Fast track — ArticlesEffect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial
Introduction
Angina pectoris is the most common symptom in patients with stable atherosclerotic coronary disease. Despite advances in its management, current treatment provides no cure, and many patients remain symptomatic. Hence, continued therapy with antianginal drugs is usually needed.
For many years, nitrates, β blockers, and calcium antagonists have been the treatments of choice for angina. These drugs have been prescribed mainly on the basis of proof of efficacy in reducing symptoms. Long-term safety has been of less concern, although safety of β blockers is lent support by positive results of trials in patients with a history of acute myocardial infarction. Before trials were done with nicorandil1 and angiotensin-converting-enzyme (ACE) inhibitors,2, 3 no hard outcome data were available from clinical trials with drugs used in patients with angina or stable coronary disease. In the mid 1990s, considerable debate took place about the long-term safety of calcium antagonists.4, 5, 6, 7, 8, 9, 10, 11, 12 Consensus arising from this discussion was the need for well-designed long-term trials in patients with hypertension or with manifestations of coronary disease such as angina. ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) was designed to investigate the effects of the long-acting calcium antagonist nifedipine on clinical outcomes in patients with stable symptomatic coronary disease.
Section snippets
Methods
ACTION was a multicentre, randomised, placebo-controlled, double-blind trial to compare the effect on clinical outcomes of long-acting nifedipine or placebo in patients with angina pectoris attributable to coronary disease. A detailed description of the trial has been published elsewhere.13 Planned follow-up ranged from 4·5 to 6 years. We undertook the study in accordance with the Declaration of Helsinki and International Conference on Harmonization guidelines for Good Clinical Practice, and
Patients
Between November, 1996, and December, 1998, we recruited patients in 291 centres from 19 countries. Three categories of ambulatory patients who were age 35 years or older, had angina pectoris that had been stable for at least 1 month, and needed oral or transdermal treatment either to treat or prevent anginal attacks were eligible for the study: (1) those with a history of myocardial infarction; (2) those with angiographic coronary artery disease but no history of myocardial infarction; and (3)
Procedures
Investigators randomly assigned patients to addition of either nifedipine GITS or matching placebo to the basic regimen that they were taking. Randomisation was blocked and stratified by centre. The starting dose of nifedipine was 30 mg once daily, increasing to 60 mg once daily within 6 weeks if no evidence of intolerance was seen. Dose reduction or interruption was allowed. Investigators allocated treatment by means of sequentially numbered study medication packs that contained either
Statistical analysis
Sample size estimation and interim analysis procedures have been described elsewhere.13 Based on the simvastatin-treated group in the Scandinavian Simvastatin Survival Study (4S),14 the assumed rate of the primary efficacy outcome in the placebo group was 5·6 per 100 patient-years (731 events). With 30000 patient-years of follow-up, the study was estimated to have 95% power to detect an 18% reduction of the primary efficacy outcome by nifedipine GITS relative to placebo at an overall 5% level
Role of the funding source
An independent research institute (SOCAR Research SA) and an independent steering committee were responsible for study design, management, data analysis, and data interpretation. The role of the sponsor was restricted to study medication supply and on-site monitoring. A representative of the sponsor (non-voting) was in attendance at steering committee meetings. The chair of the safety monitoring committee prepared the random allocation list. The sponsor's drug safety department had to contact
Results
The ACTION study was completed as planned; figure 1 shows the trial profile. Centres contributed a median of 19 patients (range 1–107); 13 centres randomised fewer than four patients. Intended follow-up (either until death, until last visit or contact within 6 weeks before planned end of follow-up, or until planned date of end-of-study visit) was 38919 patient-years (19411 nifedipine, 19 508 placebo). Actual follow-up was 37 867 patient-years (18899 nifedipine, 18 968 placebo). Follow-up was
Discussion
ACTION has established the safety of nifedipine GITS, a long-acting dihydropyridine calcium antagonist, in the treatment of patients with stable angina pectoris already on conventional treatment. No significant difference was noted with respect to the primary efficacy endpoint, but secondary endpoints for all vascular events and procedures did show benefit.
Compared with short-acting compounds, long-acting calcium antagonists have been shown to reduce the risk of cardiovascular events in
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Investigators listed in the webappendix (http://image.thelancet.com/extras/04art6402webappendix.pdf)