Some outcomes in the ACTION trial were affected by the level of blood pressure at study entry (above or below 140/90 mm Hg). Prof. Philip Poole-Wilson (Imperial College in London, UK) presented a subgroup analysis of this interaction at the 15th European Meeting of Hypertension, held June 17 to 21, 2005 in Milan, Italy. In the main study, a blood pressure below 140/90 mm Hg significantly favored nifedipine versus placebo for the primary endpoint (p=0.02).
In the subgroup analysis, new overt heart failure in the hypertensive patients, versus the normotensives, favored nifedipine, with only 47 events versus 76 with placebo.
For any stroke or any TIA, looking at the rate/100 patient years using an l’Abbe plot, the risk of an event increases as blood pressure increases regardless of treatment, and the effect of treatment with nifedipine increases as blood pressure increases. Looking at debilitating stroke using an l’Abbe plot, the greatest effect of treatment is seen at the higher levels of blood pressure.
Other blood pressure-related findings from ACTION were published in the Journal of Hypertension (2005;23:641-648).
- Nifedipine GITS reduced by 13% the combined incidence of the primary endpoint (all-cause mortality, MI, refractory angina, new overt heart failure, stroke, and peripheral revascularization) in the patients with hypertension.
- Nifedipine GITS reduced by a significant 30% the incidence of stroke or TIA in hypertensives and normotensives.
- 21% reduction in need for coronary angiography in normotensives and 16% in hypertensives.
- A significant 38% reduction in new overt heart failure.
- A 33% reduction in debilitating stroke in the hypertensives.
- A significant 32% reduction in need for CABG in the normotensive patients.
The ACTION trial was published in The Lancet.
- ACTION is the first-ever placebo-controlled clinical outcome trial in symptomatic stable angina.
- ACTION compared a long-acting calcium antagonist, nifedipine GITS, to placebo.
- ACTION was an investigator initiated and designed clinical trial, with an independent steering committee and independent study management.
- ACTION was a multicenter (291 centers), multi-national (19 countries) study, with 7,665 patients followed for 4.9 years.
- 52% of the ACTION study population had hypertension.
In ACTION, debilitating stroke (the stricter definition used in this trial) occurred in 77 of nifedipine patients and 99 of placebo patients (hazard ratio 0.78; p=0.10). The incidence of all stroke (as defined in most trials) was 187 in nifedipine patients and 258 in placebo patients (hazard ratio 0.72; p=0.00063).The main results, in brief, showed the frequency of the primary efficacy endpoint (combined all-cause mortality, MI, refractory angina, new overt heart failure, disabling stroke, or peripheral revascularization) was the same in both groups (hazard ratio 0.97; p=.054). The primary safety endpoint (death, MI, and disabling stroke) was similar in both groups (hazard ratio 1.01; p=0.86). Although any death, cardiovascular event (CV) event, or procedure was significantly less frequent in the nifedipine group (hazard ratio 0.89; p=0.0012), the frequency of CV events alone did not differ between groups. Nifedipine prolonged the mean event-free and procedure-free survival by 41 days, and reduced vascular events (hazard ratio 0.91; p=0.027).
Heart rate was reduced about 1 beat per minute (bpm) and the mean blood pressure reduction was 6/3 mm Hg.
Conclusions
In this patient population, long-acting nifedipine GITS is safe. There is a clinically important reduction in stroke, heart failure, hospitalization for angina, revascularization procedures, and importantly coronary artery bypass surgery with nifedipine GITS. Some of the events, particularly stroke, are blood pressure related, putting this patient population at high risk for heart disease.