Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

Managing chronic pain in an older adult can be a complicated task, with risks for adverse effects, under- or overmedication, and nonadherence. Pain can be alleviated in many cases, however, if you address potential complications and barriers to effective treatment when prescribing analgesic medications.

Pain is a part of daily life for many older adults

As many as 50% of community-dwelling older adults experience a chronic pain disorder, defined as pain on most days for at least 3 consecutive months.¹ Prevalence rates are typically higher (49%-84%) among residents of long-term care facilities.² Untreated chronic pain can lead to health consequences such as depression, decreased ability to socialize, impaired ambulation, impaired sleep, increased falls, malnutrition, and decreased quality of life.^1,3 Among older women, pain is the most common reported cause of impairment in activities of daily living.⁴

Arthritis and arthritis-related diseases (such as back pain) are common causes of chronic pain in older adults.⁵ Other causes include neuropathies, vertebral compression fractures, cancer and cancer treatments, and advanced chronic diseases such as end-stage heart, lung, and kidney disease.^6-10

Substantial literature documents that chronic pain is underdetected and undertreated with advancing age^11,12 and strongly supports efforts to improve pain care in later life. Treatment guidelines recommend a multimodal approach, including evidence-based nonpharmacologic treatments such as cognitive-behavioral therapy, exercise, and physical therapy.¹ At the same time, pharmacotherapies remain the primary treatment used by physicians,¹³ and studies indicate that older people use analgesics frequently:

• When 551 older black and non-Hispanic white adults with osteoarthritis were interviewed, more than 80% of each group reported regular use of prescription and over-the-counter (OTC) analgesic medications.¹⁴
• In a cross-sectional study of 272 community-dwelling older adults with chronic pain from diverse causes, 59% reported routine use of an analgesic medication.¹⁵

The following 6 steps can improve the likelihood of a successful analgesic trial when managing chronic pain in people ages 65 and older. They take into account barriers you are likely to encounter, including polypharmacy, multimorbidity, cognitive and sensory impairment, sociodemographic factors, specific health beliefs about pain and pain treatments, and age-related physiologic changes.

TABLE

Refine your approach to chronic pain in older patients with these 6 steps

Step 1. Conduct a comprehensive pain history

The first step in pain management is to perform a comprehensive pain assessment. Without a proper pain assessment, it will be difficult to effectively treat and monitor response to treatment. Whichever pain scale you decide to use, it is important to use the same pain scale consistently each time a pain assessment takes place.³ The numeric rating scale and verbal descriptor scales (or pain thermometer) are widely used and have been shown to be preferred in the older adult population.^3,16 The numeric rating scale asks a patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 being the most severe pain imaginable. The verbal descriptor scale is a measure of pain intensity on a vertical scale (typically a thermometer) from “no pain” to “excruciating.”³

Recommendations. In addition to assessing the intensity of the pain using a pain assessment tool, it is important to determine certain characteristics of the pain. What is the location and quality of the pain? Ask patients how the pain limits them. What prior treatments have been tried and failed? What has worked the best? What treatment/coping strategies are they using now? Have they had any intolerable adverse effects from specific treatments? Reliable predictors of treatment response require further definition,¹⁷ but a successful trial of a given analgesic in the past is often a good indicator of what might work again.

Step 2. Review the patient’s problem list

Use of multiple medications. Polypharmacy—with 5 or more being a typical threshold criterion—is common in people ages 65 and older and frequently complicates the pharmacologic management of chronic pain.^16,18 Complications most often occur as a result of drug-drug interactions.

Multiple coexisting chronic conditions. Multimorbidity is common in older adults with chronic pain. Consider co-occurring diabetes, hypertension, and osteoporosis when initiating any trial of a pain medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in treating pain syndromes, but their use can be hazardous in older individuals, particularly those with coexisting hypertension, cardiovascular disease, history of peptic ulcer disease or gastropathy, or impaired renal function. NSAID use has been implicated as a cause of approximately one-quarter of all hospitalizations related to drug adverse effects among adults over age 65.¹

The geriatric syndrome of frailty is defined by deficits in physiologic reserve and decreased resistance to multiple stressors.¹⁹ Risk of fracture is a particular concern of clinicians, older patients, and their caregivers. Opioids are the analgesic medications most often associated with increased fracture risk. In a recent analysis of Medicare claims data, opioid users were found to have a significantly increased fracture risk compared with users of nonselective NSAIDs.²⁰ Mechanisms underlying this association include opioid-associated cognitive dysfunction and worsening gait/balance function.

Recommendations. Obtain a full list of the patient’s medications, including all OTC and complementary preparations. Also consider chronic kidney problems, liver disease, movement disorders, and neurologic problems when selecting a pharmacologic agent. Consider what chronic conditions might be made worse by an analgesic trial or would operate as a contraindication to starting a specific pain medication. Establish which medications or comorbidities might modify your treatment choices.

Step 3. Establish the patient’s treatment goals

We recommend shared decision-making when planning treatment and monitoring outcomes for older adults with chronic pain. Use your patient’s reports of the experience of pain— including pain intensity and how pain affects daily functioning¹ —and identify his or her treatment goals, which might differ from yours. You may be aiming for the best pain relief possible, but your patient might be focused on practical issues such as increased mobility or ability to socialize. By talking openly, you can reach consensus and agree upon realistic treatment goals.

This approach can improve patients’ outcomes and satisfaction with treatment; it also has been shown to improve physician satisfaction when treating patients with chronic pain.²¹ In a recent qualitative study, older individuals varied in how much they wanted to participate in making decisions and being a “source of control” in their pain treatment. ²² Some patients—particularly those ages 80 and older—prefer to have their physicians make treatment decisions for them, whereas others embrace active participation. Regardless of how much older individuals wish to share in treatment decisions, they all value being listened to and understood by their physicians.²¹

Recommendations. The patient’s goals and expectations for treatment may or may not be the same as yours. Before starting a medication trial, address potential unrealistic expectations such as complete relief of pain or a belief that treatment is not likely to help. Come to a mutual decision as to what constitutes the most important outcomes, and you will then be able to monitor and assess treatment success.

Step 4. Identify barriers to initiating and adhering to therapy

Cognitive impairment is a strong risk factor for undertreatment of pain. It can lead to underreporting of pain by patients or difficulty for clinicians in assessing treatment response from those who are unable to communicate pain effectively. A study of nursing home residents found that only 56% of those with cognitive impairment received pain medications, compared with 80% of those with intact cognition.²³ Older patients with cognitive deficits and memory loss also may take analgesic medications inappropriately or forget when/if they took them, increasing the risk of undertreatment or overdosing.

Sensory impairment. Patients with visual deficits may have difficulty reading prescription bottle labels and information sheets. Those with auditory deficits may have trouble hearing, communicating, and understanding treatment instructions during a busy clinical encounter.

Sociodemographic factors. Many older adults live alone and have limited social support to encourage medication adherence.²⁴ Some have significant caregiving responsibilities of their own (such as a spouse in poor health), which can lead to stress and inconsistent use of prescribed medications.²⁵ Some older adults can’t afford the costs of certain pain medications and may take less than the prescribed amount.

Many older adults lack the necessary skills to read and process basic health care information, including understanding pill bottle instructions, information that appears in patient handouts, and clinicians’ instructions about possible adverse effects.^26,27 Low health literacy can lead to problems with medication adherence (taking too much or too little of an analgesic medication) and associated complications.

Health beliefs. Many older adults believe chronic pain is a natural part of aging; in one study, this was true of 61% of approximately 700 primary care patients with osteoarthritis pain.²⁸ Some older adults believe pain only gets worse over time,²⁸ and others believe treatment for pain is not likely to provide any meaningful benefit.^29,30 Beliefs such as these can lead to stoicism or acceptance of the status quo.³¹

Older adults also may endorse beliefs about pain medications that are likely to decrease their willingness to engage in, or adhere to, recommended pharmacologic interventions. Some use pain medicines sparingly because they fear addiction or dependence.^32,33 Caregivers—often a spouse or adult child—also may express fears about the possibility of addiction.³² Finally, some older adults believe that using prescription analgesic medications invariably results in adverse effects;³² those who endorse this belief report minimizing medication use except when the pain is “very bad.”³⁴

Recommendations. Elicit concerns patients may have about using analgesic medications and discuss them openly. Although not all barriers (such as economic issues) are modifiable, most (such as beliefs that pain medications are addictive) can be successfully addressed through patient education.

If other social support, such as a family member or caregiver in the home, could positively affect analgesic engagement/adherence, include these facilitators when discussing treatment decisions and in monitoring for medication effectiveness and adverse effects.

Step 5. Start low and go slow when initiating analgesia

Advancing age is associated with increased sensitivity to the anticholinergic effects of many commonly prescribed and OTC medications, including NSAIDs and opioids.³⁵ Increasing the anticholinergic load can lead to cognitive impairments, including confusion, which can be particularly troublesome for older adults.¹

Changes in pharmacokinetics (what the body does to the drug in terms of altering absorption, distribution, metabolism and excretion) and pharmacodynamics (what the drug does to the body in the form of adverse effects) occur as a function of advancing age. ¹ Body fat increases by 20% to 40% on average, which increases the volume of distribution for fat-soluble medications.¹⁶ Hepatic and renal clearance decrease, leading to an increased half-life and decreased excretion of medications cleared by the liver or kidneys. Age-associated changes in gastrointestinal (GI) absorption and function include slower GI transit times and the possibility of increased opioid-related constipation from dysmotility problems.¹

As a result of these physiologic changes, advancing age is associated with a greater incidence of drug-related adverse effects. Even so, individuals within the older population are highly heterogeneous, and no geriatric-specific dosing guidelines exist for prescribing pain medications to older adults.

Recommendations. We recommend the adage “start low and go slow” when initiating an analgesic trial for an older patient with chronic pain. This does not mean you should “start low and stay low,” which can contribute to undertreatment.³⁶ If treatment goals are not being met and the patient is tolerating the therapy, advancing the dose is reasonable before moving on to another intervention.

Step 6. Assess for effects and outcomes outside the office

Adverse effects are a primary reason older adults discontinue an analgesic trial.³⁷ Make certain the patient (or caregiver, as appropriate) understands what adverse effects might occur, and create a plan to address them if they do.

Recommendations. Because many older people are reluctant to communicate with their physicians outside of an office visit, establish how often and when communication should occur. Telephone calls and/or e-mail are practical tools for patients to communicate questions or concerns to you, and you can enhance treatment outcomes with timely replies. In the near future, mobile health technologies may play a key role in monitoring for adverse effects and communicating positive treatment outcomes.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams & Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.

CASE CONTINUED

The patient continued to feel sick and reported having three to four loose bowel movements per day and mild abdominal pain. His cough and dyspnea persisted.

He had not had contact with anyone who was ill, denied being exposed to animals or insects, and had not consumed unpasteurized dairy products; he recalled having cleaned his military-issue uniforms and equipment 2 to 3 weeks before the symptoms began. He called a military physician to get advice on what else could be causing his symptoms. This physician recommended tests based on potential exposures in Iraq. Tests for brucellosis, visceral leishmaniasis, and Q fever were ordered.

Over the next several days, he began to feel better, and at 3 to 4 weeks after the onset of his symptoms, he felt that he had returned to normal. All tests were negative.

TESTING FOR ATYPICAL PATHOGENS

2. Which of the following would be the most readily available method to confirm the diagnosis?

• Culture
• Polymerase chain reaction (PCR) testing
• Histopathologic testing
• Serologic testing

Testing for atypical pathogens was reasonable in this patient. In addition to an evaluation for parasitic causes of persistent and chronic diarrhea, an evaluation for Q fever, brucellosis, and visceral leishmaniasis via serologic testing was warranted. A variety of tests exist for all of these infections, but serologic tests are the most readily available.

Leishmaniasis testing

Visceral leishmaniasis was traditionally diagnosed by visualizing organisms in splenic or bone marrow aspirates,²⁸ but now serologic tests are available through commercial and public health laboratories such as the CDC. Immunochromatographic tests using recombinant k39 antigen are highly sensitive and specific and have been used in military cases.^29,30

Brucellosis testing

Brucella can be cultured from blood or tissue samples. The laboratory must be alerted, as special media can be used to increase the yield and precautions must be taken to prevent laboratory-acquired infection. Serologic testing is the method most commonly used for diagnosis.³¹

Q fever testing

Q fever can be diagnosed with serologic testing during its acute and convalescent phases.

PCR testing of blood is useful for diagnosing acute disease and is positive before serologic conversion, thus allowing rapid diagnosis and treatment.³² The Joint Biological Agent Identification and Diagnostic System (JBAIDS) PCR platform was studied in a Combat Support Hospital in Iraq for making the rapid diagnosis of Q fever and has since been approved by the US Food and Drug Administration for military use.³³

Culture is beyond the scope of most clinical laboratories and requires specialized cell culture or egg yolk media. In tissue, usually liver tissue obtained in an effort to evaluate hepatitis, the histologic finding of “doughnut” granulomas, or fibrin-encased granulomas, can be suggestive of C burnetii but may be nonspecific and seen with other infections.^23,34

Serologic testing with an immunofluorescence assay (IFA) remains the most common method of diagnosis. It is based on the detection of immunoglobulin G (IgG) and IgM responses against phase I and phase II antigens of C burnetii. After initial infection, the organism displays phase I antigens and is highly infectious. When grown in culture, the organism undergoes phase shifting to a less infectious form with predominantly phase II antigens. Paradoxically, after initial infection in humans, antibody response against phase II antigens is seen first, whereas in chronic infection, a phase I antibody response dominates.^26,35 Phase II antibodies appear around week 2, and 90% of samples from infected people are positive by week 3. A fourfold rise in titer between the acute-phase and convalescent-phase samples confirms the diagnosis.³⁵

A number of serologic assays are available worldwide, but they have different methods and cutoff values, so questions have arisen about the equivalence of the results.^14,36 Serologic cutoffs have been defined in Europe, where most cases of Q fever have been reported.³⁷

CHRONIC Q FEVER

3. Which of the following would be the most likely chronic manifestation of Q fever?

• Pneumonia
• Hepatitis
• Endocarditis
• Chronic fatigue
• Osteomyelitis

Chronic syndromes can develop years to months after untreated or inadequately treated infection and can be serious. Chronic infection can also result after a clinically silent initial infection.^26,38 Culture-negative endocarditis, which occurs in fewer than 1% of patients diagnosed with acute infection, is the most common chronic manifestation (Table 1). Patients with underlying valvular disease, malignancy, or immunosuppression are at greater risk.^38–40

Challenges and controversies

The diagnosis of chronic Q fever remains challenging. Traditionally, elevated phase I IgG titers were considered highly predictive of chronic disease. A cutoff of 1:800 was set, based on retrospective data from chronic cases in Europe, but its generalizability to different assays and patient populations has been unclear. ^14,36,37 Recent reviews and prospective analysis with serial serologic studies in the Dutch outbreak and other sources suggest the positive predictive value (PPV) of phase I IgG titers greater than 1:800 to be lower than previously estimated, largely due to widespread testing and resultant increased seroprevalence assessments. It has been suggested the cutoff be raised to 1:1,600, which still only carries a 59% positive predictive value.^41,42

Chronic fatigue due to Q fever remains a controversial topic and has only been described in Europe, Asia, and Australia. A direct link has yet to be established.⁴³ Additional research is needed, but small studies of prolonged antibiotic treatment have not shown benefit in these cases.⁴⁴

CASE CONTINUED

This patient did well. During a routine physical while enrolled at the Army War College in Carlisle, PA, 6 months after the original presentation, he mentioned his illness to the physician, who then repeated testing for Q fever; the test was positive (Table 2). Subsequently, serum samples from before and after his deployment were tested along with another convalescent-phase sample, and the results demonstrated Q fever seroconversion. He was well and had no physical complaints. He had no heart murmur, and a complete blood count and tests of liver enzymes and inflammatory markers were normal.

TREATMENT AND PREVENTION OF Q FEVER

4. Which of the following treatments would be appropriate, given his diagnosis of Q fever?

• Doxycycline (Vibramycin) 100 mg twice daily for 14 days
• Levofloxacin (Levaquin) 500 mg daily for 5 days
• Doxycycline 100 mg twice daily for 14 days and hydroxychloroquine (Plaquenil) 200 mg three times per day for 18 months
• No treatment

The treatment goals in Q fever are to hasten the resolution of symptoms and to prevent chronic disease. Generally, if there are no clinical findings or symptoms, treatment is not indicated. If the patient has symptoms, early treatment is preferred, but a response may be seen even when there is a delay in diagnosis.

Doxycycline 100 mg twice a day for 14 days is the treatment of choice. In addition, quinolones have in vitro activity,⁴⁵ and a recent study suggests moxifloxacin (Avelox) may be the preferred antibiotic for those who cannot tolerate doxycycline.⁴⁶ In pregnant women and in children, macrolides and trimethoprim-sulfamethoxazole (Bactrim) are preferred.^47,48

Treatment of chronic Q fever, in particular endocarditis, warrants more intensive therapy. A retrospective review of treated cases of endocarditis suggested that monotherapy with doxycycline often failed, and combination therapy with hydroxychloroquine has been advocated based on in vivo and in vitro experience.⁴⁹

PREVENTING LONG-TERM SEQUELAE OF CHRONIC Q FEVER

5. At this point, what is the next step in the management of this patient?

• No further follow-up is indicated
• Transthoracic echocardiography (TTE)
• Repeat Q fever serologic testing in 3 to 6 months
• Whole-blood PCR testing and transesophageal echocardiography (TEE)

Long-term follow-up of patients with Q fever has been advocated to monitor for the development of chronic Q fever, but recent studies question the previously devised algorithms.⁵⁰

The data the algorithms were based on suggested that preexisting valvular heart disease could be associated with up to a 39% risk of endocarditis, and a two-step approach was devised to prevent and identify early chronic infection.^51,52 Patients with Q fever would undergo TTE at baseline, and if the findings were abnormal (including mild regurgitation), then 12 months of prophylactic treatment with hydroxychloroquine and doxycycline was recommended. If TTE was normal, serial serologic testing every 3 months was recommended. If the anti-phase I IgG titer was greater than 1:800 at any point, TEE and a whole-blood PCR assay were recommended to evaluate for endocarditis.⁵¹

These recommendations were based on data from the French National Reference Center and had not been prospectively evaluated. The 2007–2008 Dutch outbreak provided a large cohort of Q fever cases. After initial screening with TTE and serologic follow-up, 59% of patients were noted to have mild valvular abnormalities, and many had phase I IgG levels greater than 1:800 during follow-up despite being clinically free of disease. The Dutch subsequently stopped screening with TTE as part of routine follow-up and elected to follow patients clinically.

Similar findings have been noted from case follow-up in France and Taiwan, also supporting using serologic cutoffs alone in determining the need for evaluation (with TEE) or treatment of chronic disease.^53,54 The usefulness of serologic testing every 3 months has also been questioned, and some have advocated extending the interval, especially since less emphasis is being placed on the results in favor of more practical clinical follow-up.³⁹

One such clinical approach at follow-up is presented in Figure 1. TTE should be reserved for patients with known valvular disease or a clear murmur. Those with underlying valvular disease and acute Q fever should be managed on an individual basis by a specialist in infectious disease, and antibiotic prophylaxis should be considered. Patients without underlying disease should have regular follow-up examinations and serologic testing every 6 months, and clinical symptoms should guide further testing (eg, with TEE and PCR testing) for chronic disease.

In this patient, phase I and II antibody titers were notably elevated (in TABLE 2, phase I titers > 1:800 and 1:1600 cutoffs). Such high titers have been common in military cases from Iraq and Afghanistan, and to date no cases of endocarditis have been diagnosed despite close follow-up. Most cases in military personnel are in relatively young patients who lack risk factors for endocarditis. Based on emerging data from large overseas outbreaks and the potential toxicity of intensive preemptive dual-antimicrobial therapy, an approach of close follow-up was taken.

PRIMARY PREVENTION OF Q FEVER

Prevention of Q fever remains a challenge, as the organism is highly persistent in the environment. An effective licensed vaccine exists in Australia under the brand name Q-Vax, but no approved vaccine is currently available in the United States.⁵⁵

THE PATIENT’S COURSE

The patient returned for follow-up about 1 year after his first presentation. He noted some ongoing fatigue but attributed this to his course work, and he said he otherwise felt well. He exercises regularly, with no shortness of breath, fevers, chills, or weight loss. He continued to have elevated Q fever titers. Because he had no symptoms, no heart murmur, and normal inflammatory markers, he had no further workup and continued to be followed with serial serologic testing and examinations.