Overview

Stable angina is a major health problem that affects over 7 million adult men and women in the United States, with an estimated 350,000 new cases annually. Symptomatic therapy is targeted at either reducing oxygen demand by decreasing the work of the heart or increasing oxygen supply by dilating coronary arteries. Acute treatment of an angina episode consists of rest and often sublingual nitroglycerin. Chronic treatment to prevent symptoms has consisted of one or a combination of beta-blockers, calcium antagonists, and long-acting nitrates.

The choice of a first-line anti-anginal drug has been controversial because all three classes have been shown to be effective in relieving symptoms. There are few long-term trials comparing these drugs in controlled studies, and it is unclear whether any of the drug classes decrease mortality or myocardial infarction in patients with stable angina.

To address these important issues, the University of California, San Francisco-Stanford Evidence-based Practice Center (EPC) conducted a thorough, systematic review and synthesis of the literature on treatment of stable angina and developed an evidence report on the topic. The topic was nominated by the American College of Cardiology, the American Heart Association, and the American College of Physicians. The EPC worked with the nominators' guideline committee to prioritize two topics for this project: (1) the relative efficacy and safety of beta-blockers, calcium antagonists, and long-acting nitrates in patients who have stable angina, and (2) the efficacy of alternative therapies in patients who have stable angina.

Reporting the Evidence

Methodology

The EPC investigators searched MEDLINE (1966--1997) and EMBASE (1974--1997) and reviewed cited references of retrieved articles to identify published studies. The search criteria were (1) the MESH heading "angina pectoris" or the text word "angina" and (2) publication type "randomized controlled trial" or text word containing a form of the word "random." Using this criteria set, the investigators searched MEDLINE then EMBASE. They also performed searches replacing the second criterion with (3) publication type "controlled" clinical trial, or or (4) text word "double-blind." Finally, the bibliographies of identified trials were reviewed to locate other relevant studies.

The review was limited to randomized controlled trials that directly compared at least two of the three major anti-anginal drug classes: long-acting nitrates, beta-blockers, and calcium antagonists. Studies with the following designs were excluded: one drug versus placebo, dose comparison of one drug, and one drug versus a two-drug combination, as were studies with duration of less than 1 week. Trials that used a study medication during a run-in period prior to randomization were excluded because patients who quickly developed side effects were not included in the randomized trial.

All randomized trials of patients who had stable angina were included. Trials comparing alternative therapies to placebo, nitrates, calcium antagonists, or beta-blockers were abstracted. Because few studies fit these criteria, no limit was imposed on study duration.

To search for alternative therapies for stable angina treatment, the same search criterion noted above was used with the following key words: meditation, prayer, naturopathy, chiropractic, osteopathic, holistic, natural medicine, homeopathy, mind-body, unorthodox, integrative ayurvedic, acupuncture, herbal, relaxation, or chelation.

Study selection was performed initially by title review; candidate abstracts were then reviewed and selected for data retrieval. Two independent reviewers abstracted data for each article on standardized data forms. The reviewers compared their results and settled any differences. In general, one of the two reviewers had cardiology expertise, and the other had expertise in epidemiology or health services research.

Standard methods of meta-analysis were used to combine outcomes data across trials. The following estimates were combined: the mean difference for angina episodes and nitroglycerin use, the standardized mean difference for exercise time, and the odds ratio for cardiac death, myocardial infarction, and all adverse events. The standardized mean difference was used to compare exercise times because exercise protocols varied across studies. The DerSimonian-Laird (random-effects) method was used to estimate summary odds ratios. The investigators examined differences between study subgroups of calcium antagonists using analysis of variance. The prespecified subgroup comparisons of interest were nifedipine versus non-nifedipine and short-acting versus long-acting calcium antagonists. Reported p values are two- tailed with statistical significance at p < 0.05.