A Randomized Comparison of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin After the Placement of Coronary Artery Stents

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1 Journal of the American College of Cardiology Vol. 41, No. 6, by the American College of Cardiology Foundation ISSN /03/$30.00 Published by Elsevier Science Inc. doi: /s (02) A Randomized Comparison of and Aspirin Versus and Aspirin After the Placement of Coronary Artery Stents Christian Mueller, MD,* Helmut Roskamm, MD, FACC,* Franz-Josef Neumann, MD, FACC,* Patrick Hunziker, MD, Stephan Marsch, MD, PHD, André Perruchoud, MD, Heinz J. Buettner, MD* Bad Krozingen, Germany; and Basel, Switzerland OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The aim of the present study was to compare clopidogrel and ticlopidine after coronary stenting with regard to cardiovascular death during long-term follow-up. Randomized trials comparing clopidogrel and ticlopidine with a restricted use of intravenous glycoprotein IIb/IIIa inhibition have reported a trend toward a higher incidence of thrombotic stent occlusion with clopidogrel at 30 days. After successful coronary stent implantation, 700 patients with 899 lesions were randomly assigned to receive a four-week course of either 500 mg ticlopidine (n 345) or 75 mg clopidogrel in addition to 100 mg aspirin. Cardiovascular death was the primary end point and was recorded during a median follow-up period of 28 months. Cardiovascular death occurred in eight patients with ticlopidine versus 26 patients with clopidogrel (hazard ratio with ticlopidine compared with clopidogrel, 0.30; 95% confidence interval [CI], 0.14 to 0.66; p 0.003). After adjustment for co-variables, ticlopidine reduced the risk of cardiovascular death by 63% compared with clopidogrel. The combined end point of cardiovascular death or nonfatal myocardial infarction was present in 19 patients assigned ticlopidine, compared with 40 patients assigned clopidogrel (hazard ratio, 0.45; p 0.005). The hazard ratio for all-cause mortality with ticlopidine as compared with clopidogrel was 0.30 (95% CI, 0.14 to 0.64; p 0.002). After the placement of coronary artery stents in unselected patients, ticlopidine was associated with a significantly lower mortality than clopidogrel. This raises concern about the current practice of substituting clopidogrel for ticlopidine after stenting and highlights the need for further long-term studies. (J Am Coll Cardiol 2003;41:969 73) 2003 by the American College of Cardiology Foundation The introduction of highly effective dual antiplatelet therapy with aspirin and ticlopidine (1) has reduced the risk of thrombotic stent occlusion (TSO) substantially. Although the true incidence of TSO has not been formally examined, TSO with complete occlusion of the stent lumen and acute coronary syndrome occurs in approximately 1% of patients (1) treated with aspirin and ticlopidine within 30 days. is a new thienopyridine derivative with excellent tolerability (2). Three randomized clinical trials (3 5) directly compared ticlopidine and clopidogrel after stenting. They unequivocally showed a reduction in allergic exanthema, nausea, and diarrhea with clopidogrel. However, the two studies (3,4) with a restricted use of intravenous glycoprotein IIb/IIIa inhibition reported a higher incidence of TSO with clopidogrel at 30 days (1.4% vs. 0.6%, p 0.13). Although this difference did not reach statistical significance, it raised concern because it may affect long-term survival. We, therefore, extended the follow-up period of our previous study (3) to further investigate this issue. From the *Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; and University Hospital Basel, Basel, Switzerland. Manuscript received June 12, 2002; revised manuscript received July 26, 2002, accepted August 19, METHODS Patient selection and study protocol. Consecutive patients with successful stent implantation were randomly assigned in equal proportions with the use of a pre-specified randomization sequence to receive either ticlopidine (250 mg twice a day) or clopidogrel (75 mg per day) orally for four weeks. The first dose of ticlopidine (500 mg) or clopidogrel (75 mg) was given immediately after stent implantation. All patients received aspirin (100 mg pd) for life. Patients were scheduled for follow-up visits at our institution at six months and whenever clinically indicated thereafter. In addition, all patients were contacted by questionnaire to assess vital and functional status as well as major adverse cardiac events two years after enrollment of the last patient. If patients did not return a signed questionnaire or any uncertainties remained, a physician interviewed the patients and their family physician over the phone. All information derived from contingent hospital re-admission records or provided by the referring physician or by the outpatient clinic was reviewed. Treatment was not blinded, but all end points were adjudicated by a clinical events committee whose members were unaware of the patients treatment assignments. The study was carried out according to the principles of the Declaration of Helsinki and approved by our local

2 970 Mueller et al. JACC Vol. 41, No. 6, 2003 Versus After Stenting March 19, 2003: Abbreviations and Acronyms CK creatine phosphokinase MI myocardial infarction TSO thrombotic stent occlusion hospital investigational review board. Informed consent was obtained from all participating patients. End points. The primary end point was cardiovascular death during the entire follow-up period. It was defined as any death for which there was no clearly documented non-cardiac cause. The secondary end point was the composite of cardiac death and myocardial infarction (MI). Myocardial infarction was defined as typical chest pain at rest followed by an increase in creatine phosphokinase (CK and CK-MB beyond 2 the upper limit of normal and 5 the upper limit of normal after coronary artery bypass grafting) or new Q waves in the electrocardiogram. In addition, we monitored all-cause mortality. Statistical analysis. All data were analyzed on an intention-to-treat basis. Comparisons were made using the t test and chi-squared test, as appropriate. Hazard ratios were determined by Cox regression analysis. Backward stepwise multivariate Cox regression analysis was used to identify independent predictors of cardiovascular death. The variables entered into the model were gender, age, previous coronary bypass grafting, acute MI, left ventricular function, number of coronary vessels diseased, left anterior descending lesion location, restenosis, intravenous platelet IIb/IIIa inhibitor use, diabetes, and treatment with ticlopidine. The time-to-event curves were generated with the Kaplan-Meier estimator. The statistical analyses were performed using the SPSS/PC (version 11.0, SPSS Inc., Chicago, Illinois) soft- Table 1. Clinical, Angiographic, and Procedural Baseline Characteristics No. (%), if Not Defined Otherwise (n 345) p Value Age (yrs) Female gender 96 (27) 90 (26) 0.78 Arterial hypertension 232 (65) 229 (66) 0.78 Diabetes mellitus 80 (23) 72 (21) 0.59 Smoking 100 (28) 109 (32) 0.32 Previous coronary bypass grafting 53 (15) 42 (12) 0.25 Previous myocardial infarction 170 (48) 153 (44) 0.29 Acute myocardial infarction 40 (11) 38 (11) 0.91 Unstable angina 141 (40) 131 (38) 0.59 Three-vessel disease 162 (46) 138 (40) 0.11 Left ventricular function 0.47 Normal 115 (32) 136 (39) Mildly depressed 136 (38) 125 (36) Moderately depressed 85 (24) 72 (21) Severely depressed 18 (5) 12 (3) Lesions Lesions per patient Lesion type B2 or C* 197 (55) 176 (51) 0.24 Restenotic lesion 46 (13) 34 (10) 0.21 Bifurcation lesion 13 (4) 17 (5) 0.52 Occluded vessel 77 (22) 80 (23) 0.75 Left anterior descending 132 (37) 145 (42) 0.19 Left circumflex 80 (23) 70 (20) 0.47 Right coronary artery 124 (35) 106 (31) 0.24 Intermediate branch 5 (1) 7 (2) 0.53 Left main 3 (1) 1 (0) 0.33 Saphenous vein graft 26 (7) 23 (7) 0.73 Max. balloon size (mm) Max. inflation pressure (atm) Stent length (mm) Type of stents used NIR Primo 180 (51) 169 (49) 0.60 ACS Multilink 66 (19) 72 (21) 0.51 CVD Enforcer 27 (8) 26 (8) 0.97 CVD Synthesis 27 (8) 24 (7) 0.76 Combination of different stents 21 (6) 25 (7) 0.51 Others 34 (10) 29 (8) 0.36 Glycoprotein IIb/IIIa receptor antagonist 40 (11) 25 (7) 0.07 Duration of procedure (min) Plus-minus values are means SD. *American Heart Association/American College of Cardiology classification is given for the first treated lesion in every patient.

3 JACC Vol. 41, No. 6, 2003 March 19, 2003: Mueller et al. Versus After Stenting 971 Table 2. Medication at Discharge (Other Than Aspirin and Study Drug) ware package. A value of p 0.05 in the two-tailed test was regarded as significant. RESULTS No. (%) (n 345) p Value Statins 305 (86) 292 (85) 0.63 Other lipid-lowering agent 2 (1) 2 (1) 0.98 ACE inhibitor* 254 (72) 242 (70) 0.68 Beta-blocker 298 (84) 273 (79) 0.10 Calcium-channel blocker 45 (13) 60 (17) 0.08 Diuretics 88 (25) 77 (22) 0.44 Long-acting nitrates 223 (63) 238 (69) 0.09 Digoxin 16 (5) 11 (3) 0.37 Alpha-blockers 7 (2) 6 (2) 0.82 Amiodarone 8 (2) 5 (1) 0.43 *Or angiotensin II receptor antagonist; Diltiazem or verapamil in patients without concomitant beta-blockers. ACE angiotensin-converting enzyme. Baseline patient characteristics and procedural details. Seven hundred patients with 899 lesions were randomly assigned to receive either ticlopidine (n 345) or clopidogrel. As shown in Tables 1 and 2, baseline clinical, angiographic, and procedural characteristics, as well as medication at discharge, were similar in both groups. Statins were used in 85% of patients. End points. Median time from randomization to last patient contact or patient death was 28 months in the ticlopidine group and 27 months in the clopidogrel group. Cardiovascular mortality was significantly lower in patients assigned to receive ticlopidine than in those assigned to clopidogrel (Table 3); it occurred in eight patients with ticlopidine versus 26 patients with clopidogrel (hazard ratio with ticlopidine compared with clopidogrel, 0.30; p 0.003). The secondary end point of cardiovascular death or nonfatal MI occurred in 19 patients assigned ticlopidine, compared with 40 patients assigned clopidogrel (hazard ratio 0.45; p 0.005). In addition, all-cause mortality was lower with ticlopidine (hazard ratio 0.30; p 0.002). Kaplan-Meier analysis showed that patients assigned ticlopidine had a significantly lower probability of death from cardiovascular causes than patients assigned clopidogrel during the entire follow-up period (Fig. 1). The association between ticlopidine and improved outcome seemed consistent among various subgroups (Fig. 2). After adjustment for covariables, ticlopidine reduced the risk of death by 63% compared with clopidogrel (Table 4). DISCUSSION To our knowledge, this is the first presentation of extended follow-up data from a randomized trial comparing clopidogrel and ticlopidine after the placement of coronary artery stents. We found a significantly lower cardiovascular mortality in patients assigned to receive ticlopidine. Mechanistic reasons. Thrombotic stent occlusion does occur beyond the first month after stenting as thienopyridine treatment is withdrawn, maybe particularly in patients with non-flow-limiting, and therefore asymptomatic, thrombus apposition by day 30 (6). Thus, the efficacy of the antithrombotic regimen given during the first month is very likely to have an effect on late events as well. This hypothesis is supported by the observation that potent periinterventional platelet inhibition with abciximab improves long-term survival (7). Statins inhibit clopidogrel. Recently, Lau et al. (8) presented evidence that clopidogrel activation requires the CYP-450 3A4 system and that antiplatelet activity of clopidogrel is substantially inhibited by atorvastatin and simvastatin, which are also metabolized by the CYP-450 3A4 system. This inhibitory effect has not been reported for ticlopidine. The frequent use of statins in our study may have induced or exaggerated differences in antiplatelet efficacy between ticlopidine or clopidogrel. Comparison with observational studies. Non-randomized observational studies have revealed conflicting findings. A meta-analysis (9) of large registries and randomized trials suggested a lower rate of cardiac events with clopidogrel at 30 days. However, a recent multicenter, nested case-control study (10) that accounted for the limitation of registry data, which were often not concurrent, showed that, after controlling for potential cofounders, the use of clopidogrel was associated with a significant increased risk of TSO in multivariate analysis. Study limitations. Patients in this study were treated with 100 mg of aspirin. It is unknown whether the 325-mg dose of aspirin used, for example, in the U.S., may have altered the findings. Table 3. Major Adverse Events No. (%) (n 345) Hazard Ratio (95% CI) p Value Cardiovascular death 26 (7.3%) 8 (2.3%) 0.30 ( ) Cardiovascular death or nonfatal MI 40 (11.3%) 19 (5.5%) 0.45 ( ) Nonfatal MI 17 (4.8%) 12 (3.5%) 0.71 ( ) Death from all causes 29 (8.2%) 9 (2.6%) 0.30 ( ) The hazard ratios are shown for patients receiving ticlopidine as compared with clopidogrel. CI confidence interval; MI myocardial infarction.

4 972 Mueller et al. JACC Vol. 41, No. 6, 2003 Versus After Stenting March 19, 2003: Figure 1. Cumulative probability of death from cardiovascular causes during follow-up in patients assigned ticlopidine versus patients assigned clopidogrel. Figure 2. The rates and hazard ratios of cardiovascular death in various subgroups for treatment with ticlopidine as compared with clopidogrel. CAD coronary artery disease; CI confidence interval; LVEF left ventricular ejection fraction.

5 JACC Vol. 41, No. 6, 2003 March 19, 2003: Mueller et al. Versus After Stenting 973 Table 4. Multivariate Association Between Cardiovascular Death and Potential Risk Factors Hazard Ratio (95% CI) p Value Treatment with ticlopidine 0.37 ( ) Age (yrs) 1.06 ( )* Left ventricular function 1.87 ( ) *For each increase in age of one year; For each increase in left ventricular dysfunction of one unit (left ventricular function was determined semiquantitatively, scale 0 3 with 0 normal function and 3 severely impaired). CI confidence interval. In conclusion, the present study demonstrates that, after the placement of coronary artery stents, patients with concomitant medication according to current secondary prevention guidelines had a significantly lower cardiovascular and all-cause mortality if they received ticlopidine than if they received clopidogrel. Thus, our study results strongly mandate that the effects of current antiplatelet regimens and the interference of concomitant medications be scrutinized and that the clinical impact be verified further by long-term studies. Reprint requests and correspondence: Dr. Christian Mueller, Medizinische Universitätsklinik, Petersgraben 4, 4031, Basel, Switzerland. chmueller@uhbs.ch. REFERENCES 1. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996;348: Mueller C, Buettner HJ, Petersen J, et al. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101: Bertrand ME, Ruppert HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000; 102: Taniuchi M, Kurz HI, Lasala JM. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001;104: Lasala JM. Stent thrombosis: it s never too late! Cathet Cardiovasc Intervent 2002;55: Anderson KM, Califf RM, Stone GW, et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2001;37: Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003;107: Bhatt DL, Bertrand ME, Berger P, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002;39: Rinaldi ML, Piana RN, Caputo RP, et al. Is clopidogrel superior to ticlopidine for the prevention of stent thrombosis? Results of a multicenter study (abstr). Circulation 2001;104 Suppl II:348.