Despite intensive research, understanding of the healing process after percutaneous transluminal coronary angioplasty (PTCA) and the pathogenesis of restenosis is incomplete. Several alternative and adjunctive therapies to prevent restenosis have been introduced (1,2), with stent implantation being the most successful of these to date. Pharmacologic interventions have also been tested in several trials. Drugs such as heparin, platelet-suppressing drugs (dipyridamole, ticlopidine, prostacyclin and thromboxane-α2 receptor blockers), and anticoagulants have all failed to improve the long-term outcome of PTCA therapy. Cholesterol-lowering interventions, which have been shown to successfully reduce the occurrence of reinfarction and angina pectoris in large multicenter trials, as well as omega-3 polyunsaturated fatty acids, have also failed to reduce the loss of minimal luminal diameter (MLD) after angioplasty (3,4). Conventional anti-ischemia drugs, including calcium channel blockers, which have been examined in five clinical trials, have also been tested. This review discusses the results of these studies and the design of the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES), in which the effects of amlodipine on restenosis and multiple clinical end points are being assessed.
Restenosis, which occurs in 10-60% of patients after PTCA (5), has been defined in several ways. Percentage diameter stenosis has been used in a number of clinical trials, but the introduction of quantitative coronary angiography and the assessment of MLD have allowed a more precise description and evaluation of the restenosis process.
PATHOPHYSIOLOGY OF RESTENOSIS
Restenosis appears to be a response to injury involving several processes related to the repair of the vessel wall, perhaps including reaccumulation or progression of atherosclerosis. Extensive angiographic examinations (6-8) have revealed that elastic recoil occurs immediately after balloon deflation but makes a negligible contribution to the further loss of coronary artery luminal dimensions, which occurs in the following 1-3 months. Animal studies suggest that subintimal platelet deposition, followed by mural thrombus formation and consequent organization, may account for the early restenosis process (9,10). In addition, fibrocellular neointimal hyperplasia is a progressive process that occurs after PTCA and may account for further luminal narrowing in the months after the procedure (11-13). In stented patients, recoil is less prominent and neointimal hyperplasia is the most important factor in loss of luminal diameter.
After bypass surgery, angiographic follow-up studies have revealed that graft occlusion occurs in 10-25% of the graft implants and is most common in grafts with reduced blood flow, i.e., blood flow less than 50 ml/min (14). Drug intervention has been tested in an attempt to improve graft patency, and impressive results have been obtained with dipyridamole (15). It was suggested that the platelet-suppressing effects of dipyridamole combined with aspirin explained reductions in bypass graft occlusion and need for angiographic reexamination. However, dipyridamole also increases coronary blood flow, especially in nonstenosed regions of the coronary arteries. It is therefore possible that the effects achieved with dipyridamole can be ascribed to its vasodilating effect, which increases blood flow at the bypass junction, thus enhancing washout of prothrombotic material that may initiate thrombotic occlusion of bypass grafts. Similarly, drugs that increase blood flow in coronary vessels injured by angioplasty may increase the washout of endogenous factors or blood platelets, which may initiate or aggravate the repair process at the site of injury.
REDUCED BLOOD FLOW AND RESTENOSIS
Given that reduced blood flow is associated with poor outcome after bypass surgery, this may also be a risk factor for post-PTCA restenosis. The calcium channel blockers are vasodilators (16,17) and have antiplatelet effects (18-20). These drugs, particularly the long-acting agents, which provide 24-h coronary vasodilatation, may therefore be effective in reducing restenosis. Calcium channel blockers also inhibit mitogens, such as platelet-derived growth factor, that stimulate smooth muscle cells (21,22). Several animal studies of vascular damage suggest that, during vessel healing, calcium channel blockers reduce luminal narrowing (23,24). Calcium channel blockers may therefore improve outcome after angioplasty by effects at the site of the coronary lesion (25). Clinical observations have also indicated an effect of calcium channel blockers on the atherosclerotic process per se (26,27).
A large proportion of patients suffer from persistent or recurrent ischemia after angioplasty (2,28,29). Calcium channel blockers are effective in reducing ischemia (30). It therefore appears appropriate to continue their use in the angioplasty patient after the procedure, to reduce persistent or recurrent ischemia and to protect against restenosis.
ISCHEMIA PROTECTION BEFORE PTCA
The stress and anxiety that can follow angiographic examination and invasive procedures may enhance the ischemic burden of the myocardium. Administration of calcium channel blockers to these patients before the procedure may therefore protect the myocardium and reduce the hazards associated with angioplasty. Animal studies have suggested that brief and severe ischemia caused by transient coronary occlusion is followed by prolonged postischemic myocardial dysfunction ("stunning"), which may be followed by a return to normal contractility (31-34). Calcium antagonists given before or during ischemia appear to protect against postischemic stunning (35-37). When the calcium antagonist nisoldipine was added before or during angioplasty, stunning was significantly reduced (38). It has also been demonstrated that intracoronary nisoldipine delays the increase in left ventricular (LV) diastolic filling pressure and development of ST depression during angioplasty (39). In another trial, blood was sampled from the great cardiac vein during angioplasty in patients with stenosis of the left anterior descending coronary artery (40). In these patients, intravenous infusion of diltiazem reduced cardiac ATP breakdown during angioplasty, but there were no changes in ST segment elevation or lactate release during or immediately after balloon inflation (40).
The effects of long-acting dihydropyridines, such as amlodipine, on ischemia after coronary artery occlusion have been studied in animal models (41). Segmental shortening of the ischemic ventricular wall was assessed in dogs before and during coronary artery occlusion. Animals pretreated with amlodipine showed a significant improvement in segmental shortening in the ischemic region after the occlusion was released. Calcium channel blockade by amlodipine did not affect the severity of the ischemic process but effectively reduced stunning (41).
Data from animal studies and clinical observations therefore suggest that dihydropyridine calcium channel blockers, such as amlodipine, offer protection to the myocardium both during occlusion and in the postischemic phase of angioplasty. The prevention of coronary artery spasm induced by intracoronary manipulation is another indication for use of dihydropyridine calcium channel blockers during angioplasty (17).
POSTANGIOPLASTY ANTI-ISCHEMIC THERAPY
There are two main reasons why patients may have persistent ischemia after angioplasty. First, the procedure is often offered to patients in whom the aim is to improve myocardial blood supply despite multivessel disease and in whom incomplete revascularization has to be accepted. Therefore, many patients have persistent stenosis after angioplasty and continue to suffer from exercise-induced ischemia. The other main reason for postangioplasty ischemia is restenosis or inadequate gain of MLD during balloon inflation. It has been well documented that postangioplasty ischemia or angina pectoris cannot be used to identify patients with restenosis (4). However, at 4 months of follow-up in patients treated with PTCA, positive exercise tests were found in 40% and angina symptoms in 30% of patients (4,28). Angiographic examinations revealed that in patients with an MLD of less than 1.1 mm, 26% had positive exercise responses and 20% had angina pectoris, whereas in patients with an MLD of more than 1.9 mm, only 2% had ischemic exercise responses and 15% had angina pectoris at follow-up (28). A prospective trial comparing angioplasty with medical therapy (29) found that, at 6 months, 95% of the medically treated patients and 91% of the PTCA-treated patients were receiving antianginal medication. Calcium channel blockers were used by 71% of the medically treated patients and by 35% of the PTCA-treated group. The difference between groups was less pronounced for use of β-adrenergic blockers, with 50% of the medical therapy group and 30% of the PTCA group receiving them. Several studies have therefore demonstrated that although angioplasty reduces the need for antianginal medication, a large proportion of patients still required β-blocker or calcium channel blocker therapy to control ischemia.
Calcium channel blockers that do not increase heart rate are likely to be most suitable in the postangioplasty phase because they reduce residual ischemia.
Calcium channel blockers have several effects that may be relevant to restenosis prevention (5). They inhibit platelet aggregation (20), reduce vasospasm (17), and inhibit mitogens, such as platelet-derived growth factors, that stimulate smooth muscle cells (22). These effects are shared by dihydropyridine and nondihydropyridine calcium channel blockers. To investigate the effects of calcium channel blockers on restenosis, five trials were performed in angioplasty patients (42-46). The results of the individual trials were unconvincing, largely because the sample sizes were too small to allow definite conclusions. Hillegass and co-workers (5) therefore undertook a meta-analysis of the combined results. The data from this meta-analysis are presented in Table 1 and Fig. 1. In total, more than 900 patients participated in these trials and angiographic follow-up was performed on average in 82% of the patients (5). Restenosis was angiographically evident in 22-62% of placebo-treated patients and was observed most commonly in the verapamil trial which, unlike the other trials, included high-risk patients (47). On average, 39% of patients given placebo had significant restenosis compared with 31% of patients given calcium channel blockers (odds ratio of 0.68 with a 95% CI of the combined data of the five trials 0.49-0.94; p = 0.03) (5). Therefore, the combined data of the five trials suggest that patients treated with calcium channel blockers had a 30% reduction in the risk for restenosis.
In the verapamil trial, patients with either stable or unstable angina pectoris were included (47). Separate analyses of the two groups revealed that verapamil had no effect on restenosis in the patients with unstable angina but was associated with a reduced incidence of restenosis in patients with stable angina pectoris.
There are no data from these trials to indicate whether platelet aggregation was reduced, mitogens were affected, or blood flow velocity at the site of angioplasty injury was increased. Therefore, the mechanisms by which these drugs may affect restenosis remain poorly understood.
The CAPARES trial was initiated in Oslo, Norway, to examine the effects of amlodipine on restenosis rates and multiple clinical end points in patients with stable angina pectoris who undergo PTCA. The rationale for undertaking the trial was the assumption that calcium channel blockers may have favorable rheologic and biochemical effects on restenosis, as well as favorable anti-ischemic activity, particularly if the calcium channel blocker used has a 24-h effect. Amlodipine has 24-h vasoactive and biochemical actions with once-daily dosing. Effective vasodilatation by amlodipine may be particularly important because increased postangioplasty blood flow at the site of vessel wall injury may reduce restenosis by promoting washout of prothrombotic material, thus reducing stimuli of thrombus formation. The well-documented anti-ischemic properties of amlodipine should be of benefit in this population (30,48). In the original trial design of CAPARES, restenosis was assessed by calculating percentage diameter stenosis before and after the intervention. Because it is now well established that MLD provides more reliable and meaningful information (46), it was decided to assess all angiograms taken before and immediately after PTCA and at 4 months' follow-up with the CAAS II system introduced in the Thorax Center in Rotterdam. Clinical end points (death, myocardial infarction, need for bypass surgery or re-PTCA before routine angiographic 4-month follow-up) were the other primary end points in the study.
The CAPARES trial is a double-blind, placebo-controlled study which will enroll a minimum of 500 patients (Fig. 2). Once-daily amlodipine (5 mg adjusted to 10 mg after 3 days) or placebo therapy is started at least 2 weeks before angioplasty to achieve a steady-state amlodipine plasma concentration. β Blocker therapy will be continued (if needed) unchanged during the 4 months of observation. All patients will be given antithrombotic prophylaxis with aspirin. Participants are examined with exercise ECG and 48-h Holter monitoring 2 weeks before the angioplasty procedure, 2 weeks after the procedure, and after 4 months of follow-up. Data on infarction, cardiac death, need for stents, and repeat PTCA or CABG surgery will be captured and analyzed. Quality of life is also being assessed. At the end of August, 1996, 450 patients had been enrolled in the CAPARES study in Oslo and in several centers in Canada. Approximately 100 additional patients treated with stents will have identical angiographic follow-up and will have the effect of the test drug on MLD assessed.
Coronary vasodilatation is most often used during angioplasty to prevent coronary spasm and to allow optimal measurement of residual vessel obstruction after angioplasty. In some patients, anti-ischemic therapy is needed after PTCA because of residual ischemia, secondary either to restenosis or to mature coronary artery disease that has not been resolved by the angioplasty procedure. The long-acting, third-generation calcium channel blocker amlodipine provides 24-h anti-ischemic efficacy. This drug offers anti-ischemic protection during the period before angioplasty and during the procedure itself.
Amlodipine may reduce restenosis by increasing blood flow at the site of vessel wall injury immediately after the procedure, thus allowing washout of endogenous active metabolites and preventing platelet deposition. The drug may also prevent smooth muscle cell proliferation and thus retard the repair process, which itself may be the cause of restenosis. By using quantitative coronary angiographic assessment of MLD in angiography patients treated with amlodipine or placebo, the CAPARES trial will provide important information on the effect of amlodipine on restenosis, and clinical outcome in patients with or without stents.
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Official Satellite Symposium for the XVIIth Congress of the European Society of Cardiology, The National Exhibition Centre, Birmingham, United Kingdom August 28, 1996