The Journal of Family Practice

I’ve always thought it was interesting that the first cases of COVID-19 were reported to the World Health Organization on December 31, 2019.¹ How close we came to having COVID-20! On January 31, 2020, the US Department of Health and Human Services declared a national public health emergency due to COVID-19, and it’s been in effect ever since.

As COVID and our knowledge about it changed, we rewrote policies dozens of times, and each time the staff retrained in a hurry.

A national public health emergency allows the Department of Health and Human Services to access and designate funds to diagnose, treat, and prevent disease in response to the emergency. The declaration also facilitates the Centers for Disease Control and Prevention response to an infectious disease emergency. There are provisions for modifications to Medicare, Medicaid, and the Children’s Health Insurance Program so clinicians can continue seeing patients and be reimbursed for doing so, even in a situation in which the emergency disrupts usual reporting and documentation requirements. The declaration is essentially a shortcut through the typical bureaucracy that too often gums up the practice of medicine²; it allows for the rapid deployment of funds and personnel to a community affected by an emergency.

Unprecedented change. In the early days, plastic partitions were erected between patients in the hospital, and the scarce supply of N-95 masks was stored in paper bags and baked at low temperatures in ovens overnight.

My hospital enacted its incident command response procedures, just as we did the day our community experienced a mass shooting—except incident command stayed open for months. We had to adapt quickly. My office never closed to in-­person visits; we decided that we took care of too many people who did not have other access to care to make closing practical. My practice partners and I spent a Friday afternoon in March 2020 writing policies. A policy for our residency practice. A policy for how to see patients who might have COVID. A policy for how to cover the residents and faculty when we inevitably got sick. A policy for how to do telehealth visits. By the following Monday, when the office reopened, we had already trained the staff on the new policies, and we were ready to implement them with our patients.

As COVID and our knowledge about it changed, we rewrote those policies dozens of times, and each time the staff retrained in a hurry. We all learned so much so quickly. So as the official public health emergency comes to an end, there are things that I think I will take from it, and things that I wish all of medicine could take from it too.

We adapted as a team. I will never forget the stress of the early days of the emergency, when the patient volume was overwhelming and the death rate was staggering. But shining through those dark times were wonderful moments of connection with the teams with which I worked. I think about the residents whose training shifted suddenly to full-time ­COVID, the nurses who learned new things every weekend for so many months, and everyone who went out on a limb to do the right thing.

We provided care without bureaucracy. I wish medicine could leave the bureaucracy behind along with the emergency. It was so much easier to practice medicine when we knew that the testing and treatment were covered, without “we’ll see” or “it depends on your insurance.” Telehealth is probably here to stay, thanks to widespread uptake by patients and clinicians alike during the pandemic. My wish is that we can make it as easy as possible to use going forward, instead of choosing to return to a more restricted and difficult path.^3,4

Family physicians have much to be proud of. We can look back on the COVID-19 public health emergency as a time when we absorbed a huge amount of rapidly changing information and showed our adaptability to a frightening and uncertain environment. We are not returning to the office, as so many Americans are these days, because we never left the many settings where family physicians practice. We remained at work during the emergency and we took care of our patients.

When the next emergency is declared—whether it be national or local—we will once again be there for our patients.

I’ve always thought it was interesting that the first cases of COVID-19 were reported to the World Health Organization on December 31, 2019.¹ How close we came to having COVID-20! On January 31, 2020, the US Department of Health and Human Services declared a national public health emergency due to COVID-19, and it’s been in effect ever since.

As COVID and our knowledge about it changed, we rewrote policies dozens of times, and each time the staff retrained in a hurry.

A national public health emergency allows the Department of Health and Human Services to access and designate funds to diagnose, treat, and prevent disease in response to the emergency. The declaration also facilitates the Centers for Disease Control and Prevention response to an infectious disease emergency. There are provisions for modifications to Medicare, Medicaid, and the Children’s Health Insurance Program so clinicians can continue seeing patients and be reimbursed for doing so, even in a situation in which the emergency disrupts usual reporting and documentation requirements. The declaration is essentially a shortcut through the typical bureaucracy that too often gums up the practice of medicine²; it allows for the rapid deployment of funds and personnel to a community affected by an emergency.

Unprecedented change. In the early days, plastic partitions were erected between patients in the hospital, and the scarce supply of N-95 masks was stored in paper bags and baked at low temperatures in ovens overnight.

My hospital enacted its incident command response procedures, just as we did the day our community experienced a mass shooting—except incident command stayed open for months. We had to adapt quickly. My office never closed to in-­person visits; we decided that we took care of too many people who did not have other access to care to make closing practical. My practice partners and I spent a Friday afternoon in March 2020 writing policies. A policy for our residency practice. A policy for how to see patients who might have COVID. A policy for how to cover the residents and faculty when we inevitably got sick. A policy for how to do telehealth visits. By the following Monday, when the office reopened, we had already trained the staff on the new policies, and we were ready to implement them with our patients.

As COVID and our knowledge about it changed, we rewrote those policies dozens of times, and each time the staff retrained in a hurry. We all learned so much so quickly. So as the official public health emergency comes to an end, there are things that I think I will take from it, and things that I wish all of medicine could take from it too.

We adapted as a team. I will never forget the stress of the early days of the emergency, when the patient volume was overwhelming and the death rate was staggering. But shining through those dark times were wonderful moments of connection with the teams with which I worked. I think about the residents whose training shifted suddenly to full-time ­COVID, the nurses who learned new things every weekend for so many months, and everyone who went out on a limb to do the right thing.

We provided care without bureaucracy. I wish medicine could leave the bureaucracy behind along with the emergency. It was so much easier to practice medicine when we knew that the testing and treatment were covered, without “we’ll see” or “it depends on your insurance.” Telehealth is probably here to stay, thanks to widespread uptake by patients and clinicians alike during the pandemic. My wish is that we can make it as easy as possible to use going forward, instead of choosing to return to a more restricted and difficult path.^3,4

Family physicians have much to be proud of. We can look back on the COVID-19 public health emergency as a time when we absorbed a huge amount of rapidly changing information and showed our adaptability to a frightening and uncertain environment. We are not returning to the office, as so many Americans are these days, because we never left the many settings where family physicians practice. We remained at work during the emergency and we took care of our patients.

When the next emergency is declared—whether it be national or local—we will once again be there for our patients.

I’ve always thought it was interesting that the first cases of COVID-19 were reported to the World Health Organization on December 31, 2019.¹ How close we came to having COVID-20! On January 31, 2020, the US Department of Health and Human Services declared a national public health emergency due to COVID-19, and it’s been in effect ever since.

As COVID and our knowledge about it changed, we rewrote policies dozens of times, and each time the staff retrained in a hurry.

A national public health emergency allows the Department of Health and Human Services to access and designate funds to diagnose, treat, and prevent disease in response to the emergency. The declaration also facilitates the Centers for Disease Control and Prevention response to an infectious disease emergency. There are provisions for modifications to Medicare, Medicaid, and the Children’s Health Insurance Program so clinicians can continue seeing patients and be reimbursed for doing so, even in a situation in which the emergency disrupts usual reporting and documentation requirements. The declaration is essentially a shortcut through the typical bureaucracy that too often gums up the practice of medicine²; it allows for the rapid deployment of funds and personnel to a community affected by an emergency.

Unprecedented change. In the early days, plastic partitions were erected between patients in the hospital, and the scarce supply of N-95 masks was stored in paper bags and baked at low temperatures in ovens overnight.

My hospital enacted its incident command response procedures, just as we did the day our community experienced a mass shooting—except incident command stayed open for months. We had to adapt quickly. My office never closed to in-­person visits; we decided that we took care of too many people who did not have other access to care to make closing practical. My practice partners and I spent a Friday afternoon in March 2020 writing policies. A policy for our residency practice. A policy for how to see patients who might have COVID. A policy for how to cover the residents and faculty when we inevitably got sick. A policy for how to do telehealth visits. By the following Monday, when the office reopened, we had already trained the staff on the new policies, and we were ready to implement them with our patients.

As COVID and our knowledge about it changed, we rewrote those policies dozens of times, and each time the staff retrained in a hurry. We all learned so much so quickly. So as the official public health emergency comes to an end, there are things that I think I will take from it, and things that I wish all of medicine could take from it too.

We adapted as a team. I will never forget the stress of the early days of the emergency, when the patient volume was overwhelming and the death rate was staggering. But shining through those dark times were wonderful moments of connection with the teams with which I worked. I think about the residents whose training shifted suddenly to full-time ­COVID, the nurses who learned new things every weekend for so many months, and everyone who went out on a limb to do the right thing.

We provided care without bureaucracy. I wish medicine could leave the bureaucracy behind along with the emergency. It was so much easier to practice medicine when we knew that the testing and treatment were covered, without “we’ll see” or “it depends on your insurance.” Telehealth is probably here to stay, thanks to widespread uptake by patients and clinicians alike during the pandemic. My wish is that we can make it as easy as possible to use going forward, instead of choosing to return to a more restricted and difficult path.^3,4

Family physicians have much to be proud of. We can look back on the COVID-19 public health emergency as a time when we absorbed a huge amount of rapidly changing information and showed our adaptability to a frightening and uncertain environment. We are not returning to the office, as so many Americans are these days, because we never left the many settings where family physicians practice. We remained at work during the emergency and we took care of our patients.

When the next emergency is declared—whether it be national or local—we will once again be there for our patients.

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ­ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

Copyright KO Studios

Much of the persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVDby ascertaining LDL-C

The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL), estimation of LDL-C is invalid.

The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very-low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC – HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴

National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵

Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ­ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

Continue to: Apolipoprotein B

Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the ­LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴

Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

Continue to: How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention:Stratification by age

40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force ­(USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

Continue to: In adults at borderline risk...

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify ­moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴

Continue to: > 75 years, without ASCVD

> 75 years, without ASCVD. In this group, the ­benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

A meta-analysis of 28 trials demonstrated that people > 75 years of age had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C.

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ­ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

Base a recommendation for preventive intervention, such as lipidlowering therapy, on the estimated 10-year risk for ASCVD.

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/­kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy

Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

Ezetimibe, a selective cholesterol-­absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴

PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23

Continue to: Inclisiran

Inclisiran, an injectable small-­interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴

Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28

Bempedoic acid is a small-molecule ­inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-­intolerant patients, bempedoic acid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰

Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL) and TG (42 mg/dL).^31,32

Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; ­HDL-C < 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

At-risk patients should follow a dietary pattern that emphasizes vegetables, fruits, and whole grains and limits sweets, sugarsweetened beverages, and red meat.

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴

CORRESPONDENCE
Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ­ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

Copyright KO Studios

Much of the persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVDby ascertaining LDL-C

The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL), estimation of LDL-C is invalid.

The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very-low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC – HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴

National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵

Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ­ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

Continue to: Apolipoprotein B

Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the ­LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴

Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

Continue to: How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention:Stratification by age

40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force ­(USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

Continue to: In adults at borderline risk...

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify ­moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴

Continue to: > 75 years, without ASCVD

> 75 years, without ASCVD. In this group, the ­benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

A meta-analysis of 28 trials demonstrated that people > 75 years of age had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C.

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ­ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

Base a recommendation for preventive intervention, such as lipidlowering therapy, on the estimated 10-year risk for ASCVD.

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/­kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy

Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

Ezetimibe, a selective cholesterol-­absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴

PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23

Continue to: Inclisiran

Inclisiran, an injectable small-­interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴

Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28

Bempedoic acid is a small-molecule ­inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-­intolerant patients, bempedoic acid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰

Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL) and TG (42 mg/dL).^31,32

Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; ­HDL-C < 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

At-risk patients should follow a dietary pattern that emphasizes vegetables, fruits, and whole grains and limits sweets, sugarsweetened beverages, and red meat.

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴

CORRESPONDENCE
Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ­ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

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Much of the persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVDby ascertaining LDL-C

The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL), estimation of LDL-C is invalid.

The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very-low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC – HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴

National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵

Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ­ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

Continue to: Apolipoprotein B

Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the ­LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴

Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

Continue to: How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention:Stratification by age

40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force ­(USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

Continue to: In adults at borderline risk...

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify ­moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴

Continue to: > 75 years, without ASCVD

> 75 years, without ASCVD. In this group, the ­benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

A meta-analysis of 28 trials demonstrated that people > 75 years of age had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C.

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ­ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

Base a recommendation for preventive intervention, such as lipidlowering therapy, on the estimated 10-year risk for ASCVD.

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/­kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy

Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

Ezetimibe, a selective cholesterol-­absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴

PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23

Continue to: Inclisiran

Inclisiran, an injectable small-­interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴

Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28

Bempedoic acid is a small-molecule ­inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-­intolerant patients, bempedoic acid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰

Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL) and TG (42 mg/dL).^31,32

Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; ­HDL-C < 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

At-risk patients should follow a dietary pattern that emphasizes vegetables, fruits, and whole grains and limits sweets, sugarsweetened beverages, and red meat.

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴

CORRESPONDENCE
Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

The patient’s recurrent indurated nodules under her arms and other intertriginous areas, often draining pus, are consistent with a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic inflammatory and suppurative skin condition that primarily involves the sweat glands.¹ The most commonly affected sites are intertriginous areas that include the axillae, groin, and perianal and inframammary regions.² Prevalence of this disorder ranges from 0.05% to 4.1% of the population with an onset from puberty to adulthood, usually at around 40 years of age.³ Its incidence is twice as high in women as men and is more common in Black individuals.^4,5

While its pathogenesis is not fully understood, it’s believed that excess proliferation of keratinocytes contributes to occlusion, leading to plugging of hair follicle ducts. Hormones, smoking, and obesity may contribute to and exacerbate HS. Intertriginous areas are prone to friction, leading to inflammation and further clogging.

The inflammation evolves into a chronic foreign body-type granulomatous inflammation with the potential for rupture, tunneling, and draining sinuses, which, although malodorous, are sterile, separating HS from an infected abscess.⁵ The result is thick, dense, scarred tissue.

The diagnosis is clinical in nature, with the history and physical exam distinguishing it from other skin disorders. In addition to the recurring physical pain, there is the emotional distress and self-consciousness about the drainage, odor, and scarring. This particular patient said that she avoided wearing sleeveless shirts due to the lesions’ appearance.

Treatment is multifactorial. Smoking and obesity are contributory factors, so smoking cessation and weight loss are recommended. For very mild HS, topical clindamycin 1% twice daily may suffice, but usually, due to the amount of inflammation, oral antibiotics are the initial therapy. (The use of antibiotics is for their anti-inflammatory component, as the nodules and unruptured tracts are sterile.)

Doxycycline 100 mg twice daily is the usual starting systemic antibiotic. In more severe or resistant cases, a combination of clindamycin and rifampin 300 mg each twice daily is used. (Worth noting: Rifampin interacts with oral contraceptives and many of these patients are women of reproductive age.) Treatment length is usually long (10 to 12 weeks) and recurrence is common.³

Spironolactone 100 mg daily and metformin 1000 mg extended release daily, which reduces insulin resistance, may be helpful. Intralesional injections of 10 mg/mL of triamcinolone in sterile saline can relieve the painful inflamed tracts. Referral for biologic agents, including infliximab, may be needed in severe cases that do not respond to other measures. Although invasive, wide debridement of the diseased tissue can reduce the disease burden.⁶

This particular patient said that she’d stopped smoking 3 years earlier and would work on losing weight. She was prescribed topical clindamycin 1% lotion twice daily along with oral clindamycin and rifampin dosed as above for 3 months. She declined metformin and intralesional injections. At a follow-up appointment 3 weeks later, she was pleased with the decrease in inflammation and had only 1 remaining tender area of fluctuance. She again declined injections and planned to continue on her oral and topical antibiotics.

‌

Photo courtesy of Daniel Stulberg, MD, FAAFP. Text courtesy of Derissa F. Raynold, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The patient’s recurrent indurated nodules under her arms and other intertriginous areas, often draining pus, are consistent with a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic inflammatory and suppurative skin condition that primarily involves the sweat glands.¹ The most commonly affected sites are intertriginous areas that include the axillae, groin, and perianal and inframammary regions.² Prevalence of this disorder ranges from 0.05% to 4.1% of the population with an onset from puberty to adulthood, usually at around 40 years of age.³ Its incidence is twice as high in women as men and is more common in Black individuals.^4,5

While its pathogenesis is not fully understood, it’s believed that excess proliferation of keratinocytes contributes to occlusion, leading to plugging of hair follicle ducts. Hormones, smoking, and obesity may contribute to and exacerbate HS. Intertriginous areas are prone to friction, leading to inflammation and further clogging.

The inflammation evolves into a chronic foreign body-type granulomatous inflammation with the potential for rupture, tunneling, and draining sinuses, which, although malodorous, are sterile, separating HS from an infected abscess.⁵ The result is thick, dense, scarred tissue.

The diagnosis is clinical in nature, with the history and physical exam distinguishing it from other skin disorders. In addition to the recurring physical pain, there is the emotional distress and self-consciousness about the drainage, odor, and scarring. This particular patient said that she avoided wearing sleeveless shirts due to the lesions’ appearance.

Treatment is multifactorial. Smoking and obesity are contributory factors, so smoking cessation and weight loss are recommended. For very mild HS, topical clindamycin 1% twice daily may suffice, but usually, due to the amount of inflammation, oral antibiotics are the initial therapy. (The use of antibiotics is for their anti-inflammatory component, as the nodules and unruptured tracts are sterile.)

Doxycycline 100 mg twice daily is the usual starting systemic antibiotic. In more severe or resistant cases, a combination of clindamycin and rifampin 300 mg each twice daily is used. (Worth noting: Rifampin interacts with oral contraceptives and many of these patients are women of reproductive age.) Treatment length is usually long (10 to 12 weeks) and recurrence is common.³

Spironolactone 100 mg daily and metformin 1000 mg extended release daily, which reduces insulin resistance, may be helpful. Intralesional injections of 10 mg/mL of triamcinolone in sterile saline can relieve the painful inflamed tracts. Referral for biologic agents, including infliximab, may be needed in severe cases that do not respond to other measures. Although invasive, wide debridement of the diseased tissue can reduce the disease burden.⁶

This particular patient said that she’d stopped smoking 3 years earlier and would work on losing weight. She was prescribed topical clindamycin 1% lotion twice daily along with oral clindamycin and rifampin dosed as above for 3 months. She declined metformin and intralesional injections. At a follow-up appointment 3 weeks later, she was pleased with the decrease in inflammation and had only 1 remaining tender area of fluctuance. She again declined injections and planned to continue on her oral and topical antibiotics.

‌

Photo courtesy of Daniel Stulberg, MD, FAAFP. Text courtesy of Derissa F. Raynold, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The patient’s recurrent indurated nodules under her arms and other intertriginous areas, often draining pus, are consistent with a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic inflammatory and suppurative skin condition that primarily involves the sweat glands.¹ The most commonly affected sites are intertriginous areas that include the axillae, groin, and perianal and inframammary regions.² Prevalence of this disorder ranges from 0.05% to 4.1% of the population with an onset from puberty to adulthood, usually at around 40 years of age.³ Its incidence is twice as high in women as men and is more common in Black individuals.^4,5

While its pathogenesis is not fully understood, it’s believed that excess proliferation of keratinocytes contributes to occlusion, leading to plugging of hair follicle ducts. Hormones, smoking, and obesity may contribute to and exacerbate HS. Intertriginous areas are prone to friction, leading to inflammation and further clogging.

The inflammation evolves into a chronic foreign body-type granulomatous inflammation with the potential for rupture, tunneling, and draining sinuses, which, although malodorous, are sterile, separating HS from an infected abscess.⁵ The result is thick, dense, scarred tissue.

The diagnosis is clinical in nature, with the history and physical exam distinguishing it from other skin disorders. In addition to the recurring physical pain, there is the emotional distress and self-consciousness about the drainage, odor, and scarring. This particular patient said that she avoided wearing sleeveless shirts due to the lesions’ appearance.

Treatment is multifactorial. Smoking and obesity are contributory factors, so smoking cessation and weight loss are recommended. For very mild HS, topical clindamycin 1% twice daily may suffice, but usually, due to the amount of inflammation, oral antibiotics are the initial therapy. (The use of antibiotics is for their anti-inflammatory component, as the nodules and unruptured tracts are sterile.)

Doxycycline 100 mg twice daily is the usual starting systemic antibiotic. In more severe or resistant cases, a combination of clindamycin and rifampin 300 mg each twice daily is used. (Worth noting: Rifampin interacts with oral contraceptives and many of these patients are women of reproductive age.) Treatment length is usually long (10 to 12 weeks) and recurrence is common.³

Spironolactone 100 mg daily and metformin 1000 mg extended release daily, which reduces insulin resistance, may be helpful. Intralesional injections of 10 mg/mL of triamcinolone in sterile saline can relieve the painful inflamed tracts. Referral for biologic agents, including infliximab, may be needed in severe cases that do not respond to other measures. Although invasive, wide debridement of the diseased tissue can reduce the disease burden.⁶

This particular patient said that she’d stopped smoking 3 years earlier and would work on losing weight. She was prescribed topical clindamycin 1% lotion twice daily along with oral clindamycin and rifampin dosed as above for 3 months. She declined metformin and intralesional injections. At a follow-up appointment 3 weeks later, she was pleased with the decrease in inflammation and had only 1 remaining tender area of fluctuance. She again declined injections and planned to continue on her oral and topical antibiotics.

‌

Photo courtesy of Daniel Stulberg, MD, FAAFP. Text courtesy of Derissa F. Raynold, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Biopsy revealed a lichenoid infiltrate in the upper dermis with thinning of the epidermis and a predominance of plasma cells. This finding, along with a red-orange, glossy lesion on the glans penis in an uncircumcised man is a classic presentation of Zoon balanitis.

Zoon balanitis is a chronic, idiopathic disorder that affects uncircumcised men who are middle-aged and older.¹ Although the exact pathogenesis is unknown, it is hypothesized to be the result of chronic irritation due to poor hygiene/urine retention with prepuce dysfunction. The classic clinical presentation is an asymptomatic, well-defined, orange-to-red glazed patch with symmetric small red “cayenne pepper” spots contained within the glans penis and/or prepuce. Often there are symmetric “kissing lesions” where a second lesion of similar morphology is apparent on the prepuce where it meets the glans penis. While this disorder is typically asymptomatic, it can be associated with itching and/or burning.

There are several other inflammatory disorders in the differential for Zoon balanitis (erosive lichen planus, lichen sclerosus, psoriasis), but the most important consideration is penile intraepithelial carcinoma, specifically erythroplasia of Queyrat. Erythroplasia of Queyrat can be difficult to distinguish clinically and often requires a biopsy. Zoon balanitis will show a plasma cell predominant lichenoid infiltrate, whereas erythroplasia of Queyrat will show squamous cell carcinoma in situ.

It is important to note that Zoon balanitis is a clinicopathologic diagnosis and that zoonoid inflammation on biopsy is not pathognomonic, as this can also be seen in other inflammatory and neoplastic conditions. It is, therefore, advisable to follow up with patients with Zoon balanitis to ensure that the lesion is resolving and/or not getting worse.

Improved hygiene measures are the mainstay of treatment; circumcision is also effective.² Both can help keep the glans clean and dry. In those with symptomatic disease, low-strength topical steroids including 1% hydrocortisone ointment or cream twice daily or topical calcineurin inhibitors (pimecrolimus 1% or tacrolimus 0.1%) twice daily can be used for symptom management.

Because this patient’s disease was asymptomatic, treatment was deferred. He was counseled to draw back the foreskin when urinating and to do the same while showering so that he could wash, then dry, the glans before returning the foreskin to its normal position. The patient is being monitored clinically.

‌

Photo courtesy of Drew Mitchell, MD. Text courtesy of Drew Mitchell, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Biopsy revealed a lichenoid infiltrate in the upper dermis with thinning of the epidermis and a predominance of plasma cells. This finding, along with a red-orange, glossy lesion on the glans penis in an uncircumcised man is a classic presentation of Zoon balanitis.

Zoon balanitis is a chronic, idiopathic disorder that affects uncircumcised men who are middle-aged and older.¹ Although the exact pathogenesis is unknown, it is hypothesized to be the result of chronic irritation due to poor hygiene/urine retention with prepuce dysfunction. The classic clinical presentation is an asymptomatic, well-defined, orange-to-red glazed patch with symmetric small red “cayenne pepper” spots contained within the glans penis and/or prepuce. Often there are symmetric “kissing lesions” where a second lesion of similar morphology is apparent on the prepuce where it meets the glans penis. While this disorder is typically asymptomatic, it can be associated with itching and/or burning.

There are several other inflammatory disorders in the differential for Zoon balanitis (erosive lichen planus, lichen sclerosus, psoriasis), but the most important consideration is penile intraepithelial carcinoma, specifically erythroplasia of Queyrat. Erythroplasia of Queyrat can be difficult to distinguish clinically and often requires a biopsy. Zoon balanitis will show a plasma cell predominant lichenoid infiltrate, whereas erythroplasia of Queyrat will show squamous cell carcinoma in situ.

It is important to note that Zoon balanitis is a clinicopathologic diagnosis and that zoonoid inflammation on biopsy is not pathognomonic, as this can also be seen in other inflammatory and neoplastic conditions. It is, therefore, advisable to follow up with patients with Zoon balanitis to ensure that the lesion is resolving and/or not getting worse.

Improved hygiene measures are the mainstay of treatment; circumcision is also effective.² Both can help keep the glans clean and dry. In those with symptomatic disease, low-strength topical steroids including 1% hydrocortisone ointment or cream twice daily or topical calcineurin inhibitors (pimecrolimus 1% or tacrolimus 0.1%) twice daily can be used for symptom management.

Because this patient’s disease was asymptomatic, treatment was deferred. He was counseled to draw back the foreskin when urinating and to do the same while showering so that he could wash, then dry, the glans before returning the foreskin to its normal position. The patient is being monitored clinically.

‌

Photo courtesy of Drew Mitchell, MD. Text courtesy of Drew Mitchell, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Biopsy revealed a lichenoid infiltrate in the upper dermis with thinning of the epidermis and a predominance of plasma cells. This finding, along with a red-orange, glossy lesion on the glans penis in an uncircumcised man is a classic presentation of Zoon balanitis.

Zoon balanitis is a chronic, idiopathic disorder that affects uncircumcised men who are middle-aged and older.¹ Although the exact pathogenesis is unknown, it is hypothesized to be the result of chronic irritation due to poor hygiene/urine retention with prepuce dysfunction. The classic clinical presentation is an asymptomatic, well-defined, orange-to-red glazed patch with symmetric small red “cayenne pepper” spots contained within the glans penis and/or prepuce. Often there are symmetric “kissing lesions” where a second lesion of similar morphology is apparent on the prepuce where it meets the glans penis. While this disorder is typically asymptomatic, it can be associated with itching and/or burning.

There are several other inflammatory disorders in the differential for Zoon balanitis (erosive lichen planus, lichen sclerosus, psoriasis), but the most important consideration is penile intraepithelial carcinoma, specifically erythroplasia of Queyrat. Erythroplasia of Queyrat can be difficult to distinguish clinically and often requires a biopsy. Zoon balanitis will show a plasma cell predominant lichenoid infiltrate, whereas erythroplasia of Queyrat will show squamous cell carcinoma in situ.

It is important to note that Zoon balanitis is a clinicopathologic diagnosis and that zoonoid inflammation on biopsy is not pathognomonic, as this can also be seen in other inflammatory and neoplastic conditions. It is, therefore, advisable to follow up with patients with Zoon balanitis to ensure that the lesion is resolving and/or not getting worse.

Improved hygiene measures are the mainstay of treatment; circumcision is also effective.² Both can help keep the glans clean and dry. In those with symptomatic disease, low-strength topical steroids including 1% hydrocortisone ointment or cream twice daily or topical calcineurin inhibitors (pimecrolimus 1% or tacrolimus 0.1%) twice daily can be used for symptom management.

Because this patient’s disease was asymptomatic, treatment was deferred. He was counseled to draw back the foreskin when urinating and to do the same while showering so that he could wash, then dry, the glans before returning the foreskin to its normal position. The patient is being monitored clinically.

‌

Photo courtesy of Drew Mitchell, MD. Text courtesy of Drew Mitchell, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

The US Preventive Services Task Force (USPSTF) recently published a draft recommendation on the use of folic acid before and during pregnancy to prevent fetal neural tube defects.¹ This reaffirmation of the 2017 recommendation states that all persons planning to or who could become pregnant should take a daily supplement of folic acid.^1,2 This is an “A” recommendation.

Neural tube defects are caused by a failure of the embryonic neural tube to close completely, which should occur in the first 28 days following fertilization. This is why folic acid is most effective if started at least 1 month before conception and continued for the first 2 to 3 months of pregnancy.

An estimated 3000 neural tube defects occur each year in the United States. Spina bifida, anencephaly, and encephalocele occur at respective rates of 3.9, 2.5, and 1.0 in 10,000 live births in the United States, which totals 7.4/10,000.³

Folic acid, if taken before and during pregnancy, can prevent about half of neural tube defects; if taken only during pregnancy, it prevents about one-third. If 50% of neural tube defects could be prevented with folic acid supplements, the number needed to treat (NNT) to prevent 1 case is about 3000.⁴

The case for supplementation. The recommended daily dose of folic acid is between 0.4 mg (400 μg) and 0.8 mg (800 μg), which is contained in many multivitamin products. Certain enriched cereal grain products in the United States have been fortified with folic acid for more than 2 decades, but it is unknown whether women in the United States are ingesting enough of these fortified foods to provide maximum prevention of neural tube defects. There are no known harms to mother or fetus from folic acid supplementation at recommended levels.

Room for improvement. Only 20% to 40% of people who are pregnant or trying to get pregnant, and 5% to 10% of people with an unplanned pregnancy, take folic acid supplements. Half of all pregnancies in the United States are unplanned.⁴ This leaves a lot of room for improvement in the prevention of neural tube defects.

An important recommendation, even if you don’t see the results. The NNT to prevent a case of neural tube defect is high; most family physicians providing perinatal care will not prevent a case during their career. And, as with most preventive interventions, we do not see the cases prevented. However, on a population-wide basis, if all women took folic acid as recommended, the number of severe birth defects prevented would be significant—making this simple recommendation worth mentioning to those of reproductive age.

The US Preventive Services Task Force (USPSTF) recently published a draft recommendation on the use of folic acid before and during pregnancy to prevent fetal neural tube defects.¹ This reaffirmation of the 2017 recommendation states that all persons planning to or who could become pregnant should take a daily supplement of folic acid.^1,2 This is an “A” recommendation.

Neural tube defects are caused by a failure of the embryonic neural tube to close completely, which should occur in the first 28 days following fertilization. This is why folic acid is most effective if started at least 1 month before conception and continued for the first 2 to 3 months of pregnancy.

An estimated 3000 neural tube defects occur each year in the United States. Spina bifida, anencephaly, and encephalocele occur at respective rates of 3.9, 2.5, and 1.0 in 10,000 live births in the United States, which totals 7.4/10,000.³

Folic acid, if taken before and during pregnancy, can prevent about half of neural tube defects; if taken only during pregnancy, it prevents about one-third. If 50% of neural tube defects could be prevented with folic acid supplements, the number needed to treat (NNT) to prevent 1 case is about 3000.⁴

The case for supplementation. The recommended daily dose of folic acid is between 0.4 mg (400 μg) and 0.8 mg (800 μg), which is contained in many multivitamin products. Certain enriched cereal grain products in the United States have been fortified with folic acid for more than 2 decades, but it is unknown whether women in the United States are ingesting enough of these fortified foods to provide maximum prevention of neural tube defects. There are no known harms to mother or fetus from folic acid supplementation at recommended levels.

Room for improvement. Only 20% to 40% of people who are pregnant or trying to get pregnant, and 5% to 10% of people with an unplanned pregnancy, take folic acid supplements. Half of all pregnancies in the United States are unplanned.⁴ This leaves a lot of room for improvement in the prevention of neural tube defects.

An important recommendation, even if you don’t see the results. The NNT to prevent a case of neural tube defect is high; most family physicians providing perinatal care will not prevent a case during their career. And, as with most preventive interventions, we do not see the cases prevented. However, on a population-wide basis, if all women took folic acid as recommended, the number of severe birth defects prevented would be significant—making this simple recommendation worth mentioning to those of reproductive age.

The US Preventive Services Task Force (USPSTF) recently published a draft recommendation on the use of folic acid before and during pregnancy to prevent fetal neural tube defects.¹ This reaffirmation of the 2017 recommendation states that all persons planning to or who could become pregnant should take a daily supplement of folic acid.^1,2 This is an “A” recommendation.

Neural tube defects are caused by a failure of the embryonic neural tube to close completely, which should occur in the first 28 days following fertilization. This is why folic acid is most effective if started at least 1 month before conception and continued for the first 2 to 3 months of pregnancy.

An estimated 3000 neural tube defects occur each year in the United States. Spina bifida, anencephaly, and encephalocele occur at respective rates of 3.9, 2.5, and 1.0 in 10,000 live births in the United States, which totals 7.4/10,000.³

Folic acid, if taken before and during pregnancy, can prevent about half of neural tube defects; if taken only during pregnancy, it prevents about one-third. If 50% of neural tube defects could be prevented with folic acid supplements, the number needed to treat (NNT) to prevent 1 case is about 3000.⁴

The case for supplementation. The recommended daily dose of folic acid is between 0.4 mg (400 μg) and 0.8 mg (800 μg), which is contained in many multivitamin products. Certain enriched cereal grain products in the United States have been fortified with folic acid for more than 2 decades, but it is unknown whether women in the United States are ingesting enough of these fortified foods to provide maximum prevention of neural tube defects. There are no known harms to mother or fetus from folic acid supplementation at recommended levels.

Room for improvement. Only 20% to 40% of people who are pregnant or trying to get pregnant, and 5% to 10% of people with an unplanned pregnancy, take folic acid supplements. Half of all pregnancies in the United States are unplanned.⁴ This leaves a lot of room for improvement in the prevention of neural tube defects.

An important recommendation, even if you don’t see the results. The NNT to prevent a case of neural tube defect is high; most family physicians providing perinatal care will not prevent a case during their career. And, as with most preventive interventions, we do not see the cases prevented. However, on a population-wide basis, if all women took folic acid as recommended, the number of severe birth defects prevented would be significant—making this simple recommendation worth mentioning to those of reproductive age.

Lab work was ordered and came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Patients also often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias.

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing. When performed, laboratory studies—including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis—are routinely normal. The differential diagnosis in this case included erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis.^1,2,4

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved, and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

‌

This case was adapted from: Cook JS, Angles A, Morley E. Urticaria and edema in a 2-year-old boy. J Fam Pract. 2021;70:353-355.

Photos courtesy of Jeffrey S. Cook, MD, FAAFP

Lab work was ordered and came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Patients also often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias.

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing. When performed, laboratory studies—including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis—are routinely normal. The differential diagnosis in this case included erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis.^1,2,4

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved, and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

‌

This case was adapted from: Cook JS, Angles A, Morley E. Urticaria and edema in a 2-year-old boy. J Fam Pract. 2021;70:353-355.

Photos courtesy of Jeffrey S. Cook, MD, FAAFP

Lab work was ordered and came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Patients also often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias.

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing. When performed, laboratory studies—including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis—are routinely normal. The differential diagnosis in this case included erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis.^1,2,4

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved, and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

‌

This case was adapted from: Cook JS, Angles A, Morley E. Urticaria and edema in a 2-year-old boy. J Fam Pract. 2021;70:353-355.

Photos courtesy of Jeffrey S. Cook, MD, FAAFP

This patient was given a diagnosis of bullous pemphigoid. Although there were a number of clues that pointed to this diagnosis, confirming that this was the case required 2 biopsies and a blood draw. (More on this in a bit.)

Although rare and potentially lethal, bullous pemphigoid is the most common autoimmune blistering disease in the elderly. Patients present with tense bullae over limited or widespread areas of the skin. The pathogenesis includes development of autoimmune antibodies that target important proteins (BP180 and BP230) that bind basal epidermal keratinocytes to the dermis. When weakened by inflammation at these sites, the skin delaminates at the dermal-epidermal junction, while the cells of the epidermis continue to bind to each other. This leads to itching, hive-like wheals, and tense fluid-filled bullae.

The differential diagnosis of an acute or semi-acute bullous disease includes bullous pemphigoid, IgA pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and Senear-Usher syndrome. In this case, the large tense bullae suggested bullous pemphigoid over the other diagnoses.

Initial diagnosis requires 2 biopsies be performed: One at the edge of a bulla for a standard pathologic exam to identify the skin level at which the bulla is forming, and another biopsy of skin near the site of inflammation (5-10 mm away) to be sent for direct immunofluorescence (DIF) in Michel’s medium or Zeus medium. In bullous pemphigoid, the separation is at the dermal-epidermal junction, and IgG and C3 are found in the DIF in the same location. There are a couple ways to differentiate this disorder from epidermolysis bullosa acquisita—a similar blistering disorder in which autoantibodies attack collagen at the dermal-epidermal junction. A common approach is to send a patient’s serum for indirect immunofluorescence. This is done because it is impossible to distinguish between the 2 clinically.

While bullous pemphigoid has historically been treated with high-dose prednisone, it is more common now to treat with whole-body topical clobetasol and oral doxycycline 100 mg twice a day to avoid the adverse effects of the prednisone. Other immunosuppressive options, such as mycophenolate mofetil and cyclosporine, can provide the potency of prednisone with a more favorable long-term safety profile. Rituximab infusions are another very powerful and durable option in refractory or severe cases.¹

This patient was treated with topical clobetasol and doxycycline 100 mg twice a day, but he had incomplete clearance after 2 to 3 weeks. At that point, mycophenolate mofetil was added to the regimen and was titrated up to 1000 mg twice daily. When clearance occurred, the clobetasol was discontinued and the mycophenolate mofetil was titrated down to 250 mg/d; the patient continues to maintain clearance at this dose. He continues on doxycycline 100 mg bid.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.