Evidence‐Based Medicine Should Be Practiced for Primary Prevention and Secondary Prevention of Cardiovascular Disease

Abstract

The author has no funding, financial relationships, or conflicts of interest to disclose.

Evidence‐based medicine should be practiced for primary prevention and secondary prevention of cardiovascular disease. Randomized clinical trials have demonstrated, on numerous occasions, no difference or a worsening of clinical cardiovascular outcomes, whereas observational studies or studies relying on surrogate end points have shown a significant reduction in cardiovascular events by a therapeutic intervention. This editorial will discuss a few of these studies.

Numerous studies have demonstrated that patients with complex ventricular arrhythmias associated with heart disease are at increased risk for new coronary events and for sudden cardiac death.1 Antiarrhythmic drugs were used in widespread practice to suppress ventricular arrhythmias to prevent sudden cardiac death prior to CAST I (Cardiac Arrhythmia Suppression Trial I).2 In fact, recruitment for this study was slowed because physicians were reluctant to allow their patients to be randomized because of a 50% chance of their patients being randomized to placebo.

CAST I was a prospective, double‐blind, randomized study in survivors of myocardial infarction with asymptomatic or mildly symptomatic ventricular arrhythmias, in which 730 patients were randomized to encainide or flecainide and 725 patients to placebo.2 Adequate suppression of ventricular arrhythmias by encainide or flecainide was required before randomization. Despite adequate suppression of ventricular arrhythmias by encainide or flecainide, at 10‐month follow‐up encainide and flecainide significantly increased mortality from arrhythmia or cardiac arrest (relative risk [RR]: 3.5, 95% confidence interval [CI]: 1.7‐8.5) and significantly increased all‐cause mortality (RR: 2.5; 95% CI: 1.6–4.5).2

Numerous studies have demonstrated that a low serum high‐density lipoprotein (HDL) cholesterol is a risk factor for coronary artery disease (CAD).3., 4. We showed by multivariate analysis at 40‐month follow‐up of 664 older men and at 48‐month follow‐up of 1488 older women that there was a 1.70 times higher probability of developing new coronary events in men and a 1.95 times higher probability of developing new coronary events in women for a decrement of 10 mg/dL of serum HDL cholesterol.4

However, does increasing serum HDL cholesterol by drug therapy reduce cardiovascular events? In a randomized double‐blind study of 15 067 patients at high cardiovascular risk, patients were randomized to torcetrapib plus atorvastatin or atorvastatin.5 At 12‐month follow‐up, patients treated with torcetrapib had a 72% increase in serum HDL cholesterol. However, patients treated with torcetrapib had a 25% increase in cardiovascular events (P = 0.001) and a 58% increase in all‐cause mortality (P = 0.006).5

Compared with simvastatin plus placebo, the combination of fenofibrate plus simvastatin did not reduce the incidence of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke at 4.7‐year follow‐up in 5518 randomized patients with type 2 diabetes mellitus at high risk for cardiovascular disease in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial.6

Niacin is used in clinical practice to reduce cardiovascular events. The AIM‐HIGH (Niacin Plus Statins to Prevent Vascular Events) randomized 3414 patients with stable CAD and a low serum HDL cholesterol (median level of 35 mg/dL) treated with simvastatin or simvastatin plus ezetimibe to 1500 to 2000 mg per day of extended‐release niacin or placebo.7 Niacin increased serum HDL cholesterol 25%, decreased serum low‐density lipoprotein cholesterol 12%, and decreased serum triglycerides 29%. The trial was stopped by the National Heart, Lung, and Blood Institute data and safety monitoring board at 3 years because the primary end point of myocardial infarction, ischemic stroke, death due to coronary heart disease, hospitalization for an acute coronary syndrome, or symptom‐driven revascularization was 16.4% in patients treated with niacin vs 16.2% in patients treated with placebo, and because niacin insignificantly increased ischemic stroke by 61% (P = 0.11).7

Numerous observational studies including the Nurses' Health Study8 supported the use of hormone replacement therapy (HRT) for prevention of cardiovascular disease in postmenopausal women. HERS (Heart Estrogen/Progestin Replacement Study) investigated in 2763 women with documented CAD the effect of HRT vs placebo on coronary events.9 At 4.1‐year follow‐up, there was no significant difference in cardiovascular events between patients treated with HRT or placebo. However, there was a 52% significantly higher incidence of nonfatal myocardial infarction or death from CAD in the first year in patients treated with HRT (95% CI: 1.01–2.29). Women on HRT also had at follow‐up a 289% significantly higher incidence of venous thromboembolic events (95% CI: 1.50–5.58) and a 38% significantly higher incidence of gallbladder disease requiring surgery (95% CI: 1.00–1.92).9 At 6.8‐year follow‐up of HERS, HRT did not reduce cardiovascular events, insignificantly increased all‐cause mortality 10%, significantly increased venous thromboembolism by 208% (95% CI: 1.28–3.40), significantly increased biliary tract surgery by 48% (95% CI: 1.12–1.95), and insignificantly increased any cancer by 19%.10

The estrogen plus progestin component of the WHI (Women's Health Initiative) study included 16 608 healthy postmenopausal women age 50 to 79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo.11 At 5.2‐year follow‐up, this component of the WHI study was discontinued by the data safety and monitoring committee because the excess risk of events included in the global index was 19 per 10 000 person‐years. Absolute excess risks per 10 000 person‐years included 7 more coronary events, 8 more strokes, 8 more episodes of pulmonary embolism, and 8 more invasive breast cancers, whereas absolute risk reductions per 10 000 person‐years included 6 fewer colorectal cancers and 5 fewer hip fractures.11

Many persons are taking antioxidants to reduce cardiovascular events. However, numerous randomized trials with antioxidant vitamins have shown no effect on mortality or an adverse effect on mortality. In 47 low‐bias randomized trials for primary and secondary prevention with 18 0938 persons, a meta‐analysis showed that the antioxidant supplements significantly increased mortality 5% (95% CI: 1.02–1.08).12 Beta carotene (RR: 1.07, 95% CI: 1.02–1.11), vitamin A (RR: 1.16, 95% CI: 1.10–1.24), and vitamin E (RR: 1.04; 95% CI: 1.01–1.07) taken singly or combined significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.12

Some physicians recommended percutaneous coronary intervention (PCI) in patients with stable CAD and myocardial ischemia to reduce mortality and myocardial infarction. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial randomized 2287 patients with stable CAD with myocardial ischemia to optimal medical therapy or to optimal medical therapy plus PCI.13 At 4.6‐year follow‐up, the cumulative incidence of all‐cause mortality and nonfatal myocardial infarction was 19.0% in patients randomized to PCI plus optimal medical therapy vs 18.5% in patients randomized to optimal medical therapy alone (P not significant).13 As an initial management strategy in patients with stable CAD, PCI did not reduce mortality, myocardial infarction, or other major cardiovascular events.

Guidelines should base their recommendations on randomized clinical trials when available. The 2011 American College of Cardiology Foundation/American Heart Association 2011 Expert Consensus Document on Hypertension in the Elderly included sections on unanswered questions and future research.14 Guidelines based on expert medical opinion need to be revised after data from randomized clinical trials are available.15