Leslie Cho, MD

Cardiac rehabilitation has a class 1 indication (ie, strong recommendation) after heart surgery, myocardial infarction, or coronary intervention, and for stable angina or peripheral artery disease. It has a class 2a indication (ie, moderate recommendation) for stable systolic heart failure. Yet it is still under­utilized despite its demonstrated benefits, endorsement by most recognized cardiovascular societies, and coverage by the US Centers for Medicare and Medicaid Services (CMS).

Here, we review cardiac rehabilitation—its benefits, appropriate indications, barriers to referral and enrollment, and efforts to increase its use.

EXERCISE: SLOW TO BE ADOPTED

In 1772, William Heberden (also remembered today for describing swelling of the distal interphalangeal joints in osteoarthritis) described¹ a patient with angina pectoris who “set himself a task of sawing wood for half an hour every day, and was nearly cured.”

Despite early clues, it would be some time before the medical community would recognize the benefits of exercise for cardiovascular health. Before the 1930s, immobilization and extended bedrest were encouraged for up to 6 weeks after a cardiovascular event, leading to significant deconditioning.² Things slowly began to change in the 1940s with Levine’s introduction of up-to-chair therapy,³ and short daily walks were introduced in the 1950s. Over time, the link between a sedentary lifestyle and cardiovascular disease was studied and led to greater investigation into the benefits of exercise, propelling us into the modern era.^4,5

CARDIAC REHABILITATION: COMPREHENSIVE RISK REDUCTION

The American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) defines cardiac rehabilitation as the provision of comprehensive long-term services involving medical evaluation, prescriptive exercise, cardiac risk-factor modification, education, counseling, and behavioral interventions.⁶ CMS defines it as a physician-supervised program that furnishes physician-prescribed exercise, cardiac risk-factor modification (including education, counseling, and behavioral intervention), psychosocial assessment, outcomes assessment, and other items and services.⁷

In general, most cardiac rehabilitation programs provide medically supervised exercise and patient education designed to improve cardiac health and functional status. Risk factors are targeted to reduce disability and rates of morbidity and mortality, to improve functional capacity, and to alleviate activity-related symptoms.

FROM HOSPITAL TO SELF-MAINTENANCE

Phase 1: Inpatient rehabilitation

Phase 1 typically takes place in the inpatient setting, often after open heart surgery (eg, coronary artery bypass grafting, valve repair or replacement, heart transplant), myocardial infarction, or percutaneous coronary intervention. This phase may last only a few days, especially in the current era of short hospital stays.

During phase 1, patients discuss their health situation and goals with their primary provider or cardiologist and receive education about recovery and cardiovascular risk factors. Early mobilization to prepare for discharge and to resume simple activities of daily living is emphasized. Depending on the institution, phase 1 exercise may involve simple ambulation on the ward or using equipment such as a stationary bike or treadmill.⁶ Phase 2 enrollment ideally is set up before discharge.

Phase 2: Limited-time outpatient rehabilitation

Phase 2 traditionally takes place in a hospital-based outpatient facility and consists of a physician-supervised multidisciplinary program. Growing evidence shows that home-based cardiac rehabilitation may be as effective as a medical facility-based program and should be an option for patients who have difficulty getting access to a traditional program.⁸

A phase 2 program takes a threefold approach, consisting of exercise, aggressive risk-factor modification, and education classes. A Cochrane review⁹ included programs that also incorporated behavioral modification and psychosocial support as a means of secondary prevention, underscoring the evolving definition of cardiac rehabilitation.

During the initial phase 2 visit, an individualized treatment plan is developed, incorporating an exercise prescription and realistic goals for secondary prevention. Sessions typically take place 3 times a week for up to 36 sessions; usually, options are available for less frequent weekly attendance for a longer period to achieve a full course. In some cases, patients may qualify for up to 72 sessions, particularly if they have not progressed as expected.

Exercise. As part of the initial evaluation, AACVPR guidelines⁶ suggest an exercise test­—eg, a symptom-limited exercise stress test, a 6-minute walk test, or use of a Rating of Perceived Exertion scale. Prescribed exercise generally targets moderate activity in the range of 50% to 70% of peak estimated functional capacity. In the appropriate clinical context, high-functioning patients can be offered high-intensity interval training instead of moderate exercise, as they confer similar benefits.¹⁰

Risk-factor reduction. Comprehensive risk-factor reduction can address smoking, hypertension, high cholesterol, diabetes, obesity, and diet, as well as psychosocial issues such as stress, anxiety, depression, and alcohol use. Sexual activity counseling may also be included.

Education classes are aimed at helping patients understand cardiovascular disease and empowering them to manage their medical treatment and lifestyle modifications.⁶

Phase 3: Lifetime maintenance

In phase 3, patients independently continue risk-factor modification and physical activity without cardiac monitoring. Most cardiac rehabilitation programs offer transition-to-maintenance classes after completion of phase 2; this may be a welcome option, particularly for those who have developed a good routine and rapport with the staff and other participants. Others may opt for an independent program, using their own home equipment or a local health club.

EXERCISE: MOSTLY SAFE, WITH PROVEN BENEFITS

The safety of cardiac rehabilitation is well established, with a low risk of major cardiovascular complications. A US study in the early 1980s of 167 cardiac rehabilitation programs found 1 cardiac arrest for every 111,996 exercise hours, 1 myocardial infarction per 293,990 exercise hours, and 1 fatality per 783,972 exercise hours.¹¹ A 2006 study of more than 65 cardiac rehabilitation centers in France found 1 cardiac event per 8,484 exercise tests and 1.3 cardiac arrests per 1 million exercise hours.¹²

The benefits of cardiac rehabilitation are numerous and substantial.^9,13–17 A 2016 Cochrane review and meta-analysis of 63 randomized controlled trials with 14,486 participants found a reduced rate of cardiovascular mortality (relative risk [RR] 0.74, 95% confidence interval [CI] 0.64–0.86), with a number needed to treat of 37, and fewer hospital re­admissions (RR 0.82, 95% CI 0.70–0.96).⁹

Reductions in mortality rates are dose-dependent. A study of more than 30,000 Medicare beneficiaries who participated in cardiac rehabilitation found that those who attended more sessions had a lower rate of morbidity and death at 4 years, particularly if they participated in more than 11 sessions. Those who attended the full 36 sessions had a mortality rate 47% lower than those who attended a single session.¹⁷ There was a 15% reduction in mortality for those who attended 36 sessions compared with 24 sessions, a 28% lower risk with attending 36 sessions compared with 12. After adjustment, each additional 6 sessions was associated with a 6% reduction in mortality. The curves continued to separate up to 4 years.

The benefits of cardiac rehabilitation go beyond risk reduction and include improved functional capacity, greater ease with activities of daily living, and improved quality of life.⁹ Patients receive structure and support from the management team and other participants, which may provide an additional layer of friendship and psychosocial support for making lifestyle changes.

Is the overall mortality rate improved?

In the modern era, with access to optimal medical therapy and drug-eluting stents, one might expect only small additional benefit from cardiac rehabilitation. The 2016 Cochrane review and meta-analysis found that although cardiac rehabilitation contributed to improved cardiovascular mortality rates and health-related quality of life, no significant reduction was detected in the rate of death from all causes.⁸ But the analysis did not necessarily support removing the claim of reduced all-cause mortality for cardiac rehabilitation: only randomized controlled trials were examined, and the quality of evidence for each outcome was deemed to be low to moderate because of a general paucity of reports, including many small trials that followed patients for less than 12 months.

A large cohort analysis¹⁵ with more than 73,000 patients who had undergone cardiac rehabilitation found a relative reduction in mortality rate of 58% at 1 year and 21% to 34% at 5 years, with elderly women gaining the most benefit. In the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, with more than 2,300 patients followed for a median of 2.5 years, exercise training for heart failure was associated with reduced rates of all-cause mortality or hospitalization (HR 0.89, 95% CI 0.81–0.99; P = .03) and of cardiovascular mortality or heart failure hospitalization (HR 0.85, 95% CI 0.74–0.99; P = .03).¹⁸

Regardless of the precise reduction in all-cause mortality, the cardiovascular and health-quality outcomes of cardiac rehabilitation clearly indicate benefit. More trials with follow-up longer than 1 year are needed to definitively determine the impact of cardiac rehabilitation on the all-cause mortality rate.

WHO SHOULD BE OFFERED CARDIAC REHABILITATION?

The 2006 CMS coverage criteria listed the indications for cardiac rehabilitation as myocardial infarction within the preceding 12 months, coronary artery bypass surgery, stable angina pectoris, heart valve repair or replacement, percutaneous coronary intervention, and heart or heart-lung transplant.

In 2014, stable chronic systolic heart failure was added to the list (Table 2). Qualifications include New York Heart Association class II (mild symptoms, slight limitation of activity) to class IV (severe limitations, symptoms at rest), an ejection fraction of 35% or less, and being stable on optimal medical therapy for at least 6 weeks.

In 2017, CMS approved supervised exercise therapy for peripheral arterial disease. Supervised exercise has a class 1 recommendation by the American Heart Association and American College of Cardiology for treating intermittent claudication. Supervised exercise therapy can increase walking distance by 180% and is superior to medical therapy alone. Unsupervised exercise has a class 2b recommendation.^19,20

Other patients may not qualify for phase 2 cardiac rehabilitation according to CMS or private insurance but could benefit from an exercise prescription and enrollment in a local phase 3 or home exercise program. Indications might include diabetes, obesity, metabolic syndrome, atrial fibrillation, postural orthostatic tachycardia syndrome, and nonalcoholic steatohepatitis. The benefits of cardiac rehabilitation after newer, less-invasive procedures for transcatheter valve repair and replacement are not well established, and more research is needed in this area.

WHEN TO REFER

Ades et al have defined cardiac rehabilitation referral as a combination of electronic medical records order, patient-physician discussion, and receipt of an order by a cardiac rehabilitation program.²¹

Ideally, referral for outpatient cardiac rehabilitation should take place at the time of hospital discharge. The AACVPR endorses a “cardiovascular continuum of care” model that emphasizes a smooth transition from inpatient to outpatient programs.⁶ Inpatient referral is a strong predictor of cardiac rehabilitation enrollment, and lack of referral in phase 1 negatively affects enrollment rates.

Depending on the diagnosis, US and Canadian guidelines recommend cardiac rehabilitation starting within 1 to 4 weeks of the index event, with acceptable wait times up to 60 days.^6,22 In the United Kingdom, referral is recommended within 24 hours of patient eligibility; assessment for a cardiovascular prevention and rehabilitation program, with a defined pathway and individual goals, is expected to be completed within 10 working days of referral.²³ Such a standard is difficult to meet in the United States, where the time from hospital discharge to cardiac rehabilitation program enrollment averages 35 days.^24,25

After an uncomplicated myocardial infarction or percutaneous coronary intervention, patients with a normal or mildly reduced left ventricular ejection fraction should start outpatient cardiac rehabilitation within 14 days of the index event. For such cases, cardiac rehabilitation has been shown to be safe within 1 to 2 weeks of hospital discharge and is associated with increased participation rates.

REHABILITATION IS STILL UNDERUSED

Despite its significant benefits, cardiac rehabilitation is underused for many reasons.

Referral rates vary

A study using the 1997 Medicare claims data­base showed national referral rates of only 14% after myocardial infarction and 31% after coronary artery bypass grafting.³¹

A later study using the National Cardiovascular Data Registry between 2009 and 2017 found that the situation had improved, with a referral rate of about 60% for patients undergoing percutaneous coronary intervention.³² Nevertheless, referral rates for cardiac rehabilitation remain highly variable and still lag behind other CMS quality measures for optimal medical therapy after acute myocardial infarction (Figure 1). Factors associated with higher referral rates included ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, care in a high-volume center for percutaneous coronary intervention, and care in a private or community hospital in a Midwestern state. Small Midwestern hospitals generally had referral rates of over 80%, while major teaching hospitals and hospital systems on the East Coast and the West Coast had referral rates of less than 20%. Unlike some studies, this study found that insurance status had little bearing on referral rates.

Other studies found lower referral rates for women and patients with comorbidities such as previous coronary artery bypass grafting, diabetes, and heart failure.^33,34

In the United Kingdom, patients with heart failure made up only 5% of patients in cardiac rehabilitation; only 7% to 20% of patients with a heart failure diagnosis were referred to cardiac rehabilitation from general and cardiology wards.³⁵

Enrollment, completion rates even lower

Rates of referral for cardiac rehabilitation do not equate to rates of enrollment or participation. Enrollment was 50% in the United Kingdom in 2016.³⁵ A 2015 US study evaluated 58,269 older patients eligible for cardiac rehabilitation after acute myocardial infarction;  62% were referred for cardiac rehabilitation at the time of discharge, but only 23% of the total attended at least 1 session, and just 5% of the total completed 36 or more sessions.³⁶

BARRIERS, OPPORTUNITIES TO IMPROVE

The underuse of cardiac rehabilitation in the United States has led to an American Heart Association presidential advisory on the referral, enrollment, and delivery of cardiac rehabilitation.³⁴ Dozens of barriers are mentioned, with several standing out as having the largest impact: lack of physician referral, weak endorsement by the prescribing provider, female sex of patients, lack of program availability, work-related hardship, low socioeconomic status, and lack of or limited healthcare insurance. Copayments have also become a major barrier, often ranging from $20 to $40 per session for patients with Medicare.

The Million Hearts Initiative has established a goal of 70% cardiac rehabilitation compliance for eligible patients by 2022, a goal they estimate could save 25,000 lives and prevent 180,000 hospitalizations annually.²¹

Lack of physician awareness and lack of referral may be the most modifiable factors with the capacity to have the largest impact. Increasing physician awareness is a top priority not only for primary care providers, but also for cardiologists. In 2014, CMS made referral for cardiac rehabilitation a quality measure that is trackable and reportable. CMS has also proposed models that would incentivize participation by increasing reimbursement for services provided, but these models have been halted.

Additional efforts to increase cardiac rehabilitation referral and participation include automated order sets, increased caregiver education, and early morning or late evening classes, single-sex classes, home or mobile-based exercise programs, and parking and transportation assistance.³⁴ Grace et al³⁷ reported that referral rates rose to 86% when a cardiac rehabilitation order was integrated into the electronic medical record and combined with a hospital liaison to educate patients about their need for cardiac rehabilitation. Lowering patient copayments would also be a good idea. We have recently seen some creative ways to reduce copayments, including philanthropy and grants.

Cardiac rehabilitation has a class 1 indication (ie, strong recommendation) after heart surgery, myocardial infarction, or coronary intervention, and for stable angina or peripheral artery disease. It has a class 2a indication (ie, moderate recommendation) for stable systolic heart failure. Yet it is still under­utilized despite its demonstrated benefits, endorsement by most recognized cardiovascular societies, and coverage by the US Centers for Medicare and Medicaid Services (CMS).

Here, we review cardiac rehabilitation—its benefits, appropriate indications, barriers to referral and enrollment, and efforts to increase its use.

EXERCISE: SLOW TO BE ADOPTED

In 1772, William Heberden (also remembered today for describing swelling of the distal interphalangeal joints in osteoarthritis) described¹ a patient with angina pectoris who “set himself a task of sawing wood for half an hour every day, and was nearly cured.”

Despite early clues, it would be some time before the medical community would recognize the benefits of exercise for cardiovascular health. Before the 1930s, immobilization and extended bedrest were encouraged for up to 6 weeks after a cardiovascular event, leading to significant deconditioning.² Things slowly began to change in the 1940s with Levine’s introduction of up-to-chair therapy,³ and short daily walks were introduced in the 1950s. Over time, the link between a sedentary lifestyle and cardiovascular disease was studied and led to greater investigation into the benefits of exercise, propelling us into the modern era.^4,5

CARDIAC REHABILITATION: COMPREHENSIVE RISK REDUCTION

The American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) defines cardiac rehabilitation as the provision of comprehensive long-term services involving medical evaluation, prescriptive exercise, cardiac risk-factor modification, education, counseling, and behavioral interventions.⁶ CMS defines it as a physician-supervised program that furnishes physician-prescribed exercise, cardiac risk-factor modification (including education, counseling, and behavioral intervention), psychosocial assessment, outcomes assessment, and other items and services.⁷

In general, most cardiac rehabilitation programs provide medically supervised exercise and patient education designed to improve cardiac health and functional status. Risk factors are targeted to reduce disability and rates of morbidity and mortality, to improve functional capacity, and to alleviate activity-related symptoms.

FROM HOSPITAL TO SELF-MAINTENANCE

Phase 1: Inpatient rehabilitation

Phase 1 typically takes place in the inpatient setting, often after open heart surgery (eg, coronary artery bypass grafting, valve repair or replacement, heart transplant), myocardial infarction, or percutaneous coronary intervention. This phase may last only a few days, especially in the current era of short hospital stays.

During phase 1, patients discuss their health situation and goals with their primary provider or cardiologist and receive education about recovery and cardiovascular risk factors. Early mobilization to prepare for discharge and to resume simple activities of daily living is emphasized. Depending on the institution, phase 1 exercise may involve simple ambulation on the ward or using equipment such as a stationary bike or treadmill.⁶ Phase 2 enrollment ideally is set up before discharge.

Phase 2: Limited-time outpatient rehabilitation

Phase 2 traditionally takes place in a hospital-based outpatient facility and consists of a physician-supervised multidisciplinary program. Growing evidence shows that home-based cardiac rehabilitation may be as effective as a medical facility-based program and should be an option for patients who have difficulty getting access to a traditional program.⁸

A phase 2 program takes a threefold approach, consisting of exercise, aggressive risk-factor modification, and education classes. A Cochrane review⁹ included programs that also incorporated behavioral modification and psychosocial support as a means of secondary prevention, underscoring the evolving definition of cardiac rehabilitation.

During the initial phase 2 visit, an individualized treatment plan is developed, incorporating an exercise prescription and realistic goals for secondary prevention. Sessions typically take place 3 times a week for up to 36 sessions; usually, options are available for less frequent weekly attendance for a longer period to achieve a full course. In some cases, patients may qualify for up to 72 sessions, particularly if they have not progressed as expected.

Exercise. As part of the initial evaluation, AACVPR guidelines⁶ suggest an exercise test­—eg, a symptom-limited exercise stress test, a 6-minute walk test, or use of a Rating of Perceived Exertion scale. Prescribed exercise generally targets moderate activity in the range of 50% to 70% of peak estimated functional capacity. In the appropriate clinical context, high-functioning patients can be offered high-intensity interval training instead of moderate exercise, as they confer similar benefits.¹⁰

Risk-factor reduction. Comprehensive risk-factor reduction can address smoking, hypertension, high cholesterol, diabetes, obesity, and diet, as well as psychosocial issues such as stress, anxiety, depression, and alcohol use. Sexual activity counseling may also be included.

Education classes are aimed at helping patients understand cardiovascular disease and empowering them to manage their medical treatment and lifestyle modifications.⁶

Phase 3: Lifetime maintenance

In phase 3, patients independently continue risk-factor modification and physical activity without cardiac monitoring. Most cardiac rehabilitation programs offer transition-to-maintenance classes after completion of phase 2; this may be a welcome option, particularly for those who have developed a good routine and rapport with the staff and other participants. Others may opt for an independent program, using their own home equipment or a local health club.

EXERCISE: MOSTLY SAFE, WITH PROVEN BENEFITS

The safety of cardiac rehabilitation is well established, with a low risk of major cardiovascular complications. A US study in the early 1980s of 167 cardiac rehabilitation programs found 1 cardiac arrest for every 111,996 exercise hours, 1 myocardial infarction per 293,990 exercise hours, and 1 fatality per 783,972 exercise hours.¹¹ A 2006 study of more than 65 cardiac rehabilitation centers in France found 1 cardiac event per 8,484 exercise tests and 1.3 cardiac arrests per 1 million exercise hours.¹²

The benefits of cardiac rehabilitation are numerous and substantial.^9,13–17 A 2016 Cochrane review and meta-analysis of 63 randomized controlled trials with 14,486 participants found a reduced rate of cardiovascular mortality (relative risk [RR] 0.74, 95% confidence interval [CI] 0.64–0.86), with a number needed to treat of 37, and fewer hospital re­admissions (RR 0.82, 95% CI 0.70–0.96).⁹

Reductions in mortality rates are dose-dependent. A study of more than 30,000 Medicare beneficiaries who participated in cardiac rehabilitation found that those who attended more sessions had a lower rate of morbidity and death at 4 years, particularly if they participated in more than 11 sessions. Those who attended the full 36 sessions had a mortality rate 47% lower than those who attended a single session.¹⁷ There was a 15% reduction in mortality for those who attended 36 sessions compared with 24 sessions, a 28% lower risk with attending 36 sessions compared with 12. After adjustment, each additional 6 sessions was associated with a 6% reduction in mortality. The curves continued to separate up to 4 years.

The benefits of cardiac rehabilitation go beyond risk reduction and include improved functional capacity, greater ease with activities of daily living, and improved quality of life.⁹ Patients receive structure and support from the management team and other participants, which may provide an additional layer of friendship and psychosocial support for making lifestyle changes.

Is the overall mortality rate improved?

In the modern era, with access to optimal medical therapy and drug-eluting stents, one might expect only small additional benefit from cardiac rehabilitation. The 2016 Cochrane review and meta-analysis found that although cardiac rehabilitation contributed to improved cardiovascular mortality rates and health-related quality of life, no significant reduction was detected in the rate of death from all causes.⁸ But the analysis did not necessarily support removing the claim of reduced all-cause mortality for cardiac rehabilitation: only randomized controlled trials were examined, and the quality of evidence for each outcome was deemed to be low to moderate because of a general paucity of reports, including many small trials that followed patients for less than 12 months.

A large cohort analysis¹⁵ with more than 73,000 patients who had undergone cardiac rehabilitation found a relative reduction in mortality rate of 58% at 1 year and 21% to 34% at 5 years, with elderly women gaining the most benefit. In the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, with more than 2,300 patients followed for a median of 2.5 years, exercise training for heart failure was associated with reduced rates of all-cause mortality or hospitalization (HR 0.89, 95% CI 0.81–0.99; P = .03) and of cardiovascular mortality or heart failure hospitalization (HR 0.85, 95% CI 0.74–0.99; P = .03).¹⁸

Regardless of the precise reduction in all-cause mortality, the cardiovascular and health-quality outcomes of cardiac rehabilitation clearly indicate benefit. More trials with follow-up longer than 1 year are needed to definitively determine the impact of cardiac rehabilitation on the all-cause mortality rate.

WHO SHOULD BE OFFERED CARDIAC REHABILITATION?

The 2006 CMS coverage criteria listed the indications for cardiac rehabilitation as myocardial infarction within the preceding 12 months, coronary artery bypass surgery, stable angina pectoris, heart valve repair or replacement, percutaneous coronary intervention, and heart or heart-lung transplant.

In 2014, stable chronic systolic heart failure was added to the list (Table 2). Qualifications include New York Heart Association class II (mild symptoms, slight limitation of activity) to class IV (severe limitations, symptoms at rest), an ejection fraction of 35% or less, and being stable on optimal medical therapy for at least 6 weeks.

In 2017, CMS approved supervised exercise therapy for peripheral arterial disease. Supervised exercise has a class 1 recommendation by the American Heart Association and American College of Cardiology for treating intermittent claudication. Supervised exercise therapy can increase walking distance by 180% and is superior to medical therapy alone. Unsupervised exercise has a class 2b recommendation.^19,20

Other patients may not qualify for phase 2 cardiac rehabilitation according to CMS or private insurance but could benefit from an exercise prescription and enrollment in a local phase 3 or home exercise program. Indications might include diabetes, obesity, metabolic syndrome, atrial fibrillation, postural orthostatic tachycardia syndrome, and nonalcoholic steatohepatitis. The benefits of cardiac rehabilitation after newer, less-invasive procedures for transcatheter valve repair and replacement are not well established, and more research is needed in this area.

WHEN TO REFER

Ades et al have defined cardiac rehabilitation referral as a combination of electronic medical records order, patient-physician discussion, and receipt of an order by a cardiac rehabilitation program.²¹

Ideally, referral for outpatient cardiac rehabilitation should take place at the time of hospital discharge. The AACVPR endorses a “cardiovascular continuum of care” model that emphasizes a smooth transition from inpatient to outpatient programs.⁶ Inpatient referral is a strong predictor of cardiac rehabilitation enrollment, and lack of referral in phase 1 negatively affects enrollment rates.

Depending on the diagnosis, US and Canadian guidelines recommend cardiac rehabilitation starting within 1 to 4 weeks of the index event, with acceptable wait times up to 60 days.^6,22 In the United Kingdom, referral is recommended within 24 hours of patient eligibility; assessment for a cardiovascular prevention and rehabilitation program, with a defined pathway and individual goals, is expected to be completed within 10 working days of referral.²³ Such a standard is difficult to meet in the United States, where the time from hospital discharge to cardiac rehabilitation program enrollment averages 35 days.^24,25

After an uncomplicated myocardial infarction or percutaneous coronary intervention, patients with a normal or mildly reduced left ventricular ejection fraction should start outpatient cardiac rehabilitation within 14 days of the index event. For such cases, cardiac rehabilitation has been shown to be safe within 1 to 2 weeks of hospital discharge and is associated with increased participation rates.

REHABILITATION IS STILL UNDERUSED

Despite its significant benefits, cardiac rehabilitation is underused for many reasons.

Referral rates vary

A study using the 1997 Medicare claims data­base showed national referral rates of only 14% after myocardial infarction and 31% after coronary artery bypass grafting.³¹

A later study using the National Cardiovascular Data Registry between 2009 and 2017 found that the situation had improved, with a referral rate of about 60% for patients undergoing percutaneous coronary intervention.³² Nevertheless, referral rates for cardiac rehabilitation remain highly variable and still lag behind other CMS quality measures for optimal medical therapy after acute myocardial infarction (Figure 1). Factors associated with higher referral rates included ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, care in a high-volume center for percutaneous coronary intervention, and care in a private or community hospital in a Midwestern state. Small Midwestern hospitals generally had referral rates of over 80%, while major teaching hospitals and hospital systems on the East Coast and the West Coast had referral rates of less than 20%. Unlike some studies, this study found that insurance status had little bearing on referral rates.

Other studies found lower referral rates for women and patients with comorbidities such as previous coronary artery bypass grafting, diabetes, and heart failure.^33,34

In the United Kingdom, patients with heart failure made up only 5% of patients in cardiac rehabilitation; only 7% to 20% of patients with a heart failure diagnosis were referred to cardiac rehabilitation from general and cardiology wards.³⁵

Enrollment, completion rates even lower

Rates of referral for cardiac rehabilitation do not equate to rates of enrollment or participation. Enrollment was 50% in the United Kingdom in 2016.³⁵ A 2015 US study evaluated 58,269 older patients eligible for cardiac rehabilitation after acute myocardial infarction;  62% were referred for cardiac rehabilitation at the time of discharge, but only 23% of the total attended at least 1 session, and just 5% of the total completed 36 or more sessions.³⁶

BARRIERS, OPPORTUNITIES TO IMPROVE

The underuse of cardiac rehabilitation in the United States has led to an American Heart Association presidential advisory on the referral, enrollment, and delivery of cardiac rehabilitation.³⁴ Dozens of barriers are mentioned, with several standing out as having the largest impact: lack of physician referral, weak endorsement by the prescribing provider, female sex of patients, lack of program availability, work-related hardship, low socioeconomic status, and lack of or limited healthcare insurance. Copayments have also become a major barrier, often ranging from $20 to $40 per session for patients with Medicare.

The Million Hearts Initiative has established a goal of 70% cardiac rehabilitation compliance for eligible patients by 2022, a goal they estimate could save 25,000 lives and prevent 180,000 hospitalizations annually.²¹

Lack of physician awareness and lack of referral may be the most modifiable factors with the capacity to have the largest impact. Increasing physician awareness is a top priority not only for primary care providers, but also for cardiologists. In 2014, CMS made referral for cardiac rehabilitation a quality measure that is trackable and reportable. CMS has also proposed models that would incentivize participation by increasing reimbursement for services provided, but these models have been halted.

Additional efforts to increase cardiac rehabilitation referral and participation include automated order sets, increased caregiver education, and early morning or late evening classes, single-sex classes, home or mobile-based exercise programs, and parking and transportation assistance.³⁴ Grace et al³⁷ reported that referral rates rose to 86% when a cardiac rehabilitation order was integrated into the electronic medical record and combined with a hospital liaison to educate patients about their need for cardiac rehabilitation. Lowering patient copayments would also be a good idea. We have recently seen some creative ways to reduce copayments, including philanthropy and grants.

Cardiac rehabilitation has a class 1 indication (ie, strong recommendation) after heart surgery, myocardial infarction, or coronary intervention, and for stable angina or peripheral artery disease. It has a class 2a indication (ie, moderate recommendation) for stable systolic heart failure. Yet it is still under­utilized despite its demonstrated benefits, endorsement by most recognized cardiovascular societies, and coverage by the US Centers for Medicare and Medicaid Services (CMS).

Here, we review cardiac rehabilitation—its benefits, appropriate indications, barriers to referral and enrollment, and efforts to increase its use.

EXERCISE: SLOW TO BE ADOPTED

In 1772, William Heberden (also remembered today for describing swelling of the distal interphalangeal joints in osteoarthritis) described¹ a patient with angina pectoris who “set himself a task of sawing wood for half an hour every day, and was nearly cured.”

Despite early clues, it would be some time before the medical community would recognize the benefits of exercise for cardiovascular health. Before the 1930s, immobilization and extended bedrest were encouraged for up to 6 weeks after a cardiovascular event, leading to significant deconditioning.² Things slowly began to change in the 1940s with Levine’s introduction of up-to-chair therapy,³ and short daily walks were introduced in the 1950s. Over time, the link between a sedentary lifestyle and cardiovascular disease was studied and led to greater investigation into the benefits of exercise, propelling us into the modern era.^4,5

CARDIAC REHABILITATION: COMPREHENSIVE RISK REDUCTION

The American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) defines cardiac rehabilitation as the provision of comprehensive long-term services involving medical evaluation, prescriptive exercise, cardiac risk-factor modification, education, counseling, and behavioral interventions.⁶ CMS defines it as a physician-supervised program that furnishes physician-prescribed exercise, cardiac risk-factor modification (including education, counseling, and behavioral intervention), psychosocial assessment, outcomes assessment, and other items and services.⁷

In general, most cardiac rehabilitation programs provide medically supervised exercise and patient education designed to improve cardiac health and functional status. Risk factors are targeted to reduce disability and rates of morbidity and mortality, to improve functional capacity, and to alleviate activity-related symptoms.

FROM HOSPITAL TO SELF-MAINTENANCE

Phase 1: Inpatient rehabilitation

Phase 1 typically takes place in the inpatient setting, often after open heart surgery (eg, coronary artery bypass grafting, valve repair or replacement, heart transplant), myocardial infarction, or percutaneous coronary intervention. This phase may last only a few days, especially in the current era of short hospital stays.

During phase 1, patients discuss their health situation and goals with their primary provider or cardiologist and receive education about recovery and cardiovascular risk factors. Early mobilization to prepare for discharge and to resume simple activities of daily living is emphasized. Depending on the institution, phase 1 exercise may involve simple ambulation on the ward or using equipment such as a stationary bike or treadmill.⁶ Phase 2 enrollment ideally is set up before discharge.

Phase 2: Limited-time outpatient rehabilitation

Phase 2 traditionally takes place in a hospital-based outpatient facility and consists of a physician-supervised multidisciplinary program. Growing evidence shows that home-based cardiac rehabilitation may be as effective as a medical facility-based program and should be an option for patients who have difficulty getting access to a traditional program.⁸

A phase 2 program takes a threefold approach, consisting of exercise, aggressive risk-factor modification, and education classes. A Cochrane review⁹ included programs that also incorporated behavioral modification and psychosocial support as a means of secondary prevention, underscoring the evolving definition of cardiac rehabilitation.

During the initial phase 2 visit, an individualized treatment plan is developed, incorporating an exercise prescription and realistic goals for secondary prevention. Sessions typically take place 3 times a week for up to 36 sessions; usually, options are available for less frequent weekly attendance for a longer period to achieve a full course. In some cases, patients may qualify for up to 72 sessions, particularly if they have not progressed as expected.

Exercise. As part of the initial evaluation, AACVPR guidelines⁶ suggest an exercise test­—eg, a symptom-limited exercise stress test, a 6-minute walk test, or use of a Rating of Perceived Exertion scale. Prescribed exercise generally targets moderate activity in the range of 50% to 70% of peak estimated functional capacity. In the appropriate clinical context, high-functioning patients can be offered high-intensity interval training instead of moderate exercise, as they confer similar benefits.¹⁰

Risk-factor reduction. Comprehensive risk-factor reduction can address smoking, hypertension, high cholesterol, diabetes, obesity, and diet, as well as psychosocial issues such as stress, anxiety, depression, and alcohol use. Sexual activity counseling may also be included.

Education classes are aimed at helping patients understand cardiovascular disease and empowering them to manage their medical treatment and lifestyle modifications.⁶

Phase 3: Lifetime maintenance

In phase 3, patients independently continue risk-factor modification and physical activity without cardiac monitoring. Most cardiac rehabilitation programs offer transition-to-maintenance classes after completion of phase 2; this may be a welcome option, particularly for those who have developed a good routine and rapport with the staff and other participants. Others may opt for an independent program, using their own home equipment or a local health club.

EXERCISE: MOSTLY SAFE, WITH PROVEN BENEFITS

The safety of cardiac rehabilitation is well established, with a low risk of major cardiovascular complications. A US study in the early 1980s of 167 cardiac rehabilitation programs found 1 cardiac arrest for every 111,996 exercise hours, 1 myocardial infarction per 293,990 exercise hours, and 1 fatality per 783,972 exercise hours.¹¹ A 2006 study of more than 65 cardiac rehabilitation centers in France found 1 cardiac event per 8,484 exercise tests and 1.3 cardiac arrests per 1 million exercise hours.¹²

The benefits of cardiac rehabilitation are numerous and substantial.^9,13–17 A 2016 Cochrane review and meta-analysis of 63 randomized controlled trials with 14,486 participants found a reduced rate of cardiovascular mortality (relative risk [RR] 0.74, 95% confidence interval [CI] 0.64–0.86), with a number needed to treat of 37, and fewer hospital re­admissions (RR 0.82, 95% CI 0.70–0.96).⁹

Reductions in mortality rates are dose-dependent. A study of more than 30,000 Medicare beneficiaries who participated in cardiac rehabilitation found that those who attended more sessions had a lower rate of morbidity and death at 4 years, particularly if they participated in more than 11 sessions. Those who attended the full 36 sessions had a mortality rate 47% lower than those who attended a single session.¹⁷ There was a 15% reduction in mortality for those who attended 36 sessions compared with 24 sessions, a 28% lower risk with attending 36 sessions compared with 12. After adjustment, each additional 6 sessions was associated with a 6% reduction in mortality. The curves continued to separate up to 4 years.

The benefits of cardiac rehabilitation go beyond risk reduction and include improved functional capacity, greater ease with activities of daily living, and improved quality of life.⁹ Patients receive structure and support from the management team and other participants, which may provide an additional layer of friendship and psychosocial support for making lifestyle changes.

Is the overall mortality rate improved?

In the modern era, with access to optimal medical therapy and drug-eluting stents, one might expect only small additional benefit from cardiac rehabilitation. The 2016 Cochrane review and meta-analysis found that although cardiac rehabilitation contributed to improved cardiovascular mortality rates and health-related quality of life, no significant reduction was detected in the rate of death from all causes.⁸ But the analysis did not necessarily support removing the claim of reduced all-cause mortality for cardiac rehabilitation: only randomized controlled trials were examined, and the quality of evidence for each outcome was deemed to be low to moderate because of a general paucity of reports, including many small trials that followed patients for less than 12 months.

A large cohort analysis¹⁵ with more than 73,000 patients who had undergone cardiac rehabilitation found a relative reduction in mortality rate of 58% at 1 year and 21% to 34% at 5 years, with elderly women gaining the most benefit. In the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, with more than 2,300 patients followed for a median of 2.5 years, exercise training for heart failure was associated with reduced rates of all-cause mortality or hospitalization (HR 0.89, 95% CI 0.81–0.99; P = .03) and of cardiovascular mortality or heart failure hospitalization (HR 0.85, 95% CI 0.74–0.99; P = .03).¹⁸

Regardless of the precise reduction in all-cause mortality, the cardiovascular and health-quality outcomes of cardiac rehabilitation clearly indicate benefit. More trials with follow-up longer than 1 year are needed to definitively determine the impact of cardiac rehabilitation on the all-cause mortality rate.

WHO SHOULD BE OFFERED CARDIAC REHABILITATION?

The 2006 CMS coverage criteria listed the indications for cardiac rehabilitation as myocardial infarction within the preceding 12 months, coronary artery bypass surgery, stable angina pectoris, heart valve repair or replacement, percutaneous coronary intervention, and heart or heart-lung transplant.

In 2014, stable chronic systolic heart failure was added to the list (Table 2). Qualifications include New York Heart Association class II (mild symptoms, slight limitation of activity) to class IV (severe limitations, symptoms at rest), an ejection fraction of 35% or less, and being stable on optimal medical therapy for at least 6 weeks.

In 2017, CMS approved supervised exercise therapy for peripheral arterial disease. Supervised exercise has a class 1 recommendation by the American Heart Association and American College of Cardiology for treating intermittent claudication. Supervised exercise therapy can increase walking distance by 180% and is superior to medical therapy alone. Unsupervised exercise has a class 2b recommendation.^19,20

Other patients may not qualify for phase 2 cardiac rehabilitation according to CMS or private insurance but could benefit from an exercise prescription and enrollment in a local phase 3 or home exercise program. Indications might include diabetes, obesity, metabolic syndrome, atrial fibrillation, postural orthostatic tachycardia syndrome, and nonalcoholic steatohepatitis. The benefits of cardiac rehabilitation after newer, less-invasive procedures for transcatheter valve repair and replacement are not well established, and more research is needed in this area.

WHEN TO REFER

Ades et al have defined cardiac rehabilitation referral as a combination of electronic medical records order, patient-physician discussion, and receipt of an order by a cardiac rehabilitation program.²¹

Ideally, referral for outpatient cardiac rehabilitation should take place at the time of hospital discharge. The AACVPR endorses a “cardiovascular continuum of care” model that emphasizes a smooth transition from inpatient to outpatient programs.⁶ Inpatient referral is a strong predictor of cardiac rehabilitation enrollment, and lack of referral in phase 1 negatively affects enrollment rates.

Depending on the diagnosis, US and Canadian guidelines recommend cardiac rehabilitation starting within 1 to 4 weeks of the index event, with acceptable wait times up to 60 days.^6,22 In the United Kingdom, referral is recommended within 24 hours of patient eligibility; assessment for a cardiovascular prevention and rehabilitation program, with a defined pathway and individual goals, is expected to be completed within 10 working days of referral.²³ Such a standard is difficult to meet in the United States, where the time from hospital discharge to cardiac rehabilitation program enrollment averages 35 days.^24,25

After an uncomplicated myocardial infarction or percutaneous coronary intervention, patients with a normal or mildly reduced left ventricular ejection fraction should start outpatient cardiac rehabilitation within 14 days of the index event. For such cases, cardiac rehabilitation has been shown to be safe within 1 to 2 weeks of hospital discharge and is associated with increased participation rates.

REHABILITATION IS STILL UNDERUSED

Despite its significant benefits, cardiac rehabilitation is underused for many reasons.

Referral rates vary

A study using the 1997 Medicare claims data­base showed national referral rates of only 14% after myocardial infarction and 31% after coronary artery bypass grafting.³¹

A later study using the National Cardiovascular Data Registry between 2009 and 2017 found that the situation had improved, with a referral rate of about 60% for patients undergoing percutaneous coronary intervention.³² Nevertheless, referral rates for cardiac rehabilitation remain highly variable and still lag behind other CMS quality measures for optimal medical therapy after acute myocardial infarction (Figure 1). Factors associated with higher referral rates included ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, care in a high-volume center for percutaneous coronary intervention, and care in a private or community hospital in a Midwestern state. Small Midwestern hospitals generally had referral rates of over 80%, while major teaching hospitals and hospital systems on the East Coast and the West Coast had referral rates of less than 20%. Unlike some studies, this study found that insurance status had little bearing on referral rates.

Other studies found lower referral rates for women and patients with comorbidities such as previous coronary artery bypass grafting, diabetes, and heart failure.^33,34

In the United Kingdom, patients with heart failure made up only 5% of patients in cardiac rehabilitation; only 7% to 20% of patients with a heart failure diagnosis were referred to cardiac rehabilitation from general and cardiology wards.³⁵

Enrollment, completion rates even lower

Rates of referral for cardiac rehabilitation do not equate to rates of enrollment or participation. Enrollment was 50% in the United Kingdom in 2016.³⁵ A 2015 US study evaluated 58,269 older patients eligible for cardiac rehabilitation after acute myocardial infarction;  62% were referred for cardiac rehabilitation at the time of discharge, but only 23% of the total attended at least 1 session, and just 5% of the total completed 36 or more sessions.³⁶

BARRIERS, OPPORTUNITIES TO IMPROVE

The underuse of cardiac rehabilitation in the United States has led to an American Heart Association presidential advisory on the referral, enrollment, and delivery of cardiac rehabilitation.³⁴ Dozens of barriers are mentioned, with several standing out as having the largest impact: lack of physician referral, weak endorsement by the prescribing provider, female sex of patients, lack of program availability, work-related hardship, low socioeconomic status, and lack of or limited healthcare insurance. Copayments have also become a major barrier, often ranging from $20 to $40 per session for patients with Medicare.

The Million Hearts Initiative has established a goal of 70% cardiac rehabilitation compliance for eligible patients by 2022, a goal they estimate could save 25,000 lives and prevent 180,000 hospitalizations annually.²¹

Lack of physician awareness and lack of referral may be the most modifiable factors with the capacity to have the largest impact. Increasing physician awareness is a top priority not only for primary care providers, but also for cardiologists. In 2014, CMS made referral for cardiac rehabilitation a quality measure that is trackable and reportable. CMS has also proposed models that would incentivize participation by increasing reimbursement for services provided, but these models have been halted.

Additional efforts to increase cardiac rehabilitation referral and participation include automated order sets, increased caregiver education, and early morning or late evening classes, single-sex classes, home or mobile-based exercise programs, and parking and transportation assistance.³⁴ Grace et al³⁷ reported that referral rates rose to 86% when a cardiac rehabilitation order was integrated into the electronic medical record and combined with a hospital liaison to educate patients about their need for cardiac rehabilitation. Lowering patient copayments would also be a good idea. We have recently seen some creative ways to reduce copayments, including philanthropy and grants.

On November 12, 2013, a joint task force for the American College of Cardiology and American Heart Association released new guidelines for treating high blood cholesterol to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults.¹

This document arrives after several years of intense deliberation, 12 years after the third Adult Treatment Panel (ATP III) guidelines,² and 8 years after an ATP III update recommending that low-density lipoprotein cholesterol (LDL-C) levels be lowered aggressively (to less than 70 mg/dL) as an option in patients at high risk.³ It represents a major shift in the approach to and management of high blood cholesterol and has sparked considerable controversy.

In the following commentary, we summarize the new guidelines and the philosophy employed by the task force in generating them. We will also examine some advantages and what we believe to be several shortcomings of the new guidelines. These latter points are illustrated through case examples.

IN RANDOMIZED CONTROLLED TRIALS WE TRUST

In collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American College of Cardiology and American Heart Association formed an expert panel task force in 2008.

The task force elected to use only evidence from randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials (and only predefined outcomes of the trials, not post hoc analyses) in formulating its recommendations, with the goal of providing the strongest possible evidence.

The authors state that “By using [randomized controlled trial] data to identify those most likely to benefit [emphasis in original] from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD.”³ They also state the guidelines are meant to “inform clinical judgment, not replace it” and that clinician judgment in addition to discussion with patients remains vital.

During the deliberations, the National Heart, Lung, and Blood Institute removed itself from participating, stating its mission no longer included drafting new guidelines. Additionally, other initial members of the task force removed themselves because of disagreement and concerns about the direction of the new guidelines.

These guidelines, and their accompanying new cardiovascular risk calculator,⁴ were released without a preliminary period to allow for open discussion, comment, and critique by physicians outside the panel. No attempt was made to harmonize the guidelines with previous versions (eg, ATP III) or with current international guidelines.

WHAT’S NEW IN THE GUIDELINES?

The following are the major changes in the new guidelines for treating high blood cholesterol:

• Treatment goals for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) are no longer recommended.
• High-intensity and moderate-intensity statin treatment is emphasized, and low-intensity statin therapy is nearly eliminated.
• “ASCVD” now includes stroke in addition to coronary heart disease and peripheral arterial disease.
• Four groups are targeted for treatment (see below).
• Nonstatin therapies have been markedly de-emphasized.
• No guidelines are provided for treating high triglyceride levels.

The new guidelines emphasize lifestyle modification as the foundation for reducing risk, regardless of cholesterol therapy. No recommendations are given for patients with New York Heart Association class II, III, or IV heart failure or for hemodialysis patients, because there were insufficient data from randomized controlled trials to support recommendations. Similarly, the guidelines apply only to people between the ages of 40 and 75 (risk calculator ages 40–79), because the authors believed there was not enough evidence from randomized controlled trials to allow development of guidelines outside of this age range.

FOUR MAJOR STATIN TREATMENT GROUPS

The new guidelines specify four groups that merit intensive or moderately intensive statin therapy (Table 1)¹:

• People with clinical ASCVD
• People with LDL-C levels of 190 mg/dL or higher
• People with diabetes, age 40 to 75
• People without diabetes, age 40 to 75, with LDL-C levels 70–189 mg/dL, and a 10-year ASCVD risk of 7.5% or higher as determined by the new risk calculator⁴ (which also calculates the lifetime risk of ASCVD).

Below, we will address each of these four groups and provide case scenarios to consider. In general, our major disagreements with the new recommendations pertain to the first and fourth categories.

GROUP 1: PEOPLE WITH CLINICAL ASCVD

Advantages of the new guidelines

• They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
• They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
• Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)

Limitations of the new guidelines

• They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
• Patients no longer have a goal to strive for or a way to monitor their progress.
• The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
• They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
• They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.

Case 1: Is LDL-C 110 mg/dL low enough?

A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m². He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:

• Total cholesterol 290 mg/dL
• HDL-C 50 mg/dL
• Triglycerides 250 mg/dL
• Calculated LDL-C 190 mg/dL.

Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:

• Total cholesterol 180 mg/dL
• HDL-C 55 mg/dL
• Triglycerides 75 mg/dL
• Calculated LDL-C 110 mg/dL.

Comment: Lack of LDL-C goals is a flaw

The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.

However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.

Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?

A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.^5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).^7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.

The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,²⁰ provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).

In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.

Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.

For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.

GROUP 2: PEOPLE WITH LDL-C ≥ 190

Advantages of the new guidelines

• They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.

Limitations of the new guidelines

• The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines

• Although high-intensity statin therapy is indicated for this group, we believe that, using the new risk calculator, some patients may receive overly aggressive treatment, thus increasing the possibility of statin side effects.
• The guidelines do not address patients younger than 40 or older than 75.
• Diabetic patients have a high residual risk of ASCVD events, even on statin therapy. Yet the guidelines ignore the potential benefits of more aggressive LDL-lowering or non-LDL secondary targets for therapy.

Case 2: How low is too low?

A 63-year-old white woman, a nonsmoker with recently diagnosed diabetes, is seen by her primary care physician. She has hypertension, for which she takes lisinopril 5 mg daily. Her fasting lipid values are:

• Total cholesterol 160 mg/dL
• HDL-C 64 mg/dL
• Triglycerides 100 mg/dL
• Calculated LDL-C 76 mg/dL.

Her systolic blood pressure is 129 mm Hg, and based on the new risk calculator, her 10-year risk of cardiovascular disease is 10.2%. According to the new guidelines, she should be started on high-intensity statin treatment (Table 1).

Although this is an acceptable initial course of action, it necessitates close vigilance, since it may actually drive her LDL-C level too low. Randomized controlled trials have typically used an LDL-C concentration of less than or equal to 25 mg/dL as the safety cutoff. With a typical LDL-C reduction of at least 50% on high-intensity statins, our patient’s expected LDL-C level will likely be in the low 30s. We believe this would be a good outcome, provided that she tolerates the medication without adverse effects. However, responses to statins vary from patient to patient.

High-intensity statin therapy may not be necessary to reduce risk adequately in all patients who have diabetes without preexisting vascular disease. The Collaborative Atorvastatin Diabetes Study¹² compared atorvastatin 10 mg vs placebo in people with type 2 diabetes, age 40 to 75, who had one or more cardiovascular risk factors but no signs or symptoms of preexisting ASCVD and who had only average or below-average cholesterol levels—precisely like this patient. The trial was terminated early because of a clear benefit (a 37% reduction in the composite end point of major adverse cardiovascular events) in the intervention group. For our patient, we believe an alternative and acceptable approach would be to begin moderate-intensity statin therapy (eg, with atorvastatin 10 mg) (Table 1).

Alternatively, in a patient with diabetes and previous atherosclerotic vascular disease or with a high 10-year risk and high LDL-C, limiting treatment to high-intensity statin therapy by itself may deny them the potential benefits of combination therapies and targeting to lower LDL-C levels or non-HDL-C secondary targets. Guidelines from the American Diabetes Association²⁸ and the American Association of Clinical Endocrinologists²⁹ continue to recommend an LDL-C goal of less than 70 mg/dL in patients at high risk, a non-HDL-C less than 100 mg/dL, an apolipoprotein B less than 80 mg/dL, and an LDL particle number less than 1,000 nmol/L.

GROUP 4: AGE 40–75, LDL-C 70–189, NO ASCVD, BUT 10-YEAR RISK ≥ 7.5%

Advantages of the new guidelines

• They may reduce ASCVD events for patients at higher risk.
• The risk calculator is easy to use and focuses on global risk, ie, all forms of ASCVD.
• The guidelines promote discussion of risks and benefits between patients and providers.

Limitations of the new guidelines

• The new risk calculator is controversial (see below).
• There is potential for overtreatment, particularly in older patients.
• There is potential for undertreatment, particularly in patients with an elevated LDL-C but whose 10-year risk is less than 7.5% because they are young.
• The guidelines do not address patients younger than 40 or older than 75.
• They do not take into account some traditional risk factors, such as family history, and nontraditional risk factors such as C-reactive protein as measured by ultrasensitive assays, lipoprotein(a), and apolipoprotein B.

Risk calculator controversy

The new risk calculator has aroused strong opinions on both sides of the aisle.

Shortly after the new guidelines were released, cardiologists Dr. Paul Ridker and Dr. Nancy Cook from Brigham and Women’s Hospital in Boston published analyses³⁰ showing that the new risk calculator, which was based on older data from several large cohorts such as the Atherosclerosis Risk in Communities study,³¹ the Cardiovascular Health Study,³² the Coronary Artery Risk Development in Young Adults study,³³ and the Framingham Heart Study,^34,35 was inaccurate in other cohorts. Specifically, in more-recent cohorts (the Women’s Health Study,³⁶ Physicians’ Health Study,³⁷ and Women’s Health Initiative³⁸), the new calculator overestimates the 10-year risk of ASCVD by 75% to 150%.³⁰ Using the new calculator would make approximately 30 million more Americans eligible for statin treatment. The concern is that patients at lower risk would be treated and exposed to potential side effects of statin therapy.

In addition, the risk calculator relies heavily on age and sex and does not include other factors such as triglyceride level, family history, C-reactive protein, or lipoprotein(a). Importantly, and somewhat ironically given the otherwise absolute adherence to randomized controlled trial data for guideline development, the risk calculator has never been verified in prospective studies to adequately show that using it reduces ASCVD events.

Based on the risk calculator, essentially any African American man in his early 60s with no other risk factors has a 10-year risk of ASCVD of 7.5% or higher and, according to the new guidelines, should receive at least moderate-intensity statin therapy.

For example, consider a 64-year-old African American man whose systolic blood pressure is 129 mm Hg, who does not smoke, does not have diabetes, and does not have hypertension, and whose total cholesterol level is 180 mg/dL, HDL-C 70 mg/dL, triglycerides 130 mg/dL, and calculated LDL-C 84 mg/dL. His calculated 10-year risk is, surprisingly, 7.5%.

Alternatively, his twin brother is a two-pack-per-day smoker with untreated hypertension and systolic blood pressure 150 mm Hg, with fasting total cholesterol 153 mg/dL, HDL-C 70 mg/dL, triglycerides 60 mg/dL, and LDL-C 71 mg/dL. His calculated 10-year risk is 10.5%, so according to the new guidelines, he too should receive high-intensity statin therapy. Yet this patient clearly needs better blood pressure control and smoking cessation as his primary risk-reduction efforts, not a statin. While assessing global risk is important, a shortcoming of the new guidelines is that they can inappropriately lead to treating the risk score, not individualizing the treatment to the patient. Because of the errors inherent in the risk calculator, some experts have called for a temporary halt on implementing the new guidelines until the risk calculator can be further validated. In November 2013, the American Heart Association and the American College of Cardiology reaffirmed their support of the new guidelines and recommended that they be implemented as planned. As of the time this manuscript goes to print, there are no plans to halt implementation of the new guidelines.

Case 4: Undertreating a primary prevention patient

A 25-year-old white man with no medical history has a total cholesterol level of 310 mg/dL, HDL-C 50 mg/dL, triglycerides 400 mg/dL, and calculated LDL-C 180 mg/dL. He does not smoke or have hypertension or diabetes but has a strong family history of premature coronary disease (his father died of myocardial infarction at age 42). His body mass index is 25 kg/m². Because he is less than 40 years old, the risk calculator does not apply to him.

If we assume he remains untreated and returns at age 40 with the same clinical factors and laboratory values, his calculated 10-year risk of an ASCVD event according to the new risk calculator will still be only 3.1%. Assuming his medical history remains unchanged as he continues to age, his 10-year risk would not reach 7.5% until he is 58. Would you feel comfortable waiting 33 years before starting statin therapy in this patient?

Waiting for dyslipidemic patients to reach middle age before starting LDL-C-lowering therapy is a failure of prevention. For practical reasons, there are no data from randomized controlled trials with hard outcomes in younger people. Nevertheless, a tenet of preventive cardiology is that cumulative exposure accelerates the “vascular age” ahead of the chronological age. This case illustrates why individualized recommendations guided by LDL-C goals as a target for therapy are needed. For this 25-year-old patient, we would recommend starting an intermediate- or high-potency statin.

Case 5: Rheumatoid arthritis

A 60-year-old postmenopausal white woman with severe rheumatoid arthritis presents for cholesterol evaluation. Her total cholesterol level is 235 mg/dL, HDL-C 50 mg/dL, and LDL-C 165 mg/dL. She does not smoke or have hypertension or diabetes. Her systolic blood pressure is 110 mm Hg. She has elevated C-reactive protein on an ultrasensitive assay and elevated lipoprotein(a).

Her calculated 10-year risk of ASCVD is 3.0%. Assuming her medical history remains the same, she would not reach a calculated 10-year risk of at least 7.5% until age 70. We suggest starting moderate- or high-dose statin therapy in this case, based on data (not from randomized controlled trials) showing an increased risk of ASCVD events in patients with rheumatologic disease, increased lipoprotein(a), and inflammatory markers like C-reactive protein. However, the current guidelines do not address this scenario, other than to suggest that clinician consideration can be given to other risk markers such as these, and that these findings should be discussed in detail with the patient. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial¹⁶ showed a dramatic ASCVD risk reduction in just such patients (Figure 1).

APPLAUSE—AND RESERVATIONS

The newest guidelines for treating high blood cholesterol represent a monumental shift away from using target levels of LDL-C and non-HDL-C and toward a focus on statin intensity for patients in the four highest-risk groups.

We applaud the expert panel for its idealistic approach of using only data from randomized controlled trials, for placing more emphasis on higher-intensity statin treatment, for including stroke in the new definition of ASCVD, and for focusing more attention on treating diabetic patients more aggressively. Simplifying the guidelines is a noble goal. Emphasizing moderate-to-high-intensity statin therapy in patients at moderate-to-high risk should have substantial long-term public health benefits.

However, as we have shown in the case examples, there are significant limitations, and some patients can end up being overtreated, while others may be undertreated.

Guidelines need to be crafted by looking at all the evidence, including the pathophysiology of the disease process, not just data from randomized controlled trials. It is difficult to implement a guideline that on one hand used randomized controlled trials exclusively for recommendations, but on the other hand used an untested risk calculator to guide therapy. Randomized controlled trials are not available for every scenario.

Further, absence of randomized controlled trial data in a given scenario should not be interpreted as evidence of lack of benefit. An example of this is a primary-prevention patient under age 40 with elevated LDL-C below the 190 mg/dL cutoff who otherwise is healthy and without risk factors (eg, Case 4). By disregarding all evidence that is not from randomized controlled trials, the expert panel fails to account for the extensive pathophysiology of ASCVD, which often begins at a young age and takes decades to develop.^5,6,39 An entire generation of patients who have not reached the age of inclusion in most randomized controlled trials with hard outcomes is excluded (unless the LDL-C level is very high), potentially setting back decades of progress in the field of prevention. Prevention only works if started. With childhood and young adult obesity sharply rising, we should not fail to address the under-40-year-old patient population in our guidelines.

Guidelines are designed to be expert opinion, not to dictate practice. Focusing on the individual patient instead of the general population at risk, the expert panel appropriately emphasizes the “importance of clinician judgment, weighing potential benefits, adverse effects, drug-drug interactions and patient preferences.” However, by excluding all data that do not come from randomized controlled trials, the panel neglects a very large base of knowledge and leaves many clinicians without as much expert opinion as we had hoped for.

LDL-C goals are important: they provide a scorecard to help the patient with lifestyle and dietary changes. They provide the health care provider guidance in making treatment decisions and focusing on treatment of a single patient, not a population. Moreover, if a patient has difficulty taking standard doses of statins because of side effects, the absence of LDL-C goals makes decision-making nearly impossible. We hope physicians will rely on LDL-C goals in such situations, falling back on the ATP III recommendations, although many patients may simply go untreated until they present with ASCVD or until they “age in” to a higher risk category.

We suggest caution in strict adherence to the new guidelines and instead urge physicians to consider a hybrid of the old guidelines (using the ATP III LDL-C goals) and the new ones (emphasizing global risk assessment and high-intensity statin treatment).

On November 12, 2013, a joint task force for the American College of Cardiology and American Heart Association released new guidelines for treating high blood cholesterol to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults.¹

This document arrives after several years of intense deliberation, 12 years after the third Adult Treatment Panel (ATP III) guidelines,² and 8 years after an ATP III update recommending that low-density lipoprotein cholesterol (LDL-C) levels be lowered aggressively (to less than 70 mg/dL) as an option in patients at high risk.³ It represents a major shift in the approach to and management of high blood cholesterol and has sparked considerable controversy.

In the following commentary, we summarize the new guidelines and the philosophy employed by the task force in generating them. We will also examine some advantages and what we believe to be several shortcomings of the new guidelines. These latter points are illustrated through case examples.

IN RANDOMIZED CONTROLLED TRIALS WE TRUST

In collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American College of Cardiology and American Heart Association formed an expert panel task force in 2008.

The task force elected to use only evidence from randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials (and only predefined outcomes of the trials, not post hoc analyses) in formulating its recommendations, with the goal of providing the strongest possible evidence.

The authors state that “By using [randomized controlled trial] data to identify those most likely to benefit [emphasis in original] from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD.”³ They also state the guidelines are meant to “inform clinical judgment, not replace it” and that clinician judgment in addition to discussion with patients remains vital.

During the deliberations, the National Heart, Lung, and Blood Institute removed itself from participating, stating its mission no longer included drafting new guidelines. Additionally, other initial members of the task force removed themselves because of disagreement and concerns about the direction of the new guidelines.

These guidelines, and their accompanying new cardiovascular risk calculator,⁴ were released without a preliminary period to allow for open discussion, comment, and critique by physicians outside the panel. No attempt was made to harmonize the guidelines with previous versions (eg, ATP III) or with current international guidelines.

WHAT’S NEW IN THE GUIDELINES?

The following are the major changes in the new guidelines for treating high blood cholesterol:

• Treatment goals for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) are no longer recommended.
• High-intensity and moderate-intensity statin treatment is emphasized, and low-intensity statin therapy is nearly eliminated.
• “ASCVD” now includes stroke in addition to coronary heart disease and peripheral arterial disease.
• Four groups are targeted for treatment (see below).
• Nonstatin therapies have been markedly de-emphasized.
• No guidelines are provided for treating high triglyceride levels.

The new guidelines emphasize lifestyle modification as the foundation for reducing risk, regardless of cholesterol therapy. No recommendations are given for patients with New York Heart Association class II, III, or IV heart failure or for hemodialysis patients, because there were insufficient data from randomized controlled trials to support recommendations. Similarly, the guidelines apply only to people between the ages of 40 and 75 (risk calculator ages 40–79), because the authors believed there was not enough evidence from randomized controlled trials to allow development of guidelines outside of this age range.

FOUR MAJOR STATIN TREATMENT GROUPS

The new guidelines specify four groups that merit intensive or moderately intensive statin therapy (Table 1)¹:

• People with clinical ASCVD
• People with LDL-C levels of 190 mg/dL or higher
• People with diabetes, age 40 to 75
• People without diabetes, age 40 to 75, with LDL-C levels 70–189 mg/dL, and a 10-year ASCVD risk of 7.5% or higher as determined by the new risk calculator⁴ (which also calculates the lifetime risk of ASCVD).

Below, we will address each of these four groups and provide case scenarios to consider. In general, our major disagreements with the new recommendations pertain to the first and fourth categories.

GROUP 1: PEOPLE WITH CLINICAL ASCVD

Advantages of the new guidelines

• They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
• They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
• Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)

Limitations of the new guidelines

• They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
• Patients no longer have a goal to strive for or a way to monitor their progress.
• The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
• They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
• They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.

Case 1: Is LDL-C 110 mg/dL low enough?

A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m². He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:

• Total cholesterol 290 mg/dL
• HDL-C 50 mg/dL
• Triglycerides 250 mg/dL
• Calculated LDL-C 190 mg/dL.

Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:

• Total cholesterol 180 mg/dL
• HDL-C 55 mg/dL
• Triglycerides 75 mg/dL
• Calculated LDL-C 110 mg/dL.

Comment: Lack of LDL-C goals is a flaw

The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.

However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.

Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?

A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.^5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).^7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.

The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,²⁰ provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).

In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.

Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.

For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.

GROUP 2: PEOPLE WITH LDL-C ≥ 190

Advantages of the new guidelines

• They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.

Limitations of the new guidelines

• The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines

• Although high-intensity statin therapy is indicated for this group, we believe that, using the new risk calculator, some patients may receive overly aggressive treatment, thus increasing the possibility of statin side effects.
• The guidelines do not address patients younger than 40 or older than 75.
• Diabetic patients have a high residual risk of ASCVD events, even on statin therapy. Yet the guidelines ignore the potential benefits of more aggressive LDL-lowering or non-LDL secondary targets for therapy.

Case 2: How low is too low?

A 63-year-old white woman, a nonsmoker with recently diagnosed diabetes, is seen by her primary care physician. She has hypertension, for which she takes lisinopril 5 mg daily. Her fasting lipid values are:

• Total cholesterol 160 mg/dL
• HDL-C 64 mg/dL
• Triglycerides 100 mg/dL
• Calculated LDL-C 76 mg/dL.

Her systolic blood pressure is 129 mm Hg, and based on the new risk calculator, her 10-year risk of cardiovascular disease is 10.2%. According to the new guidelines, she should be started on high-intensity statin treatment (Table 1).

Although this is an acceptable initial course of action, it necessitates close vigilance, since it may actually drive her LDL-C level too low. Randomized controlled trials have typically used an LDL-C concentration of less than or equal to 25 mg/dL as the safety cutoff. With a typical LDL-C reduction of at least 50% on high-intensity statins, our patient’s expected LDL-C level will likely be in the low 30s. We believe this would be a good outcome, provided that she tolerates the medication without adverse effects. However, responses to statins vary from patient to patient.

High-intensity statin therapy may not be necessary to reduce risk adequately in all patients who have diabetes without preexisting vascular disease. The Collaborative Atorvastatin Diabetes Study¹² compared atorvastatin 10 mg vs placebo in people with type 2 diabetes, age 40 to 75, who had one or more cardiovascular risk factors but no signs or symptoms of preexisting ASCVD and who had only average or below-average cholesterol levels—precisely like this patient. The trial was terminated early because of a clear benefit (a 37% reduction in the composite end point of major adverse cardiovascular events) in the intervention group. For our patient, we believe an alternative and acceptable approach would be to begin moderate-intensity statin therapy (eg, with atorvastatin 10 mg) (Table 1).

Alternatively, in a patient with diabetes and previous atherosclerotic vascular disease or with a high 10-year risk and high LDL-C, limiting treatment to high-intensity statin therapy by itself may deny them the potential benefits of combination therapies and targeting to lower LDL-C levels or non-HDL-C secondary targets. Guidelines from the American Diabetes Association²⁸ and the American Association of Clinical Endocrinologists²⁹ continue to recommend an LDL-C goal of less than 70 mg/dL in patients at high risk, a non-HDL-C less than 100 mg/dL, an apolipoprotein B less than 80 mg/dL, and an LDL particle number less than 1,000 nmol/L.

GROUP 4: AGE 40–75, LDL-C 70–189, NO ASCVD, BUT 10-YEAR RISK ≥ 7.5%

Advantages of the new guidelines

• They may reduce ASCVD events for patients at higher risk.
• The risk calculator is easy to use and focuses on global risk, ie, all forms of ASCVD.
• The guidelines promote discussion of risks and benefits between patients and providers.

Limitations of the new guidelines

• The new risk calculator is controversial (see below).
• There is potential for overtreatment, particularly in older patients.
• There is potential for undertreatment, particularly in patients with an elevated LDL-C but whose 10-year risk is less than 7.5% because they are young.
• The guidelines do not address patients younger than 40 or older than 75.
• They do not take into account some traditional risk factors, such as family history, and nontraditional risk factors such as C-reactive protein as measured by ultrasensitive assays, lipoprotein(a), and apolipoprotein B.

Risk calculator controversy

The new risk calculator has aroused strong opinions on both sides of the aisle.

Shortly after the new guidelines were released, cardiologists Dr. Paul Ridker and Dr. Nancy Cook from Brigham and Women’s Hospital in Boston published analyses³⁰ showing that the new risk calculator, which was based on older data from several large cohorts such as the Atherosclerosis Risk in Communities study,³¹ the Cardiovascular Health Study,³² the Coronary Artery Risk Development in Young Adults study,³³ and the Framingham Heart Study,^34,35 was inaccurate in other cohorts. Specifically, in more-recent cohorts (the Women’s Health Study,³⁶ Physicians’ Health Study,³⁷ and Women’s Health Initiative³⁸), the new calculator overestimates the 10-year risk of ASCVD by 75% to 150%.³⁰ Using the new calculator would make approximately 30 million more Americans eligible for statin treatment. The concern is that patients at lower risk would be treated and exposed to potential side effects of statin therapy.

In addition, the risk calculator relies heavily on age and sex and does not include other factors such as triglyceride level, family history, C-reactive protein, or lipoprotein(a). Importantly, and somewhat ironically given the otherwise absolute adherence to randomized controlled trial data for guideline development, the risk calculator has never been verified in prospective studies to adequately show that using it reduces ASCVD events.

Based on the risk calculator, essentially any African American man in his early 60s with no other risk factors has a 10-year risk of ASCVD of 7.5% or higher and, according to the new guidelines, should receive at least moderate-intensity statin therapy.

For example, consider a 64-year-old African American man whose systolic blood pressure is 129 mm Hg, who does not smoke, does not have diabetes, and does not have hypertension, and whose total cholesterol level is 180 mg/dL, HDL-C 70 mg/dL, triglycerides 130 mg/dL, and calculated LDL-C 84 mg/dL. His calculated 10-year risk is, surprisingly, 7.5%.

Alternatively, his twin brother is a two-pack-per-day smoker with untreated hypertension and systolic blood pressure 150 mm Hg, with fasting total cholesterol 153 mg/dL, HDL-C 70 mg/dL, triglycerides 60 mg/dL, and LDL-C 71 mg/dL. His calculated 10-year risk is 10.5%, so according to the new guidelines, he too should receive high-intensity statin therapy. Yet this patient clearly needs better blood pressure control and smoking cessation as his primary risk-reduction efforts, not a statin. While assessing global risk is important, a shortcoming of the new guidelines is that they can inappropriately lead to treating the risk score, not individualizing the treatment to the patient. Because of the errors inherent in the risk calculator, some experts have called for a temporary halt on implementing the new guidelines until the risk calculator can be further validated. In November 2013, the American Heart Association and the American College of Cardiology reaffirmed their support of the new guidelines and recommended that they be implemented as planned. As of the time this manuscript goes to print, there are no plans to halt implementation of the new guidelines.

Case 4: Undertreating a primary prevention patient

A 25-year-old white man with no medical history has a total cholesterol level of 310 mg/dL, HDL-C 50 mg/dL, triglycerides 400 mg/dL, and calculated LDL-C 180 mg/dL. He does not smoke or have hypertension or diabetes but has a strong family history of premature coronary disease (his father died of myocardial infarction at age 42). His body mass index is 25 kg/m². Because he is less than 40 years old, the risk calculator does not apply to him.

If we assume he remains untreated and returns at age 40 with the same clinical factors and laboratory values, his calculated 10-year risk of an ASCVD event according to the new risk calculator will still be only 3.1%. Assuming his medical history remains unchanged as he continues to age, his 10-year risk would not reach 7.5% until he is 58. Would you feel comfortable waiting 33 years before starting statin therapy in this patient?

Waiting for dyslipidemic patients to reach middle age before starting LDL-C-lowering therapy is a failure of prevention. For practical reasons, there are no data from randomized controlled trials with hard outcomes in younger people. Nevertheless, a tenet of preventive cardiology is that cumulative exposure accelerates the “vascular age” ahead of the chronological age. This case illustrates why individualized recommendations guided by LDL-C goals as a target for therapy are needed. For this 25-year-old patient, we would recommend starting an intermediate- or high-potency statin.

Case 5: Rheumatoid arthritis

A 60-year-old postmenopausal white woman with severe rheumatoid arthritis presents for cholesterol evaluation. Her total cholesterol level is 235 mg/dL, HDL-C 50 mg/dL, and LDL-C 165 mg/dL. She does not smoke or have hypertension or diabetes. Her systolic blood pressure is 110 mm Hg. She has elevated C-reactive protein on an ultrasensitive assay and elevated lipoprotein(a).

Her calculated 10-year risk of ASCVD is 3.0%. Assuming her medical history remains the same, she would not reach a calculated 10-year risk of at least 7.5% until age 70. We suggest starting moderate- or high-dose statin therapy in this case, based on data (not from randomized controlled trials) showing an increased risk of ASCVD events in patients with rheumatologic disease, increased lipoprotein(a), and inflammatory markers like C-reactive protein. However, the current guidelines do not address this scenario, other than to suggest that clinician consideration can be given to other risk markers such as these, and that these findings should be discussed in detail with the patient. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial¹⁶ showed a dramatic ASCVD risk reduction in just such patients (Figure 1).

APPLAUSE—AND RESERVATIONS

The newest guidelines for treating high blood cholesterol represent a monumental shift away from using target levels of LDL-C and non-HDL-C and toward a focus on statin intensity for patients in the four highest-risk groups.

We applaud the expert panel for its idealistic approach of using only data from randomized controlled trials, for placing more emphasis on higher-intensity statin treatment, for including stroke in the new definition of ASCVD, and for focusing more attention on treating diabetic patients more aggressively. Simplifying the guidelines is a noble goal. Emphasizing moderate-to-high-intensity statin therapy in patients at moderate-to-high risk should have substantial long-term public health benefits.

However, as we have shown in the case examples, there are significant limitations, and some patients can end up being overtreated, while others may be undertreated.

Guidelines need to be crafted by looking at all the evidence, including the pathophysiology of the disease process, not just data from randomized controlled trials. It is difficult to implement a guideline that on one hand used randomized controlled trials exclusively for recommendations, but on the other hand used an untested risk calculator to guide therapy. Randomized controlled trials are not available for every scenario.

Further, absence of randomized controlled trial data in a given scenario should not be interpreted as evidence of lack of benefit. An example of this is a primary-prevention patient under age 40 with elevated LDL-C below the 190 mg/dL cutoff who otherwise is healthy and without risk factors (eg, Case 4). By disregarding all evidence that is not from randomized controlled trials, the expert panel fails to account for the extensive pathophysiology of ASCVD, which often begins at a young age and takes decades to develop.^5,6,39 An entire generation of patients who have not reached the age of inclusion in most randomized controlled trials with hard outcomes is excluded (unless the LDL-C level is very high), potentially setting back decades of progress in the field of prevention. Prevention only works if started. With childhood and young adult obesity sharply rising, we should not fail to address the under-40-year-old patient population in our guidelines.

Guidelines are designed to be expert opinion, not to dictate practice. Focusing on the individual patient instead of the general population at risk, the expert panel appropriately emphasizes the “importance of clinician judgment, weighing potential benefits, adverse effects, drug-drug interactions and patient preferences.” However, by excluding all data that do not come from randomized controlled trials, the panel neglects a very large base of knowledge and leaves many clinicians without as much expert opinion as we had hoped for.

LDL-C goals are important: they provide a scorecard to help the patient with lifestyle and dietary changes. They provide the health care provider guidance in making treatment decisions and focusing on treatment of a single patient, not a population. Moreover, if a patient has difficulty taking standard doses of statins because of side effects, the absence of LDL-C goals makes decision-making nearly impossible. We hope physicians will rely on LDL-C goals in such situations, falling back on the ATP III recommendations, although many patients may simply go untreated until they present with ASCVD or until they “age in” to a higher risk category.

We suggest caution in strict adherence to the new guidelines and instead urge physicians to consider a hybrid of the old guidelines (using the ATP III LDL-C goals) and the new ones (emphasizing global risk assessment and high-intensity statin treatment).

On November 12, 2013, a joint task force for the American College of Cardiology and American Heart Association released new guidelines for treating high blood cholesterol to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults.¹

This document arrives after several years of intense deliberation, 12 years after the third Adult Treatment Panel (ATP III) guidelines,² and 8 years after an ATP III update recommending that low-density lipoprotein cholesterol (LDL-C) levels be lowered aggressively (to less than 70 mg/dL) as an option in patients at high risk.³ It represents a major shift in the approach to and management of high blood cholesterol and has sparked considerable controversy.

In the following commentary, we summarize the new guidelines and the philosophy employed by the task force in generating them. We will also examine some advantages and what we believe to be several shortcomings of the new guidelines. These latter points are illustrated through case examples.

IN RANDOMIZED CONTROLLED TRIALS WE TRUST

In collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American College of Cardiology and American Heart Association formed an expert panel task force in 2008.

The task force elected to use only evidence from randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials (and only predefined outcomes of the trials, not post hoc analyses) in formulating its recommendations, with the goal of providing the strongest possible evidence.

The authors state that “By using [randomized controlled trial] data to identify those most likely to benefit [emphasis in original] from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD.”³ They also state the guidelines are meant to “inform clinical judgment, not replace it” and that clinician judgment in addition to discussion with patients remains vital.

During the deliberations, the National Heart, Lung, and Blood Institute removed itself from participating, stating its mission no longer included drafting new guidelines. Additionally, other initial members of the task force removed themselves because of disagreement and concerns about the direction of the new guidelines.

These guidelines, and their accompanying new cardiovascular risk calculator,⁴ were released without a preliminary period to allow for open discussion, comment, and critique by physicians outside the panel. No attempt was made to harmonize the guidelines with previous versions (eg, ATP III) or with current international guidelines.

WHAT’S NEW IN THE GUIDELINES?

The following are the major changes in the new guidelines for treating high blood cholesterol:

• Treatment goals for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) are no longer recommended.
• High-intensity and moderate-intensity statin treatment is emphasized, and low-intensity statin therapy is nearly eliminated.
• “ASCVD” now includes stroke in addition to coronary heart disease and peripheral arterial disease.
• Four groups are targeted for treatment (see below).
• Nonstatin therapies have been markedly de-emphasized.
• No guidelines are provided for treating high triglyceride levels.

The new guidelines emphasize lifestyle modification as the foundation for reducing risk, regardless of cholesterol therapy. No recommendations are given for patients with New York Heart Association class II, III, or IV heart failure or for hemodialysis patients, because there were insufficient data from randomized controlled trials to support recommendations. Similarly, the guidelines apply only to people between the ages of 40 and 75 (risk calculator ages 40–79), because the authors believed there was not enough evidence from randomized controlled trials to allow development of guidelines outside of this age range.

FOUR MAJOR STATIN TREATMENT GROUPS

The new guidelines specify four groups that merit intensive or moderately intensive statin therapy (Table 1)¹:

• People with clinical ASCVD
• People with LDL-C levels of 190 mg/dL or higher
• People with diabetes, age 40 to 75
• People without diabetes, age 40 to 75, with LDL-C levels 70–189 mg/dL, and a 10-year ASCVD risk of 7.5% or higher as determined by the new risk calculator⁴ (which also calculates the lifetime risk of ASCVD).

Below, we will address each of these four groups and provide case scenarios to consider. In general, our major disagreements with the new recommendations pertain to the first and fourth categories.

GROUP 1: PEOPLE WITH CLINICAL ASCVD

Advantages of the new guidelines

• They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
• They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
• Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)

Limitations of the new guidelines

• They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
• Patients no longer have a goal to strive for or a way to monitor their progress.
• The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
• They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
• They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.

Case 1: Is LDL-C 110 mg/dL low enough?

A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m². He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:

• Total cholesterol 290 mg/dL
• HDL-C 50 mg/dL
• Triglycerides 250 mg/dL
• Calculated LDL-C 190 mg/dL.

Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:

• Total cholesterol 180 mg/dL
• HDL-C 55 mg/dL
• Triglycerides 75 mg/dL
• Calculated LDL-C 110 mg/dL.

Comment: Lack of LDL-C goals is a flaw

The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.

However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.

Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?

A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.^5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).^7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.

The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,²⁰ provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).

In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.

Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.

For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.

GROUP 2: PEOPLE WITH LDL-C ≥ 190

Advantages of the new guidelines

• They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.

Limitations of the new guidelines

• The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines

• Although high-intensity statin therapy is indicated for this group, we believe that, using the new risk calculator, some patients may receive overly aggressive treatment, thus increasing the possibility of statin side effects.
• The guidelines do not address patients younger than 40 or older than 75.
• Diabetic patients have a high residual risk of ASCVD events, even on statin therapy. Yet the guidelines ignore the potential benefits of more aggressive LDL-lowering or non-LDL secondary targets for therapy.

Case 2: How low is too low?

A 63-year-old white woman, a nonsmoker with recently diagnosed diabetes, is seen by her primary care physician. She has hypertension, for which she takes lisinopril 5 mg daily. Her fasting lipid values are:

• Total cholesterol 160 mg/dL
• HDL-C 64 mg/dL
• Triglycerides 100 mg/dL
• Calculated LDL-C 76 mg/dL.

Her systolic blood pressure is 129 mm Hg, and based on the new risk calculator, her 10-year risk of cardiovascular disease is 10.2%. According to the new guidelines, she should be started on high-intensity statin treatment (Table 1).

Although this is an acceptable initial course of action, it necessitates close vigilance, since it may actually drive her LDL-C level too low. Randomized controlled trials have typically used an LDL-C concentration of less than or equal to 25 mg/dL as the safety cutoff. With a typical LDL-C reduction of at least 50% on high-intensity statins, our patient’s expected LDL-C level will likely be in the low 30s. We believe this would be a good outcome, provided that she tolerates the medication without adverse effects. However, responses to statins vary from patient to patient.

High-intensity statin therapy may not be necessary to reduce risk adequately in all patients who have diabetes without preexisting vascular disease. The Collaborative Atorvastatin Diabetes Study¹² compared atorvastatin 10 mg vs placebo in people with type 2 diabetes, age 40 to 75, who had one or more cardiovascular risk factors but no signs or symptoms of preexisting ASCVD and who had only average or below-average cholesterol levels—precisely like this patient. The trial was terminated early because of a clear benefit (a 37% reduction in the composite end point of major adverse cardiovascular events) in the intervention group. For our patient, we believe an alternative and acceptable approach would be to begin moderate-intensity statin therapy (eg, with atorvastatin 10 mg) (Table 1).

Alternatively, in a patient with diabetes and previous atherosclerotic vascular disease or with a high 10-year risk and high LDL-C, limiting treatment to high-intensity statin therapy by itself may deny them the potential benefits of combination therapies and targeting to lower LDL-C levels or non-HDL-C secondary targets. Guidelines from the American Diabetes Association²⁸ and the American Association of Clinical Endocrinologists²⁹ continue to recommend an LDL-C goal of less than 70 mg/dL in patients at high risk, a non-HDL-C less than 100 mg/dL, an apolipoprotein B less than 80 mg/dL, and an LDL particle number less than 1,000 nmol/L.

GROUP 4: AGE 40–75, LDL-C 70–189, NO ASCVD, BUT 10-YEAR RISK ≥ 7.5%

Advantages of the new guidelines

• They may reduce ASCVD events for patients at higher risk.
• The risk calculator is easy to use and focuses on global risk, ie, all forms of ASCVD.
• The guidelines promote discussion of risks and benefits between patients and providers.

Limitations of the new guidelines

• The new risk calculator is controversial (see below).
• There is potential for overtreatment, particularly in older patients.
• There is potential for undertreatment, particularly in patients with an elevated LDL-C but whose 10-year risk is less than 7.5% because they are young.
• The guidelines do not address patients younger than 40 or older than 75.
• They do not take into account some traditional risk factors, such as family history, and nontraditional risk factors such as C-reactive protein as measured by ultrasensitive assays, lipoprotein(a), and apolipoprotein B.

Risk calculator controversy

The new risk calculator has aroused strong opinions on both sides of the aisle.

Shortly after the new guidelines were released, cardiologists Dr. Paul Ridker and Dr. Nancy Cook from Brigham and Women’s Hospital in Boston published analyses³⁰ showing that the new risk calculator, which was based on older data from several large cohorts such as the Atherosclerosis Risk in Communities study,³¹ the Cardiovascular Health Study,³² the Coronary Artery Risk Development in Young Adults study,³³ and the Framingham Heart Study,^34,35 was inaccurate in other cohorts. Specifically, in more-recent cohorts (the Women’s Health Study,³⁶ Physicians’ Health Study,³⁷ and Women’s Health Initiative³⁸), the new calculator overestimates the 10-year risk of ASCVD by 75% to 150%.³⁰ Using the new calculator would make approximately 30 million more Americans eligible for statin treatment. The concern is that patients at lower risk would be treated and exposed to potential side effects of statin therapy.

In addition, the risk calculator relies heavily on age and sex and does not include other factors such as triglyceride level, family history, C-reactive protein, or lipoprotein(a). Importantly, and somewhat ironically given the otherwise absolute adherence to randomized controlled trial data for guideline development, the risk calculator has never been verified in prospective studies to adequately show that using it reduces ASCVD events.

Based on the risk calculator, essentially any African American man in his early 60s with no other risk factors has a 10-year risk of ASCVD of 7.5% or higher and, according to the new guidelines, should receive at least moderate-intensity statin therapy.

For example, consider a 64-year-old African American man whose systolic blood pressure is 129 mm Hg, who does not smoke, does not have diabetes, and does not have hypertension, and whose total cholesterol level is 180 mg/dL, HDL-C 70 mg/dL, triglycerides 130 mg/dL, and calculated LDL-C 84 mg/dL. His calculated 10-year risk is, surprisingly, 7.5%.

Alternatively, his twin brother is a two-pack-per-day smoker with untreated hypertension and systolic blood pressure 150 mm Hg, with fasting total cholesterol 153 mg/dL, HDL-C 70 mg/dL, triglycerides 60 mg/dL, and LDL-C 71 mg/dL. His calculated 10-year risk is 10.5%, so according to the new guidelines, he too should receive high-intensity statin therapy. Yet this patient clearly needs better blood pressure control and smoking cessation as his primary risk-reduction efforts, not a statin. While assessing global risk is important, a shortcoming of the new guidelines is that they can inappropriately lead to treating the risk score, not individualizing the treatment to the patient. Because of the errors inherent in the risk calculator, some experts have called for a temporary halt on implementing the new guidelines until the risk calculator can be further validated. In November 2013, the American Heart Association and the American College of Cardiology reaffirmed their support of the new guidelines and recommended that they be implemented as planned. As of the time this manuscript goes to print, there are no plans to halt implementation of the new guidelines.

Case 4: Undertreating a primary prevention patient

A 25-year-old white man with no medical history has a total cholesterol level of 310 mg/dL, HDL-C 50 mg/dL, triglycerides 400 mg/dL, and calculated LDL-C 180 mg/dL. He does not smoke or have hypertension or diabetes but has a strong family history of premature coronary disease (his father died of myocardial infarction at age 42). His body mass index is 25 kg/m². Because he is less than 40 years old, the risk calculator does not apply to him.

If we assume he remains untreated and returns at age 40 with the same clinical factors and laboratory values, his calculated 10-year risk of an ASCVD event according to the new risk calculator will still be only 3.1%. Assuming his medical history remains unchanged as he continues to age, his 10-year risk would not reach 7.5% until he is 58. Would you feel comfortable waiting 33 years before starting statin therapy in this patient?

Waiting for dyslipidemic patients to reach middle age before starting LDL-C-lowering therapy is a failure of prevention. For practical reasons, there are no data from randomized controlled trials with hard outcomes in younger people. Nevertheless, a tenet of preventive cardiology is that cumulative exposure accelerates the “vascular age” ahead of the chronological age. This case illustrates why individualized recommendations guided by LDL-C goals as a target for therapy are needed. For this 25-year-old patient, we would recommend starting an intermediate- or high-potency statin.

Case 5: Rheumatoid arthritis

A 60-year-old postmenopausal white woman with severe rheumatoid arthritis presents for cholesterol evaluation. Her total cholesterol level is 235 mg/dL, HDL-C 50 mg/dL, and LDL-C 165 mg/dL. She does not smoke or have hypertension or diabetes. Her systolic blood pressure is 110 mm Hg. She has elevated C-reactive protein on an ultrasensitive assay and elevated lipoprotein(a).

Her calculated 10-year risk of ASCVD is 3.0%. Assuming her medical history remains the same, she would not reach a calculated 10-year risk of at least 7.5% until age 70. We suggest starting moderate- or high-dose statin therapy in this case, based on data (not from randomized controlled trials) showing an increased risk of ASCVD events in patients with rheumatologic disease, increased lipoprotein(a), and inflammatory markers like C-reactive protein. However, the current guidelines do not address this scenario, other than to suggest that clinician consideration can be given to other risk markers such as these, and that these findings should be discussed in detail with the patient. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial¹⁶ showed a dramatic ASCVD risk reduction in just such patients (Figure 1).

APPLAUSE—AND RESERVATIONS

The newest guidelines for treating high blood cholesterol represent a monumental shift away from using target levels of LDL-C and non-HDL-C and toward a focus on statin intensity for patients in the four highest-risk groups.

We applaud the expert panel for its idealistic approach of using only data from randomized controlled trials, for placing more emphasis on higher-intensity statin treatment, for including stroke in the new definition of ASCVD, and for focusing more attention on treating diabetic patients more aggressively. Simplifying the guidelines is a noble goal. Emphasizing moderate-to-high-intensity statin therapy in patients at moderate-to-high risk should have substantial long-term public health benefits.

However, as we have shown in the case examples, there are significant limitations, and some patients can end up being overtreated, while others may be undertreated.

Guidelines need to be crafted by looking at all the evidence, including the pathophysiology of the disease process, not just data from randomized controlled trials. It is difficult to implement a guideline that on one hand used randomized controlled trials exclusively for recommendations, but on the other hand used an untested risk calculator to guide therapy. Randomized controlled trials are not available for every scenario.

Further, absence of randomized controlled trial data in a given scenario should not be interpreted as evidence of lack of benefit. An example of this is a primary-prevention patient under age 40 with elevated LDL-C below the 190 mg/dL cutoff who otherwise is healthy and without risk factors (eg, Case 4). By disregarding all evidence that is not from randomized controlled trials, the expert panel fails to account for the extensive pathophysiology of ASCVD, which often begins at a young age and takes decades to develop.^5,6,39 An entire generation of patients who have not reached the age of inclusion in most randomized controlled trials with hard outcomes is excluded (unless the LDL-C level is very high), potentially setting back decades of progress in the field of prevention. Prevention only works if started. With childhood and young adult obesity sharply rising, we should not fail to address the under-40-year-old patient population in our guidelines.

Guidelines are designed to be expert opinion, not to dictate practice. Focusing on the individual patient instead of the general population at risk, the expert panel appropriately emphasizes the “importance of clinician judgment, weighing potential benefits, adverse effects, drug-drug interactions and patient preferences.” However, by excluding all data that do not come from randomized controlled trials, the panel neglects a very large base of knowledge and leaves many clinicians without as much expert opinion as we had hoped for.

LDL-C goals are important: they provide a scorecard to help the patient with lifestyle and dietary changes. They provide the health care provider guidance in making treatment decisions and focusing on treatment of a single patient, not a population. Moreover, if a patient has difficulty taking standard doses of statins because of side effects, the absence of LDL-C goals makes decision-making nearly impossible. We hope physicians will rely on LDL-C goals in such situations, falling back on the ATP III recommendations, although many patients may simply go untreated until they present with ASCVD or until they “age in” to a higher risk category.

We suggest caution in strict adherence to the new guidelines and instead urge physicians to consider a hybrid of the old guidelines (using the ATP III LDL-C goals) and the new ones (emphasizing global risk assessment and high-intensity statin treatment).

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.

Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.

Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease^1–3 and that supplementation with folic acid, vitamin B₆, and vitamin B₁₂ lowers homocysteine levels,^4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.

The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B₆, and vitamin B₁₂ for primary or secondary prevention of cardiovascular disease.

HISTORY OF HOMOCYSTEINE AS A RISK MARKER

Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,⁶ it was not until 1964 that Gibson et al⁷ reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully⁸ made the connection between elevated homocysteine levels and the risk of atherosclerosis.

Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.^3,9,10

In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.

CAUSES OF ELEVATED PLASMA HOMOCYSTEINE

Vitamin deficiencies. Vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.

Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.¹³

Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.

A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia¹⁴), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.¹⁵

A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.¹⁶ The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).¹⁷ Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.¹⁷

ELEVATED HOMOCYSTEINE IS COMMON

In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).^13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.

HOW GREAT IS THE RISK?

Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.

However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,^17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.^21,22

Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al¹⁷ found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.

TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS

Primary prevention of cardiovascular disease

Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B₆, and vitamin B₁₂ would decrease the risk of cardiovascular disease.

Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force ^28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.

In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.³⁰

Secondary prevention of cardiovascular disease

Bazzano et al,⁴⁷ in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.³¹

Albert et al⁴ more recently evaluated the effect of a combination pill containing folic acid, vitamin B₆, and vitamin B₁₂ on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.

Ebbing et al,⁵ in a trial published in 2008, investigated the effect of folic acid, vitamin B₁₂, and vitamin B₆ supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.

Mager et al,³² in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.

The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),³³ recently published, was a double-blind, randomized controlled trial of vitamin B₁₂ and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.

Restenosis after angioplasty

Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.

Namazi et al⁴⁸ evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.

Schnyder et al⁴⁹ evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.

Lange et al³⁵ also evaluated the effect of folic acid, vitamin B₆, and vitamin B₁₂ treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.

The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),⁵⁰ a later meta-analysis contradicts this finding.⁵¹

A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.⁵² Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.⁵³

However, immediately after the Cochrane review was published, Khandanpour et al³⁶ published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.

Kidney disease

One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.

However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).³¹ Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.^11,12,37

FUTURE DIRECTIONS AND RECOMMENDATIONS

Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B₆, and vitamin B₁₂ do not lower the risk of cardiovascular disease.^38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.⁶⁰ (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.

At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.^61,62

Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:

• Whether patients with elevated homocysteine would benefit from such treatment
• At what level it would be appropriate to start treatment
• The appropriate target homocysteine level with treatment.

Particularly given the recent finding that folic acid supplementation may increase cancer risk,⁶³ these questions need closer scrutiny.