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Meta-analysis of Trials Comparing β-Blockers, Calcium Antagonists, and Nitrates for Stable Angina

Paul A. Heidenreich, MD, MS; Kathryn M. McDonald, MM; Trevor Hastie, PhD; Bahaa Fadel, MD; Vivian Hagan; Byron K. Lee, MD; Mark A. Hlatky, MD
JAMA. 1999;281(20):1927-1936. doi:10.1001/jama.281.20.1927.
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Context Which drug is most effective as a first-line treatment for stable angina is not known.

Objective To compare the relative efficacy and tolerability of treatment with β-blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina.

Data Sources We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies.

Study Selection Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (β-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria.

Data Extraction Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine).

Data Synthesis Rates of cardiac death and myocardial infarction were not significantly different for treatment with β-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P=.79). There were 0.31 (95% CI, 0.00-0.62; P=.05) fewer episodes of angina per week with β-blockers than with calcium antagonists. β-Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between β-blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with β-blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or β-blockers to draw firm conclusions about relative efficacy.

Conclusions β-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.

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Figure 1. Odds Ratios for Cardiac Death or Myocardial Infarction With β-Blockers vs Calcium Antagonists
Graphic Jump Location
Individual odds ratios are displayed for 2 long-term trials along with the combined odds ratio for 60 short-term studies. TIBET indicates Total Ischaemic Burden European Trial; APSIS, Angina Prognosis Study in Stockholm; and error bars, 95% confidence intervals.
Figure 2. Summary Odds Ratios for Benefit With β-Blockers vs Calcium Antagonists for Cardiac Death or Myocardial Infarction and Adverse Events
Graphic Jump Location
A greater rate of adverse events leading to withdrawal was observed with calcium antagonists compared with β-blockers for the nifedipine, long-acting, and short-acting calcium antagonist subgroups. Error bars indicate 95% confidence intervals.
Figure 3. Summary Mean Difference Between β-Blockers and Calcium Antagonists for Angina Episodes per Week and Exercise Time to 1-mm ST Depression
Graphic Jump Location
Values less than 0 indicate fewer angina episodes and shorter exercise time with β-blockers. Because exercise protocols varied, a standardized mean difference in exercise time is displayed. Both nifedipine and short-acting calcium antagonists were associated with a greater frequency of angina compared with β-blockers. Error bars indicate 95% confidence intervals.
Figure 4. Individual and Summary Odds Ratios for Adverse Events With β-Blockers Compared With Calcium Antagonists
Graphic Jump Location
The summary estimate is significantly less than 1.0, indicating that there were fewer adverse events with β-blocker therapy. Only trials that reported adverse events for both calcium antagonists and β-blockers are displayed. The summary estimate is based on all trials reporting adverse events. Error bars indicate 95% confidence intervals.

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