Alzheimer’s patients and their caregivers need as much time as possible to plan accordingly, especially if they have not already discussed and finalized end-of-life planning (will, living will, health care proxy, durable power of attorney), preferences for staying at home with aides or being placed in a facility, or wishes to take final trips or enjoy final activities together before cognitive impairment worsens. Withholding a diagnosis can rob patients and caregivers of that valuable planning time.

4. Connect caregivers to resources and support groups

If caregivers have already observed issues with their loved one's driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer.

Information on the stages of the disease, available local support groups, and online resources are extremely helpful. Of the 15 people in my spouse support group, only one or 2 were referred there by a doctor. Become familiar with local support groups because that is where caregivers discuss common needs, learn and share helpful caregiving strategies and techniques, and find emotional support from others walking in similar shoes.

5. Help caregivers take away the car keys

When to take away the car keys is an extremely difficult emotional decision that often leads to heated arguments. People with Alzheimer’s rightfully fear losing their independence and only reluctantly accept they can no longer drive safely. But their caregivers worry about them getting lost or causing an accident or, worse, a death. Even though some people with Alzheimer’s can continue to drive safely for a while, the ever-worsening cognitive decline with the disease sooner or later leads to impaired judgment and the inability to drive safely.

If caregivers have already observed issues with their loved one’s driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer. And please do not routinely refer people with Alzheimer’s to driving test facilities. A person with Alzheimer’s may do very well at the particular moment of the test, yet might fail that same test if it was given an hour earlier or later.

6. Manage expectations of what medications can do

None of the current FDA-approved medications have proven to have any long-term positive effects on Alzheimer’s. Clinical trial data show that these meds may be able to slow the rate of disease progression for some people who take them, but even then the benefit is short-lived. Yet many doctors, year after year, renew these “expensive bottles of hope,” as I call them, when the thousands of dollars needed to buy them could be much better spent on day-care programs or personal aides. A candid disclosure to patients and caregivers would enable better decision-making.

What’s it like to be the caregiver for an Alzheimer’s patient? In my case, it was like being both married and widowed at the same time. Or as a person in my support group once put it: It’s a life filled with grief on the installment plan.

My wife, Clare, struggled for nearly 10 years with Alzheimer’s disease before passing away in April 2016—just one month shy of her 70th birthday and 2 months shy of our 49th wedding anniversary.

Our experience was gut-wrenching, but not unique for families coping with Alzheimer’s disease. Life as a caregiver is one of non-stop daily stress, with much sadness and anxiety, often accompanied by periods of mild or serious depression. Doubt, guilt, frustration, and many other emotions lead many caregivers to take anti-anxiety or antidepressant medication, meet regularly with therapists, take sleeping pills, or experience significant weight gain or loss. Stress drove me to my comfort foods, and I gained nearly 100 pounds while caring for Clare. Only in the last few months have I been able to start taking off that weight.

Helping a loved one who has Alzheimer’s with even the basic activities of daily living—hygiene, dressing, eating—becomes progressively difficult. Caring for a loved one who is confused, no longer remembers your name or who you are, or can occasionally become aggressive, is emotionally painful.

After being Clare’s 24/7 caregiver for 6 years, I agreed that placement in an assisted living facility was in her best interest. My role morphed from primary caregiver to primary care advocate, but the stress did not lessen. I met regularly with facility staff to ensure proper care because many staff members were not sufficiently motivated, educated, or trained to consistently provide proper care for individuals with Alzheimer’s disease.

Financial stress weighs heavily on caregivers. Unless one qualifies for Medicaid, is very wealthy, or is lucky enough to have outstanding long-term health care insurance and prescription drug coverage, caregiving costs can be astronomical. For someone with Alzheimer’s in a community such as Long Island, NY, assisted living facilities charge between $7000 and $10,000 per month, and nursing homes between $15,000 and $18,000 per month. Home health aides working 24/7 also cost around $15,000 per month. Caregiving costs can drain not just the patient’s bank account, but can wipe out the retirement life savings of the surviving caregiver.

Once Clare went into assisted living, I dealt with the daily loneliness and the enormous lifestyle changes. Being alone in my bed those first few nights after placement was painful beyond words, and learning to live alone for the first time after many years of marriage brought incredible sadness. It is no surprise to me that research points to caregiver stress as an independent risk factor for elderly caregiver mortality.¹

My experience navigating the health care system with my wife included numerous challenges and instances of unnecessary frustration. My hope in providing the following suggestions is that they will help you help other families like mine.

1. Listen carefully to caregivers

When Clare first exhibited symptoms suggestive of Alzheimer’s, I started logging them and presented written summaries to doctors at each visit. But unless Clare exhibited those same symptoms in the presence of her doctors, my observations were routinely ignored. I’d try to discuss concerns—eg, Clare getting lost while driving to familiar locations, experiencing increased aphasia—but the doctors didn’t read my logs or listen carefully to what I was trying to tell them. The January/February 2017 AARP Bulletin² noted studies showing that doctors listen for about 23 seconds before interrupting patients, but it also cited a 2001 South Carolina study³ that found patients spoke, uninterrupted, for an average of 12 seconds before being interrupted by a resident.

I eventually did learn that early Alzheimer’s symptoms can be easily misinterpreted as signs of stress, anxiety, or depression. But that underscores the need for doctors to listen carefully to caregivers, especially spouse caregivers who observe behaviors 24/7 that may not be present in a quick office visit or revealed on a brief cognitive screening test.

2. Stay up to date on screening tools that detect Alzheimer’s

The Mini-Mental State Examination, or MMSE, is the most frequently used cognitive screening tool, in part because it can be administered in less than 10 minutes. Although unquestionably valuable, a Cochrane review “did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI [mild-cognitive impairment] patients who could develop dementia.”⁴

Time-pressured doctors might consider using the AD8 screening interview, an informant questionnaire that takes only 2 to 3 minutes to administer, but has demonstrated superior sensitivity in detecting early dementia compared with the MMSE.⁵ In addition, a study in the December 2016 issue of the Journal of Alzheimer’s Disease  ⁶ confirmed the usefulness of the Sniffin’ Sticks Odor Identification Test whereby patients try to identify 16 different odors. I can attest to Clare’s rapidly deteriorating senses of taste and smell as her disease progressed.

A simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer's.

“Results suggest that a simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer’s, and even for identifying people who are at the highest risk of worsening,” according to principal investigator, David R. Roalf, PhD.⁷

Prompted by prior studies that have linked a weakening sense of smell to Alzheimer’s, doctors in a few larger dementia clinics have already begun using smell tests in their assessments. One possible reason the practice has not yet become common, however, is that the tests take about 5 to 8 minutes to administer. Roalf and his colleagues are hoping to develop a shorter test that will work as well as the longer ones. “We’re hoping to shorten the Sniffin’ Sticks test … down to 3 minutes or so … We think that will encourage more neurology clinics to do this type of screening.”⁷

Is 5 minutes too much time to take to administer a valuable screening test?

3. Be candid when speaking with patients and their caregivers

A survey reported in Time magazine on March 24, 2015, found that as many as 64% of doctors do not share a diagnosis of Alzheimer’s with their patients because of “fear of causing emotional distress in their patients” due to a lack of effective treatment or cure, and because of a “lack of time and resources to fully explain what the diagnosis means.”⁸

But Alzheimer’s patients and their caregivers need as much time as possible to plan accordingly, especially if they have not already discussed and finalized end-of-life planning (will, living will, health care proxy, durable power of attorney), preferences for staying at home with aides or being placed in a facility, or wishes to take final trips or enjoy final activities together before cognitive impairment worsens. Withholding a diagnosis can rob patients and caregivers of that valuable planning time.

4. Connect caregivers to resources and support groups

If caregivers have already observed issues with their loved one's driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer.

Information on the stages of the disease, available local support groups, and online resources are extremely helpful. Of the 15 people in my spouse support group, only one or 2 were referred there by a doctor. Become familiar with local support groups because that is where caregivers discuss common needs, learn and share helpful caregiving strategies and techniques, and find emotional support from others walking in similar shoes.

5. Help caregivers take away the car keys

When to take away the car keys is an extremely difficult emotional decision that often leads to heated arguments. People with Alzheimer’s rightfully fear losing their independence and only reluctantly accept they can no longer drive safely. But their caregivers worry about them getting lost or causing an accident or, worse, a death. Even though some people with Alzheimer’s can continue to drive safely for a while, the ever-worsening cognitive decline with the disease sooner or later leads to impaired judgment and the inability to drive safely.

If caregivers have already observed issues with their loved one’s driving ability and ask you to intervene, please help remove a major cause of caregiver stress while also making our roads safer. And please do not routinely refer people with Alzheimer’s to driving test facilities. A person with Alzheimer’s may do very well at the particular moment of the test, yet might fail that same test if it was given an hour earlier or later.

6. Manage expectations of what medications can do

None of the current FDA-approved medications have proven to have any long-term positive effects on Alzheimer’s. Clinical trial data show that these meds may be able to slow the rate of disease progression for some people who take them, but even then the benefit is short-lived. Yet many doctors, year after year, renew these “expensive bottles of hope,” as I call them, when the thousands of dollars needed to buy them could be much better spent on day-care programs or personal aides. A candid disclosure to patients and caregivers would enable better decision-making.

There is a strong relationship between the number of medications taken and the likelihood of a potentially serious drug-drug interaction.^1,2 Drug interaction software programs can help alert prescribers to potential problems, but these programs sometimes fail to detect important interactions or generate so many clinically insignificant alerts that they become a nuisance.³ This review provides guidance about 5 clinically relevant drug interactions, including those that are common (TABLE 1^4-6)—and those that are less common, but no less important (TABLE 2^6-10).

1. Antiepileptics & contraceptives

Many antiepileptic medications decrease the efficacy of certain contraceptives

Contraception management in women with epilepsy is critical due to potential maternal and fetal complications. Many antiepileptic drugs (AEDs), including carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate, and valproate, are potentially teratogenic.¹¹ A retrospective, observational study of 115 women of childbearing age who had epilepsy and were seen at a neurology clinic found that 74% were not using documented contraception.¹¹ Of the minority of study participants using contraception, most were using oral contraceptives (OCs) that could potentially interact with AEDs.

CYP inducers. Estrogen and progesterone are metabolized by the cytochrome P450 3A4 enzyme. Some AEDs induce this enzyme, which can enhance the metabolism of OCs, thus reducing their efficacy.¹² It is not known, however, if this interaction results in increased pregnancy rates.¹³ Most newer AEDs (TABLE 3⁶) do not induce cytochrome P450 3A4 and, thus, do not appear to affect OC efficacy, and may be safer for women with seizure disorders.¹² While enzyme-inducing AEDs may decrease the efficacy of progesterone-only OCs and the morning-after pill,^12,14,15 progesterone-containing intrauterine devices (IUDs), long-acting progesterone injections, and non-hormonal contraceptive methods appear to be unaffected.^14-17

OCs and seizure frequency. There is no strong evidence that OCs affect seizure frequency in epileptic women, although changes in hormone levels during the menstrual cycle do affect seizure susceptibility.¹² Combination OCs decrease lamotrigine levels and, therefore, may increase the risk of seizures, but progesterone-only pills do not produce this effect.^12,16

Do guidelines exist? There are no specific evidence-based guidelines that pertain to the use of AEDs and contraception together, but some organizations have issued recommendations.

The American College of Obstetricians and Gynecologists recommends using a 30- to 35-mcg estrogen-containing OC rather than a lower dose in women taking an enzyme-inducing AED. The group also recommends using condoms with OCs or using IUDs.¹⁸

The American Academy of Neurology suggests that women taking OCs and enzyme-inducing AEDs use an OC containing at least 50 mcg estrogen.¹⁹

The National Institute for Health and Care Excellence recommends that women taking enzyme-inducing AEDs avoid progestin-only pills.²⁰

The Faculty of Sexual and Reproductive Healthcare agrees that enzyme-inducing drugs may decrease efficacy and recommend considering IUDs and injectable contraceptive methods.²¹

2. SSRIs & NSAIDs.

SSRIs increase the GI bleeding risk associated with NSAIDs alone

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed worldwide.^22,23 A well-established adverse effect of NSAIDs is gastrointestinal (GI) bleeding, and there is increasing evidence that concomitant use of an SSRI can further increase that risk through a variety of mechanisms.²³

SSRIs decrease platelet serotonin levels resulting in defective platelet aggregation and impaired hemostasis. Studies have also shown that SSRIs increase gastric acidity, which leads to increased risk of peptic ulcer disease and GI bleeding.²³ These mechanisms, combined with the inhibition of gastroprotective prostaglandin cyclooxygenase-1 and platelets by NSAIDs, further potentiate GI bleeding risk.²⁴

Patients at high risk for bleeding with concomitant SSRIs and NSAIDs include older patients, patients with other risk factors for GI bleeding (eg, chronic steroid use), and patients with a history of GI bleeding.²³

The evidence. A 2014 meta-analysis found that when SSRIs were used in combination with NSAIDs, the risk of GI bleeding was significantly increased, compared with SSRI monotherapy.²³

Case control studies found the risk of upper GI bleeding with SSRIs had a number needed to harm (NNH) of 3177 for a low-risk population and 881 for a high-risk population with an odds ratio (OR) of 1.66 (95% confidence interval [CI], 1.44-1.92; P<.00001).²³ When SSRIs were used in combination with NSAIDs, the NNH decreased to 645 for a low-risk population and 179 for a high-risk population (OR=4.25; 95% CI, 2.82-6.42; P<.0001).²³

Another meta-analysis found that the OR for bleeding risk increased to 6.33 (95% CI, 3.40-11.8; P<.00001; NNH=106) with concomitant use of NSAIDs and SSRIs, compared with 2.36 (95% CI, 1.44-3.85; P=.0006; NNH=411) for SSRI use alone.²⁵

The studies did not evaluate results based on the indication, dose, or duration of SSRI or NSAID treatment. If both an SSRI and an NSAID must be used, select a cyclooxygenase-2 selective NSAID at the lowest effective dose and consider the addition of a proton pump inhibitor to decrease the risk of a GI bleed.^23,26

3. Direct oral anticoagulants and antiepileptics

Don’t use DOACs in patients taking certain antiepileptic medications

Drug interactions with anticoagulants, such as warfarin, are well documented and have been publicized for years, but physicians must also be aware of the potential for interaction between the direct oral anticoagulants (DOACs) and AEDs.

Apixaban, rivaroxaban, and dabigatran appear to interact withthe AEDs carbamazepine, phenytoin, and phenobarbital.^27,28 These interactions occur due to AED induction of the CYP3A4 enzyme and effects on the P-glycoprotein (P-gp) efflux pump.^27,29 When taken together, the AED induces metabolism and elimination of the DOAC medication to occur more quickly than it would normally, resulting in subtherapeutic concentrations of the DOAC. This could theoretically result in a venous thromboembolic event or stroke.

A caveat. One thing to consider is that studies demonstrating interaction between the DOAC and AED drug classes have been performed in healthy volunteers, making it difficult to extrapolate how this interaction may increase the risk for thrombotic events in other patients.

Some studies demonstrated reductions in drug levels of up to 50% with strong CYP3A4 and P-glycoprotein inducers.³⁰ Common inducers include carbamazepine, rifampin, and St. John’s Wort.⁶ Patients taking such agents could theoretically have decreased exposure to the DOAC, resulting in an increase in thromboembolic risk.³¹

4. Statins & certain CYP inhibitors

Combining simvastatin with fibrates warrants extra attention

The efficacy of statin medications in the prevention of atherosclerotic cardiovascular disease (ASCVD) is clear. However, the clinical significance of many identified drug interactions involving statins is difficult to interpret. Interactions that cause increased serum concentrations of statins can increase the risk for liver enzyme elevations and skeletal muscle abnormalities (myalgias to rhabdomyolysis).³² Strong inhibitors of CYP3A4 (amiodarone, cyclosporine, ketoconazole, etc.) significantly increase concentrations of lovastatin, simvastatin, and atorvastatin. Pitavastatin, pravastatin, and rosuvastatin are not susceptible to any CYP-mediated drug interactions;³³ therefore, rosuvastatin (a high-intensity statin) is usually recommended over other statins for patients taking strong inhibitors of CYP3A4.

When to limit simvastatin. Doses of simvastatin should not exceed 10 mg/d when combined with diltiazem, dronedarone, or verapamil, and doses should not exceed 20 mg/d when used with amiodarone, amlodipine, or ranolazine.⁶ These recommendations are in response to results from the SEARCH (Study of the Effectiveness of Additional Reductions in cholesterol and homocysteine) trial, which found a higher incidence of myopathies and rhabdomyolysis in patients taking 80 mg of simvastatin compared with those taking 20-mg doses.³⁴ CYP3A4-inducing medications, especially diltiazem, were thought to also contribute to an increased risk.³⁴

Avoid gemfibrozil with statins. Using fibrates with statins is beneficial for some patients; however, gemfibrozil significantly interacts with statins by inhibiting CYP2C8 and organic anion transporting polypeptide 1B1 (OATP1B1).³³ The safer choice is fenofibrate because it does not interfere with statin metabolism and can be safely used in combination with statins.⁶

Enzyme-inducing antiepileptic drugs can enhance the metabolism of oral contraceptives, thus reducing their efficacy.

A retrospective review of the FDA Adverse Event Reporting System (AERS) database found that 88% of fibrate and statin combinations that resulted in rhabdomyolysis were associated with gemfibrozil/cerivastatin (cerivastatin is no longer available in the United States).³⁵

5. One serotonergic drug & another

Serotonin syndrome is associated with more than just SSRIs

Serotonin syndrome is a constellation of symptoms (hyperthermia, hyperreflexia, muscle clonus, tremor and altered mental status) caused by increases in serotonin levels in the central and peripheral nervous systems that can lead to mild or life-threatening complications such as seizures, muscle breakdown, or hyperthermia. Serotonin syndrome is most likely to occur within 24 hours after a dose increase, after starting a new medication that increases serotonin levels, or after a drug overdose.³⁶

SSRIs are the most commonly reported drug associated with serotonin syndrome; however, other medications (TABLE 4³⁷) may be responsible, especially when used in combination with agents that act on serotonin receptors or in patients with impaired metabolism of the drugs being used.³⁷

Other culprits. Serotonergic effects can also be associated with illicit drugs, some nonprescription medications, and supplements. And in March 2016, the FDA issued a warning about the risks of taking opioids with serotonergic medications.³⁸ Although labeling changes have been recommended for all opioids, the cases of serotonin syndrome were reported more often with normal doses of fentanyl and methadone.

There are 2 mechanisms by which drugs may increase a patient’s risk for serotonin syndrome. The first is a pharmacodynamic interaction, which can occur when 2 or more medications act at the same receptor site (serotonin receptors in this example), which may result in an additive or synergistic effect.³⁹

There is increasing evidence that concomitant use of an SSRI and an NSAID increases the risk of gastrointestinal bleeding.

The second mechanism is a pharmacokinetic alteration (an agent alters absorption, distribution, metabolism, or excretion) of CYP enzymes.⁴⁰ Of the more commonly used antidepressants, citalopram, escitalopram, venlafaxine, and mirtazapine seem to have the least potential for clinically significant pharmacokinetic interactions.⁴¹

Guidelines? Currently there are no guidelines for preventing serotonin syndrome. Clinicians should exercise caution in patients at high risk for drug adverse events, such as the elderly, patients taking multiple medications, and patients with comorbidities. Healthy low-risk patients can generally take 2 or 3 serotonergic medications at therapeutic doses without a major risk of harm.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, 191 East Orchard Road, Suite 200, Littleton, CO 80121; [email protected].

There is a strong relationship between the number of medications taken and the likelihood of a potentially serious drug-drug interaction.^1,2 Drug interaction software programs can help alert prescribers to potential problems, but these programs sometimes fail to detect important interactions or generate so many clinically insignificant alerts that they become a nuisance.³ This review provides guidance about 5 clinically relevant drug interactions, including those that are common (TABLE 1^4-6)—and those that are less common, but no less important (TABLE 2^6-10).

1. Antiepileptics & contraceptives

Many antiepileptic medications decrease the efficacy of certain contraceptives

Contraception management in women with epilepsy is critical due to potential maternal and fetal complications. Many antiepileptic drugs (AEDs), including carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate, and valproate, are potentially teratogenic.¹¹ A retrospective, observational study of 115 women of childbearing age who had epilepsy and were seen at a neurology clinic found that 74% were not using documented contraception.¹¹ Of the minority of study participants using contraception, most were using oral contraceptives (OCs) that could potentially interact with AEDs.

CYP inducers. Estrogen and progesterone are metabolized by the cytochrome P450 3A4 enzyme. Some AEDs induce this enzyme, which can enhance the metabolism of OCs, thus reducing their efficacy.¹² It is not known, however, if this interaction results in increased pregnancy rates.¹³ Most newer AEDs (TABLE 3⁶) do not induce cytochrome P450 3A4 and, thus, do not appear to affect OC efficacy, and may be safer for women with seizure disorders.¹² While enzyme-inducing AEDs may decrease the efficacy of progesterone-only OCs and the morning-after pill,^12,14,15 progesterone-containing intrauterine devices (IUDs), long-acting progesterone injections, and non-hormonal contraceptive methods appear to be unaffected.^14-17

OCs and seizure frequency. There is no strong evidence that OCs affect seizure frequency in epileptic women, although changes in hormone levels during the menstrual cycle do affect seizure susceptibility.¹² Combination OCs decrease lamotrigine levels and, therefore, may increase the risk of seizures, but progesterone-only pills do not produce this effect.^12,16

Do guidelines exist? There are no specific evidence-based guidelines that pertain to the use of AEDs and contraception together, but some organizations have issued recommendations.

The American College of Obstetricians and Gynecologists recommends using a 30- to 35-mcg estrogen-containing OC rather than a lower dose in women taking an enzyme-inducing AED. The group also recommends using condoms with OCs or using IUDs.¹⁸

The American Academy of Neurology suggests that women taking OCs and enzyme-inducing AEDs use an OC containing at least 50 mcg estrogen.¹⁹

The National Institute for Health and Care Excellence recommends that women taking enzyme-inducing AEDs avoid progestin-only pills.²⁰

The Faculty of Sexual and Reproductive Healthcare agrees that enzyme-inducing drugs may decrease efficacy and recommend considering IUDs and injectable contraceptive methods.²¹

2. SSRIs & NSAIDs.

SSRIs increase the GI bleeding risk associated with NSAIDs alone

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed worldwide.^22,23 A well-established adverse effect of NSAIDs is gastrointestinal (GI) bleeding, and there is increasing evidence that concomitant use of an SSRI can further increase that risk through a variety of mechanisms.²³

SSRIs decrease platelet serotonin levels resulting in defective platelet aggregation and impaired hemostasis. Studies have also shown that SSRIs increase gastric acidity, which leads to increased risk of peptic ulcer disease and GI bleeding.²³ These mechanisms, combined with the inhibition of gastroprotective prostaglandin cyclooxygenase-1 and platelets by NSAIDs, further potentiate GI bleeding risk.²⁴

Patients at high risk for bleeding with concomitant SSRIs and NSAIDs include older patients, patients with other risk factors for GI bleeding (eg, chronic steroid use), and patients with a history of GI bleeding.²³

The evidence. A 2014 meta-analysis found that when SSRIs were used in combination with NSAIDs, the risk of GI bleeding was significantly increased, compared with SSRI monotherapy.²³

Case control studies found the risk of upper GI bleeding with SSRIs had a number needed to harm (NNH) of 3177 for a low-risk population and 881 for a high-risk population with an odds ratio (OR) of 1.66 (95% confidence interval [CI], 1.44-1.92; P<.00001).²³ When SSRIs were used in combination with NSAIDs, the NNH decreased to 645 for a low-risk population and 179 for a high-risk population (OR=4.25; 95% CI, 2.82-6.42; P<.0001).²³

Another meta-analysis found that the OR for bleeding risk increased to 6.33 (95% CI, 3.40-11.8; P<.00001; NNH=106) with concomitant use of NSAIDs and SSRIs, compared with 2.36 (95% CI, 1.44-3.85; P=.0006; NNH=411) for SSRI use alone.²⁵

The studies did not evaluate results based on the indication, dose, or duration of SSRI or NSAID treatment. If both an SSRI and an NSAID must be used, select a cyclooxygenase-2 selective NSAID at the lowest effective dose and consider the addition of a proton pump inhibitor to decrease the risk of a GI bleed.^23,26

3. Direct oral anticoagulants and antiepileptics

Don’t use DOACs in patients taking certain antiepileptic medications

Drug interactions with anticoagulants, such as warfarin, are well documented and have been publicized for years, but physicians must also be aware of the potential for interaction between the direct oral anticoagulants (DOACs) and AEDs.

Apixaban, rivaroxaban, and dabigatran appear to interact withthe AEDs carbamazepine, phenytoin, and phenobarbital.^27,28 These interactions occur due to AED induction of the CYP3A4 enzyme and effects on the P-glycoprotein (P-gp) efflux pump.^27,29 When taken together, the AED induces metabolism and elimination of the DOAC medication to occur more quickly than it would normally, resulting in subtherapeutic concentrations of the DOAC. This could theoretically result in a venous thromboembolic event or stroke.

A caveat. One thing to consider is that studies demonstrating interaction between the DOAC and AED drug classes have been performed in healthy volunteers, making it difficult to extrapolate how this interaction may increase the risk for thrombotic events in other patients.

Some studies demonstrated reductions in drug levels of up to 50% with strong CYP3A4 and P-glycoprotein inducers.³⁰ Common inducers include carbamazepine, rifampin, and St. John’s Wort.⁶ Patients taking such agents could theoretically have decreased exposure to the DOAC, resulting in an increase in thromboembolic risk.³¹

4. Statins & certain CYP inhibitors

Combining simvastatin with fibrates warrants extra attention

The efficacy of statin medications in the prevention of atherosclerotic cardiovascular disease (ASCVD) is clear. However, the clinical significance of many identified drug interactions involving statins is difficult to interpret. Interactions that cause increased serum concentrations of statins can increase the risk for liver enzyme elevations and skeletal muscle abnormalities (myalgias to rhabdomyolysis).³² Strong inhibitors of CYP3A4 (amiodarone, cyclosporine, ketoconazole, etc.) significantly increase concentrations of lovastatin, simvastatin, and atorvastatin. Pitavastatin, pravastatin, and rosuvastatin are not susceptible to any CYP-mediated drug interactions;³³ therefore, rosuvastatin (a high-intensity statin) is usually recommended over other statins for patients taking strong inhibitors of CYP3A4.

When to limit simvastatin. Doses of simvastatin should not exceed 10 mg/d when combined with diltiazem, dronedarone, or verapamil, and doses should not exceed 20 mg/d when used with amiodarone, amlodipine, or ranolazine.⁶ These recommendations are in response to results from the SEARCH (Study of the Effectiveness of Additional Reductions in cholesterol and homocysteine) trial, which found a higher incidence of myopathies and rhabdomyolysis in patients taking 80 mg of simvastatin compared with those taking 20-mg doses.³⁴ CYP3A4-inducing medications, especially diltiazem, were thought to also contribute to an increased risk.³⁴

Avoid gemfibrozil with statins. Using fibrates with statins is beneficial for some patients; however, gemfibrozil significantly interacts with statins by inhibiting CYP2C8 and organic anion transporting polypeptide 1B1 (OATP1B1).³³ The safer choice is fenofibrate because it does not interfere with statin metabolism and can be safely used in combination with statins.⁶

Enzyme-inducing antiepileptic drugs can enhance the metabolism of oral contraceptives, thus reducing their efficacy.

A retrospective review of the FDA Adverse Event Reporting System (AERS) database found that 88% of fibrate and statin combinations that resulted in rhabdomyolysis were associated with gemfibrozil/cerivastatin (cerivastatin is no longer available in the United States).³⁵

5. One serotonergic drug & another

Serotonin syndrome is associated with more than just SSRIs

Serotonin syndrome is a constellation of symptoms (hyperthermia, hyperreflexia, muscle clonus, tremor and altered mental status) caused by increases in serotonin levels in the central and peripheral nervous systems that can lead to mild or life-threatening complications such as seizures, muscle breakdown, or hyperthermia. Serotonin syndrome is most likely to occur within 24 hours after a dose increase, after starting a new medication that increases serotonin levels, or after a drug overdose.³⁶

SSRIs are the most commonly reported drug associated with serotonin syndrome; however, other medications (TABLE 4³⁷) may be responsible, especially when used in combination with agents that act on serotonin receptors or in patients with impaired metabolism of the drugs being used.³⁷

Other culprits. Serotonergic effects can also be associated with illicit drugs, some nonprescription medications, and supplements. And in March 2016, the FDA issued a warning about the risks of taking opioids with serotonergic medications.³⁸ Although labeling changes have been recommended for all opioids, the cases of serotonin syndrome were reported more often with normal doses of fentanyl and methadone.

There are 2 mechanisms by which drugs may increase a patient’s risk for serotonin syndrome. The first is a pharmacodynamic interaction, which can occur when 2 or more medications act at the same receptor site (serotonin receptors in this example), which may result in an additive or synergistic effect.³⁹

There is increasing evidence that concomitant use of an SSRI and an NSAID increases the risk of gastrointestinal bleeding.

The second mechanism is a pharmacokinetic alteration (an agent alters absorption, distribution, metabolism, or excretion) of CYP enzymes.⁴⁰ Of the more commonly used antidepressants, citalopram, escitalopram, venlafaxine, and mirtazapine seem to have the least potential for clinically significant pharmacokinetic interactions.⁴¹

Guidelines? Currently there are no guidelines for preventing serotonin syndrome. Clinicians should exercise caution in patients at high risk for drug adverse events, such as the elderly, patients taking multiple medications, and patients with comorbidities. Healthy low-risk patients can generally take 2 or 3 serotonergic medications at therapeutic doses without a major risk of harm.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, 191 East Orchard Road, Suite 200, Littleton, CO 80121; [email protected].

There is a strong relationship between the number of medications taken and the likelihood of a potentially serious drug-drug interaction.^1,2 Drug interaction software programs can help alert prescribers to potential problems, but these programs sometimes fail to detect important interactions or generate so many clinically insignificant alerts that they become a nuisance.³ This review provides guidance about 5 clinically relevant drug interactions, including those that are common (TABLE 1^4-6)—and those that are less common, but no less important (TABLE 2^6-10).

1. Antiepileptics & contraceptives

Many antiepileptic medications decrease the efficacy of certain contraceptives

Contraception management in women with epilepsy is critical due to potential maternal and fetal complications. Many antiepileptic drugs (AEDs), including carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate, and valproate, are potentially teratogenic.¹¹ A retrospective, observational study of 115 women of childbearing age who had epilepsy and were seen at a neurology clinic found that 74% were not using documented contraception.¹¹ Of the minority of study participants using contraception, most were using oral contraceptives (OCs) that could potentially interact with AEDs.

CYP inducers. Estrogen and progesterone are metabolized by the cytochrome P450 3A4 enzyme. Some AEDs induce this enzyme, which can enhance the metabolism of OCs, thus reducing their efficacy.¹² It is not known, however, if this interaction results in increased pregnancy rates.¹³ Most newer AEDs (TABLE 3⁶) do not induce cytochrome P450 3A4 and, thus, do not appear to affect OC efficacy, and may be safer for women with seizure disorders.¹² While enzyme-inducing AEDs may decrease the efficacy of progesterone-only OCs and the morning-after pill,^12,14,15 progesterone-containing intrauterine devices (IUDs), long-acting progesterone injections, and non-hormonal contraceptive methods appear to be unaffected.^14-17

OCs and seizure frequency. There is no strong evidence that OCs affect seizure frequency in epileptic women, although changes in hormone levels during the menstrual cycle do affect seizure susceptibility.¹² Combination OCs decrease lamotrigine levels and, therefore, may increase the risk of seizures, but progesterone-only pills do not produce this effect.^12,16

Do guidelines exist? There are no specific evidence-based guidelines that pertain to the use of AEDs and contraception together, but some organizations have issued recommendations.

The American College of Obstetricians and Gynecologists recommends using a 30- to 35-mcg estrogen-containing OC rather than a lower dose in women taking an enzyme-inducing AED. The group also recommends using condoms with OCs or using IUDs.¹⁸

The American Academy of Neurology suggests that women taking OCs and enzyme-inducing AEDs use an OC containing at least 50 mcg estrogen.¹⁹

The National Institute for Health and Care Excellence recommends that women taking enzyme-inducing AEDs avoid progestin-only pills.²⁰

The Faculty of Sexual and Reproductive Healthcare agrees that enzyme-inducing drugs may decrease efficacy and recommend considering IUDs and injectable contraceptive methods.²¹

2. SSRIs & NSAIDs.

SSRIs increase the GI bleeding risk associated with NSAIDs alone

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed worldwide.^22,23 A well-established adverse effect of NSAIDs is gastrointestinal (GI) bleeding, and there is increasing evidence that concomitant use of an SSRI can further increase that risk through a variety of mechanisms.²³

SSRIs decrease platelet serotonin levels resulting in defective platelet aggregation and impaired hemostasis. Studies have also shown that SSRIs increase gastric acidity, which leads to increased risk of peptic ulcer disease and GI bleeding.²³ These mechanisms, combined with the inhibition of gastroprotective prostaglandin cyclooxygenase-1 and platelets by NSAIDs, further potentiate GI bleeding risk.²⁴

Patients at high risk for bleeding with concomitant SSRIs and NSAIDs include older patients, patients with other risk factors for GI bleeding (eg, chronic steroid use), and patients with a history of GI bleeding.²³

The evidence. A 2014 meta-analysis found that when SSRIs were used in combination with NSAIDs, the risk of GI bleeding was significantly increased, compared with SSRI monotherapy.²³

Case control studies found the risk of upper GI bleeding with SSRIs had a number needed to harm (NNH) of 3177 for a low-risk population and 881 for a high-risk population with an odds ratio (OR) of 1.66 (95% confidence interval [CI], 1.44-1.92; P<.00001).²³ When SSRIs were used in combination with NSAIDs, the NNH decreased to 645 for a low-risk population and 179 for a high-risk population (OR=4.25; 95% CI, 2.82-6.42; P<.0001).²³

Another meta-analysis found that the OR for bleeding risk increased to 6.33 (95% CI, 3.40-11.8; P<.00001; NNH=106) with concomitant use of NSAIDs and SSRIs, compared with 2.36 (95% CI, 1.44-3.85; P=.0006; NNH=411) for SSRI use alone.²⁵

The studies did not evaluate results based on the indication, dose, or duration of SSRI or NSAID treatment. If both an SSRI and an NSAID must be used, select a cyclooxygenase-2 selective NSAID at the lowest effective dose and consider the addition of a proton pump inhibitor to decrease the risk of a GI bleed.^23,26

3. Direct oral anticoagulants and antiepileptics

Don’t use DOACs in patients taking certain antiepileptic medications

Drug interactions with anticoagulants, such as warfarin, are well documented and have been publicized for years, but physicians must also be aware of the potential for interaction between the direct oral anticoagulants (DOACs) and AEDs.

Apixaban, rivaroxaban, and dabigatran appear to interact withthe AEDs carbamazepine, phenytoin, and phenobarbital.^27,28 These interactions occur due to AED induction of the CYP3A4 enzyme and effects on the P-glycoprotein (P-gp) efflux pump.^27,29 When taken together, the AED induces metabolism and elimination of the DOAC medication to occur more quickly than it would normally, resulting in subtherapeutic concentrations of the DOAC. This could theoretically result in a venous thromboembolic event or stroke.

A caveat. One thing to consider is that studies demonstrating interaction between the DOAC and AED drug classes have been performed in healthy volunteers, making it difficult to extrapolate how this interaction may increase the risk for thrombotic events in other patients.

Some studies demonstrated reductions in drug levels of up to 50% with strong CYP3A4 and P-glycoprotein inducers.³⁰ Common inducers include carbamazepine, rifampin, and St. John’s Wort.⁶ Patients taking such agents could theoretically have decreased exposure to the DOAC, resulting in an increase in thromboembolic risk.³¹

4. Statins & certain CYP inhibitors

Combining simvastatin with fibrates warrants extra attention

The efficacy of statin medications in the prevention of atherosclerotic cardiovascular disease (ASCVD) is clear. However, the clinical significance of many identified drug interactions involving statins is difficult to interpret. Interactions that cause increased serum concentrations of statins can increase the risk for liver enzyme elevations and skeletal muscle abnormalities (myalgias to rhabdomyolysis).³² Strong inhibitors of CYP3A4 (amiodarone, cyclosporine, ketoconazole, etc.) significantly increase concentrations of lovastatin, simvastatin, and atorvastatin. Pitavastatin, pravastatin, and rosuvastatin are not susceptible to any CYP-mediated drug interactions;³³ therefore, rosuvastatin (a high-intensity statin) is usually recommended over other statins for patients taking strong inhibitors of CYP3A4.

When to limit simvastatin. Doses of simvastatin should not exceed 10 mg/d when combined with diltiazem, dronedarone, or verapamil, and doses should not exceed 20 mg/d when used with amiodarone, amlodipine, or ranolazine.⁶ These recommendations are in response to results from the SEARCH (Study of the Effectiveness of Additional Reductions in cholesterol and homocysteine) trial, which found a higher incidence of myopathies and rhabdomyolysis in patients taking 80 mg of simvastatin compared with those taking 20-mg doses.³⁴ CYP3A4-inducing medications, especially diltiazem, were thought to also contribute to an increased risk.³⁴

Avoid gemfibrozil with statins. Using fibrates with statins is beneficial for some patients; however, gemfibrozil significantly interacts with statins by inhibiting CYP2C8 and organic anion transporting polypeptide 1B1 (OATP1B1).³³ The safer choice is fenofibrate because it does not interfere with statin metabolism and can be safely used in combination with statins.⁶

Enzyme-inducing antiepileptic drugs can enhance the metabolism of oral contraceptives, thus reducing their efficacy.

A retrospective review of the FDA Adverse Event Reporting System (AERS) database found that 88% of fibrate and statin combinations that resulted in rhabdomyolysis were associated with gemfibrozil/cerivastatin (cerivastatin is no longer available in the United States).³⁵

5. One serotonergic drug & another

Serotonin syndrome is associated with more than just SSRIs

Serotonin syndrome is a constellation of symptoms (hyperthermia, hyperreflexia, muscle clonus, tremor and altered mental status) caused by increases in serotonin levels in the central and peripheral nervous systems that can lead to mild or life-threatening complications such as seizures, muscle breakdown, or hyperthermia. Serotonin syndrome is most likely to occur within 24 hours after a dose increase, after starting a new medication that increases serotonin levels, or after a drug overdose.³⁶

SSRIs are the most commonly reported drug associated with serotonin syndrome; however, other medications (TABLE 4³⁷) may be responsible, especially when used in combination with agents that act on serotonin receptors or in patients with impaired metabolism of the drugs being used.³⁷

Other culprits. Serotonergic effects can also be associated with illicit drugs, some nonprescription medications, and supplements. And in March 2016, the FDA issued a warning about the risks of taking opioids with serotonergic medications.³⁸ Although labeling changes have been recommended for all opioids, the cases of serotonin syndrome were reported more often with normal doses of fentanyl and methadone.

There are 2 mechanisms by which drugs may increase a patient’s risk for serotonin syndrome. The first is a pharmacodynamic interaction, which can occur when 2 or more medications act at the same receptor site (serotonin receptors in this example), which may result in an additive or synergistic effect.³⁹

There is increasing evidence that concomitant use of an SSRI and an NSAID increases the risk of gastrointestinal bleeding.

The second mechanism is a pharmacokinetic alteration (an agent alters absorption, distribution, metabolism, or excretion) of CYP enzymes.⁴⁰ Of the more commonly used antidepressants, citalopram, escitalopram, venlafaxine, and mirtazapine seem to have the least potential for clinically significant pharmacokinetic interactions.⁴¹

Guidelines? Currently there are no guidelines for preventing serotonin syndrome. Clinicians should exercise caution in patients at high risk for drug adverse events, such as the elderly, patients taking multiple medications, and patients with comorbidities. Healthy low-risk patients can generally take 2 or 3 serotonergic medications at therapeutic doses without a major risk of harm.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, 191 East Orchard Road, Suite 200, Littleton, CO 80121; [email protected].

While the unintended pregnancy rate for women ages 15 to 44 years decreased by 18% between 2008 and 2011, almost half of pregnancies in the United States remain unintended.¹ On a more positive note, however, women who use birth control consistently and correctly account for only 5% of unintended pregnancies.² As family physicians (FPs), we can support and facilitate our female patients’ efforts to consistently use highly effective forms of contraception. The 5 initiatives detailed here can help toward that end.

1. Routinely screen patients for their reproductive intentions

All women of reproductive age should be screened routinely for their pregnancy intentions. The American College of Obstetricians and Gynecologists (ACOG) encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive life plan, or a set of personal goals about whether or when to have children.³ The Centers for Disease Control and Prevention (CDC) has also developed a reproductive life plan tool for health professionals to encourage women and men to reflect upon their plans.⁴ So just as we regularly screen and document cigarette use and blood pressure (BP), so too, should we routinely screen women for their reproductive goals.

Ask women this one question. The Oregon Foundation for Reproductive Health launched the One Key Question Initiative, which proposes that the care team ask women ages 18 to 50: “Would you like to become pregnant in the next year?”⁵ A common workflow includes the medical assistant asking women about pregnancy intentions and providing a preconception and/or contraceptive handout, if appropriate. The physician provides additional counseling as needed. Pilot studies of One Key Question indicate that 30% to 40% of women screened needed follow-up counseling, suggesting the need for clinicians to be proactive in asking about reproductive plans. (Additional information on the Initiative is available on the Foundation’s Web site at http://www.orfrh.org/.)

This approach assumes women feel in control of their reproduction; however, this may not be the reality for many, especially low-income women.⁶ Additionally, women commonly cite planning a pregnancy as appropriate only when they are in an ideal relationship and when they are living in a financially stable environment—conditions that some women may never achieve.

ACOG encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive plan.

Another caveat is that women may not have explicit pregnancy intentions, in which case, this particular approach may not be effective. A study of low-income women found only 60% intended to use the method prescribed after contraception counseling, with 37% of those stopping because of adverse effects, 23% saying they wanted another method, and 17% citing method complexity.⁷

Reproductive coercion from male partners, ranging from pressure to become pregnant to method sabotage, is also common in low-income women.⁸ Regular conversations that prioritize a woman’s values and experience are needed to promote reproductive autonomy.

2. Decouple provision of contraception from unnecessary exams

Pelvic exams and pap smears should not be required prior to offering patients hormonal contraception, according to the Choosing Wisely campaign of the American Board of Internal Medicine and ACOG.^9,10 Hormonal contraception may instead be provided safely based on a medical history and BP assessment. Adolescents, minority groups, obese women, and victims of sexual trauma, in particular may avoid asking about birth control because of anxiety and fear of pain from these exams.¹¹ The American College of Physicians recommends against speculum and bimanual exams in asymptomatic, non-pregnant, adult women.¹² Pap smears and sexually transmitted infection (STI) testing should be performed at their normally scheduled intervals as recommended by the US Preventive Services Task Force (USPSTF) and not be tied to contraceptive provision.¹³

Assess pregnancy status using criteria,rather than a pregnancy text

Use the CDC’s criteria to assess pregnancy status rather than relying on a urine pregnancy test prior to providing contraception. Once you are reasonably sure that a woman is not pregnant (TABLE 1¹⁴), contraception may be started. Some physicians have traditionally requested that a woman delay starting contraception until the next menses to ensure that she is not already pregnant. However, given the evidence that hormonal contraception does not cause birth defects, such a delay is not warranted and puts the woman at risk of an unintended pregnancy during the gap.¹⁵

Furthermore, there is an approximate 2-week window in which a woman could have a negative urine pregnancy test despite being pregnant, so the test alone is not completely reliable. In addition, obese women may experience irregular cycles, further complicating the traditional approach.¹⁶

Another largely unnecessary step … The US Selected Practice Recommendations (US SPR) from the CDC notes that additional STI screening prior to an intrauterine device (IUD) insertion is unnecessary for most women if appropriate screening guidelines have been previously followed.¹⁴ For those who have not been screened according to guidelines, the CDC recommends same-day screening and IUD insertion. You can then treat an STI without removing the IUD. Women with purulent cervicitis or a current chlamydial or gonorrheal infection should delay IUD insertion until after treatment.

3. Expand long-acting reversible contraception counseling and access

Offer long-acting reversible contraception (LARC), such as IUDs and implants, as first-line options for most women. ACOG endorses LARC as the most effective reversible method for most women, including those who have not given birth and adolescents.¹⁷ Unfortunately, a 2012 study found that family physicians were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.¹⁸ While 79% of OB-GYNs routinely discussed IUDs with their patients, only 47% of family physicians did. In 2014, the American Academy of Pediatrics (AAP) endorsed a LARC-first tiered counseling approach for adolescents.¹⁹

A test of LARC-first counseling

The Contraceptive CHOICE project, a St. Louis, Missouri-based initiative, was launched to reduce unintended pregnancies in women ages 14 to 45 years by offering LARC-first counseling and free contraception of their choice.²⁰ This project involved more than 9000 women at high risk for unintended pregnancy. Same-day LARC insertion was available. Seventy-five percent of women chose a LARC method and they reported greater continuation at 12 and 24 months, when compared to women who did not choose a LARC method. LARC users also reported higher satisfaction at one year. Provision of contraception through the project contributed to a reduction in repeat abortions as well as decreased rates of teenage pregnancy, birth, and abortion. Three years after the start of the project, IUDs had continuation rates of nearly 70%, implants of 56%, and non-LARC methods of 31%.²¹

When counseling women, it’s important to remember that effectiveness may not be the only criterium a woman uses when choosing a method. A 2010 study found that for 91% of women at high risk for unintended pregnancy, no single method possessed all the features they deemed “extremely important.”²² Clinicians should take a patient-centered approach to find birth control that fits each patient’s priorities.

Clinicians need proper training in LARC methods

Only 20% of FPs regularly insert IUDs, and 11% offer contraceptive implants, according to estimates from physicians recertifying with the American Board of Family Medicine in 2014.²³ Access to training during residency is a key component to increasing these rates. FPs who practice obstetrics should be trained in postpartum LARC insertion and offer this option prior to hospital discharge as well as during the postpartum office visit.

Performing LARC insertions on the same day as counseling is ideal, and clinics should strive to reduce barriers to same-day procedures. Time constraints may be addressed by shifting tasks among the medical team. In the CHOICE project, contraceptive counselors—half of whom had no clinical experience—were trained to provide tiered counseling to participants. By working with a cross-trained health care team and offering prepared resources, clinicians can save time and improve access.

Physicians may want to incorporate the free online resources Bedsider.org or Stayteen.org to help women learn about contraceptive methods.²⁴ The user-friendly Web sites, operated by the National Campaign to Prevent Teen and Unplanned Pregnancy, describe various forms of contraception and offer text and email reminders. Incorporating Bedsider into the counseling workflow and discussing the various reminder tools available may improve patients’ knowledge and enhance their compliance.

Pelvic exams and pap smears should not be required before offering patients hormonal contraception.

Additional barriers for practices may include high upfront costs associated with stocking devices. Practices that may be unable to sustain the costs surrounding enhanced contraception counseling and provision can collaborate with family planning clinics that are able to offer same-day services. A study of clinics in California found that Title X clinics were more likely to provide on-site LARC services than non-Title X public and private providers.²⁵

4. Follow CDC guidelines for initiating and continuing contraception

Follow the US SPR for guidance on initiating and continuing contraceptive methods.¹⁴ The CDC’s Medical Eligibility Criteria for Contraceptive Use is another vital resource, providing recommendations for contraceptive methods to patients who have specific medical conditions or characteristics.²⁶

Utilize the “quick start” method for hormonal contraception, where birth control is started on the same day as its prescription regardless of timing of the menstrual cycle. If you can’t be reasonably certain that a woman is not pregnant based on the criteria listed in TABLE 1,¹⁴ conduct a pregnancy test (while recognizing the aforementioned 2-week window of limitations) and counsel the patient to use back-up protection for the first 7 days along with repeating a pregnancy test in 2 weeks’ time.

The quick start method may lead to higher adherence than delayed initiation.²⁷ Differences in continuation rates between women who use the quick start method and those who follow the delayed approach may disappear over time.²⁸

Prescribe and provide a year’s supply of oral contraceptive pills (OCPs) as recommended by the CDC US SPR.¹⁴ It is important to note that pharmacists are usually restricted by insurance companies to only fill a one or 3 month’s supply.

One study found that FPs were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.

In January 2016, Oregon began requiring private and state health insurance providers to reimburse for a year’s supply of prescription contraception; in January 2017, insurers in Washington, DC, were also required to offer women a year’s supply of prescription contraception.^29,30 Several other states have followed suit. The California Health Benefits Review Program estimates a savings of $42.8 million a year from fewer office visits and 15,000 fewer unintended pregnancies if their state enacts a similar policy.³¹

Pharmacist initiatives are worth watching. In January 2016, Oregon pharmacists with additional training were allowed to prescribe OCs and hormonal patches to women 18 years and older.³² In April 2016, a similar law went into effect in California, but without a minimum age requirement and with the additional coverage of vaginal rings and Depo-Provera (depo) injections.³³ Pharmacists in both states must review a health questionnaire completed by the woman and can refer to a physician as necessary.

The CDC recommends that clinicians extend the allowed window for repeat depo injections to 15 weeks.¹⁴ Common institutional protocol is to give repeat injections every 11 to 13 weeks. If past that window, protocol often dictates the woman abstain from unprotected sex for 2 weeks and then return for a negative pregnancy test (or await menses) before the next injection. However, the CDC notes that depo is effective for longer than the 13-week period.¹⁴ No additional birth control or pregnancy testing is needed and the woman can receive the next depo shot if she is up to 15 weeks from the previous shot.

One study found no additional pregnancy risks for those who were up to 4 weeks “late” for their next shot, suggesting there is potential for an even larger grace period.³⁴ The World Health Organization advises allowing a repeat injection up to 4 weeks late.³⁵ We encourage institutions to change their policies to comply with the CDC’s 15-week window.

Another initiative is over-the-counter (OTC) access to OCs, which the American Academy of Family Physicians (AAFP) and ACOG support.^36,37 ACOG notes that “no drug or intervention is completely without risk of harm” and that the risk of venous thromboembolism for OC users is lower than the risk of pregnancy.³⁷ Women can successfully self-screen for contraindications using a checklist. Concerns about women potentially being less adherent or less likely to choose LARCs are not reasons to preclude access to other methods. The AAFP supports insurance coverage of OCs, regardless of prescription status.³⁶

5. Routinely counsel about, and advance-prescribe, emergency contraception pills

Physicians should counsel and advance-prescribe emergency contraception pills (ECPs) to women, including adolescents, using less reliable contraception, as recommended by ACOG, AAP, and the CDC.^14,37,38 It’s also important to provide information on the copper IUD as the most effective method of emergency contraception, with nearly 100% efficacy if placed within 5 days.³⁹ An easy-to-read patient hand-out in English and Spanish on EC options can be found at http://beyondthepill.ucsf.edu/tools-materials.

Only 3% of respondents participating in the 2006-2010 National Survey of Family Growth received counseling about emergency contraception in the past year.⁴⁰ ECPs are most effective when used within 24 hours but have some efficacy up to 5 days.³⁷ Due to the Affordable Care Act, most insurance plans will cover ECPs if purchased with a prescription, but coverage varies by state.⁴¹ Ulipristal acetate (UPA) ECP is only available with a prescription. Advance prescriptions can alleviate financial burdens on women when they need to access ECPs quickly.

Women should wait at least 5 days before resuming or starting hormonal contraception after taking UPA-based ECP, as it may reduce the ovulation-delaying effect of the ECP.¹⁴ For IUDs, implants, and depo, which require a visit to a health care provider, physicians evaluating earlier provision should consider the risks of reduced efficacy against the many barriers to access.

UPA-based ECPs (such as ella) may be more effective for overweight and obese women than levonorgestrel-based ECPs (such as Plan B and Next Choice).¹⁴ Consider advance-prescribing UPA ECPs to women with a body mass index (BMI) >25 kg/m².⁴² Such considerations are important as the prevalence of obesity in women between 2013 and 2014 was 40.4%.⁴³

A copper IUD may be the only effective form of emergency contraception for patients with a BMI ≥35 kg/m².

In May 2016, the FDA noted that while current data are insufficient regarding whether the effectiveness of levonorgestrel ECPs is reduced in overweight or obese women, there are no safety concerns regarding their use in this population.⁴⁴ Therefore, a woman with a BMI >25 kg/m² should use UPA ECPs if available; but if not, she can still use levonorgestrel ECPs. One study, however, has found that UPA ECPs are only as effective as a placebo when BMI is ≥35 kg/m², at which point a copper IUD may be the only effective form of emergency contraception.⁴⁵

Transitioning from customary practices to best practices

Following these practical steps, FPs can improve contraceptive care for women. However, to make a significant impact, clinicians must be willing to change customary practices that are based on tradition, routines, or outdated protocols in favor of those based on current evidence.

One good place to start the transition to best practices is to familiarize yourself with the 2016 US Medical Eligibility Criteria for Contraceptive Use²⁶ and Selected Practice Recommendations for Contraceptive Use.¹⁴ TABLES 2^14,26,46,47 and 3 offer additional resources that can enhance contraceptive counseling and further promote access to contraceptive care.

The contraceptive coverage guarantee under the Affordable Care Act has allowed many women to make contraceptive choices based on personal needs and preferences rather than cost. The new contraceptive coverage exemptions issued under the Trump administration will bring cost back as the driving decision factor for women whose employers choose not to provide contraceptive coverage. Providers should be aware of the typical costs associated with the various contraceptive options offered in their practice and community.

CORRESPONDENCE
Jessica Dalby, MD, Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, 1102 South Park St, Suite 100, Madison, WI 53715; [email protected].

While the unintended pregnancy rate for women ages 15 to 44 years decreased by 18% between 2008 and 2011, almost half of pregnancies in the United States remain unintended.¹ On a more positive note, however, women who use birth control consistently and correctly account for only 5% of unintended pregnancies.² As family physicians (FPs), we can support and facilitate our female patients’ efforts to consistently use highly effective forms of contraception. The 5 initiatives detailed here can help toward that end.

1. Routinely screen patients for their reproductive intentions

All women of reproductive age should be screened routinely for their pregnancy intentions. The American College of Obstetricians and Gynecologists (ACOG) encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive life plan, or a set of personal goals about whether or when to have children.³ The Centers for Disease Control and Prevention (CDC) has also developed a reproductive life plan tool for health professionals to encourage women and men to reflect upon their plans.⁴ So just as we regularly screen and document cigarette use and blood pressure (BP), so too, should we routinely screen women for their reproductive goals.

Ask women this one question. The Oregon Foundation for Reproductive Health launched the One Key Question Initiative, which proposes that the care team ask women ages 18 to 50: “Would you like to become pregnant in the next year?”⁵ A common workflow includes the medical assistant asking women about pregnancy intentions and providing a preconception and/or contraceptive handout, if appropriate. The physician provides additional counseling as needed. Pilot studies of One Key Question indicate that 30% to 40% of women screened needed follow-up counseling, suggesting the need for clinicians to be proactive in asking about reproductive plans. (Additional information on the Initiative is available on the Foundation’s Web site at http://www.orfrh.org/.)

This approach assumes women feel in control of their reproduction; however, this may not be the reality for many, especially low-income women.⁶ Additionally, women commonly cite planning a pregnancy as appropriate only when they are in an ideal relationship and when they are living in a financially stable environment—conditions that some women may never achieve.

ACOG encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive plan.

Another caveat is that women may not have explicit pregnancy intentions, in which case, this particular approach may not be effective. A study of low-income women found only 60% intended to use the method prescribed after contraception counseling, with 37% of those stopping because of adverse effects, 23% saying they wanted another method, and 17% citing method complexity.⁷

Reproductive coercion from male partners, ranging from pressure to become pregnant to method sabotage, is also common in low-income women.⁸ Regular conversations that prioritize a woman’s values and experience are needed to promote reproductive autonomy.

2. Decouple provision of contraception from unnecessary exams

Pelvic exams and pap smears should not be required prior to offering patients hormonal contraception, according to the Choosing Wisely campaign of the American Board of Internal Medicine and ACOG.^9,10 Hormonal contraception may instead be provided safely based on a medical history and BP assessment. Adolescents, minority groups, obese women, and victims of sexual trauma, in particular may avoid asking about birth control because of anxiety and fear of pain from these exams.¹¹ The American College of Physicians recommends against speculum and bimanual exams in asymptomatic, non-pregnant, adult women.¹² Pap smears and sexually transmitted infection (STI) testing should be performed at their normally scheduled intervals as recommended by the US Preventive Services Task Force (USPSTF) and not be tied to contraceptive provision.¹³

Assess pregnancy status using criteria,rather than a pregnancy text

Use the CDC’s criteria to assess pregnancy status rather than relying on a urine pregnancy test prior to providing contraception. Once you are reasonably sure that a woman is not pregnant (TABLE 1¹⁴), contraception may be started. Some physicians have traditionally requested that a woman delay starting contraception until the next menses to ensure that she is not already pregnant. However, given the evidence that hormonal contraception does not cause birth defects, such a delay is not warranted and puts the woman at risk of an unintended pregnancy during the gap.¹⁵

Furthermore, there is an approximate 2-week window in which a woman could have a negative urine pregnancy test despite being pregnant, so the test alone is not completely reliable. In addition, obese women may experience irregular cycles, further complicating the traditional approach.¹⁶

Another largely unnecessary step … The US Selected Practice Recommendations (US SPR) from the CDC notes that additional STI screening prior to an intrauterine device (IUD) insertion is unnecessary for most women if appropriate screening guidelines have been previously followed.¹⁴ For those who have not been screened according to guidelines, the CDC recommends same-day screening and IUD insertion. You can then treat an STI without removing the IUD. Women with purulent cervicitis or a current chlamydial or gonorrheal infection should delay IUD insertion until after treatment.

3. Expand long-acting reversible contraception counseling and access

Offer long-acting reversible contraception (LARC), such as IUDs and implants, as first-line options for most women. ACOG endorses LARC as the most effective reversible method for most women, including those who have not given birth and adolescents.¹⁷ Unfortunately, a 2012 study found that family physicians were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.¹⁸ While 79% of OB-GYNs routinely discussed IUDs with their patients, only 47% of family physicians did. In 2014, the American Academy of Pediatrics (AAP) endorsed a LARC-first tiered counseling approach for adolescents.¹⁹

A test of LARC-first counseling

The Contraceptive CHOICE project, a St. Louis, Missouri-based initiative, was launched to reduce unintended pregnancies in women ages 14 to 45 years by offering LARC-first counseling and free contraception of their choice.²⁰ This project involved more than 9000 women at high risk for unintended pregnancy. Same-day LARC insertion was available. Seventy-five percent of women chose a LARC method and they reported greater continuation at 12 and 24 months, when compared to women who did not choose a LARC method. LARC users also reported higher satisfaction at one year. Provision of contraception through the project contributed to a reduction in repeat abortions as well as decreased rates of teenage pregnancy, birth, and abortion. Three years after the start of the project, IUDs had continuation rates of nearly 70%, implants of 56%, and non-LARC methods of 31%.²¹

When counseling women, it’s important to remember that effectiveness may not be the only criterium a woman uses when choosing a method. A 2010 study found that for 91% of women at high risk for unintended pregnancy, no single method possessed all the features they deemed “extremely important.”²² Clinicians should take a patient-centered approach to find birth control that fits each patient’s priorities.

Clinicians need proper training in LARC methods

Only 20% of FPs regularly insert IUDs, and 11% offer contraceptive implants, according to estimates from physicians recertifying with the American Board of Family Medicine in 2014.²³ Access to training during residency is a key component to increasing these rates. FPs who practice obstetrics should be trained in postpartum LARC insertion and offer this option prior to hospital discharge as well as during the postpartum office visit.

Performing LARC insertions on the same day as counseling is ideal, and clinics should strive to reduce barriers to same-day procedures. Time constraints may be addressed by shifting tasks among the medical team. In the CHOICE project, contraceptive counselors—half of whom had no clinical experience—were trained to provide tiered counseling to participants. By working with a cross-trained health care team and offering prepared resources, clinicians can save time and improve access.

Physicians may want to incorporate the free online resources Bedsider.org or Stayteen.org to help women learn about contraceptive methods.²⁴ The user-friendly Web sites, operated by the National Campaign to Prevent Teen and Unplanned Pregnancy, describe various forms of contraception and offer text and email reminders. Incorporating Bedsider into the counseling workflow and discussing the various reminder tools available may improve patients’ knowledge and enhance their compliance.

Pelvic exams and pap smears should not be required before offering patients hormonal contraception.

Additional barriers for practices may include high upfront costs associated with stocking devices. Practices that may be unable to sustain the costs surrounding enhanced contraception counseling and provision can collaborate with family planning clinics that are able to offer same-day services. A study of clinics in California found that Title X clinics were more likely to provide on-site LARC services than non-Title X public and private providers.²⁵

4. Follow CDC guidelines for initiating and continuing contraception

Follow the US SPR for guidance on initiating and continuing contraceptive methods.¹⁴ The CDC’s Medical Eligibility Criteria for Contraceptive Use is another vital resource, providing recommendations for contraceptive methods to patients who have specific medical conditions or characteristics.²⁶

Utilize the “quick start” method for hormonal contraception, where birth control is started on the same day as its prescription regardless of timing of the menstrual cycle. If you can’t be reasonably certain that a woman is not pregnant based on the criteria listed in TABLE 1,¹⁴ conduct a pregnancy test (while recognizing the aforementioned 2-week window of limitations) and counsel the patient to use back-up protection for the first 7 days along with repeating a pregnancy test in 2 weeks’ time.

The quick start method may lead to higher adherence than delayed initiation.²⁷ Differences in continuation rates between women who use the quick start method and those who follow the delayed approach may disappear over time.²⁸

Prescribe and provide a year’s supply of oral contraceptive pills (OCPs) as recommended by the CDC US SPR.¹⁴ It is important to note that pharmacists are usually restricted by insurance companies to only fill a one or 3 month’s supply.

One study found that FPs were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.

In January 2016, Oregon began requiring private and state health insurance providers to reimburse for a year’s supply of prescription contraception; in January 2017, insurers in Washington, DC, were also required to offer women a year’s supply of prescription contraception.^29,30 Several other states have followed suit. The California Health Benefits Review Program estimates a savings of $42.8 million a year from fewer office visits and 15,000 fewer unintended pregnancies if their state enacts a similar policy.³¹

Pharmacist initiatives are worth watching. In January 2016, Oregon pharmacists with additional training were allowed to prescribe OCs and hormonal patches to women 18 years and older.³² In April 2016, a similar law went into effect in California, but without a minimum age requirement and with the additional coverage of vaginal rings and Depo-Provera (depo) injections.³³ Pharmacists in both states must review a health questionnaire completed by the woman and can refer to a physician as necessary.

The CDC recommends that clinicians extend the allowed window for repeat depo injections to 15 weeks.¹⁴ Common institutional protocol is to give repeat injections every 11 to 13 weeks. If past that window, protocol often dictates the woman abstain from unprotected sex for 2 weeks and then return for a negative pregnancy test (or await menses) before the next injection. However, the CDC notes that depo is effective for longer than the 13-week period.¹⁴ No additional birth control or pregnancy testing is needed and the woman can receive the next depo shot if she is up to 15 weeks from the previous shot.

One study found no additional pregnancy risks for those who were up to 4 weeks “late” for their next shot, suggesting there is potential for an even larger grace period.³⁴ The World Health Organization advises allowing a repeat injection up to 4 weeks late.³⁵ We encourage institutions to change their policies to comply with the CDC’s 15-week window.

Another initiative is over-the-counter (OTC) access to OCs, which the American Academy of Family Physicians (AAFP) and ACOG support.^36,37 ACOG notes that “no drug or intervention is completely without risk of harm” and that the risk of venous thromboembolism for OC users is lower than the risk of pregnancy.³⁷ Women can successfully self-screen for contraindications using a checklist. Concerns about women potentially being less adherent or less likely to choose LARCs are not reasons to preclude access to other methods. The AAFP supports insurance coverage of OCs, regardless of prescription status.³⁶

5. Routinely counsel about, and advance-prescribe, emergency contraception pills

Physicians should counsel and advance-prescribe emergency contraception pills (ECPs) to women, including adolescents, using less reliable contraception, as recommended by ACOG, AAP, and the CDC.^14,37,38 It’s also important to provide information on the copper IUD as the most effective method of emergency contraception, with nearly 100% efficacy if placed within 5 days.³⁹ An easy-to-read patient hand-out in English and Spanish on EC options can be found at http://beyondthepill.ucsf.edu/tools-materials.

Only 3% of respondents participating in the 2006-2010 National Survey of Family Growth received counseling about emergency contraception in the past year.⁴⁰ ECPs are most effective when used within 24 hours but have some efficacy up to 5 days.³⁷ Due to the Affordable Care Act, most insurance plans will cover ECPs if purchased with a prescription, but coverage varies by state.⁴¹ Ulipristal acetate (UPA) ECP is only available with a prescription. Advance prescriptions can alleviate financial burdens on women when they need to access ECPs quickly.

Women should wait at least 5 days before resuming or starting hormonal contraception after taking UPA-based ECP, as it may reduce the ovulation-delaying effect of the ECP.¹⁴ For IUDs, implants, and depo, which require a visit to a health care provider, physicians evaluating earlier provision should consider the risks of reduced efficacy against the many barriers to access.

UPA-based ECPs (such as ella) may be more effective for overweight and obese women than levonorgestrel-based ECPs (such as Plan B and Next Choice).¹⁴ Consider advance-prescribing UPA ECPs to women with a body mass index (BMI) >25 kg/m².⁴² Such considerations are important as the prevalence of obesity in women between 2013 and 2014 was 40.4%.⁴³

A copper IUD may be the only effective form of emergency contraception for patients with a BMI ≥35 kg/m².

In May 2016, the FDA noted that while current data are insufficient regarding whether the effectiveness of levonorgestrel ECPs is reduced in overweight or obese women, there are no safety concerns regarding their use in this population.⁴⁴ Therefore, a woman with a BMI >25 kg/m² should use UPA ECPs if available; but if not, she can still use levonorgestrel ECPs. One study, however, has found that UPA ECPs are only as effective as a placebo when BMI is ≥35 kg/m², at which point a copper IUD may be the only effective form of emergency contraception.⁴⁵

Transitioning from customary practices to best practices

Following these practical steps, FPs can improve contraceptive care for women. However, to make a significant impact, clinicians must be willing to change customary practices that are based on tradition, routines, or outdated protocols in favor of those based on current evidence.

One good place to start the transition to best practices is to familiarize yourself with the 2016 US Medical Eligibility Criteria for Contraceptive Use²⁶ and Selected Practice Recommendations for Contraceptive Use.¹⁴ TABLES 2^14,26,46,47 and 3 offer additional resources that can enhance contraceptive counseling and further promote access to contraceptive care.

The contraceptive coverage guarantee under the Affordable Care Act has allowed many women to make contraceptive choices based on personal needs and preferences rather than cost. The new contraceptive coverage exemptions issued under the Trump administration will bring cost back as the driving decision factor for women whose employers choose not to provide contraceptive coverage. Providers should be aware of the typical costs associated with the various contraceptive options offered in their practice and community.

CORRESPONDENCE
Jessica Dalby, MD, Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, 1102 South Park St, Suite 100, Madison, WI 53715; [email protected].

While the unintended pregnancy rate for women ages 15 to 44 years decreased by 18% between 2008 and 2011, almost half of pregnancies in the United States remain unintended.¹ On a more positive note, however, women who use birth control consistently and correctly account for only 5% of unintended pregnancies.² As family physicians (FPs), we can support and facilitate our female patients’ efforts to consistently use highly effective forms of contraception. The 5 initiatives detailed here can help toward that end.

1. Routinely screen patients for their reproductive intentions

All women of reproductive age should be screened routinely for their pregnancy intentions. The American College of Obstetricians and Gynecologists (ACOG) encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive life plan, or a set of personal goals about whether or when to have children.³ The Centers for Disease Control and Prevention (CDC) has also developed a reproductive life plan tool for health professionals to encourage women and men to reflect upon their plans.⁴ So just as we regularly screen and document cigarette use and blood pressure (BP), so too, should we routinely screen women for their reproductive goals.

Ask women this one question. The Oregon Foundation for Reproductive Health launched the One Key Question Initiative, which proposes that the care team ask women ages 18 to 50: “Would you like to become pregnant in the next year?”⁵ A common workflow includes the medical assistant asking women about pregnancy intentions and providing a preconception and/or contraceptive handout, if appropriate. The physician provides additional counseling as needed. Pilot studies of One Key Question indicate that 30% to 40% of women screened needed follow-up counseling, suggesting the need for clinicians to be proactive in asking about reproductive plans. (Additional information on the Initiative is available on the Foundation’s Web site at http://www.orfrh.org/.)

This approach assumes women feel in control of their reproduction; however, this may not be the reality for many, especially low-income women.⁶ Additionally, women commonly cite planning a pregnancy as appropriate only when they are in an ideal relationship and when they are living in a financially stable environment—conditions that some women may never achieve.

ACOG encourages clinicians to ask women about pregnancy intendedness and encourages patients to develop a reproductive plan.

Another caveat is that women may not have explicit pregnancy intentions, in which case, this particular approach may not be effective. A study of low-income women found only 60% intended to use the method prescribed after contraception counseling, with 37% of those stopping because of adverse effects, 23% saying they wanted another method, and 17% citing method complexity.⁷

Reproductive coercion from male partners, ranging from pressure to become pregnant to method sabotage, is also common in low-income women.⁸ Regular conversations that prioritize a woman’s values and experience are needed to promote reproductive autonomy.

2. Decouple provision of contraception from unnecessary exams

Pelvic exams and pap smears should not be required prior to offering patients hormonal contraception, according to the Choosing Wisely campaign of the American Board of Internal Medicine and ACOG.^9,10 Hormonal contraception may instead be provided safely based on a medical history and BP assessment. Adolescents, minority groups, obese women, and victims of sexual trauma, in particular may avoid asking about birth control because of anxiety and fear of pain from these exams.¹¹ The American College of Physicians recommends against speculum and bimanual exams in asymptomatic, non-pregnant, adult women.¹² Pap smears and sexually transmitted infection (STI) testing should be performed at their normally scheduled intervals as recommended by the US Preventive Services Task Force (USPSTF) and not be tied to contraceptive provision.¹³

Assess pregnancy status using criteria,rather than a pregnancy text

Use the CDC’s criteria to assess pregnancy status rather than relying on a urine pregnancy test prior to providing contraception. Once you are reasonably sure that a woman is not pregnant (TABLE 1¹⁴), contraception may be started. Some physicians have traditionally requested that a woman delay starting contraception until the next menses to ensure that she is not already pregnant. However, given the evidence that hormonal contraception does not cause birth defects, such a delay is not warranted and puts the woman at risk of an unintended pregnancy during the gap.¹⁵

Furthermore, there is an approximate 2-week window in which a woman could have a negative urine pregnancy test despite being pregnant, so the test alone is not completely reliable. In addition, obese women may experience irregular cycles, further complicating the traditional approach.¹⁶

Another largely unnecessary step … The US Selected Practice Recommendations (US SPR) from the CDC notes that additional STI screening prior to an intrauterine device (IUD) insertion is unnecessary for most women if appropriate screening guidelines have been previously followed.¹⁴ For those who have not been screened according to guidelines, the CDC recommends same-day screening and IUD insertion. You can then treat an STI without removing the IUD. Women with purulent cervicitis or a current chlamydial or gonorrheal infection should delay IUD insertion until after treatment.

3. Expand long-acting reversible contraception counseling and access

Offer long-acting reversible contraception (LARC), such as IUDs and implants, as first-line options for most women. ACOG endorses LARC as the most effective reversible method for most women, including those who have not given birth and adolescents.¹⁷ Unfortunately, a 2012 study found that family physicians were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.¹⁸ While 79% of OB-GYNs routinely discussed IUDs with their patients, only 47% of family physicians did. In 2014, the American Academy of Pediatrics (AAP) endorsed a LARC-first tiered counseling approach for adolescents.¹⁹

A test of LARC-first counseling

The Contraceptive CHOICE project, a St. Louis, Missouri-based initiative, was launched to reduce unintended pregnancies in women ages 14 to 45 years by offering LARC-first counseling and free contraception of their choice.²⁰ This project involved more than 9000 women at high risk for unintended pregnancy. Same-day LARC insertion was available. Seventy-five percent of women chose a LARC method and they reported greater continuation at 12 and 24 months, when compared to women who did not choose a LARC method. LARC users also reported higher satisfaction at one year. Provision of contraception through the project contributed to a reduction in repeat abortions as well as decreased rates of teenage pregnancy, birth, and abortion. Three years after the start of the project, IUDs had continuation rates of nearly 70%, implants of 56%, and non-LARC methods of 31%.²¹

When counseling women, it’s important to remember that effectiveness may not be the only criterium a woman uses when choosing a method. A 2010 study found that for 91% of women at high risk for unintended pregnancy, no single method possessed all the features they deemed “extremely important.”²² Clinicians should take a patient-centered approach to find birth control that fits each patient’s priorities.

Clinicians need proper training in LARC methods

Only 20% of FPs regularly insert IUDs, and 11% offer contraceptive implants, according to estimates from physicians recertifying with the American Board of Family Medicine in 2014.²³ Access to training during residency is a key component to increasing these rates. FPs who practice obstetrics should be trained in postpartum LARC insertion and offer this option prior to hospital discharge as well as during the postpartum office visit.

Performing LARC insertions on the same day as counseling is ideal, and clinics should strive to reduce barriers to same-day procedures. Time constraints may be addressed by shifting tasks among the medical team. In the CHOICE project, contraceptive counselors—half of whom had no clinical experience—were trained to provide tiered counseling to participants. By working with a cross-trained health care team and offering prepared resources, clinicians can save time and improve access.

Physicians may want to incorporate the free online resources Bedsider.org or Stayteen.org to help women learn about contraceptive methods.²⁴ The user-friendly Web sites, operated by the National Campaign to Prevent Teen and Unplanned Pregnancy, describe various forms of contraception and offer text and email reminders. Incorporating Bedsider into the counseling workflow and discussing the various reminder tools available may improve patients’ knowledge and enhance their compliance.

Pelvic exams and pap smears should not be required before offering patients hormonal contraception.

Additional barriers for practices may include high upfront costs associated with stocking devices. Practices that may be unable to sustain the costs surrounding enhanced contraception counseling and provision can collaborate with family planning clinics that are able to offer same-day services. A study of clinics in California found that Title X clinics were more likely to provide on-site LARC services than non-Title X public and private providers.²⁵

4. Follow CDC guidelines for initiating and continuing contraception

Follow the US SPR for guidance on initiating and continuing contraceptive methods.¹⁴ The CDC’s Medical Eligibility Criteria for Contraceptive Use is another vital resource, providing recommendations for contraceptive methods to patients who have specific medical conditions or characteristics.²⁶

Utilize the “quick start” method for hormonal contraception, where birth control is started on the same day as its prescription regardless of timing of the menstrual cycle. If you can’t be reasonably certain that a woman is not pregnant based on the criteria listed in TABLE 1,¹⁴ conduct a pregnancy test (while recognizing the aforementioned 2-week window of limitations) and counsel the patient to use back-up protection for the first 7 days along with repeating a pregnancy test in 2 weeks’ time.

The quick start method may lead to higher adherence than delayed initiation.²⁷ Differences in continuation rates between women who use the quick start method and those who follow the delayed approach may disappear over time.²⁸

Prescribe and provide a year’s supply of oral contraceptive pills (OCPs) as recommended by the CDC US SPR.¹⁴ It is important to note that pharmacists are usually restricted by insurance companies to only fill a one or 3 month’s supply.

One study found that FPs were less likely than OB-GYNs to have enough time for contraceptive counseling and fewer than half felt competent inserting IUDs.

In January 2016, Oregon began requiring private and state health insurance providers to reimburse for a year’s supply of prescription contraception; in January 2017, insurers in Washington, DC, were also required to offer women a year’s supply of prescription contraception.^29,30 Several other states have followed suit. The California Health Benefits Review Program estimates a savings of $42.8 million a year from fewer office visits and 15,000 fewer unintended pregnancies if their state enacts a similar policy.³¹

Pharmacist initiatives are worth watching. In January 2016, Oregon pharmacists with additional training were allowed to prescribe OCs and hormonal patches to women 18 years and older.³² In April 2016, a similar law went into effect in California, but without a minimum age requirement and with the additional coverage of vaginal rings and Depo-Provera (depo) injections.³³ Pharmacists in both states must review a health questionnaire completed by the woman and can refer to a physician as necessary.

The CDC recommends that clinicians extend the allowed window for repeat depo injections to 15 weeks.¹⁴ Common institutional protocol is to give repeat injections every 11 to 13 weeks. If past that window, protocol often dictates the woman abstain from unprotected sex for 2 weeks and then return for a negative pregnancy test (or await menses) before the next injection. However, the CDC notes that depo is effective for longer than the 13-week period.¹⁴ No additional birth control or pregnancy testing is needed and the woman can receive the next depo shot if she is up to 15 weeks from the previous shot.

One study found no additional pregnancy risks for those who were up to 4 weeks “late” for their next shot, suggesting there is potential for an even larger grace period.³⁴ The World Health Organization advises allowing a repeat injection up to 4 weeks late.³⁵ We encourage institutions to change their policies to comply with the CDC’s 15-week window.

Another initiative is over-the-counter (OTC) access to OCs, which the American Academy of Family Physicians (AAFP) and ACOG support.^36,37 ACOG notes that “no drug or intervention is completely without risk of harm” and that the risk of venous thromboembolism for OC users is lower than the risk of pregnancy.³⁷ Women can successfully self-screen for contraindications using a checklist. Concerns about women potentially being less adherent or less likely to choose LARCs are not reasons to preclude access to other methods. The AAFP supports insurance coverage of OCs, regardless of prescription status.³⁶

5. Routinely counsel about, and advance-prescribe, emergency contraception pills

Physicians should counsel and advance-prescribe emergency contraception pills (ECPs) to women, including adolescents, using less reliable contraception, as recommended by ACOG, AAP, and the CDC.^14,37,38 It’s also important to provide information on the copper IUD as the most effective method of emergency contraception, with nearly 100% efficacy if placed within 5 days.³⁹ An easy-to-read patient hand-out in English and Spanish on EC options can be found at http://beyondthepill.ucsf.edu/tools-materials.

Only 3% of respondents participating in the 2006-2010 National Survey of Family Growth received counseling about emergency contraception in the past year.⁴⁰ ECPs are most effective when used within 24 hours but have some efficacy up to 5 days.³⁷ Due to the Affordable Care Act, most insurance plans will cover ECPs if purchased with a prescription, but coverage varies by state.⁴¹ Ulipristal acetate (UPA) ECP is only available with a prescription. Advance prescriptions can alleviate financial burdens on women when they need to access ECPs quickly.

Women should wait at least 5 days before resuming or starting hormonal contraception after taking UPA-based ECP, as it may reduce the ovulation-delaying effect of the ECP.¹⁴ For IUDs, implants, and depo, which require a visit to a health care provider, physicians evaluating earlier provision should consider the risks of reduced efficacy against the many barriers to access.

UPA-based ECPs (such as ella) may be more effective for overweight and obese women than levonorgestrel-based ECPs (such as Plan B and Next Choice).¹⁴ Consider advance-prescribing UPA ECPs to women with a body mass index (BMI) >25 kg/m².⁴² Such considerations are important as the prevalence of obesity in women between 2013 and 2014 was 40.4%.⁴³

A copper IUD may be the only effective form of emergency contraception for patients with a BMI ≥35 kg/m².

In May 2016, the FDA noted that while current data are insufficient regarding whether the effectiveness of levonorgestrel ECPs is reduced in overweight or obese women, there are no safety concerns regarding their use in this population.⁴⁴ Therefore, a woman with a BMI >25 kg/m² should use UPA ECPs if available; but if not, she can still use levonorgestrel ECPs. One study, however, has found that UPA ECPs are only as effective as a placebo when BMI is ≥35 kg/m², at which point a copper IUD may be the only effective form of emergency contraception.⁴⁵

Transitioning from customary practices to best practices

Following these practical steps, FPs can improve contraceptive care for women. However, to make a significant impact, clinicians must be willing to change customary practices that are based on tradition, routines, or outdated protocols in favor of those based on current evidence.

One good place to start the transition to best practices is to familiarize yourself with the 2016 US Medical Eligibility Criteria for Contraceptive Use²⁶ and Selected Practice Recommendations for Contraceptive Use.¹⁴ TABLES 2^14,26,46,47 and 3 offer additional resources that can enhance contraceptive counseling and further promote access to contraceptive care.

The contraceptive coverage guarantee under the Affordable Care Act has allowed many women to make contraceptive choices based on personal needs and preferences rather than cost. The new contraceptive coverage exemptions issued under the Trump administration will bring cost back as the driving decision factor for women whose employers choose not to provide contraceptive coverage. Providers should be aware of the typical costs associated with the various contraceptive options offered in their practice and community.

CORRESPONDENCE
Jessica Dalby, MD, Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, 1102 South Park St, Suite 100, Madison, WI 53715; [email protected].

Meniscectomy is the most common orthopedic procedure performed in the United States with 700,000 meniscectomies performed every year.¹ More than half of these procedures are performed in patients ≥45 years of age,² giving rise to the question: Does arthroscopic surgery have a role in the treatment of patients who may have osteoarthritis (OA) and another knee condition, such as a symptomatic meniscal tear? Determining the answer is especially important when you consider that the number of true and incidental tears diagnosed on magnetic resonance imaging (MRI) has been on the rise³—a result of the routine use of MRIs to identify the cause of patients’ chronic knee pain.

At a cost of roughly $5,000 per procedure, some experts have suggested that at least a portion of the approximately $4 billion annual direct medical costs associated with meniscectomy could be put to better use.^4,5 This prompted us to wonder what the literature tells us about the management of degenerative meniscus tears in middle-aged patients with OA and whether these patients would benefit from nonoperative management with optimized physical and medical therapy as a first-line approach. Our findings follow.

But first, a word about the connection between OA and meniscal tears.

What we’ve learned about meniscal damage

Research has shown that over one-third of individuals >50 years of age and three-quarters of people with knee OA have degenerative meniscal tears.⁶ In the past, the relative paucity of epidemiologic data on the prevalence of meniscal tears in the general population made it difficult to interpret the diagnostic information provided by MRI.

More recently, experts found that meniscal damage is especially prevalent among individuals with OA, and they began treating with arthroscopic partial meniscectomy (APM), as the meniscal damage was thought to be the anatomical foundation for the complaint of knee pain.⁷

However, researchers then began realizing that many patients with findings of a meniscal tear visualized on MRI reported no knee symptoms. In one study, adults in a large community-based sample found to have a meniscal tear on MRI were no more likely to have knee pain than subjects without a meniscal tear.⁶ Similarly, subjects with a meniscal tear and OA had no more severe pain than subjects with OA and no meniscal tear.⁶

Over one-third of people >50 years of age and three-quarters of people with knee osteoarthritis have degenerative meniscal tears.

In addition, the landmark Fairbank study from 1948⁸ and others since have shown that meniscectomy can lead to other problems. Removal of meniscal tissue decreases the contact stress area, which increases stress on the articular cartilage, and inevitably leads to degeneration of the involved joint.⁹ Researchers have shown that even partial meniscectomy produces late articular cartilage changes.¹⁰

Which interventions and when?

We conducted an in-depth literature review to determine which approaches were best for the treatment of OA and meniscal tears, and summarize our findings below, according to OA severity. (For details of how the literature review was conducted and an at-a-glance summary of the key findings, see the TABLE.^4,5,11-17) Of note: All of the studies reviewed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event.

The findings: Early OA and meniscal tears

The first 2 studies we identified in the literature, both published by Herrlin et al,^11,12 examined the efficacy of APM in middle-aged patients with early OA (≤grade 1), according to the Ahlbäck classification.

In the first Herrlin study, a 6-month prospective randomized trial, 90 middle-aged patients with a medial meniscal tear (without traumatic history) were assigned to either APM followed by supervised exercise or 8 weeks of supervised exercise alone.¹¹ Exercise consisted of activities for improving muscle strength, endurance, and flexibility, as well as for balance and proprioception. The authors concluded that a combination of APM and supervised exercise did not lead to greater improvements in knee function compared with supervised exercise alone.¹¹

In the second Herrlin study, a prospective randomized study involving 96 middle-aged patients with an MRI-verified medial meniscal tear and radiographic OA, the authors concluded that arthroscopic surgery followed by exercise therapy was not superior to the same exercise therapy alone.¹² The results were gleaned from both patient-reported outcomes and radiographic assessment at 2 and 5 years. Both groups reported significant improvements at 5 years, but participants did not reach the level of fitness and quality of life of similarly-aged healthy controls.

Perhaps one of the most interesting aspects of this study was that approximately one-third of patients from the exercise-only group still had disabling knee symptoms after exercise therapy, but improved to the same level as the rest of the patients after crossing over and undergoing APM.¹² Part of the observed benefit of arthroscopy in these patients has the potential to be explained by the placebo effect, especially given that invasive procedures have a stronger placebo effect than do noninvasive ones, and due to the lack of blinding.¹⁸ Additionally, limitations of the above studies include small sample sizes, lack of a control group, and short-term follow-up.

Next, a 2013 study by Yim et al looked specifically at APM vs nonoperative treatment with strengthening exercises.¹³ A total of 102 patients with an average age of 53.8 years, a Kellgren-Lawrence Classification of Osteoarthritis of <2, and an MRI-confirmed degenerative horizontal tear of the posterior horn of the medial meniscus were randomized to the 2 intervention groups. The 2 groups were highly comparable, giving the study high internal validity. These patients were then assessed at 3 months, one year, and at 2 years after treatment.

Although most patients at the outset of the study had intense knee pain with mechanical symptoms, both groups reported a decrease in experienced knee pain, improved function, and a high level of satisfaction with their prescribed treatment, with no significant difference in any of these values after 2 years of follow-up.¹³ A limitation of the study was that it used subjective questionnaires to assess pain, swelling, and activities of daily living (ADLs).

A fourth study, a 2013 multicenter, randomized, sham-controlled trial, looked at 146 patients ages 35 to 65 years who had knee symptoms consistent with a degenerative medial meniscus tear (confirmed by MRI and arthroscopic evaluation) and no knee arthritis.⁴ The subjects were assigned to either APM or sham surgery (skin incisions only). The results showed that APM was not superior to sham surgery with regard to outcomes assessed during a 12-month follow-up period.⁴

Most recently (2016), Kise et al¹⁴ published the results of a randomized controlled superiority trial conducted in Norway comparing 12 weeks of supervised exercise therapy with APM for patients with degenerative meniscus tears. Their study included 140 patients ages 36 to 60 years. Notably, most (96%), but not all, of their patients had no radiographic evidence of OA.

Many patients with MRI-verified meniscal tears have no symptoms, and many with OA and tears have no worse symptoms than those with OA alone.

At the 2-year follow-up, there were no differences in patient-reported pain or functional outcomes, with all patients improving significantly from baseline. Muscle strength was also measured and found to be significantly greater at 3 and 12 months in the exercise group. Limitations of this study were a lack of patient blinding and a 19% crossover from the exercise to the APM group.

The findings: Mild to moderate OA and meniscal tears

The authors of a 2002 double-blind, placebo-controlled trial randomly assigned 180 patients with degenerative meniscus tears and knee OA to either arthroscopic debridement, arthroscopic lavage, or placebo surgery consisting of superficial skin incisions without insertion of an arthroscope.⁵ Patients were eligible if they were ≤75 years of age and had not undergone arthroscopy of the knee within the previous 2 years. Arthritis was graded utilizing the Kellgren-Lawrence scale (0-4) and by calculating a severity score (0-12) by adding the individual scores for each of the 3 compartments of the knee; patients were excluded if they had a severity grade ≥9. One-quarter of the participants had severe arthritis, with scores of 7 or 8. Outcomes were measured over a 24-month period. At no point did either of the intervention groups report less pain or better function than the sham-surgery group.⁵

Additionally, in a single-center RCT involving 178 patients with mild to severe OA, subjects were randomly assigned to surgical lavage and arthroscopic debridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone.¹⁵ Patients were excluded if they had “bucket handle” meniscal tears detected by physical exam or by MRI, previous arthroscopic surgery, previous major knee trauma, or steroid injections in the last 3 months. All participants were required to have Kellgren-Lawrence grade 2, 3, or 4 arthritis.

The researchers used 2 validated outcome measures to evaluate pain, symptoms, and functional ability and followed the patients for 2 years after the initiation of treatment. This study failed to show that arthroscopic surgery provided any additional benefit to optimized physical and medical therapy.¹⁵

A 2013 multicenter, RCT randomly assigned 351 patients ≥45 years with a meniscal tear and radiographic evidence of mild to moderate OA to either surgery and postoperative physical therapy or to a standardized physical therapy regimen.¹⁶ Patients were required to have at least one symptom that was consistent with a meniscal tear for approximately one month. About 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. There were no significant differences between the 2 groups in the magnitude of improvement in functional status or pain at 6 or 12 months.

Finally, a prospective Scottish study consisting of 270 patients with everything from no signs of OA to advanced OA who underwent APM were sent preoperative and 6-month postop questionnaires evaluating ADLs, pain, symptoms, quality of life, and body mass index (BMI).¹⁷ Their OA was graded via preop MRI or radiographs and confirmed by the operating surgeon. The investigators were unable to demonstrate any significant benefit associated with arthroscopic meniscectomy, and, therefore, could not recommend the procedure for patients with moderate to advanced OA.

However, in their analysis, 3 subgroup populations were found to benefit from APM: those with greater body habitus (BMI >30 kg/m²), those without signs of OA, and those with early OA. Limitations of this study included the lack of randomization, blinding, a control, and long-term follow up, and that the authors didn’t use established OA grading criteria.¹⁷

The bottom line: Nonoperative treatment benefits most patients

Physical therapy is an appropriate first-line treatment for degenerative meniscus tears in middle-aged patients. In fact, a trial of nonoperative treatment is likely to benefit the majority of patients. In addition, avoiding surgery eliminates surgical complications and decreases overall health care costs.

Reserve APM for those patients without significant OA who fail to improve after physical therapy, who have mechanical symptoms, or who have intra-articular loose bodies.

Consider a trial of nonoperative treatment, as it is likely to benefit the majority of patients with degenerative meniscal tears.

In addition, exercise therapy is an effective treatment for patients with knee OA. It improves function and limits joint pain in both acute arthritic flares and more long-term, chronic situations. There is strong evidence that strengthening plays a critical role in reducing symptoms and improving muscle strength, physical ability, and quality of life.¹⁹ It has been suggested that physical exercise 3 times a week for 4 months could lead to >35% improvement of knee function.²⁰ In contrast, other studies reported that while 91% of patients 11.5 years after APM considered their knees “normal or almost normal,” patients actually experienced a reduction in postoperative physical activity and quality of life.²¹

The most recent American Academy of Orthopaedic Surgeons (AAOS) guidelines²² do not recommend for or against arthroscopic partial meniscectomy in patients with knee OA and a torn meniscus. In middle-aged patients, MRI abnormalities of the meniscus do not consistently correlate with symptoms. Many meniscus lesions are asymptomatic or not the primary source of pain in the setting of OA.³

Potential harms and considerations. Deep venous thrombosis is the most frequently reported adverse event of arthroscopic surgery, with an approximate incidence of 4.13 per 1000 procedures, followed by less frequent complications such as infection, pulmonary embolism, and death.¹⁸

It is important to note that the degenerative meniscus tears that occur in middle age and that are associated with OA are not the same as acute, traumatic meniscus tears. All of the studies discussed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event. Many of the studies excluded patients with bucket-handle tears or severe mechanical symptoms (ie, locking). APM may be indicated for these meniscus tears regardless of age or OA status.

Making a sensible choice. Ultimately, physicians and their patients must use the best evidence available to make sensible clinical decisions. The ability to retain native meniscal tissue is of utmost importance to maintaining the longevity of their knee. According to previous studies, OA progression is more likely to occur after meniscectomy than after nonoperative treatment.²³

CORRESPONDENCE
William Bassett, MD, Department of Orthopedics, Rutgers-Robert Wood Johnson Medical School, 51 French St., PO Box 19, New Brunswick, NJ 08903; [email protected]. 

Meniscectomy is the most common orthopedic procedure performed in the United States with 700,000 meniscectomies performed every year.¹ More than half of these procedures are performed in patients ≥45 years of age,² giving rise to the question: Does arthroscopic surgery have a role in the treatment of patients who may have osteoarthritis (OA) and another knee condition, such as a symptomatic meniscal tear? Determining the answer is especially important when you consider that the number of true and incidental tears diagnosed on magnetic resonance imaging (MRI) has been on the rise³—a result of the routine use of MRIs to identify the cause of patients’ chronic knee pain.

At a cost of roughly $5,000 per procedure, some experts have suggested that at least a portion of the approximately $4 billion annual direct medical costs associated with meniscectomy could be put to better use.^4,5 This prompted us to wonder what the literature tells us about the management of degenerative meniscus tears in middle-aged patients with OA and whether these patients would benefit from nonoperative management with optimized physical and medical therapy as a first-line approach. Our findings follow.

But first, a word about the connection between OA and meniscal tears.

What we’ve learned about meniscal damage

Research has shown that over one-third of individuals >50 years of age and three-quarters of people with knee OA have degenerative meniscal tears.⁶ In the past, the relative paucity of epidemiologic data on the prevalence of meniscal tears in the general population made it difficult to interpret the diagnostic information provided by MRI.

More recently, experts found that meniscal damage is especially prevalent among individuals with OA, and they began treating with arthroscopic partial meniscectomy (APM), as the meniscal damage was thought to be the anatomical foundation for the complaint of knee pain.⁷

However, researchers then began realizing that many patients with findings of a meniscal tear visualized on MRI reported no knee symptoms. In one study, adults in a large community-based sample found to have a meniscal tear on MRI were no more likely to have knee pain than subjects without a meniscal tear.⁶ Similarly, subjects with a meniscal tear and OA had no more severe pain than subjects with OA and no meniscal tear.⁶

Over one-third of people >50 years of age and three-quarters of people with knee osteoarthritis have degenerative meniscal tears.

In addition, the landmark Fairbank study from 1948⁸ and others since have shown that meniscectomy can lead to other problems. Removal of meniscal tissue decreases the contact stress area, which increases stress on the articular cartilage, and inevitably leads to degeneration of the involved joint.⁹ Researchers have shown that even partial meniscectomy produces late articular cartilage changes.¹⁰

Which interventions and when?

We conducted an in-depth literature review to determine which approaches were best for the treatment of OA and meniscal tears, and summarize our findings below, according to OA severity. (For details of how the literature review was conducted and an at-a-glance summary of the key findings, see the TABLE.^4,5,11-17) Of note: All of the studies reviewed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event.

The findings: Early OA and meniscal tears

The first 2 studies we identified in the literature, both published by Herrlin et al,^11,12 examined the efficacy of APM in middle-aged patients with early OA (≤grade 1), according to the Ahlbäck classification.

In the first Herrlin study, a 6-month prospective randomized trial, 90 middle-aged patients with a medial meniscal tear (without traumatic history) were assigned to either APM followed by supervised exercise or 8 weeks of supervised exercise alone.¹¹ Exercise consisted of activities for improving muscle strength, endurance, and flexibility, as well as for balance and proprioception. The authors concluded that a combination of APM and supervised exercise did not lead to greater improvements in knee function compared with supervised exercise alone.¹¹

In the second Herrlin study, a prospective randomized study involving 96 middle-aged patients with an MRI-verified medial meniscal tear and radiographic OA, the authors concluded that arthroscopic surgery followed by exercise therapy was not superior to the same exercise therapy alone.¹² The results were gleaned from both patient-reported outcomes and radiographic assessment at 2 and 5 years. Both groups reported significant improvements at 5 years, but participants did not reach the level of fitness and quality of life of similarly-aged healthy controls.

Perhaps one of the most interesting aspects of this study was that approximately one-third of patients from the exercise-only group still had disabling knee symptoms after exercise therapy, but improved to the same level as the rest of the patients after crossing over and undergoing APM.¹² Part of the observed benefit of arthroscopy in these patients has the potential to be explained by the placebo effect, especially given that invasive procedures have a stronger placebo effect than do noninvasive ones, and due to the lack of blinding.¹⁸ Additionally, limitations of the above studies include small sample sizes, lack of a control group, and short-term follow-up.

Next, a 2013 study by Yim et al looked specifically at APM vs nonoperative treatment with strengthening exercises.¹³ A total of 102 patients with an average age of 53.8 years, a Kellgren-Lawrence Classification of Osteoarthritis of <2, and an MRI-confirmed degenerative horizontal tear of the posterior horn of the medial meniscus were randomized to the 2 intervention groups. The 2 groups were highly comparable, giving the study high internal validity. These patients were then assessed at 3 months, one year, and at 2 years after treatment.

Although most patients at the outset of the study had intense knee pain with mechanical symptoms, both groups reported a decrease in experienced knee pain, improved function, and a high level of satisfaction with their prescribed treatment, with no significant difference in any of these values after 2 years of follow-up.¹³ A limitation of the study was that it used subjective questionnaires to assess pain, swelling, and activities of daily living (ADLs).

A fourth study, a 2013 multicenter, randomized, sham-controlled trial, looked at 146 patients ages 35 to 65 years who had knee symptoms consistent with a degenerative medial meniscus tear (confirmed by MRI and arthroscopic evaluation) and no knee arthritis.⁴ The subjects were assigned to either APM or sham surgery (skin incisions only). The results showed that APM was not superior to sham surgery with regard to outcomes assessed during a 12-month follow-up period.⁴

Most recently (2016), Kise et al¹⁴ published the results of a randomized controlled superiority trial conducted in Norway comparing 12 weeks of supervised exercise therapy with APM for patients with degenerative meniscus tears. Their study included 140 patients ages 36 to 60 years. Notably, most (96%), but not all, of their patients had no radiographic evidence of OA.

Many patients with MRI-verified meniscal tears have no symptoms, and many with OA and tears have no worse symptoms than those with OA alone.

At the 2-year follow-up, there were no differences in patient-reported pain or functional outcomes, with all patients improving significantly from baseline. Muscle strength was also measured and found to be significantly greater at 3 and 12 months in the exercise group. Limitations of this study were a lack of patient blinding and a 19% crossover from the exercise to the APM group.

The findings: Mild to moderate OA and meniscal tears

The authors of a 2002 double-blind, placebo-controlled trial randomly assigned 180 patients with degenerative meniscus tears and knee OA to either arthroscopic debridement, arthroscopic lavage, or placebo surgery consisting of superficial skin incisions without insertion of an arthroscope.⁵ Patients were eligible if they were ≤75 years of age and had not undergone arthroscopy of the knee within the previous 2 years. Arthritis was graded utilizing the Kellgren-Lawrence scale (0-4) and by calculating a severity score (0-12) by adding the individual scores for each of the 3 compartments of the knee; patients were excluded if they had a severity grade ≥9. One-quarter of the participants had severe arthritis, with scores of 7 or 8. Outcomes were measured over a 24-month period. At no point did either of the intervention groups report less pain or better function than the sham-surgery group.⁵

Additionally, in a single-center RCT involving 178 patients with mild to severe OA, subjects were randomly assigned to surgical lavage and arthroscopic debridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone.¹⁵ Patients were excluded if they had “bucket handle” meniscal tears detected by physical exam or by MRI, previous arthroscopic surgery, previous major knee trauma, or steroid injections in the last 3 months. All participants were required to have Kellgren-Lawrence grade 2, 3, or 4 arthritis.

The researchers used 2 validated outcome measures to evaluate pain, symptoms, and functional ability and followed the patients for 2 years after the initiation of treatment. This study failed to show that arthroscopic surgery provided any additional benefit to optimized physical and medical therapy.¹⁵

A 2013 multicenter, RCT randomly assigned 351 patients ≥45 years with a meniscal tear and radiographic evidence of mild to moderate OA to either surgery and postoperative physical therapy or to a standardized physical therapy regimen.¹⁶ Patients were required to have at least one symptom that was consistent with a meniscal tear for approximately one month. About 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. There were no significant differences between the 2 groups in the magnitude of improvement in functional status or pain at 6 or 12 months.

Finally, a prospective Scottish study consisting of 270 patients with everything from no signs of OA to advanced OA who underwent APM were sent preoperative and 6-month postop questionnaires evaluating ADLs, pain, symptoms, quality of life, and body mass index (BMI).¹⁷ Their OA was graded via preop MRI or radiographs and confirmed by the operating surgeon. The investigators were unable to demonstrate any significant benefit associated with arthroscopic meniscectomy, and, therefore, could not recommend the procedure for patients with moderate to advanced OA.

However, in their analysis, 3 subgroup populations were found to benefit from APM: those with greater body habitus (BMI >30 kg/m²), those without signs of OA, and those with early OA. Limitations of this study included the lack of randomization, blinding, a control, and long-term follow up, and that the authors didn’t use established OA grading criteria.¹⁷

The bottom line: Nonoperative treatment benefits most patients

Physical therapy is an appropriate first-line treatment for degenerative meniscus tears in middle-aged patients. In fact, a trial of nonoperative treatment is likely to benefit the majority of patients. In addition, avoiding surgery eliminates surgical complications and decreases overall health care costs.

Reserve APM for those patients without significant OA who fail to improve after physical therapy, who have mechanical symptoms, or who have intra-articular loose bodies.

Consider a trial of nonoperative treatment, as it is likely to benefit the majority of patients with degenerative meniscal tears.

In addition, exercise therapy is an effective treatment for patients with knee OA. It improves function and limits joint pain in both acute arthritic flares and more long-term, chronic situations. There is strong evidence that strengthening plays a critical role in reducing symptoms and improving muscle strength, physical ability, and quality of life.¹⁹ It has been suggested that physical exercise 3 times a week for 4 months could lead to >35% improvement of knee function.²⁰ In contrast, other studies reported that while 91% of patients 11.5 years after APM considered their knees “normal or almost normal,” patients actually experienced a reduction in postoperative physical activity and quality of life.²¹

The most recent American Academy of Orthopaedic Surgeons (AAOS) guidelines²² do not recommend for or against arthroscopic partial meniscectomy in patients with knee OA and a torn meniscus. In middle-aged patients, MRI abnormalities of the meniscus do not consistently correlate with symptoms. Many meniscus lesions are asymptomatic or not the primary source of pain in the setting of OA.³

Potential harms and considerations. Deep venous thrombosis is the most frequently reported adverse event of arthroscopic surgery, with an approximate incidence of 4.13 per 1000 procedures, followed by less frequent complications such as infection, pulmonary embolism, and death.¹⁸

It is important to note that the degenerative meniscus tears that occur in middle age and that are associated with OA are not the same as acute, traumatic meniscus tears. All of the studies discussed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event. Many of the studies excluded patients with bucket-handle tears or severe mechanical symptoms (ie, locking). APM may be indicated for these meniscus tears regardless of age or OA status.

Making a sensible choice. Ultimately, physicians and their patients must use the best evidence available to make sensible clinical decisions. The ability to retain native meniscal tissue is of utmost importance to maintaining the longevity of their knee. According to previous studies, OA progression is more likely to occur after meniscectomy than after nonoperative treatment.²³

CORRESPONDENCE
William Bassett, MD, Department of Orthopedics, Rutgers-Robert Wood Johnson Medical School, 51 French St., PO Box 19, New Brunswick, NJ 08903; [email protected]. 

Meniscectomy is the most common orthopedic procedure performed in the United States with 700,000 meniscectomies performed every year.¹ More than half of these procedures are performed in patients ≥45 years of age,² giving rise to the question: Does arthroscopic surgery have a role in the treatment of patients who may have osteoarthritis (OA) and another knee condition, such as a symptomatic meniscal tear? Determining the answer is especially important when you consider that the number of true and incidental tears diagnosed on magnetic resonance imaging (MRI) has been on the rise³—a result of the routine use of MRIs to identify the cause of patients’ chronic knee pain.

At a cost of roughly $5,000 per procedure, some experts have suggested that at least a portion of the approximately $4 billion annual direct medical costs associated with meniscectomy could be put to better use.^4,5 This prompted us to wonder what the literature tells us about the management of degenerative meniscus tears in middle-aged patients with OA and whether these patients would benefit from nonoperative management with optimized physical and medical therapy as a first-line approach. Our findings follow.

But first, a word about the connection between OA and meniscal tears.

What we’ve learned about meniscal damage

Research has shown that over one-third of individuals >50 years of age and three-quarters of people with knee OA have degenerative meniscal tears.⁶ In the past, the relative paucity of epidemiologic data on the prevalence of meniscal tears in the general population made it difficult to interpret the diagnostic information provided by MRI.

More recently, experts found that meniscal damage is especially prevalent among individuals with OA, and they began treating with arthroscopic partial meniscectomy (APM), as the meniscal damage was thought to be the anatomical foundation for the complaint of knee pain.⁷

However, researchers then began realizing that many patients with findings of a meniscal tear visualized on MRI reported no knee symptoms. In one study, adults in a large community-based sample found to have a meniscal tear on MRI were no more likely to have knee pain than subjects without a meniscal tear.⁶ Similarly, subjects with a meniscal tear and OA had no more severe pain than subjects with OA and no meniscal tear.⁶

Over one-third of people >50 years of age and three-quarters of people with knee osteoarthritis have degenerative meniscal tears.

In addition, the landmark Fairbank study from 1948⁸ and others since have shown that meniscectomy can lead to other problems. Removal of meniscal tissue decreases the contact stress area, which increases stress on the articular cartilage, and inevitably leads to degeneration of the involved joint.⁹ Researchers have shown that even partial meniscectomy produces late articular cartilage changes.¹⁰

Which interventions and when?

We conducted an in-depth literature review to determine which approaches were best for the treatment of OA and meniscal tears, and summarize our findings below, according to OA severity. (For details of how the literature review was conducted and an at-a-glance summary of the key findings, see the TABLE.^4,5,11-17) Of note: All of the studies reviewed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event.

The findings: Early OA and meniscal tears

The first 2 studies we identified in the literature, both published by Herrlin et al,^11,12 examined the efficacy of APM in middle-aged patients with early OA (≤grade 1), according to the Ahlbäck classification.

In the first Herrlin study, a 6-month prospective randomized trial, 90 middle-aged patients with a medial meniscal tear (without traumatic history) were assigned to either APM followed by supervised exercise or 8 weeks of supervised exercise alone.¹¹ Exercise consisted of activities for improving muscle strength, endurance, and flexibility, as well as for balance and proprioception. The authors concluded that a combination of APM and supervised exercise did not lead to greater improvements in knee function compared with supervised exercise alone.¹¹

In the second Herrlin study, a prospective randomized study involving 96 middle-aged patients with an MRI-verified medial meniscal tear and radiographic OA, the authors concluded that arthroscopic surgery followed by exercise therapy was not superior to the same exercise therapy alone.¹² The results were gleaned from both patient-reported outcomes and radiographic assessment at 2 and 5 years. Both groups reported significant improvements at 5 years, but participants did not reach the level of fitness and quality of life of similarly-aged healthy controls.

Perhaps one of the most interesting aspects of this study was that approximately one-third of patients from the exercise-only group still had disabling knee symptoms after exercise therapy, but improved to the same level as the rest of the patients after crossing over and undergoing APM.¹² Part of the observed benefit of arthroscopy in these patients has the potential to be explained by the placebo effect, especially given that invasive procedures have a stronger placebo effect than do noninvasive ones, and due to the lack of blinding.¹⁸ Additionally, limitations of the above studies include small sample sizes, lack of a control group, and short-term follow-up.

Next, a 2013 study by Yim et al looked specifically at APM vs nonoperative treatment with strengthening exercises.¹³ A total of 102 patients with an average age of 53.8 years, a Kellgren-Lawrence Classification of Osteoarthritis of <2, and an MRI-confirmed degenerative horizontal tear of the posterior horn of the medial meniscus were randomized to the 2 intervention groups. The 2 groups were highly comparable, giving the study high internal validity. These patients were then assessed at 3 months, one year, and at 2 years after treatment.

Although most patients at the outset of the study had intense knee pain with mechanical symptoms, both groups reported a decrease in experienced knee pain, improved function, and a high level of satisfaction with their prescribed treatment, with no significant difference in any of these values after 2 years of follow-up.¹³ A limitation of the study was that it used subjective questionnaires to assess pain, swelling, and activities of daily living (ADLs).

A fourth study, a 2013 multicenter, randomized, sham-controlled trial, looked at 146 patients ages 35 to 65 years who had knee symptoms consistent with a degenerative medial meniscus tear (confirmed by MRI and arthroscopic evaluation) and no knee arthritis.⁴ The subjects were assigned to either APM or sham surgery (skin incisions only). The results showed that APM was not superior to sham surgery with regard to outcomes assessed during a 12-month follow-up period.⁴

Most recently (2016), Kise et al¹⁴ published the results of a randomized controlled superiority trial conducted in Norway comparing 12 weeks of supervised exercise therapy with APM for patients with degenerative meniscus tears. Their study included 140 patients ages 36 to 60 years. Notably, most (96%), but not all, of their patients had no radiographic evidence of OA.

Many patients with MRI-verified meniscal tears have no symptoms, and many with OA and tears have no worse symptoms than those with OA alone.

At the 2-year follow-up, there were no differences in patient-reported pain or functional outcomes, with all patients improving significantly from baseline. Muscle strength was also measured and found to be significantly greater at 3 and 12 months in the exercise group. Limitations of this study were a lack of patient blinding and a 19% crossover from the exercise to the APM group.

The findings: Mild to moderate OA and meniscal tears

The authors of a 2002 double-blind, placebo-controlled trial randomly assigned 180 patients with degenerative meniscus tears and knee OA to either arthroscopic debridement, arthroscopic lavage, or placebo surgery consisting of superficial skin incisions without insertion of an arthroscope.⁵ Patients were eligible if they were ≤75 years of age and had not undergone arthroscopy of the knee within the previous 2 years. Arthritis was graded utilizing the Kellgren-Lawrence scale (0-4) and by calculating a severity score (0-12) by adding the individual scores for each of the 3 compartments of the knee; patients were excluded if they had a severity grade ≥9. One-quarter of the participants had severe arthritis, with scores of 7 or 8. Outcomes were measured over a 24-month period. At no point did either of the intervention groups report less pain or better function than the sham-surgery group.⁵

Additionally, in a single-center RCT involving 178 patients with mild to severe OA, subjects were randomly assigned to surgical lavage and arthroscopic debridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone.¹⁵ Patients were excluded if they had “bucket handle” meniscal tears detected by physical exam or by MRI, previous arthroscopic surgery, previous major knee trauma, or steroid injections in the last 3 months. All participants were required to have Kellgren-Lawrence grade 2, 3, or 4 arthritis.

The researchers used 2 validated outcome measures to evaluate pain, symptoms, and functional ability and followed the patients for 2 years after the initiation of treatment. This study failed to show that arthroscopic surgery provided any additional benefit to optimized physical and medical therapy.¹⁵

A 2013 multicenter, RCT randomly assigned 351 patients ≥45 years with a meniscal tear and radiographic evidence of mild to moderate OA to either surgery and postoperative physical therapy or to a standardized physical therapy regimen.¹⁶ Patients were required to have at least one symptom that was consistent with a meniscal tear for approximately one month. About 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. There were no significant differences between the 2 groups in the magnitude of improvement in functional status or pain at 6 or 12 months.

Finally, a prospective Scottish study consisting of 270 patients with everything from no signs of OA to advanced OA who underwent APM were sent preoperative and 6-month postop questionnaires evaluating ADLs, pain, symptoms, quality of life, and body mass index (BMI).¹⁷ Their OA was graded via preop MRI or radiographs and confirmed by the operating surgeon. The investigators were unable to demonstrate any significant benefit associated with arthroscopic meniscectomy, and, therefore, could not recommend the procedure for patients with moderate to advanced OA.

However, in their analysis, 3 subgroup populations were found to benefit from APM: those with greater body habitus (BMI >30 kg/m²), those without signs of OA, and those with early OA. Limitations of this study included the lack of randomization, blinding, a control, and long-term follow up, and that the authors didn’t use established OA grading criteria.¹⁷

The bottom line: Nonoperative treatment benefits most patients

Physical therapy is an appropriate first-line treatment for degenerative meniscus tears in middle-aged patients. In fact, a trial of nonoperative treatment is likely to benefit the majority of patients. In addition, avoiding surgery eliminates surgical complications and decreases overall health care costs.

Reserve APM for those patients without significant OA who fail to improve after physical therapy, who have mechanical symptoms, or who have intra-articular loose bodies.

Consider a trial of nonoperative treatment, as it is likely to benefit the majority of patients with degenerative meniscal tears.

In addition, exercise therapy is an effective treatment for patients with knee OA. It improves function and limits joint pain in both acute arthritic flares and more long-term, chronic situations. There is strong evidence that strengthening plays a critical role in reducing symptoms and improving muscle strength, physical ability, and quality of life.¹⁹ It has been suggested that physical exercise 3 times a week for 4 months could lead to >35% improvement of knee function.²⁰ In contrast, other studies reported that while 91% of patients 11.5 years after APM considered their knees “normal or almost normal,” patients actually experienced a reduction in postoperative physical activity and quality of life.²¹

The most recent American Academy of Orthopaedic Surgeons (AAOS) guidelines²² do not recommend for or against arthroscopic partial meniscectomy in patients with knee OA and a torn meniscus. In middle-aged patients, MRI abnormalities of the meniscus do not consistently correlate with symptoms. Many meniscus lesions are asymptomatic or not the primary source of pain in the setting of OA.³

Potential harms and considerations. Deep venous thrombosis is the most frequently reported adverse event of arthroscopic surgery, with an approximate incidence of 4.13 per 1000 procedures, followed by less frequent complications such as infection, pulmonary embolism, and death.¹⁸

It is important to note that the degenerative meniscus tears that occur in middle age and that are associated with OA are not the same as acute, traumatic meniscus tears. All of the studies discussed here included patients with chronic knee pain and excluded patients with sudden onset pain from a single physical event. Many of the studies excluded patients with bucket-handle tears or severe mechanical symptoms (ie, locking). APM may be indicated for these meniscus tears regardless of age or OA status.

Making a sensible choice. Ultimately, physicians and their patients must use the best evidence available to make sensible clinical decisions. The ability to retain native meniscal tissue is of utmost importance to maintaining the longevity of their knee. According to previous studies, OA progression is more likely to occur after meniscectomy than after nonoperative treatment.²³

CORRESPONDENCE
William Bassett, MD, Department of Orthopedics, Rutgers-Robert Wood Johnson Medical School, 51 French St., PO Box 19, New Brunswick, NJ 08903; [email protected]. 

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4-6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14-39). These medications have the potential to not only limit weight gain, but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

Weight loss secondary to lifestyle changes can lead to adaptive physiologic responses, which increase appetite and reduce energy expenditure. Pharmacotherapy can counteract this.

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—namely family practitioners—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehensive treatment plan that includes diet, physical activity, and behavioral modification.

[polldaddy:9840472]

CASE 1 Melissa C, a 27-year-old woman with obesity (BMI 33 kg/m²), hyperlipidemia, and migraine headaches, presents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she’s taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for Ms. C?

Discussion

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .”

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30-34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24-26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.
 

CASE 2 Norman S, a 52-year-old overweight man (BMI 29 kg/m²) with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma, has recently hit a plateau with his weight loss. He lost 45 pounds secondary to diet and exercise, but hasn’t been able to lose any more. He also struggles with constant hunger. His medications include metformin 1000 mg bid, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until he undergoes a left knee replacement. Labora­tory values are normal except for a hemoglobin A1c of 7.2%.

Mr. S is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

Discussion

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. He has worked hard to lose a significant number of pounds, and is now at high risk of regaining them. That’s because his appetite has increased with his new exercise regimen, but his energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of his opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

He could try orlistat, especially if he struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for his diabetes and may also promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOM-DM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of his initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomic testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 Kathryn M, a 38-year-old woman with obesity (BMI 42 kg/m²), obstructive sleep apnea, gastroesophageal reflux disease, and depression, is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

Naltrexone SR/bupropion SR is a good choice for patients who describe debilitating cravings and addictive behavior surrounding food.

Ms. M smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discussion

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like Ms. M, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to Ms. M that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for Ms. M because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion could also help Ms. M quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses Ms. M’s problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg could also be used and should certainly be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 William P, a 65-year-old man with obesity (BMI 39 kg/m2) who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about his weight. He lost 100 lbs following surgery and maintained his weight for 3 years, but then regained 30 lbs. He comes in for an office visit because he’s concerned about his increasing blood sugar and wants to prevent further weight gain. His medications include metformin 1000 mg bid, lisinopril 5 mg/d, carvedilol 12.5 mg bid, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A1c of 8%. He denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for Mr. P?

Discussion

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of his heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given his need for further glucose control.

Medication is a great option for patients who are regaining weight after bariatric surgery.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide;⁴⁸ however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37-39 Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

CORRESPONDENCE
Katherine H. Saunders, MD, DABOM, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4-6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14-39). These medications have the potential to not only limit weight gain, but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

Weight loss secondary to lifestyle changes can lead to adaptive physiologic responses, which increase appetite and reduce energy expenditure. Pharmacotherapy can counteract this.

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—namely family practitioners—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehensive treatment plan that includes diet, physical activity, and behavioral modification.

[polldaddy:9840472]

CASE 1 Melissa C, a 27-year-old woman with obesity (BMI 33 kg/m²), hyperlipidemia, and migraine headaches, presents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she’s taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for Ms. C?

Discussion

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .”

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30-34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24-26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.
 

CASE 2 Norman S, a 52-year-old overweight man (BMI 29 kg/m²) with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma, has recently hit a plateau with his weight loss. He lost 45 pounds secondary to diet and exercise, but hasn’t been able to lose any more. He also struggles with constant hunger. His medications include metformin 1000 mg bid, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until he undergoes a left knee replacement. Labora­tory values are normal except for a hemoglobin A1c of 7.2%.

Mr. S is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

Discussion

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. He has worked hard to lose a significant number of pounds, and is now at high risk of regaining them. That’s because his appetite has increased with his new exercise regimen, but his energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of his opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

He could try orlistat, especially if he struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for his diabetes and may also promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOM-DM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of his initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomic testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 Kathryn M, a 38-year-old woman with obesity (BMI 42 kg/m²), obstructive sleep apnea, gastroesophageal reflux disease, and depression, is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

Naltrexone SR/bupropion SR is a good choice for patients who describe debilitating cravings and addictive behavior surrounding food.

Ms. M smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discussion

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like Ms. M, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to Ms. M that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for Ms. M because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion could also help Ms. M quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses Ms. M’s problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg could also be used and should certainly be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 William P, a 65-year-old man with obesity (BMI 39 kg/m2) who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about his weight. He lost 100 lbs following surgery and maintained his weight for 3 years, but then regained 30 lbs. He comes in for an office visit because he’s concerned about his increasing blood sugar and wants to prevent further weight gain. His medications include metformin 1000 mg bid, lisinopril 5 mg/d, carvedilol 12.5 mg bid, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A1c of 8%. He denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for Mr. P?

Discussion

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of his heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given his need for further glucose control.

Medication is a great option for patients who are regaining weight after bariatric surgery.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide;⁴⁸ however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37-39 Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

CORRESPONDENCE
Katherine H. Saunders, MD, DABOM, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Modest weight loss of 5% to 10% among patients who are overweight or obese can result in a clinically relevant reduction in cardiovascular (CV) disease risk.¹ This amount of weight loss can increase insulin sensitivity in adipose tissue, liver, and muscle, and have a positive impact on blood sugar, blood pressure, triglycerides, and high-density lipoprotein cholesterol.^1,2

All patients who are obese or overweight with increased CV risk should be counseled on diet, exercise, and other behavioral interventions.³ Weight loss secondary to lifestyle modification alone, however, leads to adaptive physiologic responses, which increase appetite and reduce energy expenditure.^4-6

Pharmacotherapy can counteract this metabolic adaptation and lead to sustained weight loss. Antiobesity medication can be considered if a patient has a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.^3,7

Until recently, there were few pharmacologic options approved by the US Food and Drug Administration (FDA) for the management of obesity. The mainstays of treatment were phentermine (Adipex-P, Ionamin, Suprenza) and orlistat (Alli, Xenical). Since 2012, however, 4 agents have been approved as adjuncts to a reduced-calorie diet and increased physical activity for long-term weight management.^8,9 Phentermine/topiramate extended-release (ER) (Qsymia) and lorcaserin (Belviq) were approved in 2012,^10,11 and naltrexone sustained release (SR)/bupropion SR (Contrave) and liraglutide 3 mg (Saxenda) were approved in 2014^12,13 (TABLE^9,14-39). These medications have the potential to not only limit weight gain, but also promote weight loss and, thus, improve blood pressure, cholesterol, glucose, and insulin.⁴⁰

Despite the growing obesity epidemic and the availability of several additional medications for chronic weight management, use of antiobesity pharmacotherapy has been limited. Barriers to use include inadequate training of health care professionals, poor insurance coverage for new agents, and low reimbursement for office visits to address weight.⁴¹

Weight loss secondary to lifestyle changes can lead to adaptive physiologic responses, which increase appetite and reduce energy expenditure. Pharmacotherapy can counteract this.

In addition, the number of obesity medicine specialists, while increasing, is still not sufficient. Therefore, it is imperative for other health care professionals—namely family practitioners—to be aware of the treatment options available to patients who are overweight or obese and to be adept at using them.

In this review, we present 4 cases that depict patients who could benefit from the addition of antiobesity pharmacotherapy to a comprehensive treatment plan that includes diet, physical activity, and behavioral modification.

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CASE 1 Melissa C, a 27-year-old woman with obesity (BMI 33 kg/m²), hyperlipidemia, and migraine headaches, presents for weight management. Despite a calorie-reduced diet and 200 minutes per week of exercise for the past 6 months, she has been unable to lose weight. The only medications she’s taking are oral contraceptive pills and sumatriptan, as needed. She suffers from migraines 3 times a month and has no anxiety. Laboratory test results are normal with the exception of an elevated low-density lipoprotein (LDL) level.

Which medication is an appropriate next step for Ms. C?

Discussion

When considering an antiobesity agent for any patient, there are 2 important questions to ask:

• Are there contraindications, drug-drug interactions, or undesirable adverse effects associated with this medication that could be problematic for the patient?
• Can this medication improve other symptoms or conditions the patient has?

In addition, see “Before prescribing antiobesity medication . . .”

Phentermine/topiramate ER is a good first choice for this young patient with class I (BMI 30-34.9 kg/m²) obesity and migraines, as she can likely tolerate a stimulant and her migraines might improve with topiramate. Before starting the medication, ask about insomnia and nephrolithiasis in addition to anxiety and other contraindications (ie, glaucoma, hyperthyroidism, recent monoamine oxidase inhibitor use, or a known hypersensitivity or idiosyncrasy to sympathomimetic amines).²³ The most common adverse events reported in phase III trials were dry mouth, paresthesia, and constipation.^24-26

Not for pregnant women. Women of childbearing age must have a negative pregnancy test before starting phentermine/topiramate ER and every month while taking the medication. The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) to inform prescribers and patients about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to topiramate during the first trimester of pregnancy.⁴² REMS focuses on the importance of pregnancy prevention, the consistent use of birth control, and the need to discontinue phentermine/topiramate ER immediately if pregnancy occurs.

Flexible dosing. Phentermine/topiramate ER is available in 4 dosages: phentermine 3.75 mg/topiramate 23 mg ER; phentermine 7.5 mg/topiramate 46 mg ER; phentermine 11.25 mg/topiramate 69 mg ER; and phentermine 15 mg/topiramate 92 mg ER. Gradual dose escalation minimizes risks and adverse events.²³

Monitor patients frequently to evaluate for adverse effects and ensure adherence to diet, exercise, and lifestyle modifications. If weight loss is slower or less robust than expected, check for dietary indiscretion, as medications have limited efficacy without appropriate behavioral changes.

Discontinue phentermine/topiramate ER if the patient does not achieve 5% weight loss after 12 weeks on the maximum dose, as it is unlikely that she will achieve and sustain clinically meaningful weight loss with continued treatment.²³ In this case, consider another agent with a different mechanism of action. Any of the other antiobesity medications could be appropriate for this patient.
 

CASE 2 Norman S, a 52-year-old overweight man (BMI 29 kg/m²) with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma, has recently hit a plateau with his weight loss. He lost 45 pounds secondary to diet and exercise, but hasn’t been able to lose any more. He also struggles with constant hunger. His medications include metformin 1000 mg bid, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until he undergoes a left knee replacement. Labora­tory values are normal except for a hemoglobin A1c of 7.2%.

Mr. S is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

Discussion

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. He has worked hard to lose a significant number of pounds, and is now at high risk of regaining them. That’s because his appetite has increased with his new exercise regimen, but his energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of his opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

He could try orlistat, especially if he struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for his diabetes and may also promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOM-DM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of his initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomic testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

CASE 3 Kathryn M, a 38-year-old woman with obesity (BMI 42 kg/m²), obstructive sleep apnea, gastroesophageal reflux disease, and depression, is eager to get better control over her weight. Her medications include lansoprazole 30 mg/d and a multivitamin. She reports constantly thinking about food and not being able to control her impulses to buy large quantities of unhealthy snacks. She is so preoccupied by thoughts of food that she has difficulty concentrating at work.

Naltrexone SR/bupropion SR is a good choice for patients who describe debilitating cravings and addictive behavior surrounding food.

Ms. M smokes a quarter of a pack of cigarettes daily, but she is ready to quit. She views bariatric surgery as a “last resort” and has no anxiety, pain, or history of seizures. Which medication is appropriate for this patient?

Discussion

This patient with class III obesity (BMI ≥40 kg/m²) is eligible for bariatric surgery; however, she is not interested in pursuing it at this time. It is important to discuss all of her options before deciding on a treatment plan. For patients like Ms. M, who would benefit from more than modest weight loss, consider a multidisciplinary approach including lifestyle modifications, pharmacotherapy, devices (eg, an intragastric balloon), and/or surgery. You would need to make clear to Ms. M that she may still be eligible for insurance coverage for surgery if she changes her mind after pursuing other treatments as long as her BMI remains ≥35 kg/m² with obesity-related comorbidities.

Naltrexone SR/bupropion SR is a good choice for Ms. M because she describes debilitating cravings and addictive behavior surrounding food. Patients taking naltrexone SR/bupropion SR in the Contrave Obesity Research (COR)-I and COR-II phase III trials experienced a reduced frequency of food cravings, reduced difficulty in resisting food cravings, and an increased ability to control eating compared with those assigned to placebo.^32,33

Added benefits. Bupropion could also help Ms. M quit smoking and improve her mood, as it is FDA-approved for smoking cessation and depression. She denies anxiety and seizures, so bupropion is not contraindicated. Even if a patient denies a history of seizure, ask about any conditions that predispose to seizures, such as anorexia nervosa or bulimia or the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Opioid use. Although the patient denies pain, ask about potential opioid use, as naltrexone is an opioid receptor antagonist. Patients should be informed that opioids may be ineffective if they are required unexpectedly (eg, for trauma) and that naltrexone SR/bupropion SR should be withheld for any planned surgical procedure potentially requiring opioid use.

Other options. While naltrexone SR/bupropion SR is the most appropriate choice for this patient because it addresses Ms. M’s problematic eating behaviors while potentially improving mood and assisting with smoking cessation, phentermine/topiramate ER, lorcaserin, and liraglutide 3 mg could also be used and should certainly be tried if naltrexone SR/bupropion SR does not produce the desired weight loss.

Adverse effects. Titrate naltrexone SR/bupropion SR slowly to the treatment dose to minimize risks and adverse events.³¹ The most common adverse effects reported in phase III trials were nausea, constipation, and headache.^34,35,45,46 Discontinue naltrexone SR/bupropion SR if the patient does not achieve 5% weight loss at 16 weeks (after 12 weeks at the maintenance dose).³¹

CASE 4 William P, a 65-year-old man with obesity (BMI 39 kg/m2) who underwent Roux-en-Y gastric bypass surgery and who has type 2 diabetes, congestive heart failure, coronary artery disease, hypertension, and hyperlipidemia, remains concerned about his weight. He lost 100 lbs following surgery and maintained his weight for 3 years, but then regained 30 lbs. He comes in for an office visit because he’s concerned about his increasing blood sugar and wants to prevent further weight gain. His medications include metformin 1000 mg bid, lisinopril 5 mg/d, carvedilol 12.5 mg bid, simvastatin 20 mg/d, and aspirin 81 mg/d. Laboratory test results are normal except for a hemoglobin A1c of 8%. He denies pancreatitis and a personal or family history of thyroid cancer.

Which medication is an appropriate next step for Mr. P?

Discussion

Pharmacotherapy is a great option for this patient, who is regaining weight following bariatric surgery. Phentermine/topiramate ER is the only medication that would be contraindicated because of his heart disease. Lorcaserin and naltrexone SR/bupropion SR could be considered, but liraglutide 3 mg is the most appropriate option, given his need for further glucose control.

Medication is a great option for patients who are regaining weight after bariatric surgery.

Furthermore, the recent LEADER (Liraglutide effect and action in diabetes: evaluation of CV outcome results) trial reported a significant mortality benefit with liraglutide 1.8 mg/d among patients with type 2 diabetes and high CV risk.⁴⁷ The study found that liraglutide was superior to placebo in reducing CV events.

Contraindications. Ask patients about a history of pancreatitis before starting liraglutide 3 mg given the possible increased risk. In addition, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors have been found in rodents given supratherapeutic doses of liraglutide;⁴⁸ however, there is no evidence of liraglutide causing C-cell tumors in humans.

For patients taking a medication that can cause hypoglycemia, such as insulin or a sulfonylurea, monitor blood sugar and consider reducing the dose of that medication when starting liraglutide.

Administration and titration. Liraglutide is injected subcutaneously once daily. The dose is titrated up weekly to reduce gastrointestinal symptoms.³⁶ The most common adverse effects reported in phase III trials were nausea, diarrhea, and constipation.^37-39 Discontinue liraglutide 3 mg if the patient does not lose at least 4% of baseline body weight after 16 weeks.⁴⁹

CORRESPONDENCE
Katherine H. Saunders, MD, DABOM, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

The discipline of family medicine is committed to providing patient-centered care through recommendations that are grounded both in evidence and in patients’ personal values.^1,2 The current health care environment, however, often demands heavy reliance on outcome-based performance metrics that can be insensitive to patient preferences.³ This tension necessitates models of decision-making that maximize reliance on measured performance, yet fulfill the clinician’s fiduciary responsibility to prioritize patients’ interests. The philosophy and practice of shared decision-making (SDM) can facilitate these aims.

The 3 elements of shared decision-making

SDM provides a framework for offering everyday medical advice and facilitating informed consent.⁴ Its 3 elements are:

• discussing with patients relevant information about their health conditions, possible treatments, and likely outcomes,
• clarifying and understanding a patient’s unique values and priorities and how they relate to the treatment options, and
• enabling a patient to select a care plan that is in keeping with his or her personal goals.⁵

This model is significant not only from a theoretical perspective, but also from a practical one. Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.^6,7

Unfortunately, there is evidence that some decision-making practices in primary care settings remain inadequate. For example, unlike the standard disclosure of procedure risks in surgical settings, the burdens of cancer screening are frequently omitted from primary care discussions.⁸ Moreover, agreement about what should be disclosed, as well as how to disclose it, is still not sufficient. The following 3 recommendations, one for each element of SDM, aim to help clinicians effectively engage patients in everyday decision-making.

1. Provide patients with relevant information

The first element of SDM requires discussing the health-related information that is relevant to the patient’s decision-making process. The literature about informed consent supports explaining the risks that are common, as well as those that are particularly dangerous, and the likely benefits of recommended treatment, nontreatment, and alternative treatments.⁹ Moreover, adequate informed consent requires identifying what a reasonable person in a particular patient’s position would want to know.¹⁰

Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.

Accounting for “a patient’s position” is significant because it signals that personal factors (eg, the individual’s beliefs, goals, and familial responsibilities) are as important as the patient’s external clinical situation and what can be known by reviewing medical evidence. Incorporating a patient’s particular circumstances distinguishes patient-centered care from the mechanical application of generic best practices. This is the standard for what information should be provided.

When evidence is lacking. Clinicians facilitating decisions for which data is lacking should convey the best available evidence, including the inherent uncertainties. Like evidence-based medicine (EBM), the principles of SDM should be at work in most clinical encounters. The extent to which one engages in SDM depends upon the seriousness of the proposed interventions, the degree to which the decision is preference-sensitive, and the availability of evidence.

Statistics: Explain absolute and baseline risk

It is generally better to provide absolute risk rather than relative risk, because people perceive absolute risk reductions more accurately.¹¹ Presentation of risks, in terms of relative risk or relative risk reduction, typically exaggerates the benefits of treatment, especially when the risk is small. This exaggeration makes it more likely that patients will accept interventions they might otherwise have rejected after reviewing the data more fully. Furthermore, relative risk statistics can impact clinicians’ perceptions, leading them to recommend an intervention more often than they might when absolute risk statistics are discussed.¹²

But even absolute risk, if presented on its own, can be misleading. A reasonable person trying to determine the value of an intervention needs to know his or her baseline risk of an event, in addition to his or her absolute risk with the intervention. For example, a hypothetical absolute risk reduction associated with a breast cancer treatment of 10% has different meanings, depending upon whether the baseline risk is 10% or 80%. A reduction from 10% to 0% would be a miraculous cure, while going from 80% to 70% may be viewed as only a slight improvement. Try as we might to present a single neat statistic, presenting both baseline risk and absolute risk with intervention is often necessary.¹³

How to effectively communicate medical information

Many patients struggle with processing information that is expressed as a probability.¹⁴ Patients process frequencies (eg, 10 in 100) better than probabilities (eg, 10%), and there is evidence that they understand best when decision aids are used.¹⁵ Decision aids, such as pictographs (FIGURE¹⁶), are supplementary, evidence-based tools for effectively communicating with patients and their families in a way that facilitates comparison between available options. Such aids are readily available online for many conditions or can be created using various software tools.^16,17

Pictographs reveal that there is a values-sensitive decision to be made and visually demonstrate the outcomes associated with each option. Both pictographs and bar graphs have been shown to improve patient understanding and satisfaction.¹¹ The benefit of pictographs is their ability to effectively, and simultaneously, convey both the numerator and the denominator in frequency statistics.^12,18

There is high-quality evidence demonstrating that decision aids enhance an individual’s knowledge about the treatment and screening options available to them. A 2014 Cochrane review of the effects of decision aids found that they increased average knowledge scores when compared to usual care.¹⁵ Decision aids also improved accurate perception of risk.¹⁵ It is our belief that one of the reasons pictographs work so well is that they combine the salience of absolute risks with and without intervention.^12,13

Beyond increased understanding, the Cochrane review also found high-quality evidence indicating that people who make decisions using decision aids feel less decisional conflict when compared to usual care.¹⁵ Moreover, in the context of SDM, decisional conflict may contribute to patients passing the decision-making responsibility to their clinician.¹⁹ And finally, there is moderate-quality evidence that patients are more likely to participate in decision-making when given tools such as pictographs.¹⁵

A potential barrier to putting pictographs into practice concerns perceptions that decision aids increase the length of office visits. Indeed, previous studies have identified perceived time constraints as one of the major barriers to enacting SDM in clinical settings.²⁰ On this topic, the Cochrane review offers variable yet potentially promising results: Studies of the effects on appointment length ranged from a decrease of 8 minutes to an increase of 23 minutes.¹⁵ These results suggest that, under the right circumstances, pictographs can be used to facilitate SDM within the constraints of current clinical practice. More research is needed to determine the optimal circumstances that promote efficient SDM.

2. Elicit the patient’s unique values and priorities

Formalized approaches to building rapport with patients have been popular for more than 2 decades,^21,22 and they are now routinely part of medical training. Nevertheless, there is always room for improvement when it comes to aligning treatment and screening recommendations with patient values. Some decision aids are designed to offer the added benefit of clarifying individual values and, thus, increase the likelihood that patients will make decisions that are more in line with their goals.¹⁵

There is evidence that decision aids, such as pictographs, enhance patients' knowledge about the treatment and screening options available to them.

When decision aids are not available to elicit patient values, clinicians can integrate preference-clarifying questions as part of the standard patient encounter.²³ These questions are aimed at surfacing the values underlying what the patient wants, what the patient does not want, and most importantly, why.

“Why” matters because it ultimately helps the clinician understand the patient’s mindset, enabling the clinician to help the patient make choices that serve his or her values.²⁴ Eliciting values not only promotes patient well-being and self-determination, but also facilitates the development of empathic patient-clinician partnerships.

Categorizing decisions. Regardless of the particular method chosen to elicit patient values, the underlying questions faced by many patients often fit into one of 2 categories: 1) Do I prefer quality of life over length of life? or 2) Am I willing to be inconvenienced now to prevent more severe illness later? Clarifying the category into which a decision falls may open the conversation and help to explore patients’ values and priorities. Alternatively, asking questions such as, “Thinking about this decision, what is the most important aspect for you to consider?”²⁵ may facilitate the conversation.

Much of the research on techniques geared to elicit values comes from the palliative care and oncology literature.²⁶ Although this research generally focuses on decisions about serious illness or end-of-life preferences, preference-sensitive decisions in primary care settings create a need for clinicians who are effective in eliciting patient values.

The more serious and preference-sensitive the decision, the deeper the clinician needs to explore the patient’s personal goals. Despite scant literature about seemingly innocuous decisions, we recommend that clinicians elicit from their patients a brief, but overt, acknowledgement of the values guiding their choice for most preference-sensitive decisions.

3. Offer a professional recommendation

Once clinicians have a sense of an individual’s values and priorities, they are positioned to make a professional recommendation that aligns with these values and priorities, and leaves room for the patient to reach a decision. Historically, one of the clinician’s major roles was to provide advice and recommendations to patients. For a long time, this was done without the patient’s involvement in the decision-making.²⁷

With an increasing emphasis on patient self-determination over the last 50 years, there has been some concern that the pendulum is swinging too far in the opposite direction, with clinicians shying away from providing specific recommendations.²⁸ Although this line of thinking acknowledges the power of the clinician to influence patients, it falls short of distinguishing between a personal recommendation and a professional one. While personal recommendations have no place in medical decision-making, clinicians should offer patients a professional recommendation, along with their rationale.

How do personal and professional recommendations differ?

Personal recommendations arise from clinicians considering what they themselves might decide if they were in the patient’s position. Such recommendations are inappropriate because every person has unique values and priorities.

In contrast, professional recommendations stem from the clinician’s knowledge of the best available evidence, his or her understanding of the patient’s values, and his or her weaving of these pieces together in the context of the patient’s specific clinical presentation. Experienced clinicians bring all 3 elements of SDM to bear in making professional recommendations, even if these recommendations are at odds with what they might choose for themselves.

EBM and SDM: Not so different after all?

Another way to understand the legitimacy of a professional recommendation is to view the parallels between SDM and EBM. From the outset, EBM positioned itself as arising from the best available evidence, the patient’s values, and clinical expertise²⁹—elements that are strikingly similar to the components of SDM.

Although commonly overlooked, the concept of EBM recognizes that established evidence alone is not sufficient for decision-making.³⁰ Additionally, EBM allows for making a recommendation that may not appear to be guideline-based, because guidelines typically do not take into account individual patient preferences.^30-32 What’s more, both EBM and SDM highlight the essential contribution of the clinician’s judgment about his or her patient’s unique presentation.

While personal recommendations have no place in medical decision-making, clinicians should offer a professional recommendation, along with the rationale.

Thus, both EBM and SDM are dependent on the professional communicating a recommendation to the patient. This communication involves not only making clear what one recommends, but also why one recommends it. For example, a clinician might say the following to a patient with worsening asthma symptoms:

“The asthma guidelines give us 2 treatment options. We can either double the dose of your inhaled corticosteroid, or start a 5-day course of corticosteroid pills. Given your concerns about the adverse effects of the pills, and the moderate severity of this exacerbation, I recommend doubling the dose of your inhaled corticosteroid. We can reconsider the pills if your symptoms worsen or if you don’t improve within the next week. How does that sound to you?”

An informed choice. Explaining the evidence, articulating the patient’s values, and summarizing the clinical elements that went into the clinician’s recommendation clarifies and signals to the patient that this is a professional recommendation. Ultimately, the process of SDM concludes with the patient considering the clinician’s recommendation and making an informed choice from the available options.

CORRESPONDENCE
David J. Satin, MD, 2020 E 28th St., Minneapolis, MN 55407; [email protected].

The discipline of family medicine is committed to providing patient-centered care through recommendations that are grounded both in evidence and in patients’ personal values.^1,2 The current health care environment, however, often demands heavy reliance on outcome-based performance metrics that can be insensitive to patient preferences.³ This tension necessitates models of decision-making that maximize reliance on measured performance, yet fulfill the clinician’s fiduciary responsibility to prioritize patients’ interests. The philosophy and practice of shared decision-making (SDM) can facilitate these aims.

The 3 elements of shared decision-making

SDM provides a framework for offering everyday medical advice and facilitating informed consent.⁴ Its 3 elements are:

• discussing with patients relevant information about their health conditions, possible treatments, and likely outcomes,
• clarifying and understanding a patient’s unique values and priorities and how they relate to the treatment options, and
• enabling a patient to select a care plan that is in keeping with his or her personal goals.⁵

This model is significant not only from a theoretical perspective, but also from a practical one. Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.^6,7

Unfortunately, there is evidence that some decision-making practices in primary care settings remain inadequate. For example, unlike the standard disclosure of procedure risks in surgical settings, the burdens of cancer screening are frequently omitted from primary care discussions.⁸ Moreover, agreement about what should be disclosed, as well as how to disclose it, is still not sufficient. The following 3 recommendations, one for each element of SDM, aim to help clinicians effectively engage patients in everyday decision-making.

1. Provide patients with relevant information

The first element of SDM requires discussing the health-related information that is relevant to the patient’s decision-making process. The literature about informed consent supports explaining the risks that are common, as well as those that are particularly dangerous, and the likely benefits of recommended treatment, nontreatment, and alternative treatments.⁹ Moreover, adequate informed consent requires identifying what a reasonable person in a particular patient’s position would want to know.¹⁰

Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.

Accounting for “a patient’s position” is significant because it signals that personal factors (eg, the individual’s beliefs, goals, and familial responsibilities) are as important as the patient’s external clinical situation and what can be known by reviewing medical evidence. Incorporating a patient’s particular circumstances distinguishes patient-centered care from the mechanical application of generic best practices. This is the standard for what information should be provided.

When evidence is lacking. Clinicians facilitating decisions for which data is lacking should convey the best available evidence, including the inherent uncertainties. Like evidence-based medicine (EBM), the principles of SDM should be at work in most clinical encounters. The extent to which one engages in SDM depends upon the seriousness of the proposed interventions, the degree to which the decision is preference-sensitive, and the availability of evidence.

Statistics: Explain absolute and baseline risk

It is generally better to provide absolute risk rather than relative risk, because people perceive absolute risk reductions more accurately.¹¹ Presentation of risks, in terms of relative risk or relative risk reduction, typically exaggerates the benefits of treatment, especially when the risk is small. This exaggeration makes it more likely that patients will accept interventions they might otherwise have rejected after reviewing the data more fully. Furthermore, relative risk statistics can impact clinicians’ perceptions, leading them to recommend an intervention more often than they might when absolute risk statistics are discussed.¹²

But even absolute risk, if presented on its own, can be misleading. A reasonable person trying to determine the value of an intervention needs to know his or her baseline risk of an event, in addition to his or her absolute risk with the intervention. For example, a hypothetical absolute risk reduction associated with a breast cancer treatment of 10% has different meanings, depending upon whether the baseline risk is 10% or 80%. A reduction from 10% to 0% would be a miraculous cure, while going from 80% to 70% may be viewed as only a slight improvement. Try as we might to present a single neat statistic, presenting both baseline risk and absolute risk with intervention is often necessary.¹³

How to effectively communicate medical information

Many patients struggle with processing information that is expressed as a probability.¹⁴ Patients process frequencies (eg, 10 in 100) better than probabilities (eg, 10%), and there is evidence that they understand best when decision aids are used.¹⁵ Decision aids, such as pictographs (FIGURE¹⁶), are supplementary, evidence-based tools for effectively communicating with patients and their families in a way that facilitates comparison between available options. Such aids are readily available online for many conditions or can be created using various software tools.^16,17

Pictographs reveal that there is a values-sensitive decision to be made and visually demonstrate the outcomes associated with each option. Both pictographs and bar graphs have been shown to improve patient understanding and satisfaction.¹¹ The benefit of pictographs is their ability to effectively, and simultaneously, convey both the numerator and the denominator in frequency statistics.^12,18

There is high-quality evidence demonstrating that decision aids enhance an individual’s knowledge about the treatment and screening options available to them. A 2014 Cochrane review of the effects of decision aids found that they increased average knowledge scores when compared to usual care.¹⁵ Decision aids also improved accurate perception of risk.¹⁵ It is our belief that one of the reasons pictographs work so well is that they combine the salience of absolute risks with and without intervention.^12,13

Beyond increased understanding, the Cochrane review also found high-quality evidence indicating that people who make decisions using decision aids feel less decisional conflict when compared to usual care.¹⁵ Moreover, in the context of SDM, decisional conflict may contribute to patients passing the decision-making responsibility to their clinician.¹⁹ And finally, there is moderate-quality evidence that patients are more likely to participate in decision-making when given tools such as pictographs.¹⁵

A potential barrier to putting pictographs into practice concerns perceptions that decision aids increase the length of office visits. Indeed, previous studies have identified perceived time constraints as one of the major barriers to enacting SDM in clinical settings.²⁰ On this topic, the Cochrane review offers variable yet potentially promising results: Studies of the effects on appointment length ranged from a decrease of 8 minutes to an increase of 23 minutes.¹⁵ These results suggest that, under the right circumstances, pictographs can be used to facilitate SDM within the constraints of current clinical practice. More research is needed to determine the optimal circumstances that promote efficient SDM.

2. Elicit the patient’s unique values and priorities

Formalized approaches to building rapport with patients have been popular for more than 2 decades,^21,22 and they are now routinely part of medical training. Nevertheless, there is always room for improvement when it comes to aligning treatment and screening recommendations with patient values. Some decision aids are designed to offer the added benefit of clarifying individual values and, thus, increase the likelihood that patients will make decisions that are more in line with their goals.¹⁵

There is evidence that decision aids, such as pictographs, enhance patients' knowledge about the treatment and screening options available to them.

When decision aids are not available to elicit patient values, clinicians can integrate preference-clarifying questions as part of the standard patient encounter.²³ These questions are aimed at surfacing the values underlying what the patient wants, what the patient does not want, and most importantly, why.

“Why” matters because it ultimately helps the clinician understand the patient’s mindset, enabling the clinician to help the patient make choices that serve his or her values.²⁴ Eliciting values not only promotes patient well-being and self-determination, but also facilitates the development of empathic patient-clinician partnerships.

Categorizing decisions. Regardless of the particular method chosen to elicit patient values, the underlying questions faced by many patients often fit into one of 2 categories: 1) Do I prefer quality of life over length of life? or 2) Am I willing to be inconvenienced now to prevent more severe illness later? Clarifying the category into which a decision falls may open the conversation and help to explore patients’ values and priorities. Alternatively, asking questions such as, “Thinking about this decision, what is the most important aspect for you to consider?”²⁵ may facilitate the conversation.

Much of the research on techniques geared to elicit values comes from the palliative care and oncology literature.²⁶ Although this research generally focuses on decisions about serious illness or end-of-life preferences, preference-sensitive decisions in primary care settings create a need for clinicians who are effective in eliciting patient values.

The more serious and preference-sensitive the decision, the deeper the clinician needs to explore the patient’s personal goals. Despite scant literature about seemingly innocuous decisions, we recommend that clinicians elicit from their patients a brief, but overt, acknowledgement of the values guiding their choice for most preference-sensitive decisions.

3. Offer a professional recommendation

Once clinicians have a sense of an individual’s values and priorities, they are positioned to make a professional recommendation that aligns with these values and priorities, and leaves room for the patient to reach a decision. Historically, one of the clinician’s major roles was to provide advice and recommendations to patients. For a long time, this was done without the patient’s involvement in the decision-making.²⁷

With an increasing emphasis on patient self-determination over the last 50 years, there has been some concern that the pendulum is swinging too far in the opposite direction, with clinicians shying away from providing specific recommendations.²⁸ Although this line of thinking acknowledges the power of the clinician to influence patients, it falls short of distinguishing between a personal recommendation and a professional one. While personal recommendations have no place in medical decision-making, clinicians should offer patients a professional recommendation, along with their rationale.

How do personal and professional recommendations differ?

Personal recommendations arise from clinicians considering what they themselves might decide if they were in the patient’s position. Such recommendations are inappropriate because every person has unique values and priorities.

In contrast, professional recommendations stem from the clinician’s knowledge of the best available evidence, his or her understanding of the patient’s values, and his or her weaving of these pieces together in the context of the patient’s specific clinical presentation. Experienced clinicians bring all 3 elements of SDM to bear in making professional recommendations, even if these recommendations are at odds with what they might choose for themselves.

EBM and SDM: Not so different after all?

Another way to understand the legitimacy of a professional recommendation is to view the parallels between SDM and EBM. From the outset, EBM positioned itself as arising from the best available evidence, the patient’s values, and clinical expertise²⁹—elements that are strikingly similar to the components of SDM.

Although commonly overlooked, the concept of EBM recognizes that established evidence alone is not sufficient for decision-making.³⁰ Additionally, EBM allows for making a recommendation that may not appear to be guideline-based, because guidelines typically do not take into account individual patient preferences.^30-32 What’s more, both EBM and SDM highlight the essential contribution of the clinician’s judgment about his or her patient’s unique presentation.

While personal recommendations have no place in medical decision-making, clinicians should offer a professional recommendation, along with the rationale.

Thus, both EBM and SDM are dependent on the professional communicating a recommendation to the patient. This communication involves not only making clear what one recommends, but also why one recommends it. For example, a clinician might say the following to a patient with worsening asthma symptoms:

“The asthma guidelines give us 2 treatment options. We can either double the dose of your inhaled corticosteroid, or start a 5-day course of corticosteroid pills. Given your concerns about the adverse effects of the pills, and the moderate severity of this exacerbation, I recommend doubling the dose of your inhaled corticosteroid. We can reconsider the pills if your symptoms worsen or if you don’t improve within the next week. How does that sound to you?”

An informed choice. Explaining the evidence, articulating the patient’s values, and summarizing the clinical elements that went into the clinician’s recommendation clarifies and signals to the patient that this is a professional recommendation. Ultimately, the process of SDM concludes with the patient considering the clinician’s recommendation and making an informed choice from the available options.

CORRESPONDENCE
David J. Satin, MD, 2020 E 28th St., Minneapolis, MN 55407; [email protected].

The discipline of family medicine is committed to providing patient-centered care through recommendations that are grounded both in evidence and in patients’ personal values.^1,2 The current health care environment, however, often demands heavy reliance on outcome-based performance metrics that can be insensitive to patient preferences.³ This tension necessitates models of decision-making that maximize reliance on measured performance, yet fulfill the clinician’s fiduciary responsibility to prioritize patients’ interests. The philosophy and practice of shared decision-making (SDM) can facilitate these aims.

The 3 elements of shared decision-making

SDM provides a framework for offering everyday medical advice and facilitating informed consent.⁴ Its 3 elements are:

• discussing with patients relevant information about their health conditions, possible treatments, and likely outcomes,
• clarifying and understanding a patient’s unique values and priorities and how they relate to the treatment options, and
• enabling a patient to select a care plan that is in keeping with his or her personal goals.⁵

This model is significant not only from a theoretical perspective, but also from a practical one. Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.^6,7

Unfortunately, there is evidence that some decision-making practices in primary care settings remain inadequate. For example, unlike the standard disclosure of procedure risks in surgical settings, the burdens of cancer screening are frequently omitted from primary care discussions.⁸ Moreover, agreement about what should be disclosed, as well as how to disclose it, is still not sufficient. The following 3 recommendations, one for each element of SDM, aim to help clinicians effectively engage patients in everyday decision-making.

1. Provide patients with relevant information

The first element of SDM requires discussing the health-related information that is relevant to the patient’s decision-making process. The literature about informed consent supports explaining the risks that are common, as well as those that are particularly dangerous, and the likely benefits of recommended treatment, nontreatment, and alternative treatments.⁹ Moreover, adequate informed consent requires identifying what a reasonable person in a particular patient’s position would want to know.¹⁰

Studies have shown that both health outcomes and patient satisfaction improve when patients participate more actively in health care decision-making.

Accounting for “a patient’s position” is significant because it signals that personal factors (eg, the individual’s beliefs, goals, and familial responsibilities) are as important as the patient’s external clinical situation and what can be known by reviewing medical evidence. Incorporating a patient’s particular circumstances distinguishes patient-centered care from the mechanical application of generic best practices. This is the standard for what information should be provided.

When evidence is lacking. Clinicians facilitating decisions for which data is lacking should convey the best available evidence, including the inherent uncertainties. Like evidence-based medicine (EBM), the principles of SDM should be at work in most clinical encounters. The extent to which one engages in SDM depends upon the seriousness of the proposed interventions, the degree to which the decision is preference-sensitive, and the availability of evidence.

Statistics: Explain absolute and baseline risk

It is generally better to provide absolute risk rather than relative risk, because people perceive absolute risk reductions more accurately.¹¹ Presentation of risks, in terms of relative risk or relative risk reduction, typically exaggerates the benefits of treatment, especially when the risk is small. This exaggeration makes it more likely that patients will accept interventions they might otherwise have rejected after reviewing the data more fully. Furthermore, relative risk statistics can impact clinicians’ perceptions, leading them to recommend an intervention more often than they might when absolute risk statistics are discussed.¹²

But even absolute risk, if presented on its own, can be misleading. A reasonable person trying to determine the value of an intervention needs to know his or her baseline risk of an event, in addition to his or her absolute risk with the intervention. For example, a hypothetical absolute risk reduction associated with a breast cancer treatment of 10% has different meanings, depending upon whether the baseline risk is 10% or 80%. A reduction from 10% to 0% would be a miraculous cure, while going from 80% to 70% may be viewed as only a slight improvement. Try as we might to present a single neat statistic, presenting both baseline risk and absolute risk with intervention is often necessary.¹³

How to effectively communicate medical information

Many patients struggle with processing information that is expressed as a probability.¹⁴ Patients process frequencies (eg, 10 in 100) better than probabilities (eg, 10%), and there is evidence that they understand best when decision aids are used.¹⁵ Decision aids, such as pictographs (FIGURE¹⁶), are supplementary, evidence-based tools for effectively communicating with patients and their families in a way that facilitates comparison between available options. Such aids are readily available online for many conditions or can be created using various software tools.^16,17

Pictographs reveal that there is a values-sensitive decision to be made and visually demonstrate the outcomes associated with each option. Both pictographs and bar graphs have been shown to improve patient understanding and satisfaction.¹¹ The benefit of pictographs is their ability to effectively, and simultaneously, convey both the numerator and the denominator in frequency statistics.^12,18

There is high-quality evidence demonstrating that decision aids enhance an individual’s knowledge about the treatment and screening options available to them. A 2014 Cochrane review of the effects of decision aids found that they increased average knowledge scores when compared to usual care.¹⁵ Decision aids also improved accurate perception of risk.¹⁵ It is our belief that one of the reasons pictographs work so well is that they combine the salience of absolute risks with and without intervention.^12,13

Beyond increased understanding, the Cochrane review also found high-quality evidence indicating that people who make decisions using decision aids feel less decisional conflict when compared to usual care.¹⁵ Moreover, in the context of SDM, decisional conflict may contribute to patients passing the decision-making responsibility to their clinician.¹⁹ And finally, there is moderate-quality evidence that patients are more likely to participate in decision-making when given tools such as pictographs.¹⁵

A potential barrier to putting pictographs into practice concerns perceptions that decision aids increase the length of office visits. Indeed, previous studies have identified perceived time constraints as one of the major barriers to enacting SDM in clinical settings.²⁰ On this topic, the Cochrane review offers variable yet potentially promising results: Studies of the effects on appointment length ranged from a decrease of 8 minutes to an increase of 23 minutes.¹⁵ These results suggest that, under the right circumstances, pictographs can be used to facilitate SDM within the constraints of current clinical practice. More research is needed to determine the optimal circumstances that promote efficient SDM.

2. Elicit the patient’s unique values and priorities

Formalized approaches to building rapport with patients have been popular for more than 2 decades,^21,22 and they are now routinely part of medical training. Nevertheless, there is always room for improvement when it comes to aligning treatment and screening recommendations with patient values. Some decision aids are designed to offer the added benefit of clarifying individual values and, thus, increase the likelihood that patients will make decisions that are more in line with their goals.¹⁵

There is evidence that decision aids, such as pictographs, enhance patients' knowledge about the treatment and screening options available to them.

When decision aids are not available to elicit patient values, clinicians can integrate preference-clarifying questions as part of the standard patient encounter.²³ These questions are aimed at surfacing the values underlying what the patient wants, what the patient does not want, and most importantly, why.

“Why” matters because it ultimately helps the clinician understand the patient’s mindset, enabling the clinician to help the patient make choices that serve his or her values.²⁴ Eliciting values not only promotes patient well-being and self-determination, but also facilitates the development of empathic patient-clinician partnerships.

Categorizing decisions. Regardless of the particular method chosen to elicit patient values, the underlying questions faced by many patients often fit into one of 2 categories: 1) Do I prefer quality of life over length of life? or 2) Am I willing to be inconvenienced now to prevent more severe illness later? Clarifying the category into which a decision falls may open the conversation and help to explore patients’ values and priorities. Alternatively, asking questions such as, “Thinking about this decision, what is the most important aspect for you to consider?”²⁵ may facilitate the conversation.

Much of the research on techniques geared to elicit values comes from the palliative care and oncology literature.²⁶ Although this research generally focuses on decisions about serious illness or end-of-life preferences, preference-sensitive decisions in primary care settings create a need for clinicians who are effective in eliciting patient values.

The more serious and preference-sensitive the decision, the deeper the clinician needs to explore the patient’s personal goals. Despite scant literature about seemingly innocuous decisions, we recommend that clinicians elicit from their patients a brief, but overt, acknowledgement of the values guiding their choice for most preference-sensitive decisions.

3. Offer a professional recommendation

Once clinicians have a sense of an individual’s values and priorities, they are positioned to make a professional recommendation that aligns with these values and priorities, and leaves room for the patient to reach a decision. Historically, one of the clinician’s major roles was to provide advice and recommendations to patients. For a long time, this was done without the patient’s involvement in the decision-making.²⁷

With an increasing emphasis on patient self-determination over the last 50 years, there has been some concern that the pendulum is swinging too far in the opposite direction, with clinicians shying away from providing specific recommendations.²⁸ Although this line of thinking acknowledges the power of the clinician to influence patients, it falls short of distinguishing between a personal recommendation and a professional one. While personal recommendations have no place in medical decision-making, clinicians should offer patients a professional recommendation, along with their rationale.

How do personal and professional recommendations differ?

Personal recommendations arise from clinicians considering what they themselves might decide if they were in the patient’s position. Such recommendations are inappropriate because every person has unique values and priorities.

In contrast, professional recommendations stem from the clinician’s knowledge of the best available evidence, his or her understanding of the patient’s values, and his or her weaving of these pieces together in the context of the patient’s specific clinical presentation. Experienced clinicians bring all 3 elements of SDM to bear in making professional recommendations, even if these recommendations are at odds with what they might choose for themselves.

EBM and SDM: Not so different after all?

Another way to understand the legitimacy of a professional recommendation is to view the parallels between SDM and EBM. From the outset, EBM positioned itself as arising from the best available evidence, the patient’s values, and clinical expertise²⁹—elements that are strikingly similar to the components of SDM.

Although commonly overlooked, the concept of EBM recognizes that established evidence alone is not sufficient for decision-making.³⁰ Additionally, EBM allows for making a recommendation that may not appear to be guideline-based, because guidelines typically do not take into account individual patient preferences.^30-32 What’s more, both EBM and SDM highlight the essential contribution of the clinician’s judgment about his or her patient’s unique presentation.

While personal recommendations have no place in medical decision-making, clinicians should offer a professional recommendation, along with the rationale.

Thus, both EBM and SDM are dependent on the professional communicating a recommendation to the patient. This communication involves not only making clear what one recommends, but also why one recommends it. For example, a clinician might say the following to a patient with worsening asthma symptoms:

“The asthma guidelines give us 2 treatment options. We can either double the dose of your inhaled corticosteroid, or start a 5-day course of corticosteroid pills. Given your concerns about the adverse effects of the pills, and the moderate severity of this exacerbation, I recommend doubling the dose of your inhaled corticosteroid. We can reconsider the pills if your symptoms worsen or if you don’t improve within the next week. How does that sound to you?”

An informed choice. Explaining the evidence, articulating the patient’s values, and summarizing the clinical elements that went into the clinician’s recommendation clarifies and signals to the patient that this is a professional recommendation. Ultimately, the process of SDM concludes with the patient considering the clinician’s recommendation and making an informed choice from the available options.

CORRESPONDENCE
David J. Satin, MD, 2020 E 28th St., Minneapolis, MN 55407; [email protected].

Family physicians encounter skin rashes on a daily basis. First steps in making the diagnosis include identifying the characteristics of the rash and determining whether the eruption is accompanied by fever or any other symptoms. In the article that follows, we review 8 viral exanthems of childhood that range from the common (chickenpox) to the not-so-common (Gianotti-Crosti syndrome).

Varicella-zoster virus

Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus that causes a primary infection commonly known as chickenpox (varicella).¹ This disease is usually mild and resolves spontaneously.

This highly contagious virus is transmitted by directly touching the blisters, saliva, or mucus of an infected person. It is also transmitted through the air by coughing and sneezing. VZV initiates primary infection by inoculating the respiratory mucosa. It then establishes a lifelong presence in the sensory ganglionic neurons and, thus, can reactivate later in life causing herpes zoster (shingles), which can affect cranial, thoracic, and lumbosacral dermatomes. Acute or chronic neurologic disorders, including cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders, have been reported after VZV reactivation resulting in herpes-zoster.¹

Presentation. With varicella, an extremely pruritic rash follows a brief prodromal stage consisting of a low-grade fever, upper respiratory tract symptoms, tiredness, and fatigue. This exanthem develops rapidly, often beginning on the chest, trunk, or scalp and then spreading to the arms and legs (centrifugally) (FIGURE 1). Varicella also affects mucosal areas of the body, such as the conjunctiva, mouth, rectum, and vagina.

The lesions are papules that rapidly become vesicular with clear fluid inside. Subsequently, the lesions begin to crust. Scabbing occurs within 10 to 14 days. A sure sign of chickenpox is the presence of papules, vesicles, and crusting lesions in close proximity.

Complications. The most common complications of chickenpox—especially in children—are invasive streptococcal and staphylococcal infections.² The most serious complication occurs when the virus invades the spinal cord, causing myelitis or affecting the cerebral arteries, leading to vasculopathy. Diagnosis of VZV in the central nervous system is based on isolation of the virus in cerebral spinal fluid by polymerase chain reaction (PCR). Early diagnosis is important to minimize morbidity and mortality.

Reactivation is sometimes associated with post-herpetic neuralgia (PHN), a severe neuropathic pain syndrome isolated to the dermatomes affected by VZV. PHN can cause pain and suffering for years after shingles resolves, and sometimes is refractory to treatment. PHN may reflect a chronic varicella virus ganglionitis.

A number of treatment choices exist for shingles, but not so much for varicella

Oral treatment. Oral medications such as acyclovir and its prodrug valacyclovir are the current gold standards for the treatment of VZV.³

Famciclovir, the prodrug of penciclovir, is more effective than valacyclovir at resolving acute herpes zoster rash and shortening the duration of PHN.⁴ Gabapentinoids (eg, pregabalin) are the only oral medications approved by the US Food and Drug Administration (FDA) to treat PHN.⁵

Topical medications can also be used. Lidocaine 5% is favored as first-line therapy for the amelioration of pain due to shingles, as it provides modest pain relief with a better safety and tolerability profile than capsaicin 8% patch, which is a second-line choice. The latter must be applied multiple times daily, has minimal analgesic efficacy, and frequently causes initial pain upon application.

Gabapentinoids and topical analgesics can be used in combination due to the low propensity for drug interactions.^6,7 The treatment of choice for focal vasculopathy is intravenous acyclovir, usually for 14 days, although immunocompromised patients should be treated for a longer period of time. Also consider 5 days of steroid therapy for patients with VZV vasculopathy.⁸

Non-FDA approved treatments include tricyclic antidepressants (TCA), such as amitriptyline, nortriptyline, and desipramine, which are sometimes used as first-line therapy for shingles. TCAs may not work well in patients with burning pain, and can have significant adverse effects, including possible cardiotoxicity.⁹

Opioids, including oxycodone, morphine, methadone, and tramadol, are sometimes used in pain management, but concern exists for abuse. Because patients may develop physical dependence, use opioids with considerable caution.¹⁰

Prevention. The United States became the first country to institute a routine varicella immunization program after a varicella vaccine (Varivax) was licensed in 1995.¹¹ The vaccine has reduced the number of varicella infection cases dramatically.¹¹ Vaccine effectiveness is high, and protective herd immunity is obtained after 2 doses.^11-13 The vaccine is administered to children after one year of age with a booster dose administered after the fourth birthday.

A live, attenuated VZV vaccine (Zostavax) is given to individuals ≥60 years of age to prevent or attenuate herpes zoster infection. This vaccine is used to boost VZV-specific cell-mediated immunity in adults, thereby decreasing the burden of herpes zoster and the pain associated with PHN.¹⁴

Roseola

Roseola infantum, also known as exanthema subitum and sixth disease, is a common mild acute febrile illness of childhood caused by infection with human herpesvirus (HHV) 6 (the primary agent causing roseola) or 7 (a secondary causal agent for roseola).¹⁵ HHV-6 has 2 variants (HHV-6a and HHV-6b). Roseola infantum is mostly associated with the HHV-6b variant, which predominantly affects children 6 to 36 months of age.¹⁶

The virus replicates in the salivary glands and is shed through saliva, which is the route of transmission. After a 10- to 15-day incubation period, it remains latent in lymphocytes and monocytes, thus persisting in cells and tissues. It may reactivate late in life, particularly in immunosuppressed individuals. Reactivated infection in immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy. In patients who have received a bone marrow transplant, it can induce graft vs host disease.¹⁷

Presentation. The virus causes a 5- to 6-day illness characterized by high fever (temperature as high as 105°-106° F), miringitis (inflammation of tympanic membranes), and irritability. Once defervescence occurs, an erythematous morbilliform exanthem appears.The rash, which has a discrete macular/papular soft-pink appearance, starts on the trunk and spreads centrifugally to the extremities, neck, and face (FIGURE 2). It usually resolves within one to 2 days.

Complications. The most common complication of roseola is febrile seizures.¹⁷ Less common ones include encephalitis, encephalopathy, fatal hemophagocytic syndrome,¹⁸ or fulminant hepatitis.¹⁹

Treatment and prevention. Treatment depends on symptoms and may include antipyretics for fever management and liquids to maintain hydration. Recovery is usually complete with no significant sequelae. If a child develops a seizure, no antiepileptic drugs are recommended. No vaccine exists.

Fifth disease

Human parvovirus B19, a minute ssDNA virus, was first associated with human disease in 1981, when it was linked to an aplastic crisis in a patient with sickle cell disease.²⁰ Since then researchers have determined that it is also the cause of erythema infectiosum or fifth disease of childhood. The B19 virus can also cause anemia in the fetus as well as hydrops fetalis. It has been linked to arthralgia and arthritis (especially in adults). There is an association with autoimmune diseases with characteristics similar to rheumatoid arthritis.²⁰

More than 70% of the adult population is seropositive for fifth disease.

The B19 virus is transmitted via aerosolized respiratory secretions, contaminated blood, or the placenta. The virus replicates in erythroid cells in bone marrow and peripheral blood, thus inhibiting erythropoiesis.²¹ Once the rash appears, the virus is no longer infectious.²² Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year.²³ More than 70% of the adult population is seropositive for this virus.²⁰

Presentation. Erythema infectiosum is a mild illness in childhood with an incubation period of 6 to 18 days. It presents with a characteristic malar rash on the face that gives patients a slapped cheek appearance (FIGURE 3A). A softer pink-colored “lacy” reticulated rash that blanches when touched may appear on the trunk, arms, and legs (FIGURE 3B).

Another presentation, which involves the hands and feet (glove and sock syndrome) (FIGURES 3C and 3D), consists of a purpuric eruption with painful edema and numerous small confluent petechiae.^22,24 A majority of patients present with inflammatory symptoms that tend to resolve without sequelae within 3 weeks of infection.²³

A rash is not as prevalent in adults as in children. Adults often present with more systemic systems, such as a debilitating influenza-like illness, arthropathy, transient aplastic anemia in sickle cell-affected individuals, and persistent viral suppression of erythrocyte production in immunocompromised patients and organ-transplant recipients.

Complications. The B19 virus can cause spontaneous abortion in pregnant women and anemia and hydrops fetalis in the fetus.²² Arthritis can occur in children, but is more common in adults, especially in women. The arthritis tends to be symmetrical and affects small joints such as the hands, wrists, and knees.

In one study of parvovirus B19 involving 633 children with sickle cell disease, 68 children developed transient red cell aplasia, 19% of them developed splenic sequestration, and 12% developed acute chest syndrome, a lung-related complication of sickle cell disease that can lower the level of oxygen in the blood and can be fatal.²⁵

Treatment and prevention. Treatment of B19 infection is symptomatic; for example, nonsteroidal anti-inflammatory drugs (NSAIDs) are used if joint pain develops. No vaccine exists.

Hand, foot, and mouth disease

Hand, foot, and mouth disease (HFMD) is caused by the picornavirus family, including the Coxsackievirus, Enterovirus, and Echovirus. Infections commonly occur in the spring, summer, and fall. The virus primarily affects infants and children <10 years of age with the infection typically lasting 7 to 10 days.²⁶

Presentation. The disease usually presents with a febrile episode, progressing to nasal congestion and malaise. One to 2 days later, the classic rash appears. Patients with HFMD usually present with papular or vesicular lesions on the hands and feet and painful oral lesions (FIGURES 4A, 4B, and 4C). The rash may also affect other parts of the body including the legs and buttocks. Desquamation of nails may occur up to one month after the HFM infection.²⁷ Most cases are diagnosed by clinical presentation, but infection can be confirmed by PCR of vesicular lesion fluid.

Complications. In addition to being caused by Coxsackievirus, HFMD may be caused by human Enterovirus A serotype 71 (HEVA-71), which is associated with a high prevalence of acute neurologic disease including aseptic meningitis, poliomyelitis-like paralysis, and encephalitis.²⁶ Of 764 HFMD patients enrolled in a prospective study, 214 cases were associated with Coxsackievirus A 16 (CVA16) infection and 173 cases were associated with HEVA-71 infection. Rare cases of HFMD have led to encephalitis, meningitis, flaccid paralysis, and death.²⁶

Treatment and prevention. HFMD is usually self-limited, and treatment is supportive. There has been interest in developing an HFMD vaccine, but no products are as yet commercially available.

Rubella

Rubella, also known as the German measles or the 3-day measles, is caused by the rubella virus, which is transmitted via respiratory droplets. Up to half of rubella infections are asymptomatic.^28-30

Presentation. Rubella typically has an incubation period of 12 to 24 days, with a 5-day prodromal period characterized by fever, headache, and other symptoms typical of an upper respiratory infection, including sore throat, arthralgia, and tender lymphadenopathy.²⁸

The rash often starts as erythematous or as rose-pink macules on the face that progress down the body. The rash can cover the trunk and extremities within 24 hours. (For photos, see https://www.cdc.gov/rubella/about/photos.html.)

Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome.

Patients are infectious from 7 days prior to the appearance of the rash to 7 days after resolution of the rash. Given the potentially prolonged infectious period, patients hospitalized for rubella infection should be placed on droplet precautions, and children should be kept from day care and school for 7 days after the appearance of the rash.²⁸

Rubella is typically a mild disease in immunocompetent patients; however, immunocompromised patients may develop pneumonia, coagulopathies, or neurologic sequelae including encephalitis.

Complications. Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome (CRS), a condition characterized by congenital cataracts and “blueberry muffin” skin lesions.³¹ Infants affected by CRS can also have heart defects, intellectual disabilities, deafness, and low birth weight. Diagnosis of primary maternal infection should be made with serologic tests. Fetal infection can be determined by detection of fetal serum IgM after 22 to 24 weeks of gestation or with viral culture of amniotic fluid.³¹

Treatment and prevention. Currently, no antiviral treatments are available; however, vaccines are highly effective at preventing infection. Rubella vaccine is usually given as part of the measles, mumps, rubella (MMR) vaccine, which is administered at age 12 to 15 months and again between 4 and 6 years of age.

Measles

Measles is a highly contagious disease caused by a virus that belongs to the Morbillivirus genus of the family Paramyxoviridae. Infection occurs through inhalation of, or direct contact with, respiratory droplets from infected people.³²

Presentation. People with measles often present with what starts as a macular rash on the face that then spreads downward to the neck, trunk, and extremities (for photos, see http://www.cdc.gov/measles/hcp/index.html). As the disease progresses, papules can develop and the lesions may coalesce.

The rash is often preceded by 3 to 4 days of malaise and fever (temperature often greater than 104° F), along with the classic symptom triad of cough, coryza, and conjunctivitis. Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.³³

Measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious/personal beliefs or safety concerns.

Because the symptoms of measles are easily confused with other viral infections, suspected cases of measles should be confirmed via IgG and IgM antibody tests, by reverse transcription-PCR, or both.^34,35 For limited and unusual cases, the Centers for Disease Control and Prevention can perform a plaque reduction neutralization assay.³⁵

Complications. Measles infection is self-limited in immunocompetent patients. The most common complications are diarrhea and ear infections, but more serious complications, such as pneumonia, hearing loss, and encephalitis, can occur. Children <2 years of age, particularly boys, are at an increased risk of developing subacute sclerosing panencephalitis, a fatal neurologic disorder that can develop years after the initial measles infection.^33,36

Treatment and prevention. Treatment is supportive and usually consists of acetaminophen or NSAIDs and fluids.

Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.

A live attenuated version of the measles vaccine is highly effective against the measles virus and has greatly reduced the number of measles cases globally.³⁷ The measles vaccine is usually given in 2 doses—the first one after one year of age, and the second one before entering kindergarten. The most common adverse reactions to the vaccine are pain at the injection site and fever. Despite the fact that the MMR vaccine is effective and relatively benign, measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious or other personal beliefs or safety concerns.³⁸

Molluscum contagiosum

Molluscum contagiosum (MC) is caused by the MC virus, a member of the poxvirus family. The virus is transmitted by direct contact with the skin lesions. This skin condition is seen mainly in children, although it can occur in adults.

A study conducted in England and Wales that obtained information from the Royal College of General Practitioners reported an incidence of 15.0-17.2/1000 population over a 10-year period (1994-2003) with no variation between sexes.³⁹ There is an association between atopic dermatitis and MC; 24% of children with atopic dermatitis develop MC.⁴⁰ There might also be an association between recent swimming in a public pool and development of MC lesions.⁴¹

Presentation. Lesions caused by MC are small, discrete, waxy dome-shaped papules with central umbilication that are usually 3 to 5 mm in diameter (FIGURE 5).^42,43 In immunocompetent patients, there are usually fewer than 20 lesions, which resolve within a year. However, in immunocompromised patients, the number of lesions is usually higher, and the diameter of each may be greater than 1 cm.⁴²

Complications. The lesions are usually self-limited, but on occasion can become secondarily infected, usually with gram-positive organisms such as Staphylococcus aureus. Very rarely, abscesses develop requiring topical and/or systemic antimicrobials and perhaps incision and drainage.⁴⁴

Treatment and prevention. Because the infection is often self-limited and benign, the preferred therapeutic modality is watchful waiting. Other treatments for MC include curettage, chemical agents, immune modulators, and antiviral drugs. A 2009 Cochran review of 11 studies involving 495 patients found “no single intervention to be convincingly effective in the treatment of molluscum contagiosum.”⁴⁵ And no vaccine exists.

Gianotti-Crosti syndrome

Gianotti-Crosti syndrome (GCS), also known as papular acrodermatitis of childhood, is a relatively rare, self-limited exanthema that usually affects infants and children 6 months to 12 years of age (peak occurrence is in one- to 6-year-olds). Although there have been reports of adults with this syndrome, it is unusual in this age group.

Pathogenesis is still unknown. Although GCS itself isn’t contagious, the viruses that can cause it may be. Initially, researchers believed that GCS was linked to acute hepatitis B virus infection, but more recently other viral and bacterial infections have been associated with the condition.⁴⁶

The most commonly associated virus in the United States is Epstein-Barr virus; other viruses include hepatitis A virus, cytomegalovirus, coxsackievirus, respiratory syncytial virus, parainfluenza virus, rotavirus, the mumps virus, parvovirus, and molluscum contagiosum.

Bacterial infections, such as those caused by Bartonella henselae, Mycoplasma pneumoniae, and group A streptococci may trigger GCS.^47-49

Vaccines that have been implicated in GCS include those for polio, diphtheria/pertussis/tetanus, MMR, hepatitis A and B, as well as the influenza vaccine.^48-51

Presentation. While GCS is relatively rare, its presentation is classic, making it easy to diagnose once it’s included in the differential. The pruritic rash usually consists of acute-onset monomorphous, flat-topped or dome-shaped red-brown papules and papulovesicles, one to 10 mm in size, located symmetrically on the face (FIGURE 6), the extensor surfaces of the arms and legs, and, less commonly, the buttocks. It rarely affects other parts of the body.⁴⁸

The diagnosis is usually based on the characteristic rash and the benign nature of the condition; other than the rash, patients are typically asymptomatic and healthy. Sometimes a biopsy is performed and it reveals a dense lichenoid lymphohistiocytic infiltrate with a strong cytoplasmic immunopositivity for beta-defensin-4 in the stratum corneum, granulosum, and spinosum.⁵²

Although Gianotti-Crosti syndrome is relatively rare, its presentation is classic, making it easy to diagnose once it's included in the differential.

The lesions spontaneously resolve within 8 to 12 weeks. GCS usually presents during spring and early summer and affects both sexes equally.⁴⁶

Treatment and prevention. Treatment is usually symptomatic, with the use of oral antihistamines if the lesions become pruritic. Topical steroids may be used, and, in a few cases, oral corticosteroids may be considered. No vaccine exists.

CORRESPONDENCE
Carlos A. Arango, MD, 8399 Bayberry Road, Jacksonville, FL 32256; [email protected].

Family physicians encounter skin rashes on a daily basis. First steps in making the diagnosis include identifying the characteristics of the rash and determining whether the eruption is accompanied by fever or any other symptoms. In the article that follows, we review 8 viral exanthems of childhood that range from the common (chickenpox) to the not-so-common (Gianotti-Crosti syndrome).

Varicella-zoster virus

Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus that causes a primary infection commonly known as chickenpox (varicella).¹ This disease is usually mild and resolves spontaneously.

This highly contagious virus is transmitted by directly touching the blisters, saliva, or mucus of an infected person. It is also transmitted through the air by coughing and sneezing. VZV initiates primary infection by inoculating the respiratory mucosa. It then establishes a lifelong presence in the sensory ganglionic neurons and, thus, can reactivate later in life causing herpes zoster (shingles), which can affect cranial, thoracic, and lumbosacral dermatomes. Acute or chronic neurologic disorders, including cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders, have been reported after VZV reactivation resulting in herpes-zoster.¹

Presentation. With varicella, an extremely pruritic rash follows a brief prodromal stage consisting of a low-grade fever, upper respiratory tract symptoms, tiredness, and fatigue. This exanthem develops rapidly, often beginning on the chest, trunk, or scalp and then spreading to the arms and legs (centrifugally) (FIGURE 1). Varicella also affects mucosal areas of the body, such as the conjunctiva, mouth, rectum, and vagina.

The lesions are papules that rapidly become vesicular with clear fluid inside. Subsequently, the lesions begin to crust. Scabbing occurs within 10 to 14 days. A sure sign of chickenpox is the presence of papules, vesicles, and crusting lesions in close proximity.

Complications. The most common complications of chickenpox—especially in children—are invasive streptococcal and staphylococcal infections.² The most serious complication occurs when the virus invades the spinal cord, causing myelitis or affecting the cerebral arteries, leading to vasculopathy. Diagnosis of VZV in the central nervous system is based on isolation of the virus in cerebral spinal fluid by polymerase chain reaction (PCR). Early diagnosis is important to minimize morbidity and mortality.

Reactivation is sometimes associated with post-herpetic neuralgia (PHN), a severe neuropathic pain syndrome isolated to the dermatomes affected by VZV. PHN can cause pain and suffering for years after shingles resolves, and sometimes is refractory to treatment. PHN may reflect a chronic varicella virus ganglionitis.

A number of treatment choices exist for shingles, but not so much for varicella

Oral treatment. Oral medications such as acyclovir and its prodrug valacyclovir are the current gold standards for the treatment of VZV.³

Famciclovir, the prodrug of penciclovir, is more effective than valacyclovir at resolving acute herpes zoster rash and shortening the duration of PHN.⁴ Gabapentinoids (eg, pregabalin) are the only oral medications approved by the US Food and Drug Administration (FDA) to treat PHN.⁵

Topical medications can also be used. Lidocaine 5% is favored as first-line therapy for the amelioration of pain due to shingles, as it provides modest pain relief with a better safety and tolerability profile than capsaicin 8% patch, which is a second-line choice. The latter must be applied multiple times daily, has minimal analgesic efficacy, and frequently causes initial pain upon application.

Gabapentinoids and topical analgesics can be used in combination due to the low propensity for drug interactions.^6,7 The treatment of choice for focal vasculopathy is intravenous acyclovir, usually for 14 days, although immunocompromised patients should be treated for a longer period of time. Also consider 5 days of steroid therapy for patients with VZV vasculopathy.⁸

Non-FDA approved treatments include tricyclic antidepressants (TCA), such as amitriptyline, nortriptyline, and desipramine, which are sometimes used as first-line therapy for shingles. TCAs may not work well in patients with burning pain, and can have significant adverse effects, including possible cardiotoxicity.⁹

Opioids, including oxycodone, morphine, methadone, and tramadol, are sometimes used in pain management, but concern exists for abuse. Because patients may develop physical dependence, use opioids with considerable caution.¹⁰

Prevention. The United States became the first country to institute a routine varicella immunization program after a varicella vaccine (Varivax) was licensed in 1995.¹¹ The vaccine has reduced the number of varicella infection cases dramatically.¹¹ Vaccine effectiveness is high, and protective herd immunity is obtained after 2 doses.^11-13 The vaccine is administered to children after one year of age with a booster dose administered after the fourth birthday.

A live, attenuated VZV vaccine (Zostavax) is given to individuals ≥60 years of age to prevent or attenuate herpes zoster infection. This vaccine is used to boost VZV-specific cell-mediated immunity in adults, thereby decreasing the burden of herpes zoster and the pain associated with PHN.¹⁴

Roseola

Roseola infantum, also known as exanthema subitum and sixth disease, is a common mild acute febrile illness of childhood caused by infection with human herpesvirus (HHV) 6 (the primary agent causing roseola) or 7 (a secondary causal agent for roseola).¹⁵ HHV-6 has 2 variants (HHV-6a and HHV-6b). Roseola infantum is mostly associated with the HHV-6b variant, which predominantly affects children 6 to 36 months of age.¹⁶

The virus replicates in the salivary glands and is shed through saliva, which is the route of transmission. After a 10- to 15-day incubation period, it remains latent in lymphocytes and monocytes, thus persisting in cells and tissues. It may reactivate late in life, particularly in immunosuppressed individuals. Reactivated infection in immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy. In patients who have received a bone marrow transplant, it can induce graft vs host disease.¹⁷

Presentation. The virus causes a 5- to 6-day illness characterized by high fever (temperature as high as 105°-106° F), miringitis (inflammation of tympanic membranes), and irritability. Once defervescence occurs, an erythematous morbilliform exanthem appears.The rash, which has a discrete macular/papular soft-pink appearance, starts on the trunk and spreads centrifugally to the extremities, neck, and face (FIGURE 2). It usually resolves within one to 2 days.

Complications. The most common complication of roseola is febrile seizures.¹⁷ Less common ones include encephalitis, encephalopathy, fatal hemophagocytic syndrome,¹⁸ or fulminant hepatitis.¹⁹

Treatment and prevention. Treatment depends on symptoms and may include antipyretics for fever management and liquids to maintain hydration. Recovery is usually complete with no significant sequelae. If a child develops a seizure, no antiepileptic drugs are recommended. No vaccine exists.

Fifth disease

Human parvovirus B19, a minute ssDNA virus, was first associated with human disease in 1981, when it was linked to an aplastic crisis in a patient with sickle cell disease.²⁰ Since then researchers have determined that it is also the cause of erythema infectiosum or fifth disease of childhood. The B19 virus can also cause anemia in the fetus as well as hydrops fetalis. It has been linked to arthralgia and arthritis (especially in adults). There is an association with autoimmune diseases with characteristics similar to rheumatoid arthritis.²⁰

More than 70% of the adult population is seropositive for fifth disease.

The B19 virus is transmitted via aerosolized respiratory secretions, contaminated blood, or the placenta. The virus replicates in erythroid cells in bone marrow and peripheral blood, thus inhibiting erythropoiesis.²¹ Once the rash appears, the virus is no longer infectious.²² Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year.²³ More than 70% of the adult population is seropositive for this virus.²⁰

Presentation. Erythema infectiosum is a mild illness in childhood with an incubation period of 6 to 18 days. It presents with a characteristic malar rash on the face that gives patients a slapped cheek appearance (FIGURE 3A). A softer pink-colored “lacy” reticulated rash that blanches when touched may appear on the trunk, arms, and legs (FIGURE 3B).

Another presentation, which involves the hands and feet (glove and sock syndrome) (FIGURES 3C and 3D), consists of a purpuric eruption with painful edema and numerous small confluent petechiae.^22,24 A majority of patients present with inflammatory symptoms that tend to resolve without sequelae within 3 weeks of infection.²³

A rash is not as prevalent in adults as in children. Adults often present with more systemic systems, such as a debilitating influenza-like illness, arthropathy, transient aplastic anemia in sickle cell-affected individuals, and persistent viral suppression of erythrocyte production in immunocompromised patients and organ-transplant recipients.

Complications. The B19 virus can cause spontaneous abortion in pregnant women and anemia and hydrops fetalis in the fetus.²² Arthritis can occur in children, but is more common in adults, especially in women. The arthritis tends to be symmetrical and affects small joints such as the hands, wrists, and knees.

In one study of parvovirus B19 involving 633 children with sickle cell disease, 68 children developed transient red cell aplasia, 19% of them developed splenic sequestration, and 12% developed acute chest syndrome, a lung-related complication of sickle cell disease that can lower the level of oxygen in the blood and can be fatal.²⁵

Treatment and prevention. Treatment of B19 infection is symptomatic; for example, nonsteroidal anti-inflammatory drugs (NSAIDs) are used if joint pain develops. No vaccine exists.

Hand, foot, and mouth disease

Hand, foot, and mouth disease (HFMD) is caused by the picornavirus family, including the Coxsackievirus, Enterovirus, and Echovirus. Infections commonly occur in the spring, summer, and fall. The virus primarily affects infants and children <10 years of age with the infection typically lasting 7 to 10 days.²⁶

Presentation. The disease usually presents with a febrile episode, progressing to nasal congestion and malaise. One to 2 days later, the classic rash appears. Patients with HFMD usually present with papular or vesicular lesions on the hands and feet and painful oral lesions (FIGURES 4A, 4B, and 4C). The rash may also affect other parts of the body including the legs and buttocks. Desquamation of nails may occur up to one month after the HFM infection.²⁷ Most cases are diagnosed by clinical presentation, but infection can be confirmed by PCR of vesicular lesion fluid.

Complications. In addition to being caused by Coxsackievirus, HFMD may be caused by human Enterovirus A serotype 71 (HEVA-71), which is associated with a high prevalence of acute neurologic disease including aseptic meningitis, poliomyelitis-like paralysis, and encephalitis.²⁶ Of 764 HFMD patients enrolled in a prospective study, 214 cases were associated with Coxsackievirus A 16 (CVA16) infection and 173 cases were associated with HEVA-71 infection. Rare cases of HFMD have led to encephalitis, meningitis, flaccid paralysis, and death.²⁶

Treatment and prevention. HFMD is usually self-limited, and treatment is supportive. There has been interest in developing an HFMD vaccine, but no products are as yet commercially available.

Rubella

Rubella, also known as the German measles or the 3-day measles, is caused by the rubella virus, which is transmitted via respiratory droplets. Up to half of rubella infections are asymptomatic.^28-30

Presentation. Rubella typically has an incubation period of 12 to 24 days, with a 5-day prodromal period characterized by fever, headache, and other symptoms typical of an upper respiratory infection, including sore throat, arthralgia, and tender lymphadenopathy.²⁸

The rash often starts as erythematous or as rose-pink macules on the face that progress down the body. The rash can cover the trunk and extremities within 24 hours. (For photos, see https://www.cdc.gov/rubella/about/photos.html.)

Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome.

Patients are infectious from 7 days prior to the appearance of the rash to 7 days after resolution of the rash. Given the potentially prolonged infectious period, patients hospitalized for rubella infection should be placed on droplet precautions, and children should be kept from day care and school for 7 days after the appearance of the rash.²⁸

Rubella is typically a mild disease in immunocompetent patients; however, immunocompromised patients may develop pneumonia, coagulopathies, or neurologic sequelae including encephalitis.

Complications. Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome (CRS), a condition characterized by congenital cataracts and “blueberry muffin” skin lesions.³¹ Infants affected by CRS can also have heart defects, intellectual disabilities, deafness, and low birth weight. Diagnosis of primary maternal infection should be made with serologic tests. Fetal infection can be determined by detection of fetal serum IgM after 22 to 24 weeks of gestation or with viral culture of amniotic fluid.³¹

Treatment and prevention. Currently, no antiviral treatments are available; however, vaccines are highly effective at preventing infection. Rubella vaccine is usually given as part of the measles, mumps, rubella (MMR) vaccine, which is administered at age 12 to 15 months and again between 4 and 6 years of age.

Measles

Measles is a highly contagious disease caused by a virus that belongs to the Morbillivirus genus of the family Paramyxoviridae. Infection occurs through inhalation of, or direct contact with, respiratory droplets from infected people.³²

Presentation. People with measles often present with what starts as a macular rash on the face that then spreads downward to the neck, trunk, and extremities (for photos, see http://www.cdc.gov/measles/hcp/index.html). As the disease progresses, papules can develop and the lesions may coalesce.

The rash is often preceded by 3 to 4 days of malaise and fever (temperature often greater than 104° F), along with the classic symptom triad of cough, coryza, and conjunctivitis. Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.³³

Measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious/personal beliefs or safety concerns.

Because the symptoms of measles are easily confused with other viral infections, suspected cases of measles should be confirmed via IgG and IgM antibody tests, by reverse transcription-PCR, or both.^34,35 For limited and unusual cases, the Centers for Disease Control and Prevention can perform a plaque reduction neutralization assay.³⁵

Complications. Measles infection is self-limited in immunocompetent patients. The most common complications are diarrhea and ear infections, but more serious complications, such as pneumonia, hearing loss, and encephalitis, can occur. Children <2 years of age, particularly boys, are at an increased risk of developing subacute sclerosing panencephalitis, a fatal neurologic disorder that can develop years after the initial measles infection.^33,36

Treatment and prevention. Treatment is supportive and usually consists of acetaminophen or NSAIDs and fluids.

Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.

A live attenuated version of the measles vaccine is highly effective against the measles virus and has greatly reduced the number of measles cases globally.³⁷ The measles vaccine is usually given in 2 doses—the first one after one year of age, and the second one before entering kindergarten. The most common adverse reactions to the vaccine are pain at the injection site and fever. Despite the fact that the MMR vaccine is effective and relatively benign, measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious or other personal beliefs or safety concerns.³⁸

Molluscum contagiosum

Molluscum contagiosum (MC) is caused by the MC virus, a member of the poxvirus family. The virus is transmitted by direct contact with the skin lesions. This skin condition is seen mainly in children, although it can occur in adults.

A study conducted in England and Wales that obtained information from the Royal College of General Practitioners reported an incidence of 15.0-17.2/1000 population over a 10-year period (1994-2003) with no variation between sexes.³⁹ There is an association between atopic dermatitis and MC; 24% of children with atopic dermatitis develop MC.⁴⁰ There might also be an association between recent swimming in a public pool and development of MC lesions.⁴¹

Presentation. Lesions caused by MC are small, discrete, waxy dome-shaped papules with central umbilication that are usually 3 to 5 mm in diameter (FIGURE 5).^42,43 In immunocompetent patients, there are usually fewer than 20 lesions, which resolve within a year. However, in immunocompromised patients, the number of lesions is usually higher, and the diameter of each may be greater than 1 cm.⁴²

Complications. The lesions are usually self-limited, but on occasion can become secondarily infected, usually with gram-positive organisms such as Staphylococcus aureus. Very rarely, abscesses develop requiring topical and/or systemic antimicrobials and perhaps incision and drainage.⁴⁴

Treatment and prevention. Because the infection is often self-limited and benign, the preferred therapeutic modality is watchful waiting. Other treatments for MC include curettage, chemical agents, immune modulators, and antiviral drugs. A 2009 Cochran review of 11 studies involving 495 patients found “no single intervention to be convincingly effective in the treatment of molluscum contagiosum.”⁴⁵ And no vaccine exists.

Gianotti-Crosti syndrome

Gianotti-Crosti syndrome (GCS), also known as papular acrodermatitis of childhood, is a relatively rare, self-limited exanthema that usually affects infants and children 6 months to 12 years of age (peak occurrence is in one- to 6-year-olds). Although there have been reports of adults with this syndrome, it is unusual in this age group.

Pathogenesis is still unknown. Although GCS itself isn’t contagious, the viruses that can cause it may be. Initially, researchers believed that GCS was linked to acute hepatitis B virus infection, but more recently other viral and bacterial infections have been associated with the condition.⁴⁶

The most commonly associated virus in the United States is Epstein-Barr virus; other viruses include hepatitis A virus, cytomegalovirus, coxsackievirus, respiratory syncytial virus, parainfluenza virus, rotavirus, the mumps virus, parvovirus, and molluscum contagiosum.

Bacterial infections, such as those caused by Bartonella henselae, Mycoplasma pneumoniae, and group A streptococci may trigger GCS.^47-49

Vaccines that have been implicated in GCS include those for polio, diphtheria/pertussis/tetanus, MMR, hepatitis A and B, as well as the influenza vaccine.^48-51

Presentation. While GCS is relatively rare, its presentation is classic, making it easy to diagnose once it’s included in the differential. The pruritic rash usually consists of acute-onset monomorphous, flat-topped or dome-shaped red-brown papules and papulovesicles, one to 10 mm in size, located symmetrically on the face (FIGURE 6), the extensor surfaces of the arms and legs, and, less commonly, the buttocks. It rarely affects other parts of the body.⁴⁸

The diagnosis is usually based on the characteristic rash and the benign nature of the condition; other than the rash, patients are typically asymptomatic and healthy. Sometimes a biopsy is performed and it reveals a dense lichenoid lymphohistiocytic infiltrate with a strong cytoplasmic immunopositivity for beta-defensin-4 in the stratum corneum, granulosum, and spinosum.⁵²

Although Gianotti-Crosti syndrome is relatively rare, its presentation is classic, making it easy to diagnose once it's included in the differential.

The lesions spontaneously resolve within 8 to 12 weeks. GCS usually presents during spring and early summer and affects both sexes equally.⁴⁶

Treatment and prevention. Treatment is usually symptomatic, with the use of oral antihistamines if the lesions become pruritic. Topical steroids may be used, and, in a few cases, oral corticosteroids may be considered. No vaccine exists.

CORRESPONDENCE
Carlos A. Arango, MD, 8399 Bayberry Road, Jacksonville, FL 32256; [email protected].

Family physicians encounter skin rashes on a daily basis. First steps in making the diagnosis include identifying the characteristics of the rash and determining whether the eruption is accompanied by fever or any other symptoms. In the article that follows, we review 8 viral exanthems of childhood that range from the common (chickenpox) to the not-so-common (Gianotti-Crosti syndrome).

Varicella-zoster virus

Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus that causes a primary infection commonly known as chickenpox (varicella).¹ This disease is usually mild and resolves spontaneously.

This highly contagious virus is transmitted by directly touching the blisters, saliva, or mucus of an infected person. It is also transmitted through the air by coughing and sneezing. VZV initiates primary infection by inoculating the respiratory mucosa. It then establishes a lifelong presence in the sensory ganglionic neurons and, thus, can reactivate later in life causing herpes zoster (shingles), which can affect cranial, thoracic, and lumbosacral dermatomes. Acute or chronic neurologic disorders, including cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders, have been reported after VZV reactivation resulting in herpes-zoster.¹

Presentation. With varicella, an extremely pruritic rash follows a brief prodromal stage consisting of a low-grade fever, upper respiratory tract symptoms, tiredness, and fatigue. This exanthem develops rapidly, often beginning on the chest, trunk, or scalp and then spreading to the arms and legs (centrifugally) (FIGURE 1). Varicella also affects mucosal areas of the body, such as the conjunctiva, mouth, rectum, and vagina.

The lesions are papules that rapidly become vesicular with clear fluid inside. Subsequently, the lesions begin to crust. Scabbing occurs within 10 to 14 days. A sure sign of chickenpox is the presence of papules, vesicles, and crusting lesions in close proximity.

Complications. The most common complications of chickenpox—especially in children—are invasive streptococcal and staphylococcal infections.² The most serious complication occurs when the virus invades the spinal cord, causing myelitis or affecting the cerebral arteries, leading to vasculopathy. Diagnosis of VZV in the central nervous system is based on isolation of the virus in cerebral spinal fluid by polymerase chain reaction (PCR). Early diagnosis is important to minimize morbidity and mortality.

Reactivation is sometimes associated with post-herpetic neuralgia (PHN), a severe neuropathic pain syndrome isolated to the dermatomes affected by VZV. PHN can cause pain and suffering for years after shingles resolves, and sometimes is refractory to treatment. PHN may reflect a chronic varicella virus ganglionitis.

A number of treatment choices exist for shingles, but not so much for varicella

Oral treatment. Oral medications such as acyclovir and its prodrug valacyclovir are the current gold standards for the treatment of VZV.³

Famciclovir, the prodrug of penciclovir, is more effective than valacyclovir at resolving acute herpes zoster rash and shortening the duration of PHN.⁴ Gabapentinoids (eg, pregabalin) are the only oral medications approved by the US Food and Drug Administration (FDA) to treat PHN.⁵

Topical medications can also be used. Lidocaine 5% is favored as first-line therapy for the amelioration of pain due to shingles, as it provides modest pain relief with a better safety and tolerability profile than capsaicin 8% patch, which is a second-line choice. The latter must be applied multiple times daily, has minimal analgesic efficacy, and frequently causes initial pain upon application.

Gabapentinoids and topical analgesics can be used in combination due to the low propensity for drug interactions.^6,7 The treatment of choice for focal vasculopathy is intravenous acyclovir, usually for 14 days, although immunocompromised patients should be treated for a longer period of time. Also consider 5 days of steroid therapy for patients with VZV vasculopathy.⁸

Non-FDA approved treatments include tricyclic antidepressants (TCA), such as amitriptyline, nortriptyline, and desipramine, which are sometimes used as first-line therapy for shingles. TCAs may not work well in patients with burning pain, and can have significant adverse effects, including possible cardiotoxicity.⁹

Opioids, including oxycodone, morphine, methadone, and tramadol, are sometimes used in pain management, but concern exists for abuse. Because patients may develop physical dependence, use opioids with considerable caution.¹⁰

Prevention. The United States became the first country to institute a routine varicella immunization program after a varicella vaccine (Varivax) was licensed in 1995.¹¹ The vaccine has reduced the number of varicella infection cases dramatically.¹¹ Vaccine effectiveness is high, and protective herd immunity is obtained after 2 doses.^11-13 The vaccine is administered to children after one year of age with a booster dose administered after the fourth birthday.

A live, attenuated VZV vaccine (Zostavax) is given to individuals ≥60 years of age to prevent or attenuate herpes zoster infection. This vaccine is used to boost VZV-specific cell-mediated immunity in adults, thereby decreasing the burden of herpes zoster and the pain associated with PHN.¹⁴

Roseola

Roseola infantum, also known as exanthema subitum and sixth disease, is a common mild acute febrile illness of childhood caused by infection with human herpesvirus (HHV) 6 (the primary agent causing roseola) or 7 (a secondary causal agent for roseola).¹⁵ HHV-6 has 2 variants (HHV-6a and HHV-6b). Roseola infantum is mostly associated with the HHV-6b variant, which predominantly affects children 6 to 36 months of age.¹⁶

The virus replicates in the salivary glands and is shed through saliva, which is the route of transmission. After a 10- to 15-day incubation period, it remains latent in lymphocytes and monocytes, thus persisting in cells and tissues. It may reactivate late in life, particularly in immunosuppressed individuals. Reactivated infection in immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy. In patients who have received a bone marrow transplant, it can induce graft vs host disease.¹⁷

Presentation. The virus causes a 5- to 6-day illness characterized by high fever (temperature as high as 105°-106° F), miringitis (inflammation of tympanic membranes), and irritability. Once defervescence occurs, an erythematous morbilliform exanthem appears.The rash, which has a discrete macular/papular soft-pink appearance, starts on the trunk and spreads centrifugally to the extremities, neck, and face (FIGURE 2). It usually resolves within one to 2 days.

Complications. The most common complication of roseola is febrile seizures.¹⁷ Less common ones include encephalitis, encephalopathy, fatal hemophagocytic syndrome,¹⁸ or fulminant hepatitis.¹⁹

Treatment and prevention. Treatment depends on symptoms and may include antipyretics for fever management and liquids to maintain hydration. Recovery is usually complete with no significant sequelae. If a child develops a seizure, no antiepileptic drugs are recommended. No vaccine exists.

Fifth disease

Human parvovirus B19, a minute ssDNA virus, was first associated with human disease in 1981, when it was linked to an aplastic crisis in a patient with sickle cell disease.²⁰ Since then researchers have determined that it is also the cause of erythema infectiosum or fifth disease of childhood. The B19 virus can also cause anemia in the fetus as well as hydrops fetalis. It has been linked to arthralgia and arthritis (especially in adults). There is an association with autoimmune diseases with characteristics similar to rheumatoid arthritis.²⁰

More than 70% of the adult population is seropositive for fifth disease.

The B19 virus is transmitted via aerosolized respiratory secretions, contaminated blood, or the placenta. The virus replicates in erythroid cells in bone marrow and peripheral blood, thus inhibiting erythropoiesis.²¹ Once the rash appears, the virus is no longer infectious.²² Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year.²³ More than 70% of the adult population is seropositive for this virus.²⁰

Presentation. Erythema infectiosum is a mild illness in childhood with an incubation period of 6 to 18 days. It presents with a characteristic malar rash on the face that gives patients a slapped cheek appearance (FIGURE 3A). A softer pink-colored “lacy” reticulated rash that blanches when touched may appear on the trunk, arms, and legs (FIGURE 3B).

Another presentation, which involves the hands and feet (glove and sock syndrome) (FIGURES 3C and 3D), consists of a purpuric eruption with painful edema and numerous small confluent petechiae.^22,24 A majority of patients present with inflammatory symptoms that tend to resolve without sequelae within 3 weeks of infection.²³

A rash is not as prevalent in adults as in children. Adults often present with more systemic systems, such as a debilitating influenza-like illness, arthropathy, transient aplastic anemia in sickle cell-affected individuals, and persistent viral suppression of erythrocyte production in immunocompromised patients and organ-transplant recipients.

Complications. The B19 virus can cause spontaneous abortion in pregnant women and anemia and hydrops fetalis in the fetus.²² Arthritis can occur in children, but is more common in adults, especially in women. The arthritis tends to be symmetrical and affects small joints such as the hands, wrists, and knees.

In one study of parvovirus B19 involving 633 children with sickle cell disease, 68 children developed transient red cell aplasia, 19% of them developed splenic sequestration, and 12% developed acute chest syndrome, a lung-related complication of sickle cell disease that can lower the level of oxygen in the blood and can be fatal.²⁵

Treatment and prevention. Treatment of B19 infection is symptomatic; for example, nonsteroidal anti-inflammatory drugs (NSAIDs) are used if joint pain develops. No vaccine exists.

Hand, foot, and mouth disease

Hand, foot, and mouth disease (HFMD) is caused by the picornavirus family, including the Coxsackievirus, Enterovirus, and Echovirus. Infections commonly occur in the spring, summer, and fall. The virus primarily affects infants and children <10 years of age with the infection typically lasting 7 to 10 days.²⁶

Presentation. The disease usually presents with a febrile episode, progressing to nasal congestion and malaise. One to 2 days later, the classic rash appears. Patients with HFMD usually present with papular or vesicular lesions on the hands and feet and painful oral lesions (FIGURES 4A, 4B, and 4C). The rash may also affect other parts of the body including the legs and buttocks. Desquamation of nails may occur up to one month after the HFM infection.²⁷ Most cases are diagnosed by clinical presentation, but infection can be confirmed by PCR of vesicular lesion fluid.

Complications. In addition to being caused by Coxsackievirus, HFMD may be caused by human Enterovirus A serotype 71 (HEVA-71), which is associated with a high prevalence of acute neurologic disease including aseptic meningitis, poliomyelitis-like paralysis, and encephalitis.²⁶ Of 764 HFMD patients enrolled in a prospective study, 214 cases were associated with Coxsackievirus A 16 (CVA16) infection and 173 cases were associated with HEVA-71 infection. Rare cases of HFMD have led to encephalitis, meningitis, flaccid paralysis, and death.²⁶

Treatment and prevention. HFMD is usually self-limited, and treatment is supportive. There has been interest in developing an HFMD vaccine, but no products are as yet commercially available.

Rubella

Rubella, also known as the German measles or the 3-day measles, is caused by the rubella virus, which is transmitted via respiratory droplets. Up to half of rubella infections are asymptomatic.^28-30

Presentation. Rubella typically has an incubation period of 12 to 24 days, with a 5-day prodromal period characterized by fever, headache, and other symptoms typical of an upper respiratory infection, including sore throat, arthralgia, and tender lymphadenopathy.²⁸

The rash often starts as erythematous or as rose-pink macules on the face that progress down the body. The rash can cover the trunk and extremities within 24 hours. (For photos, see https://www.cdc.gov/rubella/about/photos.html.)

Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome.

Patients are infectious from 7 days prior to the appearance of the rash to 7 days after resolution of the rash. Given the potentially prolonged infectious period, patients hospitalized for rubella infection should be placed on droplet precautions, and children should be kept from day care and school for 7 days after the appearance of the rash.²⁸

Rubella is typically a mild disease in immunocompetent patients; however, immunocompromised patients may develop pneumonia, coagulopathies, or neurologic sequelae including encephalitis.

Complications. Rubella infection, especially during the first trimester, can lead to spontaneous abortion, stillbirth, or congenital rubella syndrome (CRS), a condition characterized by congenital cataracts and “blueberry muffin” skin lesions.³¹ Infants affected by CRS can also have heart defects, intellectual disabilities, deafness, and low birth weight. Diagnosis of primary maternal infection should be made with serologic tests. Fetal infection can be determined by detection of fetal serum IgM after 22 to 24 weeks of gestation or with viral culture of amniotic fluid.³¹

Treatment and prevention. Currently, no antiviral treatments are available; however, vaccines are highly effective at preventing infection. Rubella vaccine is usually given as part of the measles, mumps, rubella (MMR) vaccine, which is administered at age 12 to 15 months and again between 4 and 6 years of age.

Measles

Measles is a highly contagious disease caused by a virus that belongs to the Morbillivirus genus of the family Paramyxoviridae. Infection occurs through inhalation of, or direct contact with, respiratory droplets from infected people.³²

Presentation. People with measles often present with what starts as a macular rash on the face that then spreads downward to the neck, trunk, and extremities (for photos, see http://www.cdc.gov/measles/hcp/index.html). As the disease progresses, papules can develop and the lesions may coalesce.

The rash is often preceded by 3 to 4 days of malaise and fever (temperature often greater than 104° F), along with the classic symptom triad of cough, coryza, and conjunctivitis. Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.³³

Measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious/personal beliefs or safety concerns.

Because the symptoms of measles are easily confused with other viral infections, suspected cases of measles should be confirmed via IgG and IgM antibody tests, by reverse transcription-PCR, or both.^34,35 For limited and unusual cases, the Centers for Disease Control and Prevention can perform a plaque reduction neutralization assay.³⁵

Complications. Measles infection is self-limited in immunocompetent patients. The most common complications are diarrhea and ear infections, but more serious complications, such as pneumonia, hearing loss, and encephalitis, can occur. Children <2 years of age, particularly boys, are at an increased risk of developing subacute sclerosing panencephalitis, a fatal neurologic disorder that can develop years after the initial measles infection.^33,36

Treatment and prevention. Treatment is supportive and usually consists of acetaminophen or NSAIDs and fluids.

Koplik spots—clustered white lesions on the buccal mucosa—are often present prior to the measles rash and are pathognomonic for measles infection.

A live attenuated version of the measles vaccine is highly effective against the measles virus and has greatly reduced the number of measles cases globally.³⁷ The measles vaccine is usually given in 2 doses—the first one after one year of age, and the second one before entering kindergarten. The most common adverse reactions to the vaccine are pain at the injection site and fever. Despite the fact that the MMR vaccine is effective and relatively benign, measles outbreaks continue to occur, as some parents forego routine childhood immunizations because of religious or other personal beliefs or safety concerns.³⁸

Molluscum contagiosum

Molluscum contagiosum (MC) is caused by the MC virus, a member of the poxvirus family. The virus is transmitted by direct contact with the skin lesions. This skin condition is seen mainly in children, although it can occur in adults.

A study conducted in England and Wales that obtained information from the Royal College of General Practitioners reported an incidence of 15.0-17.2/1000 population over a 10-year period (1994-2003) with no variation between sexes.³⁹ There is an association between atopic dermatitis and MC; 24% of children with atopic dermatitis develop MC.⁴⁰ There might also be an association between recent swimming in a public pool and development of MC lesions.⁴¹

Presentation. Lesions caused by MC are small, discrete, waxy dome-shaped papules with central umbilication that are usually 3 to 5 mm in diameter (FIGURE 5).^42,43 In immunocompetent patients, there are usually fewer than 20 lesions, which resolve within a year. However, in immunocompromised patients, the number of lesions is usually higher, and the diameter of each may be greater than 1 cm.⁴²

Complications. The lesions are usually self-limited, but on occasion can become secondarily infected, usually with gram-positive organisms such as Staphylococcus aureus. Very rarely, abscesses develop requiring topical and/or systemic antimicrobials and perhaps incision and drainage.⁴⁴

Treatment and prevention. Because the infection is often self-limited and benign, the preferred therapeutic modality is watchful waiting. Other treatments for MC include curettage, chemical agents, immune modulators, and antiviral drugs. A 2009 Cochran review of 11 studies involving 495 patients found “no single intervention to be convincingly effective in the treatment of molluscum contagiosum.”⁴⁵ And no vaccine exists.

Gianotti-Crosti syndrome

Gianotti-Crosti syndrome (GCS), also known as papular acrodermatitis of childhood, is a relatively rare, self-limited exanthema that usually affects infants and children 6 months to 12 years of age (peak occurrence is in one- to 6-year-olds). Although there have been reports of adults with this syndrome, it is unusual in this age group.

Pathogenesis is still unknown. Although GCS itself isn’t contagious, the viruses that can cause it may be. Initially, researchers believed that GCS was linked to acute hepatitis B virus infection, but more recently other viral and bacterial infections have been associated with the condition.⁴⁶

The most commonly associated virus in the United States is Epstein-Barr virus; other viruses include hepatitis A virus, cytomegalovirus, coxsackievirus, respiratory syncytial virus, parainfluenza virus, rotavirus, the mumps virus, parvovirus, and molluscum contagiosum.

Bacterial infections, such as those caused by Bartonella henselae, Mycoplasma pneumoniae, and group A streptococci may trigger GCS.^47-49

Vaccines that have been implicated in GCS include those for polio, diphtheria/pertussis/tetanus, MMR, hepatitis A and B, as well as the influenza vaccine.^48-51

Presentation. While GCS is relatively rare, its presentation is classic, making it easy to diagnose once it’s included in the differential. The pruritic rash usually consists of acute-onset monomorphous, flat-topped or dome-shaped red-brown papules and papulovesicles, one to 10 mm in size, located symmetrically on the face (FIGURE 6), the extensor surfaces of the arms and legs, and, less commonly, the buttocks. It rarely affects other parts of the body.⁴⁸

The diagnosis is usually based on the characteristic rash and the benign nature of the condition; other than the rash, patients are typically asymptomatic and healthy. Sometimes a biopsy is performed and it reveals a dense lichenoid lymphohistiocytic infiltrate with a strong cytoplasmic immunopositivity for beta-defensin-4 in the stratum corneum, granulosum, and spinosum.⁵²

Although Gianotti-Crosti syndrome is relatively rare, its presentation is classic, making it easy to diagnose once it's included in the differential.

The lesions spontaneously resolve within 8 to 12 weeks. GCS usually presents during spring and early summer and affects both sexes equally.⁴⁶

Treatment and prevention. Treatment is usually symptomatic, with the use of oral antihistamines if the lesions become pruritic. Topical steroids may be used, and, in a few cases, oral corticosteroids may be considered. No vaccine exists.

CORRESPONDENCE
Carlos A. Arango, MD, 8399 Bayberry Road, Jacksonville, FL 32256; [email protected].

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

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Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

[polldaddy:9818133]

Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].

CASE 1 An 82-year-old black woman comes in for an annual exam. She has no medical concerns. She volunteers at a hospice, walks daily, and maintains a healthy diet. Her past medical history (PMH) includes osteopenia and osteoarthritis, and her medications include acetaminophen as needed and vitamin D. She has no drug allergies. Her exam reveals a blood pressure (BP) of 148/70 mm Hg, a body mass index of 31, and a heart rate (HR) of 71 beats per minute (bpm). Cardiac and pulmonary exams are normal, and she shows no signs of peripheral edema.

CASE 2 An 88-year-old white man presents to the office for a 3-month follow-up of his hypertension. His systolic BP at home has ranged from 140 to 170 mm Hg. He denies chest pain, shortness of breath, or lower extremity edema. He lives with his wife and frequently swims for exercise. His PMH is significant for depression and degenerative disc disease. His medications include hydrochlorothiazide 12.5 mg/d, sertraline 50 mg/d, and naproxen 250 mg bid. His BP is 160/80 mm Hg and his HR is 70 bpm with normal cardiovascular (CV) and pulmonary exams.

CASE 3 An 80-year-old white man with diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD) presents for a 3-month follow-up visit. His home systolic BP has been in the 140s to 150s. He is functional in all of his activities of daily living (ADLs), but is starting to require assistance with medications, finances, and transportation. He takes aspirin 81 mg/d, chlorthalidone 25 mg/d, and atenolol 50 mg/d. Remarkable laboratory test results include a hemoglobin A1c of 8.6%, a serum creatinine of 1.9 mg/dL (normal range: 0.6-1.2 mg/dL), and an albumin-creatinine ratio of 250 mg/g (normal range: <30 mg/g). During the exam, his BP is 143/70 mm Hg, his HR is 70 bpm, he is alert and oriented to person, place, and time, and he has normal CV and pulmonary exams with no signs of peripheral edema. He has decreased sensation in his feet, but normal reflexes.

How would you proceed with the care of these 3 patients?

Hypertension is the most common diagnosis made during physician office visits in the United States.¹ Nearly one-third of the population has hypertension, and its prevalence increases with age, such that 67% of men and 79% of women ≥75 years of age have the condition.²

Evidence indicates that hypertension is a modifiable risk factor for CV and all-cause mortality (TABLE W1^3-6). All adults ≥75 years of age are at increased CV risk based on Framingham criteria,⁷ making hypertension management paramount. Complicating the situation are findings that indicate nearly half of adults with hypertension have inadequate BP control.²

A systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age, but if this places an undue burden on the patient, a goal of <140 mm Hg also provides benefit.

Clinicians require clear direction about optimal BP targets, how best to adjust antihypertensive medications for comorbidities, and how to incorporate frailty and cognitive impairment into management strategies. This article presents recommendations derived from recent evidence and consensus guidelines regarding the management of hypertension in adults ≥75 years of age.

[polldaddy:9818133]

Diagnosing hypertension

According to the seventh report of the Joint National Committee (JNC 7), hypertension is defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg.⁸ The JNC’s more recent report (JNC 8), however, does not define hypertension; instead, it sets forth treatment thresholds (eg, that there is strong evidence to support treating individuals ≥60 years of age when BP ≥150/90 mm Hg).⁹

It starts with an accurate BP measurement. Ensuring the accuracy of a BP measurement requires multiple readings over time. White coat hypertension and masked hypertension can complicate BP measurement. Home measurements better correlate with atherosclerotic cardiovascular disease (ASCVD) risk than do office measurements.^10-12 In fact, the US Preventive Services Task Force recommends obtaining measurements outside of the clinic setting prior to initiating treatment for hypertension.¹³

Educate staff on the proper technique for obtaining BP measurements in the office (ie, taking measurements using an appropriately sized cuff when patients have been seated for at least 5 minutes with feet uncrossed and with their arm supported at heart level). Cold temperatures, coffee consumption, talking, and recent tobacco use can transiently raise BP. TABLE 1¹⁰ outlines the initial work-up after confirming the diagnosis of hypertension. No other routine tests are recommended for the management of hypertension except those associated with medication monitoring (outlined in TABLE 2^10,11,14,15).

What’s the optimal BP target for older patients? No consensus exists on an optimal BP target for older patients. JNC 8 recommends a target BP <150/90 mm Hg in patients ≥60 years of age.⁹ The American College of Physicians recommends a systolic BP target <140 mm Hg in patients ≥60 years of age with increased stroke or CV risk.¹¹ A subgroup analysis of patients ≥75 years of age from the Systolic BP Intervention Trial (SPRINT)³ was stopped early because of the clear composite CV and mortality benefits associated with targeting a systolic BP <120 mm Hg as compared with <140 mm Hg (TABLE W1^3-6). Although a criticism of this trial and its results is that the researchers included only adults with high CV risk, all adults ≥75 years of age are considered to have high CV risk by the SPRINT study.³ Another criticism is that early suspension of the trial may have exaggerated treatment effects.⁶

Lastly, results were seemingly discrepant from previous trials, most notably, the Action to Control CV Risk in Diabetes (ACCORD) trial.^6,16 However, on closer review, the ACCORD trial¹⁶ included only patients with DM, while the SPRINT³ trial excluded patients with DM, and ACCORD comprised a younger population than the SPRINT subgroup analysis. Also, the ACCORD trial did demonstrate stroke reduction and non-significant reduction in CV events, albeit, at the cost of increased adverse events, such as hypotension, bradycardia, and hypokalemia, with tighter BP control.¹⁶

Common pharmacotherapeutic contributors to uncontrolled BP include NSAIDs, glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.

Population differences presumably explain the discrepancy in results, and a systolic BP target of <120 mm Hg is appropriate in community-dwelling, non-diabetic adults ≥75 years of age. If this target goal cannot be achieved without undue burden (ie, without syncope, hypotension, bradycardia, electrolyte disturbance, renal impairment, or substantial medication burden), a recent meta-analysis found evidence that a systolic BP goal <140 mm Hg also provides benefit.⁶

Initiate treatment, watch for age-related changes

Lifestyle modifications (including appropriate weight loss; reduced caffeine, salt, and alcohol intake; increased physical activity; and smoking cessation) are important in the initial and ongoing management of hypertension.^10,11,17,18 JNC 8 recommends initial treatment with a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the nonblack population, and a CCB or thiazide diuretic in the black population.⁹ Specific initial medication choices for comorbid conditions are outlined in TABLE W2^3,10,17-22. JNC 8 recommends against the use of a beta-blocker or alpha blocker for initial treatment of hypertension.⁹

Start a second drug instead of maximizing the dose of the first

If the target BP cannot be achieved within one month of initiating medication, JNC 8 recommends increasing the dose of the initial drug or adding a second drug without preference for one strategy over the other.⁹ However, a meta-analysis demonstrates that approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of the medication; this is true for thiazide-type diuretics, ACE inhibitors/ARBs, beta-blockers, and CCBs.²³

Approximately 80% of the antihypertensive effect of a drug can be achieved with half of the standard dose of many medications.

Furthermore, due to fewer adverse effects and positive synergies, studies show that combining low doses of 2 medications is more beneficial than high-dose monotherapy.^19,23,24 Prescribing combination pills can be helpful to limit pill burden. It is appropriate to combine any of the 4 classes of medications recommended as initial therapy by JNC 8 except for an ACE inhibitor combined with an ARB. If the target BP cannot be achieved with 3 drugs in those classes, other medications such as potassium-sparing diuretics or beta-blockers can be added.⁹

Changes associated with aging

Changes associated with aging include atherosclerosis and stiffening of blood vessels, increased systolic BP, widened pulse pressure, reduced glomerular filtration rate, reduced sodium elimination and volume expansion, sinoatrial node cellular dropout, and decreased sensitivity of baroreceptors.¹⁰ Because of these alterations, antihypertensive requirements may change, and resistant hypertension may develop. In addition, older patients may be more susceptible to orthostatic hypotension, heart block, electrolyte derangements, and other antihypertensive adverse effects.

When hypertension is difficult to control. Resistant hypertension is defined as hypertension that cannot be controlled with 3 drugs from 3 different antihypertensive classes, one of which is a diuretic. Cognitive impairment, polypharmacy, and multimorbidity may contribute to difficult-to-control hypertension in older adults and should be assessed prior to work-up for other secondary causes of poorly controlled hypertension.

• Cognitive impairment is often unrecognized and may impact medication adherence, which can masquerade as treatment failure. Assess for cognitive impairment on an ongoing basis with the aging patient, especially when medication adherence appears poor.
• Polypharmacy may also contribute to uncontrolled BP. Common pharmacotherapeutic contributors to uncontrolled BP include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, high-dose decongestants, and selective norepinephrine reuptake inhibitors.²⁵
• Multimorbidity describes 2 or more chronic medical conditions in one patient. These patients are medically complex. Comorbidities can increase pill burden and make medication adherence difficult for patients. Other poorly controlled disease states can worsen hypertension (eg, renal dysfunction secondary to diabetes). Optimize treatment of comorbid conditions.

Secondary causes. If resistant hypertension persists despite confirming medication adherence and eliminating offending medications, a work-up should ensue for secondary causes of hypertension, as well as end-organ damage. Causes of secondary hypertension include sleep apnea (see this month's HelpDesk), renal dysfunction (renal artery stenosis), aldosterone-mediated hypertension (often with hypokalemia), and thyroid disease. Evaluation for secondary causes of hypertension and end-organ damage is outlined in TABLE 1.¹⁰ Patients with well-controlled hypertension do not require repeated assessments for end-organ damage unless new symptoms—such as chest pain or edema—develop.

Consider comorbidities

Clinical trials implicitly or explicitly exclude patients with multiple comorbidities. JNC 8 provided minimal guidance for adjusting BP targets based on comorbidity with only nondiabetic CKD and DM specifically addressed.⁹ Guidelines from specialty organizations and recent trials provide some additional guidance in these situations and are outlined in TABLE W2^3,10,17-22.

Heart failure. Hypertension is a major risk factor for heart failure. Long-term treatment of systolic and diastolic hypertension can reduce the incidence of heart failure by approximately half with increased benefit in patients with prior myocardial infarction.²² Research demonstrates clear mortality benefits of certain antihypertensive drug classes, including diuretics, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, combination hydralazine and nitrates, and angiotensin receptor-neprilysin inhibitors.^21,22 The overall treatment goal in heart failure is to optimize drugs with mortality benefit, while lowering BP to a goal <130/80 mm Hg in patients ≥75 years of age.²²

Increased risk for CV disease. The SPRINT trial³ defined high risk of CV disease as clinical or subclinical CV disease, CKD, 10-year ASCVD risk of ≥15%, or age ≥75 years. SPRINT supports a systolic BP goal <120 mm Hg, but, as a reminder, SPRINT excluded patients with diabetes. The American College of Cardiology Foundation Task Force and the American Heart Association define high CV risk as a 10-year ASCVD risk ≥10% and recommend a BP goal <130/80 mm Hg.¹⁰

Diabetes mellitus. A BP >115/75 mm Hg is associated with increased CV events and mortality in patients with DM.¹⁸ The American Diabetes Association (ADA) and JNC 8 recommend a BP target <140/90 mm Hg.^9,18 ADA suggests a lower target of 130/80 mm Hg in patients with high CV risk if it is achievable without undue burden.¹⁸

Studies show increased mortality associated with initiating additional treatment once a systolic goal <140 mm Hg has been achieved in patients with DM.²⁶ The ACCORD trial found increased adverse events with aggressive BP lowering to <120/80 mm Hg.¹⁶

For patients with DM requiring more than one antihypertensive agent, there are CV mortality benefits associated with administering at least one antihypertensive drug at night, likely related to the beneficial effect of physiologic nocturnal dipping.²⁷

Chronic kidney disease. JNC 8 specifically recommends an ACE inhibitor or ARB for initial or add-on treatment in patients with CKD and a BP goal <140/90 mm Hg.⁹ The Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommends a BP target ≤140/90 mm Hg in patients without albuminuria and ≤130/80 mm Hg in patients with albuminuria to protect against the progression of nephropathy.¹⁷ The SPRINT trial³ included patients with CKD, and KDIGO has not yet updated its guidelines to reflect SPRINT.

Frailty is a clinical syndrome that has been defined as a state of increased vulnerability that is associated with a decline in reserve and function.²⁸ The largest hypertension studies in older adults address frailty, although often the most frail patients are excluded from these studies (TABLE W1^3-6).

The Hypertension in the Very Elderly Trial (HYVET) categorized patients as frail, pre-frail, or robust and found a consistent benefit of antihypertensive treatment on stroke, CV events, and total mortality—regardless of baseline frailty status.²⁹ The SPRINT trial included only community-dwelling adults.³ Other studies suggest that hypertension actually has a protective effect by lowering overall mortality in frail older adults, especially in the frailest and oldest nursing home populations.^30,31

Due to fewer adverse effects and positive synergies, studies show that low doses of 2 drugs is more beneficial than high-dose monotherapy.

Although there is a paucity of data to direct the management of hypertension in frail older patients, physicians should prioritize the condition and focus on adverse events from antihypertensives and on slow titration of medications. The JNC 8 BP target of <150/90 mm Hg is a reasonable BP goal in this population, given the lack of evidence for lower or higher targets.⁹ Many frail patients have one or more of the comorbidities described earlier, and it is reasonable to strive for the comorbidity-specific target, provided it can be achieved without undue burden.

Cognitive impairment and dementia. The association between hypertension and dementia/cognitive impairment is evolving. Hypertension may impact various forms of dementia, such as Alzheimer’s disease (AD) or vascular dementia, differently. There is evidence linking hypertension to AD.³² The relationship between BP and brain perfusion is complex with the potential existence of an age-adjusted relationship such that mid-life hypertension may increase the risk of dementia while late-life hypertension may not.³³

A number of studies reveal the evolving nature of our understanding of these 2 conditions:

• A recent systematic review and meta-analysis examining intensive BP treatments in older adults demonstrated that lower BP targets did not increase cognitive decline.⁶
• HYVET’s cognitive function assessment did not find a significant reduction in the incidence of dementia with BP reduction over a short follow-up period, but when results were combined in a meta-analysis with other placebo-controlled, double-blind trials of antihypertensive treatments, there was significant reduction in incident dementia in patients randomized to antihypertensive treatment.³⁴
• The ACCORD Memory in Diabetes trial (ACCORD-MIND) had the unexpected outcome that intensive lowering of systolic BP to a target <120 mm Hg resulted in a greater decline in total brain volume, compared with the standard BP goal <140 mm Hg. This was measured with magnetic resonance imaging in older adults with type 2 DM.³⁵
• Results from the SPRINT sub-analysis Memory and Cognition in Decreased Hypertension trial are forthcoming and aim to determine the effects of BP reduction on dementia.³⁶

The JNC 8⁹ BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia. In a systematic review of observational studies in patients with hypertension and dementia, diuretics, CCBs, ACE inhibitors/ARBs, and beta-blockers were commonly used medications with a trend toward prescribing CCBs and ACE inhibitors/ARBs.³⁷

A BP target <150/90 mm Hg or a comorbidity-specific target, if achievable without undue burden, is reasonable in patients with dementia.

As previously highlighted, cognitive impairment may lead to problems with medication adherence and even inadvertent improper medication use, potentially resulting in adverse events from antihypertensives. If cognitive impairment or dementia is suspected, ensure additional measures (such as medication assistance or supervision) are in place before prescribing antihypertensives.

Certain diseases, such as Parkinson’s-related dementia and multiple system atrophy, can cause autonomic instability, which can increase the risk of falls and complicate hypertension management. Carefully monitor patients for signs of orthostasis.

CASE 1 Repeat the BP measurement in the office once the patient has been seated for ≥5 minutes, and have the patient monitor her BP at home; schedule a follow-up visit in 2 weeks. If hypertension is confirmed with home measurements, then, in addition to lifestyle modifications, initiate treatment with a CCB or thiazide diuretic to achieve a systolic BP goal <120 mm Hg. Titrate medications slowly while monitoring for adverse effects.

CASE 2 Consistent with the office measurement, the patient has home BP readings that are above the BP target (<120 mm Hg systolic). He has been taking a single antihypertensive for longer than one month. Discontinue his NSAID prior to adding any new medications. If his BP is still above target without NSAIDs, then add a second agent, such as a low dose of an ACE inhibitor, ARB, or CCB, rather than maximizing the dose of hydrochlorothiazide.

CASE 3 Given the patient’s diabetes, CKD, and albuminuria, a target BP goal <130/80 mm Hg is reasonable. An ACE inhibitor or ARB is a better medication choice than atenolol in this patient with albuminuria. Because of the deterioration in his ADLs, careful assessment of mobility, functionality, comorbidities, frailty, and cognitive function should take place at each office visit and inform adjustments to the patient’s BP target. Employ cautious medication titration with monitoring for adverse effects, especially hypotension and syncope. If his functional status declines, adverse effects develop, or the medication regimen becomes burdensome, relax the target BP goal to 150/90 mm Hg.

CORRESPONDENCE
Julienne K. Kirk, PharmD, Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected].