### Evidence Report/Technology Assessment: Number 10

# Evaluation of Beta-Blockers, Calcium Antagonists, Nitrates, and Alternative Therapies for Stable Angina

## Summary

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Under its Evidence-based Practice Program, the Agency for Health Care Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities. 

Overview / Methodology / Findings / Future Research / Availability of Full Report

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## 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 cases annually. Symptomatic therapy is targetedat 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:

- The relative efficacy and safety of beta-blockers, calcium antagonists, and long-acting nitrates in patients who have stable angina.
- The efficacy of alternative therapies in patients who have stable angina.

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## Reporting the Evidence

The following key questions defined the parameters of the investigation:

-  Is one class of anti-anginals (beta-blockers, nitrates, or calcium antagonists) superior as monotherapy in terms of occurrence of angina, nitroglycerin use, exercise tolerance, or adverse events leading to study withdrawal in patients with stable angina?
-  Is one class of drugs superior when outcomes over a longer period of time—such as recurrent myocardial infarction or death—are examined?
-  Are there any alternative medical treatments—including chelation therapy, acupuncture, herbal medications, and garlic—that are superior to placebo in any outcome measure for patients with stable angina?

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## Methodology

The EPC investigators searched MEDLINE (1966-97) and EMBASE (1974-97) and reviewed cited references of retrieved articles to identify published studies. The search criteria were:

- The MESH heading "angina pectoris" or the text word "angina."
-  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:

-  Publication type "controlled" clinical trial.
-  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.
- Calcium antagonists.

Studies with the following designs were excluded:

- One drug versus placebo.
- Dose comparison of one drug.
- One drug versus a two-drug combination.
- 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.
- 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.

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## Findings

- Beta-blockers were associated with fewer episodes of angina when compared with calcium antagonists in general and with nifedipine in particular.
- Important differences in mortality could not be determined because the trials were short in duration (median 4 weeks).
- Fewer adverse events leading to study withdrawal occurred with beta-blockers compared with calcium antagonists.
- Commonly reported side effects were similar or greater in the calcium antagonists group compared with the beta-blocker group.
- There were no obvious differences in any outcome measures between beta-blockers and non-nifedipine calcium antagonists.
- Few studies compared long-acting nitrates with beta-blockers or with calcium antagonists.
- Randomized trials of alternative therapies for patients with stable angina were too small and too few to provide conclusive findings.

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## Future Research

Few long-term studies have compared treatment with beta-blockers, calcium antagonists, and long-acting nitrates in patients who have stable angina. Additional large randomized trials are needed to determine if clinically important differences in patient survival exist between classes of anti-anginal medication. Further studies are needed to examine the effects of treatments for stable angina in patients with comorbidity such as heart failure or chronic obstructive pulmonary disease. Additional randomized controlled trials of alternative therapies in this patient population are necessary to reach conclusions about efficacy and safety.

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## Availability of the Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Health Care Research and Quality by the University of California, San Francisco-Stanford Evidence-based Practice Center under contract 290-97-0013. Print copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 1-800-358-9295. Requesters should as for Evidence Report/Technology Assessment Number 10, *An Evaluation of Beta-Blockers, Calcium Antagonists, Nitrates, and Alternative Therapies for Stable Angina*, (AHCPR Publication  No. 00-E003). 

The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.

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*AHCPR Publication Number 00-E002Current as of November 1999*

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**Internet Citation:**

*Evaluation of Beta-Blockers, Calcium Antagonists, Nitrates, and Alternative Therapies for Stable Angina*. Summary, Evidence Report/Technology Assessment: Number 10. AHCPR Publication  No. 00-E002, November 1999. Agency for Health Care Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/anginasum.htm

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