CLINICAL STUDIES
Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the coronary AngioPlasty Amlodipine REStenosis Study (CAPARES)
Bjørn Jørgensen, MD*,
Svein Simonsen, MD, PhD*,
Knut Endresen, MD, PhD*,
Kolbjørn Forfang, MD, PhD*,
Karleif Vatne, MD*,
James Hansen, MD ,
John Webb, MD ,
Christopher Buller, MD ,
Gilles Goulet, MD||,
Jan Erikssen, MD, PhD¶ and
Erik Thaulow, MD, PhD, FACC*
* Department of Cardiology, Rikshospitalet, University of Oslo, Oslo, Norway
Foothills Hospital, University of Calgary, Calgary, Canada
St. Paul Hospital, Vancouver, Canada
Hospital Saint-Luc, Montreal, Canada
|| Cardiology Research, Vancouver Hospital, Vancouver, Canada
¶ Sentralsykehuset i Akershus, Nordbyhagen, Norway
Manuscript received March 12, 1999;
revised manuscript received October 5, 1999,
accepted November 17, 1999.
Reprint requests and correspondence: Dr. Bjørn Jørgensen, Medisinsk avdeling, Bærum sykehus, Postboks 34, 1355 Bærum Postterminal, Sandvika, Norway
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Abstract
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OBJECTIVES
Our intent was to investigate the effect of the dihydropyridine calcium channel blocker amlodipine on restenosis and clinical outcome in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).
BACKGROUND
Amlodipine has sustained vasodilatory effects and relieves coronary spasm, which may reduce luminal loss and clinical complications after PTCA.
METHODS
In a prospective, double-blind design, 635 patients were randomized to 10 mg of amlodipine or placebo. Pretreatment with the study drug started two weeks before PTCA and continued until four months after PTCA. The primary angiographic end point was loss in minimal lumen diameter (MLD) from post-PTCA to follow-up, as assessed by quantitative coronary angiography (QCA). Clinical end points were death, myocardial infarction, coronary artery bypass graft surgery and repeat PTCA (major adverse clinical events).
RESULTS
Angioplasty was performed in 585 patients (92.1%); 91 patients (15.6%) had coronary stents implanted. Follow-up angiography suitable for QCA analysis was done in 236 patients in the amlodipine group and 215 patients in the placebo group (per-protocol group). The mean loss in MLD was 0.30 ± 0.45 mm in the amlodipine group versus 0.29 ± 0.49 mm in the placebo group (p = 0.84). The need for repeat PTCA was significantly lower in the amlodipine versus the placebo group (10 [3.1%] vs. 23 patients [7.3%], p = 0.02, relative risk ratio [RR]: 0.45, 95% confidence interval [CI]: 0.22 to 0.91), and the composite incidence of clinical events (30 [9.4%] vs. 46 patients (14.5%), p = 0.049, RR: 0.65, CI: 0.43 to 0.99) within the four months follow-up period (intention-to-treat analysis).
CONCLUSIONS
Amlodipine therapy starting two weeks before PTCA did not reduce luminal loss, but the incidence of repeat PTCA and the composite major adverse clinical events were significantly reduced during the four-month follow-up period after PTCA with amlodipine as compared with placebo.
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Abbreviations and Acronyms
| | CABG | = coronary artery bypass graft surgery | | CAPARES | = Coronary AngioPlasty Amlodipine REStenosis Study | | CCB | = calcium channel blockers | | CK | = creatine kinase | | MI | = myocardial infarction | | MLD | = minimal lumen diameter | | PTCA | = percutaneous transluminal coronary angioplasty | | QCA | = quantitative coronary angiography | | RR | = relative risk |
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Restenosis after percutaneous transluminal coronary angioplasty (PTCA) compromises the clinical advantage of the method (1). Furthermore, although PTCA is accomplished with a high success rate initially, the patients are still at risk of cardiovascular complications and the need for repeat revascularization (2–6). Intracoronary stent implantation has reduced the incidence of restenosis and complications, but it is an expensive alternative without complete inhibition of postinterventional luminal renarrowing (7,8). The pathophysiology of restenosis has been extensively studied and seems to be related to coronary spasm, recoil, platelet aggregation, thrombus formation, intimal hyperplasia and late vascular shrinkage (remodeling) (9–11). Several pharmacologic trials have been done to study prevention of restenosis, mostly without positive results (12). In five previous restenosis trials with calcium channel blockers (CCBs), no confident results were shown (13–17). These studies had different study designs and important limitations, such as lack of quantitative coronary angiography (QCA), adequate follow-up angiography and relative poor sample size. A meta-analysis of five CCB trials has suggested a reduction in the odds of angiographic restenosis in the CCB-treated patients (18).
The dihydropyridine CCBs have been shown to inhibit platelet aggregation in humans (19–21), especially in combination with aspirin (22), and experimental data indicate that they exert inhibitory effects on smooth muscle cell proliferation (23). The vasodilatory effect of the dihydropyridine CCB, amlodipine, is mainly in the peripheral and coronary arteries and has been shown to be effective in relieving coronary spasms (24–26). These actions seem feasible in terms of reducing spasms and recoil induced by angioplasty and promoting flow in the target vessel, which may attenuate thrombus formation at the angioplasty site. Furthermore, amlodipine has a gradual onset and long duration of action (27). Pretreatment with amlodipine before angioplasty, which has not been a part of the previous CCB restenosis trials, may therefore be beneficial.
The Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES) was carried out to investigate the effect of amlodipine on restenosis and clinical outcome in patients undergoing PTCA.
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Methods
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Study group.
From 1992 to 1996, 635 patients suitable for elective balloon angioplasty of one or more of the major coronary arteries were included in the study from one Norwegian (n = 473) and four Canadian (n = 162) centers. Included were patients with stable angina pectoris and those with de-novo lesions on native coronary arteries not totally occluded at the initial diagnostic angiographic study. Stenosis with a reference lumen diameter <2 mm, visually judged from the initial diagnostic angiogram, were not included. The study was carried out in accordance with the declaration of Helsinki and was approved by the local Ethics Committees. Written, informed consent was obtained from all patients.
Study protocol.
CAPARES is a double-blind, placebo-controlled study. Two weeks before PTCA, all patients were randomized to receive either amlodipine or placebo starting at 5 mg once daily the first week and then increasing to 10 mg once daily. Clinical examinations and treatment evaluation were performed two weeks and the day before PTCA and two weeks and four months after PTCA as follow-up. To achieve similar coronary vascular tone during PTCA, 20 mg of nifedipine was administered (in a blinded manner) orally twice before and once soon after PTCA to patients randomized to receive placebo, and corresponding placebo (nifedipine) tablets were given to the amlodipine-treated patients. Nifedipine was administered as described at follow-up angiography. All patients received aspirin. Cholesterol-lowering drugs, angiotensin-converting enzyme inhibitors, diuretic agents, beta-blockers and noncardiovascular drugs were continued throughout the trial if they were used before study entry. Nontest CCB treatment was discontinued before study inclusion, but patients stopped participating in the trial if discontinuation led to crescendo angina or hypertension. Successful PTCA was defined as satisfactory post-PTCA results (<50% diameter stenosis as visually assessed by the operator) without major in-hospital adverse cardiac events (death, myocardial infarction [MI], coronary artery bypass graft surgery [CABG] or repeat PTCA). Stents were only implanted in bail-out situations or because of an unsatisfactory post-PTCA result. Patients with stents were not evaluated in the angiographic per-protocol analysis.
Angioplasty procedure and follow-up angiography.
Balloon angioplasty was performed using the femoral approach using an 8F guiding catheter. A bolus of 10,000 IU of heparin was given intravenously before the procedure. During prolonged procedures (>1 h), an additional 5,000 IU of heparin per hour was given. In case of angiographically visible dissections, 10 IU of heparin per kg of body weight per hour was given until the next morning. The same angiographic views were obtained immediately before and after PTCA and at follow-up. For study purposes, the settings of the X-ray equipment (table height, field magnification and projection angulations) were recorded for each lesion, and an attempt was made to obtain two orthogonal views, avoiding overlapping side branches and foreshortening of the lesions. The angiograms were analyzed using the Cardiovascular Angiography Analysis System (CAAS II, Pie Medical Imaging, Maastricht, the Netherlands) (28) by a core laboratory (Norway), with the investigators blinded to the treatment allocation. End-diastolic frames were selected for edge-detection analysis, and the tip of the catheter was used as a scaling device. Quantitative coronary angiography was done as previously described (29).
End points.
The primary angiographic end point was the intrapatient mean loss in minimal lumen diameter (MLD) (MLD after PTCA – MLD at follow-up). For patients who had more than one lesion dilated, the average MLD of all successfully dilated lesions was used for this analysis. The secondary angiographic end point was the restenosis rate at follow-up, defined as a diameter stenosis  50% at follow-up angiography in patients successfully dilated. The clinical end points were death (all-cause), MI, CABG or repeat PTCA performed before the scheduled follow-up investigation. Myocardial infarction was determined by the investigator at each site and was defined as chest pain combined with either pathologic electrocardiographic changes (new pathologic Q waves) or elevation of creatine kinase (CK) or CK-MB fraction to more than twofold the upper normal limit, or both. Cardiac enzymes (creatine kinase) were checked before and after PTCA in all patients. Interventions after successful PTCA (either CABG or repeat PTCA) were clinically driven and only performed in patients with escalating angina symptoms that led to a premature angiographic examination. End points for every patient were categorized into a composite end point, with only one end point counting for each patient when more than one event occurred. Clinical end points were primarily evaluated in all randomized patients (intention-to-treat analysis) and also in those who underwent PTCA while on study medication. Patients with successful angioplasty without stent implantation and who completed the study with angiography suitable for QCA analysis were included in the angiographic end point analysis (per-protocol analysis).
Statistical analysis.
The number of patients in the study was initially based on the concept of restenosis as a categoric dichotomous end point. We initially calculated that 150 patients were required in each treatment group on the assumption of a restenosis rate of 30% in the placebo group and 15% in the amlodipine-treated group. After the study was started, QCA became the "gold standard" for coronary artery luminal measurements (30), and MLD, a continuous variable, the main outcome variable in restenosis trials (31). The protocol was adjusted and the number of patients recalculated to be 233 in each treatment group (32).
Data are presented as the mean value ± SD or number (percent). The Student t test was used to compare continuous variables, and for categoric variables, the chi-square test or, when appropriate, the Fisher exact test was used, applying a two-tailed alpha level of 0.05. Relative risk (RR) for the clinical end points are given. Statistical analysis was performed with use of StatView, version 5.0.
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Results
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A total of 635 patients were randomized—318 received amlodipine and 317 placebo. There were no statistical differences in the baseline variables between the treatment groups (Table 1). Ten patients in the amlodipine group discontinued the study medication (owing to edema in five patients, hypertension in one, nausea in one, abdominal pain in one, unstable angina in one and delay of the planned PTCA in one) and seven in the placebo group (owing to unstable angina in four patients, hypertension in one, urinary retention in one and nausea in one). Angioplasty was performed in 585 patients (92.1%), and stents were implanted in 91 patients (15.6%) (38 in the amlodipine group and 53 in the placebo group). In total, 451 patients (236 in the amlodipine group and 215 in the placebo group) had follow-up angiography suitable for QCA analysis (per-protocol analysis). There was no difference in baseline clinical and angiographic variables between those adhering to the protocol versus those not adhering to it, except that those adhering were younger (two years, p = 0.01) and more of them (11.2%, p = 0.01) had single-vessel disease. The patient flowchart is shown in Table 2. The median time to follow-up angiography was 132 days (range 21 to 167) in the amlodipine group and 131 days (range 27 to 179) in the placebo group (p = NS).
Angiographic results.
Angiographic baseline characteristics (per-protocol analysis) did not differ significantly between the two groups (Table 3). There were no significant differences in reference diameter or MLD immediately before and after angioplasty or at follow-up between the two groups (Table 4). Both groups achieved the same gain in MLD (from pre-PTCA to post-PTCA), and there was no significant difference in loss of MLD (from post-PTCA to follow-up) between the two groups (mean difference 0.01 mm, 95% confidence interval [CI] –0.08 to 0.10 mm). The cumulative distribution curves for MLD before and after PTCA and at follow-up are shown in Figure 1. The restenosis rates (per patient) were 28.1% in the amlodipine group and 28.4% in the placebo group (p = 0.95). Analyzed per vessel, the restenosis rates were 29.7% in the amlodipine group and 29.9% in the placebo group (p = 0.97).
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Figure 1 Cumulative distribution curves for MLD in the amlodipine (n = 236) and placebo (n = 215) groups (per-protocol group) before and immediately after PTCA and at four-month follow-up after PTCA.
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Clinical results.
There was a 4.2% (p = 0.02) absolute reduction in the clinically driven need for repeat PTCA before the scheduled follow-up angiography, and a 5.1% (p = 0.049) reduction in the incidence of major adverse clinical events in the amlodipine group as compared with the placebo group (intention-to-treat analysis). The outcome for all patients randomized and for the patients who underwent PTCA while on the study drug are shown in Table 5. One patient in the placebo group died of ventricular fibrillation 6 h after PTCA, and one patient without PTCA also in the placebo group, had a cardiac death three months after study inclusion. One patient in the amlodipine group died of metastatic pancreatic cancer that was not diagnosed before study inclusion. Three patients in the amlodipine group had an MI after discontinuation of the study drug. Five patients in the amlodipine group and nine in the placebo group had a MI in-hospital after PTCA, and two patients in the placebo group had an MI after hospital discharge. Nine patients in the amlodipine group and five in the placebo group were referred for elective CABG without the scheduled PTCA being performed. Urgent CABG was performed in the hospital in three patients in the amlodipine group and seven in the placebo group. Two patients in the amlodipine group and six in the placebo group underwent CABG after hospital discharge. One patient in the amlodipine group who discontinued the study medication before the scheduled PTCA had a repeat PTCA. Five patients in the placebo group underwent urgent repeat PTCA in the hospital. Nine patients the amlodipine group and 18 in the placebo group underwent repeat PTCA after hospital discharge, before follow-up angiography.
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Table 5 Clinical End Points in All Randomized Patients (Intention-to-Treat) and All Patients Who Underwent the Scheduled Percutaneous Transluminal Coronary Angioplasty
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Discussion
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In the present study, amlodipine starting two weeks before PTCA did not prevent luminal loss or restenosis as assessed by angiography four months after successful PTCA. In the amlodipine group, the need for target vessel repeat PTCA and the composite incidence of major adverse clinical events were significantly lower, both in the intention-to-treat analysis and by analysis of those patients who underwent PTCA (treatment group), but no difference in the incidence of death and MI was seen.
Lack of effect on angiographic variables.
A lack of effect of amlodipine on MLD and restenosis is in agreement with previous CCB restenosis trials (13–17,33). In these trials three different types of CCBs were used and study designs varied—coronary artery measurements were mostly without QCA, a small number of patients were enrolled and the proportions of patients without angiographic follow-up were relatively high. In the present study, a sufficient number of patients were enrolled, angiographic follow-up was carried out in 91% of patients and QCA was used. Thus, this trial is presently the largest CCB restenosis trial to date.
In the present study, follow-up angiography was done four months after PTCA based on the studies by Serruys et al. (34) and Nobuyoshi et al. (35), which demonstrated that luminal renarrowing is a time-related phenomenon developing during the first four months after angioplasty. Although repeat angiography is usually done six months after PTCA in most restenosis trials, it is unlikely that further luminal changes would occur from the fourth to the sixth month. The present angiographic results are nearly identical to those of Rensing et al. (31), who examined 1,445 successfully dilated lesions with QCA before and immediately after balloon angioplasty and at six-month follow-up. The mean values ± SD of the reference diameter of the target lesions in both treatment groups were similar to those in the study by Rensing et al. (31), in which nitroglycerin was used to control vascular tone. Thus, adequate vasodilation was provided by the use of amlodipine or nifedipine at angioplasty and repeat angiography.
The development of restenosis has mainly been explained by thrombus formation, smooth muscle cell proliferation and extracellular matrix formation resulting in intimal hyperplasia (36). Elastic recoil and vascular spasm have also been proposed as early factors in the complex chain of events (37). Previous pharmacologic trials on restenosis prevention have been aimed at interfering with thrombus formation and intimal hyperplasia, but the results have mostly been negative (12). The lack of effect of pharmacologic agents may be explained by additional factors leading to restenosis. Intravascular ultrasound examination, which delineates the vessel wall structures (38), suggests that shrinkage of the vessel wall, with only slight intimal thickening, is the predominant cause of postinterventional luminal loss (remodeling) (9,10,39). Pharmacologic agents administered in therapeutic doses seem to be inadequate to limit the shrinkage of the vessel wall at the lesion site, and this may explain the failure of restenosis reduction in this study and most other studies.
Clinical outcome.
Clinical events were included in only one of the previous CCB restenosis trials, and in this trial diltiazem did not reduce cardiac events after PTCA (17). In the present study, the incidence of repeat PTCA and the composite major clinical events were reduced, despite the apparent lack of effect on angiographic variables. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) (40), amlodipine failed to reduce progression of coronary atherosclerosis as assessed by QCA, but major vascular procedures were significantly reduced in the amlodipine group.
The discrepancy between the angiographic and clinical results may be attributable to the limited angiographic area under investigation—that is, the target lesion only. Vasoconstriction and spasms may facilitate occlusion of the dilated artery and thus lead to infarction or the need for urgent revascularization. Amlodipine has been shown to induce sustained relaxation of coronary arteries, which augments the total myocardial blood flow without reflex tachycardia (26,41,42). Enhancement of the subendocardial and collateral blood flow may also reduce the myocardium in jeopardy. In animals subjected to coronary artery occlusion, amlodipine decreased the size of the ischemic regions and improved myocardial segmental function of the reperfused region, and amlodipine has also been shown to reduce myocardial oxygen consumption, coronary vascular resistance and infarct size (43,44). Thus, the anti-ischemic effects of amlodipine (45–47) most probably reflect the reduced need for target vessel revascularization before the scheduled repeat angiography.
Study limitations.
The fact that intracoronary nitroglycerin was not given routinely to all patients before angiography deviates from standard study design when assessing angiographic end points (48), although the CCBs given provided satisfactory vasomotor control.
The clinical events were observed from a study population in which the power and sample size calculations were based on a 30% reduction in mean loss of MLD, that is angiographic end points. Taking into consideration the relative short time to follow-up, it is possible that the rates of events could have been different if six months of follow-up had been used instead of four months. The effect of amlodipine should be tested in another prospective, randomized study with a longer follow-up time, designed and powered for evaluating clinical end points in patients after successful coronary angioplasty.
Conclusions.
In the present study, amlodipine treatment starting two weeks before angioplasty and continuing for four months after angioplasty did not reduce restenosis after PTCA. The incidence of composite major adverse clinical events was significantly reduced in the patients treated with amlodipine, but the difference was mainly due to a reduction in the number of repeat PTCAs. The need for repeat PTCA was driven by ischemic symptoms, attributed to the anti-ischemic effects by amlodipine. The clinical results should be confirmed in a larger trial with longer follow-up. Appendix.
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Appendix
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Participating centers and principal investigators in CAPARES.
Bjørn Jørgensen, Rikshospitalet, Oslo, Norway (Primary investigator and core angiographic laboratory); James Hansen, University of Calgary, Foothills Hospital, Canada; John Webb, St. Paul Hospital, Vancouver, Canada; Christopher Buller, Cardiology Research, Vancouver Hospital, Canada; and Gilles Goulet, Hospital Saint-Luc, Montreal, Canada.
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Acknowledgments
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We thank research assistant Johanna Andreassen for her invaluable assistance.
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Footnotes
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This study was supported by a grant from Pfizer Inc., New York, to Medinnova, Rikshospitalet, Oslo, Norway.
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References
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