Journal of the American College of Cardiology Vol. 43, No. 12, by the American College of Cardiology Foundation ISSN /04/$30.

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1 Journal of the American College of Cardiology Vol. 43, No. 12, by the American College of Cardiology Foundation ISSN /04/$30.00 Published by Elsevier Inc. doi: /j.jacc CLINICAL RESEARCH Evaluation of the Effect of Oral on Clinical Outcome and Angiographic Restenosis After Percutaneous Coronary Intervention The Randomized, Double-Blind, -Controlled, Multicenter Slow-Release for Prevention of Cardiovascular Events After Angioplasty (VESPA) Trial Hans-Peter Bestehorn, MD,* Franz-Josef Neumann, MD,* Heinz Joachim Büttner, MD,* Peter Betz, MD, PHD,* Peter Stürzenhofecker, MD, Eberhard von Hodenberg, MD, Antoine Verdun, MD, Laszlo Levai, MD, Jean Pierre Monassier, MD, Helmut Roskamm, MD* Bad Krozingen, Bad Neustadt, and Lahr, Germany; and Colmar and Mulhouse, France Clinical Trials OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We investigated the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention (PCI). Thus far, there is no established systemic pharmacologic approach for the prevention of restenosis after PCIs. Five small studies reported encouraging results for calcium channel blockers. Our randomized double-blind trial included 700 consecutive patients with successful PCI of a native coronary artery. Patients received the calcium channel blocker verapamil, 240 mg twice daily for six months, or placebo. Primary clinical end point was the composite rate of death, myocardial infarction, and target vessel revascularization (TVR) during one-year follow-up; the angiographic end point was late lumen loss at the six-month follow-up angiography. We obtained complete clinical follow-up in 95% of the patients, and scheduled angiography was performed in 94%. The proportion of patients treated with stents was 83%. The primary clinical end point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89]; p 0.002). This difference between the groups was driven by TVR (17.5% with verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p 0.006). Late lumen loss was mm with verapamil and mm with placebo (p 0.11). Compared with placebo, verapamil reduced the rate of restenosis 75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p 0.014). compared with placebo improves long-term clinical outcome after PCI of native coronary arteries by reducing the need for TVR. This was caused by a reduction in the rate of high-grade restenosis. (J Am Coll Cardiol 2004;43:2160 5) 2004 by the American College of Cardiology Foundation The long-term benefit from percutaneous coronary interventions (PCI) is limited by restenosis (1). Despite intensive research in recent years, it is still controversial whether any systemic drug therapy can prevent this adverse outcome. To this end, various drugs with promising efficacy in animal experiments have been tested in patients. Yet, most of the studies failed to show an unequivocal beneficial effect of systemic drug therapy on restenosis. There is reasonable skepticism whether systemic administration can achieve the local drug levels needed to suppress restenosis (2 4). Calcium channel blockers are among the few drugs with promising results in the prevention of restenosis. The From the *Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; Herz-und Gefäßklinik Bad Neustadt, Bad Neustadt, Germany; Herz-Zentrum Lahr, Lahr, Germany; Clinic St. Joseph Colmar, Colmar, France; and Hospital Emil Müller, Mulhouse, France. Supported, in part, by a grant from Abbott GmbH & Co., KG Ludwigshafen, Germany. Manuscript received May 7, 2003; revised manuscript received January 2, 2004, accepted February 10, putative antirestenotic properties of calcium channel blockers have been attributed to concentration-dependent inhibition of smooth muscle cell transformation and proliferation after stimulation with platelet-derived growth factor (5 7). Meta-analysis (8) of five small studies (9 13) yielded a significant 30% relative reduction in the risk of restenosis by calcium channel blockers as compared with placebo. This finding, however, has not been tested in an adequately powered trial. Therefore, we conducted the multicenter, randomized, double-blind, placebo-controlled, Slow-Release for Prevention of cardiovascular Events After Angioplasty (VESPA) trial to assess the effect of the calcium channel blocker verapamil on clinical outcome and angiographic restenosis after PCI. METHODS Patients selection and stent placement. Patients of age 35 and 80 years with successful PCI of a native coronary

2 JACC Vol. 43, No. 12, 2004 June 16, 2004: Bestehorn et al. Oral and Restenosis After PCI 2161 Abbreviations and Acronyms CABG coronary artery bypass grafting CAD coronary artery disease CI confidence interval MI myocardial infarction MLD minimal lumen diameter PCI percutaneous coronary intervention PTCA percutaneous transluminal coronary angioplasty RR relative risk TVR target vessel revascularization VESPA Slow-Release for Prevention of Cardiovascular Events After Angioplasty trial artery were eligible for the study. Successful intervention was defined by residual stenosis 30% on visual estimation and in case of stenting desired position of stent. We excluded patients with restenotic lesions, occlusions, lesions in bypass grafts, and left main location as well as patients with unstable angina, acute myocardial infarction (MI), ad-hoc and multistage PCI, insulin-dependent diabetes, renal insufficiency, sick sinus syndrome, atrioventricular node block, congestive heart failure and/or left ventricular ejection fraction 40%, severe concomitant diseases, contraindications to verapamil, and patients with inability to provide informed consent for participation. The study was approved by the institutional ethical review board of each hospital, and all patients gave written informed consent before inclusion in the study. Although the use of stents was encouraged, the percutaneous treatment modality was left to the operator s discretion. All patients received aspirin 100 mg, once daily, indefinitely and, in case of stenting, ticlopidine 250 mg, twice daily, or clopidogrel 75 mg, once daily, for four weeks. Thienopyridines were started immediately after the intervention. Study protocol. We designed our study as a prospective, multicenter, randomized, double-blind, placebo-controlled trial. Within 30 min after PCI, we assigned eligible patients to receive either verapamil, 240 mg slow-release tablets, or identical-appearing placebo twice daily. At each participating center, allocation to the study treatment was based on computer-generated random numbers that were used for double-blind labeling. In patients undergoing multivessel PCI (n 83), the most clinically relevant lesion was defined as the study lesion at the time of randomization. The study drug was started immediately after PCI and was continued until three days before six-month follow-up angiography. After PCI, we determined plasma concentrations of creatine kinase and its MB isoenzyme systematically for 48 h. We scheduled outpatient visits at one and three months after randomization for clinical follow-up including 12-lead electrocardiogram recordings. Patients returned to the hospital for routine angiographic restudy and clinical evaluation including bicycle ergometry at six months. Follow-up angiography was performed earlier if the patient had recurrent symptoms or signs of ischemia. Patients who had undergone angiography at 4 months after recruitment without meeting the criteria for a clinical end point were encouraged to undergo repeat angiography at six months. At each follow-up visit, we assessed compliance by pill counts. Quantitative angiography. Angiographic images were stored on compact discs (one center) or grabbed from cine films (other centers) and analyzed before the study was unblinded. Quantitative analysis was performed as described previously (14 16). Using the same two orthogonal views throughout the study, we obtained minimal luminal diameter (MLD), reference diameter, percent diameter stenosis, and the diameter of the maximally inflated balloon from the analysis system (Cardiovascular Angiographic Analysis System, Department of Medical Informatics, University of Limburg, Limburg, the Netherlands). Acute gain was calculated as the difference between post-stenting and predilation MLD, late loss as the difference between post-stenting MLD and MLD at follow-up, net gain as the difference between MLD at follow-up, and predilation MLD and loss index was calculated as the ratio of late loss to acute gain. All measurements were performed by the same blinded operator; intraobserver variability was 0.10 mm for MLD and 2.58% for diameter stenosis. Study end points. Our clinical primary end point was the combined incidence of death, MI, and target vessel revascularization (TVR). Myocardial infarction was defined as the presence of new Q waves ( 40 ms) in two or more contiguous electrocardiographic leads or an elevation of creatine kinase or its MB isoenzyme to at least 3 the upper limit of normal (80 U/l, 10 U/l, respectively) in two samples during hospitalization or to 2 the upper limit of normal after discharge. We defined TVR as coronary artery bypass surgery or repeat percutaneous angioplasty involving the treated vessel and performed for symptoms or signs of ischemia in the presence of angiographic restenosis ( 50%). Target vessel revascularization by coronary artery bypass surgery, which was indicated at the time of follow-up angiography, was counted as an event, even when performed during subsequent hospital admission. As our primary angiographic end point, we assessed late loss. We also analyzed other angiographic indexes of restenosis, including loss index, percent diameter stenosis, and the incidence of severe restenosis, defined as diameter stenosis 75%. Sample size estimation and statistical analysis. For calculation of sample size, we assumed a 25% incidence of our primary clinical end point (17). We designed the study to have a power of 80% to detect a 40% reduction in our primary clinical end point by verapamil as compared with placebo with a two-sided alpha value of According to these assumptions, 325 patients were required in each treatment arm. To account for losses to follow-up, we intended to include 700 patients. Assuming a normal distribution with a standard deviation of 0.5 mm for late loss (17) and allowing for missing angiograms in 100 patients,

3 2162 Bestehorn et al. JACC Vol. 43, No. 12, 2004 Oral and Restenosis After PCI June 16, 2004: Table 1. Baseline Demographic and Clinical Characteristics of the Study Cohort (n 352) p Value Age (yrs) Women 59 (17.0) 65 (18.5) 0.60 BMI (kg/m 2 ) Active smoker 74 (21.3) 84 (23.9) 0.41 Family history of CAD 122 (35.1) 128 (36.4) 0.72 Hypercholesterolemia 278 (79.9) 285 (81.0) 0.72 Hypertension 219 (62.9) 217 (61.6) 0.73 Diabetes 49 (14.1) 45 (12.9) 0.62 Multivessel disease 167 (48.0) 158 (44.9) 0.41 Previous balloon angioplasty 44 (12.6) 39 (11.1) 0.52 Previous coronary bypass 9 (2.6) 15 (4.3) 0.22 operation Previous myocardial infarction 115 (33.1) 120 (34.1) 0.77 Data are expressed as mean value SD or number of patients (%). BMI body mass index; CAD coronary artery disease. Figure 1. Trial profile. PCI percutaneous catheter intervention. this sample size gave us an 80% power to detect a 0.13 mm difference in late loss with a two-sided alpha value of All analyses were performed according to the intentionto-treat principle. Data are presented as mean SD or as counts or proportions. We assessed differences between the groups with use of a two-sided chi-square test for categorical variables. For continuous variables we used the unpaired t test. A value of p 0.05 in the two-tailed test was considered to statistically significant. The impact of baseline characteristics and other pertinent covariables on the primary clinical end point was adjusted using multivariate logistic regression. To account for the double primary end point, we adjusted the level of significance for our primary end points to p For all statistical analyses, we used SAS 6.12 software package (SAS Institute, Cary, North Carolina). RESULTS Study cohort and follow-up. The trial population is shown in Figure 1. The study enrolled 700 patients; 348 were assigned to verapamil and 352 to placebo. A coronary stent was placed in 581 patients (83%). The study groups were homogeneous with respect to baseline demographic, clinical, and angiographic characteristics (Tables 1 to 3). Thirty-seven patients were lost to clinical follow-up, and five additional patients refused second angiography. Thirteen patients of the verapamil group and 33 patients of the placebo group underwent follow-up angiography prematurely. Of the patients on verapamil, 19.5% (68 of 348) discontinued their study medication because of constipation (n 23), second- or a third-degree heart block (n 8), or other cardiovascular side effects (n 37). In the placebo group, the discontinuation rate was 15.6% (55 of 352). In addition, 11.8% (n 41) of the verapamil group and 10.8% (n 38) of the placebo group had a pill count that differed by more than 30% from the expected pill count. Clinical events. The primary clinical end point was reached in 19.3% (67 of 348) of the verapamil group and in 29.3% (103 of 352) of the placebo group (Table 4). Thus, adverse cardiac events were significantly (p 0.002) fewer in the verapamil group than in the placebo group with a relative risk (RR) reduction by verapamil of 34% (Table 4). The difference in the incidence of our primary end point was driven by a reduction in TVRs (Table 4). There were no appreciable differences in the incidences of death or MI. The risk reduction for the TVR by verapamil as compared with placebo was similar in patients receiving a stent and in patients treated with plain percutaneous transluminal coronary angioplasty (PTCA): (RR, 0.74 [95% confidence Table 2. Medication at Discharge (n 352) p Value Aspirin 338 (97.1) 342 (97.2) 0.98 Thienopyridines 297 (85.3) 305 (86.6) 0.62 Nitrates 174 (50.0) 160 (45.5) 0.23 CSE inhibitors 239 (68.7) 248 (70.5) 0.61 ACE inhibitors 153 (44.0) 156 (44.3) 0.93 AT-II receptor blockers 9 (2.6) 10 (2.8) 0.84 Diuretics 26 (7.5) 35 (9.9) 0.25 Data are expressed as number of patients (%). ACE angiotensin-converting enzyme; AT-II angiotensin-ii; CSE cholesterol synthesis enzyme.

4 JACC Vol. 43, No. 12, 2004 June 16, 2004: Bestehorn et al. Oral and Restenosis After PCI 2163 Table 3. Baseline Angiographic and Procedural Characteristics of the Study Cohort (n 352) p Value Complex lesions (AHA/ACC type B2, C) 169 (48.6) 169 (48.0) 0.94 Lesions per patient Vessel size, mm Before PCI MLD, mm Diameter stenosis, % Procedural variables Balloon-to-vessel ratio Inflation pressure, atm Stent placement 290 (83.3) 291 (82.7) 0.82 In-stented patients: Number of stents per stented study lesion Stented length, mm After PCI MLD, mm Acute gain (mm) Diameter stenosis, % Data are expressed as mean value SD or number of patients (%). AHA/ACC American Heart Association/American College of Cardiology; MLD minimum luminal diameter; PCI percutaneous coronary intervention. interval (CI) 0.52 to 1.05]; p 0.05 vs. RR 0.50 [95% CI 0.21 to 1.15]; p 0.06). In a multivariable logistic regression model that took into account baseline variables listed in Tables 1 and 3, the adjusted odds ratio was 0.52 (95% CI 0.32 to 0.84; p 0.007) for the clinical primary end point comparing both treatment strategies. Angiographic indexes of restenosis. Mean late loss was mm in the verapamil group and mm in the placebo group (Table 5); thus, our primary angiographic end point did not reach statistical significance (p 0.11). The cumulative distribution of percent diameter stenosis at follow-up (Fig. 2) shows a separation of the curves in the region of more severe stenoses. Accordingly, we found a significant reduction in the rate of high-grade restenosis ( 75%) by verapamil as compared with placebo, but only a trend towards a reduction in restenosis rate according to the 50% criterion (Table 5). Other indices of restenosis confirmed the trend towards attenuated restenosis by verapamil, but did not reach statistical significance either. The differences in late loss between the verapamil and placebo groups were similar after stenting ( mm vs mm; p 0.20) and after plain balloon angioplasty ( mm vs mm; p 0.67), as were the risk reductions for high-grade restenosis (RR 0.56 [95% CI 0.33 to 0.97]; p 0.03 vs. RR 0.58 [95% CI 0.12 to 1.75]; p 0.30). DISCUSSION Our randomized, placebo-controlled multicenter trial investigated the effect of verapamil on the clinical and angiographic outcome after PCI., administered for six months after PCI, reduced the incidence of major adverse cardiac events, our primary clinical end point, by reducing the need for repeat TVR. Consistent with this outcome, we found a significant reduction in the incidence of high-grade restenosis, although our primary angiographic end point, late loss, failed to show significant differences. Previous trials on calcium channel blockers were flawed by small sizes and methodological issues, such as subjective evaluation of restenosis. To our knowledge, our trial is the first adequately powered study addressing the effect of verapamil on restenosis with the use of quantitative coronary angiography. Although the impact of verapamil on restenosis was con- Table 4. Clinical Events (n 352) p Value RR (95% CI) Any cardiac event 67 (19.3) 103 (29.3) ( ) Death or MI 6 (1.7) 11 (3.1) ( ) Death 2 (0.6) 1 (0.3) ( ) Nonfatal MI 4 (1.2) 10 (2.8) ( ) TVR 61 (17.5) 92 (26.2) ( ) PCI 58 (16.7) 87 (24.8) ( ) CABG 3 (0.9) 5 (1.4) ( ) Data are expressed as number of patients (%). CABG coronary artery bypass grafting; MI myocardial infarction; PCI percutaneous coronary intervention; RR relative risk; TVR target vessel revascularization; CI confidence interval.

5 2164 Bestehorn et al. JACC Vol. 43, No. 12, 2004 Oral and Restenosis After PCI June 16, 2004: Table 5. Quantitative Angiographic Data at Angiographic Follow-Up (n 321) (n 335) RR (95% CI) p Value Late loss, mm MLD, mm Diameter stenosis, % Loss index Net gain, mm Diameter stenosis 50% 82 (25.7) 108 (32.3) 0.79 ( ) 0.06 Diameter stenosis 75% 25 (7.8) 46 (13.7) 0.57 ( ) Data are expressed as numbers (percentages) or mean value SD. Abbreviations as in Tables 3 and 4. siderably smaller than anticipated based on the earlier studies, the principle effect is confirmed. With the weight of the present study, currently available evidence suggests that calcium antagonists are capable of interfering with mechanisms involved in restenosis formation. Mechanisms that could be targeted by calcium antagonists include smooth muscle cell transformation, and migration and proliferation, as well as elaboration of extracellular matrix proteins (18 20). Our analyses, specifically the cumulative distributions of percent diameter stenosis, suggest a predominant effect of verapamil in the prevention of excessive restenosis formation. Previous studies revealed a bimodal distribution of restenosis formation after plain PTCA and after stenting (21). This bimodal distribution delineates two populations, which develop distinctively different degrees of lumen renarrowing. From our findings, it is conceivable that verapamil acts predominantly on the population with the strongest propensity to renarrowing. In this population, the antiproliferative properties of verapamil that have been described in experimental studies may become particularly effective. Study limitations. Of a large number of patients screened, only 6% were eventually included in the study. This was largely due to the strict inclusion criteria avoiding high-risk patients such as those with acute coronary syndromes and patients who were unlikely to complete follow-up (Fig. 1). Notably, only 2.1% were excluded because of contraindications to verapamil. On the other hand, the dosage of verapamil had to be reduced or withdrawn in about onethird of the patients. The possibility has to be considered that the reduction in TVR was caused by the antianginal properties of verapamil. To reduce this effect, the study protocol mandated bicycle ergometry before follow-up angiography and after discontinuation of study medication for three days. Nevertheless, the role of antianginal properties of verapamil cannot be completely ruled out. Although the majority of our patients were treated with stents, there was some admixture from patients who underwent plain PTCA. The mechanisms of restenosis differ substantially between the two treatment modalities. Neointima formation accounts for about 90% of the lumen loss after stenting (22,23). After plain PTCA, neointima formation is less pronounced, and about twothirds of lumen loss are caused by early elastic recoil and late vessel shrinkage. We cannot assume a uniform action of verapamil on each of these mechanisms. The low number of patients treated with plain PTCA prevented the detection of differences between the two percutaneous treatment modalities, but may have contributed to scatter. Clinical implications. Although the effect of verapamil on restenosis formation was statistically detectable, its extent was limited and has to be weighed against the disadvantages of withholding beta-blockers. In the meantime, stents releasing antiproliferative agents have proven, by far, to be more powerful tools in the prevention of restenosis (24). However, these devices are costly, and there is concern that the impairment of vascular healing processes after intervention might pose a substantial risk of late thrombotic events (25). Therefore, there is continued interest in the search for alternative approaches (26). To this end, the results of our study demonstrate the potential that resides in systemic administration of antiproliferative agents. Reprint requests and correspondence: Dr. Hans-Peter Bestehorn, Herz-Zentrum Bad Krozingen, Südring 15, Bad Krozingen, Germany. hans-peter.bestehorn@herzzentrum.de. REFERENCES Figure 2. Cumulative distribution curves for percent diameter stenosis at follow-up in the two treatment groups. 1. McBride W, Lange RA, Hillis LD. Restenosis after successful coronary angioplasty: pathophysiology and prevention. N Engl J Med 1988;318:

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