Over the past decade, research on calcium channel blockers, which were originally developed as vasodilators for use in the treatment of cardiovascular disease, has revealed additional properties of these drugs unrelated to their hemodynamic effects and which may influence the progression of vascular wall pathology in hypertension and atherosclerosis. There is now mounting evidence from molecular and cellular studies, together with in vivo data derived from animal models and human subjects, these drugs have antiatherosclerotic potential.
Calcium ions play an integral role in many of the fundamental cellular processes involved in the pathogenesis of atherosclerosis. In this supplement, Winifred Nayler reviews the evidence that calcium channel blockers inhibit monocyte adhesion to endothelial cells, slow migration and proliferation of vascular smooth muscle cells, diminish the release of growth factors, reduce cholesterol uptake by macrophages, and protect against lipid peroxidation.
These observations provide a likely explanation for the protection seen with the administration of calcium channel blockers in animal models of atherosclerosis, including the cholesterol-fed rabbit and, perhaps of more relevance to humans, nonhuman primate, the cynomolgus monkey, in which atherosclerosis is induced by a cholesterol-enriched diet.
In addition, a number of cellular actions of calcium channel blockers are particularly relevant to the potential prevention of the neointimal proliferative response to vascular injury that leads to restenosis of blood vessels after angioplasty. Many different classes of drugs have been reported to prevent this proliferative response in a variety of animal models of vascular injury. However, when tested in humans in the context of angioplasty, the results have been universally disappointing. Erik Thaulow reviews the evidence that calcium channel blockers may prevent restenosis by virtue of their effects in reducing platelet aggregation and minimization of vasospasm, together with the antiproliferative and antimigratory properties oulined by Dr. Nayler. He points out the results of isolated studies in humans designed to investigate the influence of calcium channel blockers on restenosis were inconclusive, perhaps because of small patient numbers, but a recent meta-analysis of five studies shows a significant (32%) reduction in the rate of restenosis in patients receiving calcium channel blockers compared with placebo. On the basis of this, the coronary angioplasty amlodipine restenosis study (CAPA-RES) was initiated. In addition, few if any studies calculated the effects of calcium channel blockers on clinical outcomes.
Thomas Tulenko and colleagues describe additional properties of the dihydropyridine amlodipine, which in recent studies has been shown to inhibit cholesterol-induced increase in calcium permeability in vascular smooth muscle cells, to repair abnormal membrane structure, and to possess a marked antioxidant action in membrane bilayers. These findings, again in animal model systems, formed the basis for the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the primary objective of which is to evaluate the effectiveness of amlodipine compared with placebo in the development and progression of atherosclerotic lesions in the coronary and carotid arteries in patients with coronary heart disease.
In the light of several reports concerning the potential adverse effects of calcium channel blockers derived from retrospective and often poorly controlled studies, it is timely that large-scale prospective randomized trials with dihydropyridines are now in progress, One such study [Systemic Hypertension in Europe (SYST-EUR)] has recently reported the substantial benefits of lowering blood pressure with nitrendipine in terms of stroke prevention, and this trial refuted many of the unsubstantiated claims of adverse effects of calcium channel blockers from the earlier retrospective studies.
Suzanne Oparil reviews two major prospective, ongoing studies in hypertension, in which different antihypertensive drugs and regimens are being compared, the primary objective being a reduction in coronary heart disease events.
In the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), more than 40,000 high-risk patients have been enrolled to compare monotherapies to which various other drugs might be added if the single agent failed to control blood pressure to prespecified target levels. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) involves 18,000 patients and compared two regimens-a more classical regimen of a β-blocker to which a diuretic may be added-with a calcium channel blocker to which an angiotensin-converting enzyme inhibitor is added. In both of these studies, amlodipine has been selected as the calcium channel blocker. In addition, both studies have factored in a subgroup in which the additional benefit of lipid lowering with pravastatin or atorvastatin is being compared with placebo.
In a final trial in heart failure, reviewed by Dr. Oparil, patients receiving conventional treatment have been randomized to amlodipine or placebo. The safety of the drug was established in this high-risk group, and beneficial effects observed in a subgroup of "nonischemic" heart failure patients are being further investigated in a second study.
Given the burden of hypertension in contemporary society, currently one of the world's leading causes of death, and the projections for the ascendance of coronary heart disease to the world's leading cause of death within the next 20 years, it is timely that the major morbidity/mortality studies with different classes of agents are under way to define optimal treatment strategies for the prevention of coronary heart disease and other vascular diseases in the twenty-first century.
Pfizer, Inc., the sponsor of the symposium on which this supplement is based, is to be congratulated for its support of many important outcome studies.
Official Satellite Symposium for the XVIIth Congress of the European Society of Cardiology, The National Exhibition Centre, Birmingham, United Kingdom August 28, 1996