Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for a “magic bullet”

Abstract

Percutaneous transluminal coronary angioplasty (PTCA) is an accepted treatment for providing relief of angina pectoris in patients with single-and multivessel disease. Increased experience and advances in technology have resulted in a high primary success rate (90 % to 95 % ) and a lower complication rate (4 % to 5 % ). Despite the therapeutic success of coronary angioplasty, the exact mechanisms of dilatation remain speculative and involve multiple processes including stretching of the vessel at the site of the dilatation and disruption and fissuring of the plaque.’ Angiographic renarrowing at the site of PTCA, frequently accompanied by recurrence of symptoms of angina, is a common phenomenon (30 % ) and has a negative bearing on the long-term results of PTCA. This usually occurs within the first 6 months after PTCA.“, ” Although many of the risk factors for restenosis have been identified (Table 1),4-25 most of these are difficult to influence. Until now we have not found a technical or pharmacologic cure, and we are unable to predict which patients or vessel segments will have restenosis. The reason why a clinically significant restenosis occurs in only a minority of the dilated vessels (30%) remains an enigma. Although the typical restenotic lesion differs from the usual atherosclerotic plaque in architecture and lipid content, both contain smooth muscle cells and fibrous tissue,P6. 27 and it is even likely that the factors responsible for restenosis are similar to those that effect de novo atherosclerosis. In some cases of “restenosis” it is conceivable that it is caused by progression of the preexisting atherosclerotic plaque. An important step in the restenosis process is activation of the hemostatic system with platelet adhesion, platelet aggregation, and fibrin formation. This is followed by smooth muscle cell proliferation, which is mediated by growth factors produced by cellular constituents in the blood and damaged vessel wa11.2”~2g Each of these steps could be sites of intervention that might halt the restenosis process. The drugs that could reduce or prevent restenosis in the animal model are listed in Table II. Some of these have been investigated in prospective randomized angioplasty trials and although efficacy has not been demonstrated, they continue to be used and prescribed in daily routine. In this review we will concentrate on the drugs (Fig. 1) that have been tested to prevent restenosis in the animal model (Table III) and in postangioplasty patients (Table IV). Animal models are of limited value in restenosis research because it is impossible to create arterial stenoses in animals (e.g., pigs, rabbits, or dogs) that resemble human coronary artery disease (Table V). Most models use an inflated balloon to “injure” the intimal and medial layers of the vessel wall, although infused air has also been used. Some investigators have performed experiments in iliac or carotid arteries rather than in coronary arteries; others have fed the animals an atherogenic diet for brief periods of time to induce an “atherosclerotic lesion.” Several studies in animals have examined the degree of platelet deposition after arterial injury to test the hypothesis that platelet aggregation and platelet-derived substances are responsible for the restenosis process.2g-“’ Other studies use angiographic or histologic findings in damaged arteries to assess restenosis (Table IV). Recently a model of human restenosis