Retardation of coronary artery disease in humans by the calcium-channel blocker nifedipine: Results of the INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy)

Abstract

Experimental studies have demonstrated a 30-50% reduction in the development of atheromatous lesions of the aorta in rabbits fed a diet rich in cholesterol when they were treated with nifedipine. Based on these favorable results, we designed a multicenter, placebo (PL)-controlled, randomized, double-blind study, to test the effect of 80 mg nifedipine (NIF) per day versus placebo on the progression of mild coronary artery disease (CAD) (further development of existing stenoses, especially formation of new stenoses and occlusions) over a duration of 3 years. Progression of CAD was assessed by coronary angiograms performed at entrance and at completion of the study, using a computer-assisted analysis system (CAAS) to quantitate various stenosis parameters (percent degree of stenosis and minimal stenosis diameter). Of the 425 patients enrolled, 348 (82%) underwent a second angiogram; 66 of them, however, terminated treatment prematurely after an average of 359 (placebo) and 467 days (nifedipine). A total of 282 patients (148 on placebo, 134 on nifedipine) completed the trial with full-length treatment. There were no differences between the two groups in the progression of the existing stenoses. Patients on nifedipine, however, demonstrated significantly fewer new lesions (stenoses greater than 20% or occlusions) than those on placebo: In the 282 patients undergoing the full-length treatment, there were 73 patients on placebo (49%) with 118 new lesions (0.8/patient) and 54 patients on nifedipine (40%) with 78 new lesions (0.58/patient), a difference of -27% (p = 0.031 by Cochran's linear trend test). The difference was greatest in the left anterior descending branch, with 28 patients on placebo developing 33 new lesions (0.22/patient), versus 16 patients on nifedipine with 18 new lesions (0.13/patient) (-40%; p = 0.045); and in the left circumflex branch, where 34 patients on placebo exhibited 39 new lesions (0.26/patient) versus 23 patients on nifedipine with 22 new lesions (0.16/patient) (-38%, p = 0.033). No differences were observed in the right coronary artery, the vessel with the highest number of existing and new lesions [PL] versus 0.27 [NIF] new lesions/patient) (-7.6%, p = 0.381). Hence, INTACT confirmed the previous experimental studies and demonstrates a significant reduction in newly formed coronary lesions in patients on nifedipine when compared with those on placebo, especially in the presence of early coronary artery disease.

Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

“…12,13 As NO has important antiatherogenic properties, 47 whereas endothelial dysfunction and production of oxidative stress, which are characteristic not only of hypertension but also of the most important cardiovascular risk factors, 44 are associated with cardiovascular events, [17][18][19] it is conceivable that the possibility of restoring NO availability could represent an additional effect of calcium entry blockers, one that would help to prevent the development of atherosclerosis and possibly of clinical events. In line with this interpretation, several clinical studies demonstrate that a calcium antagonist-based treatment can reduce the progression of new atherosclerotic coronary 48 or carotid lesions. 49 However, the suggestion that restoration of endothelial function by calcium antagonists or by other drug classes active on endothelium-dependent vasodilation could contribute to reduction of cardiovascular events, not only in hypertensive patients but also in subjects with cardiovascular disease, is at the present time only an attractive hypothesis that needs to be demonstrated by specific clinical trials.…”

International nifedipine trial on anti-atherosclerotic therapy (INTACT) — methodologic implications and results of a coronary angiographic follow-up study using computer-assisted film analysis

“…When all 348 patients with and without protocol violations who underwent two study angiograms, were considered in the analysis of data, again no significant differences were found between the two study groups with regard to changes in preexisting lesions [35]. The significant difference between the two treatment groups in the number of new lesions per patient, however, was confirmed by this 'in- For definitions see Table 4; stenoses changing to occlusions are excluded.…”

“…In either treatment group, angina pectoris symptoms were slightly reduced during the study. For further informations on protocol violations and clinical follow-up see references [31,[34][35][36].…”

“…All angiographic and clinical baseline data (number of coronary stenoses and occlusions, coronary risk factors, previous myocardial infarctions, previous PTCA, angina pectoris etc.) were not different between the two treatment groups (for details see 35,36).…”

Calcium channel blockers: do they have pleiotropic effects on atherosclerosis?

“…After analysing these studies, it is clear that the CCBs controversies have not been elucidated yet. 35,36 For example, the INTACT study 31,37,38 showed a reduced atherosclerotic plaque progression in the nifedipine group than in the control group (angiographically). Nevertheless, cardiovascular mortality was larger in the nifedipine group.…”