Abstract & Commentary
Synopsis: The addition of nifedipine to conventional treatment in patients with chronic stable angina did not affect overall event-free survival, but was safe and reduced the need for coronary interventions.
Source: Poole-Wilson PA, et al. Effect of Long-acting Nifedipine on Mortality and Cardiovascular Morbidity in Patients With Stable Angina Requiring Treatment (ACTION Trial): Randomized, Controlled Trial. Lancet. 2004;364:849-857.
Although effective for preventing symptoms, long-acting dihydroperidine calcium antagonists are still controversial with regard to long-term safety. Hence, Poole-Wilson and colleagues designed the A Coronary Disease Trial Investigating Outcome with Nifedipine GITS (ACTION) to study clinical outcomes in patients with stable symptomatic coronary artery disease. This multicenter, placebo-controlled, double-blind trial randomized 3825 patients to long-acting nifedipine vs 3840 to placebo. The primary end point was a combination of death, acute myocardial infarction, refractory angina, new heart failure, stoke, or peripheral revascularization. The patients were followed for a mean of 5 years, and an intention-to-treat analysis was used.
The patients all had angina, requiring medical therapy and either: were post myocardial infarction; had angiographically proven coronary artery disease; or had a positive exercise or perfusion study. Those undergoing a coronary intervention were excluded, as were those intolerant to nifedipine or had other confounders that could affect outcome (eg, left ventricular dysfunction). Nifedipine was started at 30 mg per day, and increased to 60 mg if tolerated. All other cardiovascular drugs were permitted except other calcium blockers, digoxin, class I antiarrhymics, and certain other noncardiac drugs which might interfere with nifedipine (eg, cimetidine). About 80% of both groups were on beta-blockers, and 99% were on either nitrates, beta-blockers, or both.
Results: In the nifedipine group, 310 patients died vs 291 in the placebo group (HR, 1.07; CI, .91-1.25; P = .41). The composite primary end point was not different between the groups (HR, 0.97; CI, .88-1.07; P = .54). However, death or any cardiovascular procedure was reduced in the nifedipine group (HR, 0.89; CI, .83-.95; P = .0012) because of reduced rates of coronary interventions. The rate of myocardial infarction and stroke were not affected by nifedipine, but new heart failure was reduced (HR, 0.71; CI, .54-.94; P = .015). Nifedipine significantly reduced blood pressure, and the hypertensive subgroup was the only one in which nifedipine clearly showed improvement vs placebo (P = .015).
Nifedipine safety was excellent and comparable to placebo (HR, 1.01; CI, .9-1.14; P = .86). Poole-Wilson and colleagues concluded that the addition of nifedipine to conventional treatment in patients with chronic stable angina did not affect overall event-free survival, but was safe and reduced the need for coronary interventions.
Comment by Michael H. Crawford, MD
Recently, I asked a resident what she would do for a patient on beta-blockers and nitrates with persistent angina who was not a candidate for revascularization. Her first response was disbelief that we could not revascularize the patient, and when I was persistent, she said ACE inhibitors. I understand the disbelief that we could not revascularize the patient since this seems true for very few patients today. It makes you wonder how Poole-Wilson et al in this long-term study found more than 7000 patients in this category. Since all 291 centers were either in Europe, Canada, or Israel, it may be that different criteria for whom to revascularize were used than those in the United States. Regardless, this is a large trial definitively showing that a long-acting dihydroperidine calcium blocker was safe and reduced symptoms and the need for coronary interventions in patients with chronic stable angina. Not surprisingly, based upon previous studies, there was no beneficial effect on mortality or myocardial infarction.
Given the mortality reducing effects of beta-blockers, they should be first-line therapy, but clearly calcium blockers are a legitimate second-line therapy, as nitrates have no proven benefit on cardiovascular outcomes either. Also, the safety of nifedipine GITS was impressive. New heart failure rates were reduced on nifedipine. Adverse effects were minor: edema in 139 vs 20 on placebo and headache in 43 vs 20. Study drugs were continued in 79% on nifedipine and 82% on placebo. Dose reductions to one-half (30 mg nifedipine) were done in 16% on nifedipine and 6% on placebo. The major mechanistic difference shown was a significant reduction in blood pressure on nifedipine.
The placebo mortality rate was 1.5 per 100 patient-years vs 1.6 for nifedipine (NS), and other cardiovascular events were also infrequent. Thus, in patients treated with beta-blockers (80%) and lipid-lowering drugs (68%) with these low event rates, it may be unrealistic to expect further reductions by another drug. With regard to the resident’s answer of ACE inhibitors for my patient, there have been trials of patients with risk factors for coronary disease or some manifestation of it that showed benefits in mortality (HOPE, EUROPA), but studies in patients with angina have failed to show improvement in symptoms with ACE inhibitors. Also, in HOPE and EUROPA, fewer patients were on beta-blockers (39% and 62%, respectively) and lipid-lowering drugs (28% and 57%). Hence, an ACE inhibitor may be beneficial to my patient for longevity, but would not address his persistent angina on beta-blockers and nitrates. This study shows that long-acting dihydroperidine calcium blockers are safe and effective treatment for the relief of angina.
Dr. Crawford, Professor of Medicine, Chief of Clinical Cardiology University of California San Francisco, is Editor of Clinical Cardiology Alert.