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Coronary disease trial investigating outcome with nifedipine GITS - ACTION
Description:
The goal of the trial was to evaluate the effect of the calcium antagonist nifedipine compared with placebo on long-term outcomes among patients with stable angina pectoris.
Study Design
Study Design:
Patients Enrolled: 7,665
Mean Follow Up: Mean 4.9 years
Mean Patient Age: Mean age 63.5 years
Female: 21
Patient Populations:
Age ≥35 years; angina pectoris that had been stable for at least one month; need for oral or transdermal treatment either to treat or prevent anginal attack; and ejection fraction ≥40%. Also had to have one of the following: 1) history of MI, 2) angiographic coronary artery disease but no history of MI, and 3) positive exercise test or perfusion defect who had never had coronary angiography and had no history of MI.
Exclusions:
Overt heart failure; any major cardiovascular event or intervention within the past three months; planned coronary angiography or intervention; known intolerance to dihydropyridines; clinically significant valvular or pulmonary disease; unstable insulin-dependent diabetes mellitus; any gastrointestinal disorder that could compromise absorption of nifedipine GITS or passage of the tablet; any condition other than coronary artery disease that limited life expectancy; symptomatic orthostatic hypotension or supine systolic blood pressure ≤90 mm Hg; systolic blood pressure at least 200 mm Hg, diastolic blood pressure at least 105 mm Hg, or both; creatinine more than twice the local upper limit of normal; and alanine or aspartate transaminase greater than three times the local upper limit of normal
Primary Endpoints:
Efficacy: Combination of death, acute MI, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularization.
Safety: Combination of death from any cause, acute MI, and debilitating stroke.
Secondary Endpoints:
Any cardiovascular event; any death, cardiovascular event, or procedure; and any vascular event or procedure
Drug/Procedures Used:
Patients were randomized to nifedipine GITS (gastrointestinal therapeutic system) (60 mg once daily; n=3,825) or placebo (n=3,840). Follow-up visits were performed at least every six months.
Principal Findings:
Study drugs were well tolerated in both groups, with the study drug taken during 79% of follow-up time in the nifedipine group and 82% of follow-up time in the placebo group. The study drug was permanently discontinued in 34% of patients in the nifedipine group and 31% in the placebo group. Blood pressure was lowered and heart rate was increased in the nifedipine group. Blood pressure of 140/90 mm Hg during follow-up was 35% in the nifedipine group versus 47% in the placebo arm.
There was no difference in mortality by treatment group, with 310 deaths in the nifedipine group (1.64 per 100 patient-years) versus 291 deaths in the placebo group (1.53 per 100 patient-years; hazard ratio [HR] 1.07, p=0.41). There was also no difference in the composite primary endpoint of death, myocardial infarction (MI), refractory angina, heart failure, stroke, or revascularization (4.60 per 100 patient-years for nifedipine vs. 4.75 per 100 patient-years for placebo, HR 0.97, p=0.54).
The primary safety endpoint did not differ by treatment group (HR 1.01, p=0.86). The composite endpoint of death, any cardiovascular event, or procedure was lower in the nifedipine group (9.32 vs. 10.50 per 100 patient-years, HR 0.89, p=0.0012), primarily driven by a reduction in coronary angiography (5.46 vs. 6.69 per 100 patient-years, HR 0.82, p<0.0001) and bypass surgery (1.62 vs. 2.06 per 100 patient-years, HR 0.79, p=0.0021). New overt heart failure was lower in the nifedipine group (0.46 vs. 0.65 per 100 patient-years, HR 0.71, p=0.015). There was no difference in the rate of MI (1.46 vs. 1.39 per 100 patient-years, HR 1.04, p=0.62). The rate of peripheral vascular-related interventions trended higher in the nifedipine group (0.79 vs. 0.63 per 100 patient-years, HR 1.25, p=0.073).
Interpretation:
Among patients with stable angina pectoris, treatment with the calcium antagonist nifedipine was not associated with a reduction in the primary endpoint compared with placebo. Benefit was observed in the secondary endpoints of coronary interventions and heart failure. Several studies in patients with hypertension have shown a benefit in treatment with nifedipine, but the present trial is one of the first large-scale trials to evaluate its use in patients with coronary heart disease.
Indeed, nifedipine was associated with a lowering of blood pressure in the present study. The formulation of nifedipine in the present trial was a long-acting, slow-release formula unlike the earlier short-acting formulation. The authors speculated that some of the lack of benefit in the primary endpoint may be due to the fact that patients were already on optimal medical therapy, with 80% of patients receiving beta-blockers and 68% on lipid-lowering drugs.
References:
Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004;364:849-57.
Poole-Wilson PA. ACTION: A Coronary Disease Trial Investigating Outcome With Nifedipine GITS. Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.
Keywords: Stroke, Myocardial Infarction, Coronary Artery Disease, Angina, Stable, Blood Pressure, Nifedipine, Heart Rate, Calcium Channel Blockers, Coronary Angiography, Heart Failure, Hypertension, Exercise Test
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