The atherosclerotic process begins in childhood and manifests clinically in adulthood as an acute atherothrombotic event (acute coronary syndrome or stroke) or as symptomatic obstructive disease (angina or claudication) ( Fig. 28.1 ). The major risk factors for atherosclerotic cardiovascular disease (ASCVD) are well characterized in populations around the world (advancing age, male sex, increased total and low-density lipoprotein cholesterol [LDL-C], low high-density lipoprotein cholesterol [HDL-C], smoking, elevated blood pressure, and diabetes mellitus) and are largely driven by unhealthy lifestyle habits over the life course.
Adherence to healthy lifestyle habits should be encouraged for all children and adults. Avoidance of smoking, a Mediterranean-type diet, regular physical activity, and avoidance of obesity are all associated with a lower risk of ASCVD events. Drug treatment is recommended to reduce an increased risk of ASCVD events in many higher-risk individuals with advancing age and in those with familial or genetic hypercholesterolemia. After age 75, trajectories of comorbidity begin to widely differ among individuals, and preventive efforts may be of less importance for some patients.Thus, the priorities for clinical intervention shift throughout the lifespan ( Table 28.1 ).
| 20–49 Years | 50–75 Years | > 75 Years |
|---|---|---|
| HEALTHY LIFESTYLE HABITS Avoid smoking – Healthy diet – Regular physical activity – Control obesity Moderate sodium intake – Alcohol in moderation | ||
Statins
| Statins
| Statins
|
Antihypertensive drugs
| Antihypertensive drugs
| Antihypertensive drugs
|
| Aspirin 50–59 years: Low-dose aspirin if ≥ 10-year ASCVD risk at low risk for bleeding 60–69 years: Consider in selected patients with ≥ 10 year ASCVD risk at low risk for bleeding | ||
| EMPHASIZE ADHERENCE TO LIFESTYLE AND DRUG THERAPY | ||
This chapter will focus on the primary prevention of ASCVD in adults of 20 years of age or older. Recommendations from the 2013 prevention guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) are the focus because they were based on a rigorous systematic evidence review performed under the direction of the National Heart, Lung, and Blood Institute (NHLBI). A similar approach to statin initiation is recommended by current cholesterol treatment guidelines from the American Diabetes Association and the United Kingdom National Institute for Health and Care Excellence. The 2013 ACC/AHA recommendations are contrasted with the 2016 European Society of Cardiology (ESC)/ European Atherosclerosis Society (EAS), which are similar to the previous 2012 ESC/EAS prevention guidelines. Additional recommendations from other groups are also discussed, including recent guidelines from the Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force.
Those interested in ASCVD prevention in children and adolescents are referred to the NHLBI pediatric guidelines. However, clinicians should be aware that if a parent has an LDL-C of 190 mg/dL or higher, the offspring, as well as other first-degree relatives, should be screened for familial hypercholesterolemia.
Encourage Long-Term Adherence
As part of an ongoing therapeutic relationship with the patient, adherence to lifestyle and drug therapy should be reinforced at each visit. Blood pressure and body mass index (BMI) should be assessed regularly. A fasting lipid panel should be performed at the initial visit, every 4–6 years as part of ASCVD risk assessment in patients who are not receiving statins, and annually in those receiving statins, or more frequently as needed.
Barriers to adherence should be addressed. Adverse effects during drug therapy often occur and should be addressed in a systematic fashion as outlined in Box 28.1 .
Choice of statin and dose
To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD∗ risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present.
Characteristics predisposing individuals to statin adverse effects include but are not limited to:
- •
Multiple or serious comorbidities, including impaired renal or hepatic function.
- •
History of previous statin intolerance or muscle disorders.
- •
Unexplained ALT elevations > 3 times ULN.
- •
Patient characteristics or concomitant use of drugs affecting statin metabolism.
- •
Age >75 years.
Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to:
- •
History of hemorrhagic stroke.
- •
Asian ancestry
Management of symptoms
The large majority of patients with symptoms during statin therapy can be successfully rechallenged with statin therapy. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm:
- •
To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy.
- •
If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK and creatinine and performing urinalysis for myoglobinuria.
- •
If mild to moderate muscle symptoms develop during statin therapy:
- ○
Discontinue the statin until the symptoms can be evaluated.
- ○
Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
- ○
If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
- ○
If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
- ○
Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
- ○
If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above.
- ○
If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.
- ○
Other symptoms are very unlikely to be due to statin therapy and can be managed using a similar strategy of discontinuation and rechallenge.
Monitoring
- •
Creatine kinase
Do not routinely measure creatine kinase levels (although baseline levels may be helpful in patients with a history of statin intolerance, or if muscle symptoms develop)
- •
Hepatic transaminases
Do not routinely measure hepatic transaminases (unless baseline alanine aminotransferase (ALT) is elevated or symptoms of hepatoxoicity develop)
- •
Glucose and hemoglobin A1c
Do not routinely monitor glycemic parameters. Patients should be monitored as recommended by expert guidelines.
Overview of Primary Prevention Priorities by Age Group
Lifestyle and drug treatment priorities may be different in those 20–49 years, 50–75 years, and over age 75 years (see Table 28.1 ). Therefore, the main recommendations from the US and European guidelines are summarized by age. Guideline recommendations and randomized trial evidence are discussed in more detail in the respective sections on cholesterol, blood pressure, and aspirin therapy. ASCVD risk prediction is discussed in more detail in the cholesterol section, and links to online resources are provided.
Before Age 50
Lifestyle
Adherence to healthy lifestyle habits should be strongly encouraged as the foundation for ASCVD prevention. Changes in lifestyle habits have been shown to slow progression of atherosclerosis in this age group. Smoking cessation is a necessity and should be addressed at every visit.
Cholesterol
Statin therapy is recommended for primary prevention in high-risk patients older than 50 years if they have:
- •
Familial or other genetic hypercholesterolemia (cut-off in the United States, LDL-C ≥ 190 mg/dL; in Europe, total cholesterol > 8 mmol/L or 310 mg/dL).
- •
Diabetes (in the United States, age ≥ 40 years; in Europe, depends on LDL-C level).
- •
Multiple or severe risk factor elevations (in Europe, this includes moderate chronic kidney disease).
For lower-risk primary prevention patients, 10-year cardiovascular risk should be estimated using calculators appropriate to the population under treatment. In the United States, the 2013 ACC/AHA Pooled Cohort Equations should be used as the starting point for estimating 10-year ASCVD risk for those aged 40–75 years if LDL-C is greater than 190 mg/dL. Statin therapy should be considered for those with a 7.5% or higher 10-year ASCVD risk and may be reasonable for those with a 5% to < 7.5% 10-year ASCVD risk. Selected lower-risk patients may also benefit from statin therapy.
In Europe, the Systematic Coronary Risk Estimation (SCORE) equations should be the starting point for estimating 10-year risk of fatal ASCVD in Caucasians who are not otherwise characterized as high risk. The calculated SCORE 10-year fatal ASCVD risk can then characterize patient risk in individuals aged 40–65 years and be used to identify an LDL-C treatment goal: very high risk (≥ 10%; LDL-C goal < 1.8 mmol/L or 70 mg/dL), high risk (5 to < 10%; LDL-C goal < 2.6 mmol/L or 100 mg/dL), moderate (≥ 1% to < 5%; LDL-C goal < 3.0 mmol/L or 115 mg/dL), or low (< 1%; LDL-C goal < 3.0 mmol/L or 115 mg/dL).
Race/ethnic-specific equations (QRISK2) for major cardiovascular disease have been developed for the United Kingdom.
Blood Pressure
Elevated blood pressure should first be addressed through lifestyle modification, including weight loss, increasing regular physical activity, and reducing sodium intake. Although there is little clinical trial evidence in individuals under 50 years of age, antihypertensive drug therapy can be considered if systolic blood pressure remains greater than 140 mm Hg or diastolic blood pressure remains higher than 90 mm Hg on multiple occasions both in and outside the office, especially if other risk factors are present.
Aspirin
There is no indication for aspirin therapy in individuals under 50 years of age.
Age 50-75 Years
Lifestyle
Smoking avoidance and healthy lifestyle habits should continue to be encouraged. However, the primary clinical focus should turn to consideration of preventive drug therapies. The largest body of evidence for preventive drug therapy comes from randomized trials in those aged 50–75 years.
In this age group, atherosclerosis is usually well advanced (see Fig. 28.1 ), with extensive fibrocalcific plaque development in most individuals. The risk of clinical events is significantly increased, and more aggressive risk factor reduction is needed. The randomized trials of drug therapy were all performed on a background of advice to maintain a healthy diet and regular physical activity. However, the modest changes in risk factor levels associated with these lifestyle interventions have not been shown to reduce ASCVD events in this age group.
Cholesterol
Statin therapy is strongly recommended for individuals aged 50–75 years with:
- •
Familial or other genetic hypercholesterolemia (cut-off in the United States, LDL-C ≥ 190 mg/dL; in Europe, total cholesterol > 8 mmol/L or 310 mg/dL).
- •
Diabetes (in the United States, age ≥ 40 years; in Europe, depends on LDL-C level).
- •
Multiple or severe risk factor elevations (in Europe, this includes moderate chronic kidney disease).
- •
Increased ASCVD risk based on risk prediction equations.
In the United States, statins should be considered in individuals up to age 75 years with a 7.5% or greater 10-year ASCVD risk and may be reasonable in those with 5% to < 7.5% 10-year ASCVD risk. Lower-risk patients in the 50–75-year age group may also benefit from statin therapy.
In Europe, SCORE charts can be used for estimating 10-year risk of fatal ASCVD in Caucasians aged 40–65 years who are not otherwise characterized as high risk. The calculated SCORE 10-year fatal ASCVD risk can then characterize patient risk in individuals aged 40–65 years and be used to identify an LDL-C treatment goal: very high risk (≥ 10%; LDL-C goal < 1.8 mmol/L or 70 mg/dL), high risk (5 to < 10%; LDL-C goal < 2.6 mmol/L or 100 mg/dL), moderate (≥ 1% to < 5%; LDL-C goal < 3.0 mmol/L or 115 mg/dL), or low (< 1%; LDL-C goal < 3.0 mmol/L or 115 mg/dL).
Blood Pressure
Antihypertensive drug therapy is recommended in those aged 50 or older if systolic blood pressure remains at 140 mm Hg or higher or diastolic blood pressure remains at 90 mm Hg or higher on multiple occasions both in and outside the office. Greater absolute risk reduction occurs from antihypertensive therapy in higher-risk individuals, and there are little data for those without cardiovascular risk factors less than 80 years of age. In selected high-risk individuals tolerating the current drug regimen, another antihypertensive drug could be considered if systolic blood pressure remains greater than 120 mm Hg.
Aspirin
Aspirin therapy can be considered for those aged 50–59 years at low risk of bleeding and is reasonable to consider in those 60–69 years, with a 10-year or greater ASCVD risk at low risk of bleeding.
Age over 75 Years
Lifestyle
Smoking avoidance and healthy lifestyle habits should continue to be encouraged. Observational evidence suggests health benefits occur from smoking cessation at any age. Regular physical activity, although not shown to reduce ASCVD events or mortality, may be beneficial for improving quality of life.
Cholesterol
Persons in good to excellent health at age 75 are likely to live at least another 10–15 years and so may benefit from preventive drug therapy. Less evidence for primary prevention with statins is available for individuals greater than 75 years, and the randomized trials that are available have conflicting results. The absolute risk of ASCVD events is highest after age 75, but high rates of competing causes of mortality and morbidity may alter the potential net benefit from statin therapy.
In the United States, after age 75 years, there are no strong recommendations for primary prevention statin therapy. Patient preferences for prevention, and concerns about safety, should contribute to the decision to initiate (or continue) statin therapy.
In Europe, age over 75 years is not mentioned as a factor in the decision to initiate statin therapy. The SCORE charts do not estimate 10-year fatal ASCVD risk after age 65 years.
Blood Pressure
Numerous randomized trials have evaluated the effect of antihypertensive therapy on ASCVD outcomes, heart failure, and mortality in generally healthy persons over 75 years. The strongest evidence for those over 75 years supports treating blood pressure greater than 150/or greater than 90 mm Hg, but recent evidence suggests a benefit from treating to blood pressure levels less than 140/<90 mm Hg in persons 75 years of age or older.
Aspirin
Few randomized trial data are available for aspirin in persons over 75 years of age, and aspirin therapy is generally not recommended for primary prevention in this age group due to the excess risk of bleeding in older individuals.
Lifestyle Recommendations
A healthy lifestyle is the foundation of health promotion and disease prevention efforts and should be addressed at every visit ( Table 28.2 ). Regular counseling to improve diet or increase physical activity changes health behaviors and is associated with small improvements in adiposity, blood pressure, and lipid levels. Smoking cessation is discussed in Chapter 18 .
| Diet | Class/LOE |
|---|---|
| I A |
| I A |
| I A |
| I A |
| I A |
| IIa B |
| Physical Activity | |
| CDC |
| IIa A |
Lifestyle Interventions
Diet
The 2013 ACC/AHA lifestyle guideline, ESC/EAS prevention guidelines, and other guidelines recommend a dietary pattern rich in fruits, vegetables, and whole grains that includes low-fat dairy products, poultry, fish, legumes, nuts, and non-tropical vegetable oils (see Table 28.2 ). Intake of sweets, sugar-sweetened beverages, and red meats should be limited. Saturated fat intake should be limited to 5% to 6% of calories and trans fats should be avoided. The caloric content of the diet should be based on the need of the patient to lose, maintain, or gain weight. Alcohol consumption should be limited to two glasses per day (20 g/day of alcohol) for men and one glass per day for women (10 g/day). This dietary pattern can be achieved by following plans such as the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, the United States Department of Agriculture (USDA) Food Pattern, or the American Heart Association Diet.
Randomized trials of the DASH dietary pattern have been shown to reduce blood pressure, and the effect of this diet is enhanced by reducing sodium intake. Restricting sodium to no more than 2400 mg daily is advised for those who would benefit from lowering blood pressure, and greater restriction may be beneficial for some patients.
Physical Activity
For important health benefits, the CDC and the ESC/EAS prevention guidelines recommend at least 150 minutes of moderate-intensity physical activity (e.g., walking) every week, along with muscle strengthening activities on two or more days a week that work all major muscle groups (legs, back, abdomen, chest, shoulders, and arms) (see Table 28.2 ). Alternatively, more vigorous activity (such as jogging or running) can be performed for 75 minutes each week. Activity can be performed throughout the day, as long as moderate to intense effort occurs for at least 10 minutes. Even greater health benefits accrue by increasing moderate-intensity physical activity to 300 minutes per week or vigorous-intensity physical activity to 150 minutes per week.
The 2013 ACC/AHA lifestyle guideline recommends that adults in general should be advised to engage in regular aerobic physical activity to reduce LDL-C, non–HDL-C, and blood pressure. The systematic review of randomized trials performed by the guideline panel found that three to four sessions of moderate-to vigorous-intensity physical activity lasting on average 40 minutes significantly reduced all three risk factors. Reducing sedentary activity, independent of physical activity levels, also appears to have benefits for cardiovascular health.
Obesity Prevention and Control
Maintenance of a healthy weight is recommended by all primary prevention guidelines. Obese or overweight individuals may aim to reduce weight in order to lower blood pressure, improve lipid levels, and reduce the risk of developing type 2 diabetes mellitus. Recommendations from the 2013 AHA/ACC/The Obesity Society (TOS) obesity guideline are summarized in Table 28.3 .
| Obesity | Class/LOE |
|---|---|
| |
| I C |
| I B |
| I B |
| IIa B |
| |
| I A |
| |
| I A |
| I A |
| |
| I A |
| I A |
| IIa A |
| IIa A |
| IIa A |
| I A |
| I A |
| |
| IIa A |
| — |
| IIb C |
BMI (weight in kilograms divided by height in meters squared) should be assessed annually. A BMI of 25.0–29.9 kg/m 2 is considered overweight and a BMI of 30 kg/m 2 or greater is considered obese. The higher the BMI above 25 kg/m 2 , the greater the risk of ASCVD, diabetes, other morbidities, and mortality from all causes. However, cut-points for BMI may not apply to nonwhite racial groups. BMI cut-points that confer increased ASCVD risk may be higher for individuals of African ancestry due to greater muscle mass, and lower in individuals of Asian, Pacific Islander, or Native American ancestry.
Increasing waist circumference and waist/hip ratio also confers an increased risk of ASCVD. These indices may be a better measure for identifying at-risk individuals (see Table 28.3 ). Waist circumference cut-points may differ for various racial/ethnic groups.
Overweight and obese adults with cardiovascular risk factors should be advised to lose and sustain a 3% to 5% reduction in body weight. The systematic review of randomized trials performed by the 2013 AHA/ACC/TOS guideline panel found numerous randomized trials demonstrating that this amount of weight loss reduces blood glucose, hemoglobin A1c, and triglycerides, and reduces the risk of developing type 2 diabetes mellitus. A greater than 5% weight loss results in further reductions in blood pressure, down-titration of antihypertensive medications, further reductions in blood glucose and triglycerides, and increases in HDL-C.
Once it has been determined that a patient may benefit from weight loss, a comprehensive lifestyle program should be advised. Participation in structured weight loss programs, whether provided though healthcare systems or community, commercial, or internet or phone-based programs, has been shown to be helpful. Once the patient achieves the desired weight loss, participation in weight maintenance programs should be encouraged.
Compared with nonsurgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome, although long-term follow-up data are sparse. Based on this evidence, the 2013 ACC/AHA obesity guideline recommended consideration of bariatric surgery for patients with BMI of 40 kg/m 2 or greater and obesity-related comorbid conditions who have not responded to behavioral treatment with or without pharmacotherapy with sufficient weight loss to achieve targeted health outcomes, who are motivated to lose weight. They considered there to be insufficient evidence to support bariatric surgery in those with BMI less than 40 kg/m 2 . In 2016, however, the American Diabetes Association recommended consideration of bariatric surgery in adults with type 2 diabetes whose BMI is greater than 35 kg/m 2 , especially if their diabetes is difficult to control or associated comorbidities are difficult to control with lifestyle and pharmacologic therapy. Bariatric surgery and its complications are costly, and outcomes vary depending on the procedure and experience of the surgeon. Long-term disadvantages may include weight regain, dumping syndrome, and vitamin and mineral deficiencies.
Cholesterol Management
Overview
Total cholesterol and LDL-C levels are associated with an increased risk of ASCVD events across the adult lifespan. Family and genetic epidemiology studies show that individuals with high LDL-C levels are at high risk of premature ASCVD and, conversely, those with low LDL-C are at low lifetime ASCVD risk. Support for a causal role for LDL-C in ASCVD comes from Mendelian randomization studies that have shown that elevated LDL-C levels due to genetic polymorphisms are associated with increased ASCVD risk. Long-term epidemiologic studies have shown that individuals whose non–HDL-C level remains below 130 mg/dL during young adulthood through middle age are at minimal risk of developing advanced atherosclerosis. This correlates with an LDL-C below 100 mg/dL.
The causal role of LDL-C is now conclusively established through the numerous cardiovascular outcomes trials of statin therapy and in a cardiovascular outcomes trial with ezetimibe. Although statins have non–LDL-C effects (often called pleiotropic ), these effects are not associated with cardiovascular risk reduction beyond that expected from the magnitude of LDL-C lowering. LDL-C lowering with statin therapy is the most effective method of reducing cardiovascular risk over a period of 2 to 5 years. However, it is critical to consider the potential for a net benefit from statin or nonstatin therapy when deciding whom to treat. The magnitude of ASCVD risk reduction, adverse effects, cost, and patient preferences all need to be considered before initiating drug therapy to reduce ASCVD risk.
Limited controversy still exists regarding the use of statins for primary prevention. However, recent analyses overwhelmingly support the use of statins for cardiovascular prevention even in low-risk adults, who experience an even greater reduction in the relative risk of cardiovascular events than do higher-risk patients. Statins also reduce total mortality in both high-risk and low-risk individuals.
Although muscle and other symptoms are common in statin-treated patients, the rates of muscle, hepatic, and other adverse effects were similar in placebo and statin-treated patients in randomized trials. Notably, double-blind placebo-controlled trials have found that the large majority of patients intolerant to two or more statins are able to tolerate a moderate-intensity statin on rechallenge. An approach to the management of symptoms on statins is outlined hereafter.
Screening
Systematic cardiovascular risk assessment, including a lipid panel, is recommended in the United States starting at age 21, and in Europe after age 40 in men and age 50 in women. Screening should be repeated every 4 to 6 years thereafter. Although a fasting lipid panel is preferred, a nonfasting lipid panel will identify those with total cholesterol over 200 mg/dL who should then undergo further assessment with a fasting lipid panel.
In the United States, screening for familial hypercholesterolemia should begin in childhood (universal screening at age 9–11 years and again at age 17–20 years; targeted screening at age 2 if a family history of premature ASCVD or familial hypercholesterolemia). Once an individual with suspected familial hypercholesterolemia, or an LDL-C of 190 mg/dL or greater, is identified, cascade screening of family members is recommended by familial hypercholesterolemia experts around the world.
Overview of the 2013 ACC/AHA Cholesterol Guideline
The 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults was based on a rigorous systematic review of randomized drug therapy trials with cardiovascular outcomes. Recommendations were based on the strength of evidence for a net ASCVD risk-reduction benefit from a drug therapy. Consequently, statins were recommended for four groups of patients: those with (1) clinical ASCVD, (2) untreated LDL-C of 190 mg/dL or greater, (3) diabetes and aged between 40 and 75 years, and (4) a 7.5% or greater 10-year ASCVD risk ( Fig. 28.2 ). Moderate evidence supports the use of statins in those with a 5% to < 7.5% 10-year ASCVD risk.
The focus on the reduction in nonfatal and fatal ASCVD risk is an important advance over previous guidelines that addressed only coronary heart disease risk. The risk of stroke increases with advancing age, especially in white women and African-American women and men. In addition to reducing coronary events, statins also reduce the risk of ischemic and total stroke, as well as peripheral arterial disease events.
The 2013 ACC/AHA cholesterol guideline was a major paradigm shift from previous guidelines, as well as the recent 2016 ESC/EAS guidelines, which focus on achieving specific cholesterol targets. Multiple analyses have confirmed that the 2013 ACC/AHA cholesterol guideline approach, when compared to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines and the 2012 ESC/EAS guidelines, better identifies individuals at high ASCVD risk for the appropriate intensity of statin therapy and avoids statin treatment in lower-risk patients. Comparisons with the 2016 ESC/EAS guideline have not yet been performed.
An important consequence of the LDL-C goal approach used in previous guidelines is that these goals may turn into LDL-C thresholds for treatment. Thus, higher-risk patients who are “at goal” are unlikely to be treated, despite evidence of benefit from additional LDL-C lowering from randomized cardiovascular outcomes trials ( Fig. 28.3 ).
There appears to be additional ASCVD risk-reduction benefit when LDL-C levels below the previously recommended targets (<30, <100, or <70 mg/dL) are achieved with statin therapy ( Figs. 28.4 and 28.5 ). Thus, it is not clear what the optimal target should be. Nor is there sufficient data to determine the potential for net benefit (e.g., benefits − adverse effects) from adding nonstatin therapies to maximal statin therapy to achieve a specific cholesterol goal. Additional rationales supporting the move away from LDL-C goals are provided in Box 28.2 .
- 1.
The difficulty of giving up the treat-to-goal paradigm was deliberated extensively over a 3-year period. Many clinicians use targets such as LDL-C < 70 mg/dL and LDL-C < 100 mg/dL for secondary and primary ASCVD prevention (non–HDL-C targets are 30 mg/dL higher). However, the RCT evidence clearly shows that ASCVD events are reduced by using the maximum-tolerated statin intensity in those groups shown to benefit. After a comprehensive review, no RCTs were identified that titrated drug therapy to specific LDL-C or non–HDL-C goals to improve ASCVD outcomes. However, one RCT was identified that showed no additional ASCVD event reduction from the addition of nonstatin therapy to further treat non–HDL-C levels once an LDL-C goal was reached. In AIM-HIGH, the additional reduction in non–HDL-C levels (as well as additional reductions in Apo B, Lp(a), and triglycerides in addition to HDL-C increases) with niacin therapy DID NOT further reduce ASCVD risk in individuals treated to LDL-C levels of 40–80 mg/dL.
- 2.
Use of LDL-C targets may result in under treatment with evidence-based statin therapy or overtreatment with nonstatin drugs that have not been shown to reduce ASCVD events in RCTs (even though the drug may additionally lower LDL-C and/or non–HDL-C). Implications of treating to an LDL-C goal may mean that a suboptimal intensity of statin is used because the goal has been achieved, or that adding a nonstatin therapy to achieve a specific target results in downtitration of the evidence-based intensity of statin for safety reasons. However, when RCT evidence is available that a nonstatin therapy further reduces ASCVD events when added to statin therapy, the nonstatin therapy may be considered.
- 3.
Modest physiologic or laboratory measurement variations in LDL-C and non–HDL-C with little impact on the pathophysiology of atherosclerosis may result in excursions above or below goal, resulting in therapeutic changes that may provide little or no additional net ASCVD risk reduction benefit to the patient.
- 4.
Some examples comparing a strategy based on the four statin benefit groups to a strategy using LDL-C/non–HDL-C targets:
- A.
Secondary prevention – evidence supports high-intensity statin therapy for this group to maximally lower LDL-C. It does not support the use of an LDL-C target. For example, if a secondary-prevention patient achieves an LDL-C of 78 mg/dL on a dose of 80 mg of atorvastatin, the patient is receiving evidence-based therapy. As of yet, there are no data to show that adding nonstatin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk-reduction benefit with an acceptable margin of safety. Indeed, AIM-HIGH demonstrated the futility of adding niacin in individuals with low HDL-C and high triglycerides, and ACCORD demonstrated the futility of adding fenofibrate in persons with diabetes. Although an ACCORD subgroup analysis of those with high triglycerides and low HDL-C levels suggested that fenofibrate may reduce ASCVD events in patients with diabetes, this is hypothesis generating and needs further testing in comparison to the evidence-based use of a high-intensity statin. In addition, not having a goal of < 70 mg/dL for LDL-C means that the patient who is adhering to optimal lifestyle management and receiving a high-intensity statin avoids additional, non–evidence-based therapy just because his/her LDL-C is higher than an arbitrary cut-point. Indeed, the LDL-C goal approach can make this patient unnecessarily feel like a failure.
- B.
Familial hypercholesterolemia with LDL-C ≥ 190 mg/dL – In many cases, individuals with familial hypercholesterolemia are unable to achieve an LDL-C goal < 100 mg/dL. For example, an individual with familial hypercholesterolemia may achieve an LDL-C of only 120 mg/dL despite use of three cholesterol-lowering drugs. Although this individual may have fallen short of the 100 mg/dL goal, he/she has decreased his/her LDL-C by > 50% (starting from an untreated LDL-C level of ∼325–400 mg/dL). These patients are not treatment failures, as observational data has shown significant reductions in ASCVD events without achieving specific LDL-C targets. This is an area where observational data supports the recommended approach.
- C.
Type 2 diabetes – For those 40–75 years of age with risk factors, the potential benefits of LDL-C lowering with a high-intensity statin are substantial. Because those with diabetes often have lower LDL-C levels than those without diabetes, “goal”-directed therapy often encourages use of a lower statin dose than is supported by the RCTs, and nonstatin drugs may be added to address low HDL-C or high triglycerides, for which RCT evidence of an ASCVD event reduction is lacking. Giving a maximally tolerated statin intensity should receive primary emphasis because it most accurately reflects the data that statins reduce the relative risk of ASCVD events similarly in individuals with and without diabetes, and in primary and secondary prevention in those with diabetes, along with evidence that high-intensity statins reduce ASCVD events more than moderate-intensity statins.
- D.
Estimated 10-year ASCVD risk ≥ 7.5% – data have shown that statins used for primary prevention have substantial ASCVD risk-reduction benefits across the range of LDL-C levels of 70–189 mg/dL. Moreover, the Cochrane meta-analysis, as well as a meta-analysis by the Cholesterol Treatment Trialists confirms that primary prevention with statins reduces total mortality as well as nonfatal ASCVD events.
- A.
ACC, American College of Cardiology; ACCORD, Action to Control Cardiovascular Risk in Diabetes; AHA, American Heart Association; AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial.
For primary prevention in individuals aged between 40 and 75 years with LDL-C below 190 mg/dL, assessment of 10-year ASCVD risk is recommended to inform the decision to initiate statin therapy. The 2013 ACC/AHA risk assessment guideline recommends the use of the Pooled Cohort Equations for white and African-American men and women. Other factors such as premature family history of ASCVD, lifetime ASCVD risk, coronary artery calcification, reduced ankle-brachial index, and elevated C-reactive protein, race, and ethnicity may be considered for informing risk assessment.
The potential for an ASCVD risk-reduction benefit from adding a nonstatin to further lower LDL-C is of particular importance in lower-risk primary prevention in patients with LDL-C below 190 mg/dL, where the margin of ASCVD risk-reduction benefit may be smaller, yet the burden of additional therapy, costs, and risk of adverse effects is unchanged. Ezetimibe is the preferred nonstatin due to clear demonstration that it reduces ASCVD events when added to background statin therapy with an excellent margin of safety.
Overview of the 2016 ESC/EAS Cholesterol Guideline
The 2016 ESC/EAS prevention guideline continues to use the risk stratification and LDL-C goal paradigm of previous ESC/EAS guidelines ( Box 28.3 ). Patients are stratified into four groups: (1) very high risk (documented cardiovascular disease), diabetes with target organ damage or a major cardiovascular risk factor, severe chronic kidney disease, or a calculated SCORE greater than or equal to 10%; (2) high risk (marked elevation of single risk factors, in particular total cholesterol > 8 mmol/L or > 310 mg/dL), other people with diabetes mellitus, moderate chronic kidney disease, or a calculated SCORE of 5% to less than 10%; (3) moderate risk (SCORE ≥ 1% and < 5%); and (4) low risk (SCORE < 1%) (see Table 28.4 ). Premature family history of ASCVD, psychosocial factors, coronary artery calcium, carotid plaque, ankle-brachial index, and the presence of autoimmune disease can also be considered as part of the risk assessment.
Suspicion of white-coat or masked hypertension
- •
High office BP in individuals without organ damage and at low total CV risk.
- •
Normal office BP in individuals with organ damage or at high total CV risk.
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Considerable variability of office BP over the same or different visits.
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Autonomic, postural, postprandial, siesta- and drug-induced hypotension.
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Elevated office BP or suspected pre-eclampsia in pregnant women.
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Identification of true and false resistant hypertension.
Specific indications for ABPM
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Marked discordance between office BP and home BP.
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Assessment of dipping status.
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Suspicion of nocturnal hypertension or absence of dipping, such as in patients with sleep apnea, CKD, or DM.
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Assessment of BP variability.
ABPM, Ambulatory blood pressure monitoring; BP, blood pressure; CKD, chronic kidney disease; CV, cardiovascular; DM, diabetes mellitus.
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