C J Pepine1, G Faich, R Makuch. 1. University of Florida College of Medicine, Gainesville 32610, USA.
Abstract
BACKGROUND: Several reports have questioned the lack of safety data on calcium antagonists as a drug class. Because this drug class is heterogeneous, unique features of certain calcium antagonists may set them apart in terms of safety and efficacy. HYPOTHESIS: With in excess of 7,000 person-years of observation from randomized clinical trials, verapamil was selected to evaluate whether there was evidence of harm in patients with cardiovascular disease. METHODS: MEDLINE search of English-language articles, Science Citation Index, Current Contents, manual review of cited references, pharmaceutical files, and investigator correspondence was performed. Independent review of 66 articles identified 14 randomized, parallel-group studies for inclusion. Independent, duplicate assessments were made of patient outcomes and trial characteristics (including study design, treatment dosage and schedule, duration of treatment, inclusion criteria, and sample size). Standard meta-analytic techniques were employed for analysis and interpretation of results. RESULTS: Based on over 4,000 person-years of observation, patients with acute myocardial infarction (MI) treated with verapamil had a decreased risk of nonfatal reinfarction compared with placebo (relative risk 0.79; 2-sided 95% confidence interval 0.65.0.97; p = 0.024). Verapamil had no significant effect on overall mortality compared with placebo (relative risk ranged from 0.93; 2-sided 95% confidence interval 0.78, 1.10; p = 0.40 to 0.86; 2-sided 95% confidence interval 0.71, 1.04; p = 0.13) depending on rules used to include or exclude patients from the pooling process. For the combined outcome of death or reinfarction, verapamil use was associated with a decreased risk compared with placebo (relative risk 0.82; 2-sided 95% confidence interval 0.70, 0.97; p = 0.016). In patients with angina involving a wide spectrum of disease severity, data were limited to 2,900 person-years of observation, and verapamil use did not appear to be associated with an apparent effect on mortality or MI. Data available from randomized studies of verapamil in patients with hypertension were too limited to reach conclusions (50 person-years of observation, with no deaths or MIs reported). Subgroups of hypertensive patients in two of the largest post-MI studies and the largest angina study, involving over 600 patients, yielded little useful added information. CONCLUSIONS: In patients with MI, the risks of both nonfatal reinfarction and the combined outcome of death or nonfatal MI were reduced over intermediate-term follow-up among patients treated with verapamil compared with controls (p = 0.024 and p = 0.016, respectively). In patients with angina, no evidence for harm was noted, but in hypertension the data were too limited to draw conclusions. These findings support the need to distinguish among different calcium antagonist compounds and to emphasize the need for more data in patients with hypertension.
BACKGROUND: Several reports have questioned the lack of safety data on calcium antagonists as a drug class. Because this drug class is heterogeneous, unique features of certain calcium antagonists may set them apart in terms of safety and efficacy. HYPOTHESIS: With in excess of 7,000 person-years of observation from randomized clinical trials, verapamil was selected to evaluate whether there was evidence of harm in patients with cardiovascular disease. METHODS: MEDLINE search of English-language articles, Science Citation Index, Current Contents, manual review of cited references, pharmaceutical files, and investigator correspondence was performed. Independent review of 66 articles identified 14 randomized, parallel-group studies for inclusion. Independent, duplicate assessments were made of patient outcomes and trial characteristics (including study design, treatment dosage and schedule, duration of treatment, inclusion criteria, and sample size). Standard meta-analytic techniques were employed for analysis and interpretation of results. RESULTS: Based on over 4,000 person-years of observation, patients with acute myocardial infarction (MI) treated with verapamil had a decreased risk of nonfatal reinfarction compared with placebo (relative risk 0.79; 2-sided 95% confidence interval 0.65.0.97; p = 0.024). Verapamil had no significant effect on overall mortality compared with placebo (relative risk ranged from 0.93; 2-sided 95% confidence interval 0.78, 1.10; p = 0.40 to 0.86; 2-sided 95% confidence interval 0.71, 1.04; p = 0.13) depending on rules used to include or exclude patients from the pooling process. For the combined outcome of death or reinfarction, verapamil use was associated with a decreased risk compared with placebo (relative risk 0.82; 2-sided 95% confidence interval 0.70, 0.97; p = 0.016). In patients with angina involving a wide spectrum of disease severity, data were limited to 2,900 person-years of observation, and verapamil use did not appear to be associated with an apparent effect on mortality or MI. Data available from randomized studies of verapamil in patients with hypertension were too limited to reach conclusions (50 person-years of observation, with no deaths or MIs reported). Subgroups of hypertensivepatients in two of the largest post-MI studies and the largest angina study, involving over 600 patients, yielded little useful added information. CONCLUSIONS: In patients with MI, the risks of both nonfatal reinfarction and the combined outcome of death or nonfatal MI were reduced over intermediate-term follow-up among patients treated with verapamil compared with controls (p = 0.024 and p = 0.016, respectively). In patients with angina, no evidence for harm was noted, but in hypertension the data were too limited to draw conclusions. These findings support the need to distinguish among different calcium antagonist compounds and to emphasize the need for more data in patients with hypertension.