Journal of the American College of Cardiology Vol. 47, No. 7, by the American College of Cardiology Foundation ISSN /06/$32.

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1 Journal of the American College of Cardiology Vol. 47, No. 7, by the American College of Cardiology Foundation ISSN /06/$32.00 Published by Elsevier Inc. doi: /j.jacc Sirolimus-Eluting Stents Remain Superior to Bare-Metal Stents at Two Years Medium-Term Results From the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) Registry Andrew T. L. Ong, MBBS, FRACP, Ron T. van Domburg, PHD, Jiro Aoki, MD, Karel Sonnenschein, Pedro A. Lemos, MD, PHD, Patrick W. Serruys, MD, PHD, FACC Rotterdam, the Netherlands OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS The purpose of this study was to investigate the medium-term (two year) outcome of the unrestricted utilization of sirolimus-eluting stents () in an all-comer population. Despite the implantation of in over a million patients to date, limited data exist on long-term outcomes. Sirolimus-eluting stents were used as the default strategy as part of the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry. A total of 508 consecutive patients with de novo lesions exclusively treated with were compared with 450 patients who received bare stents in the immediately preceding period (pre- group). Patients in the group more frequently had multivessel disease, more type C lesions, received more stents, and had more bifurcation stenting. At two years, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was 15.4% in the group and 22.0% in the pre- group (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.50 to 0.91; p 0.01). The two-year risk of target vessel revascularization in the group and in the pre- group was 8.2% and 14.8%, respectively (HR 0.53, 95% CI 0.36 to 0.79; p 0.002). In an unrestricted population, the beneficial effects of sirolimus-eluting stent implantation extend out to two years compared with bare-metal stents, driven by a reduction in re-intervention rates. These findings should be confirmed by the results of the large randomized trials. (J Am Coll Cardiol 2006;47: ) 2006 by the American College of Cardiology Foundation In the two years since the introduction of drug-eluting stents worldwide, the take-up has been astounding. Drugeluting stents now comprise at least 70% of the stent market in the U.S. and 40% in Europe, and they are increasing with See page 1361 time. To date, over 1 million patients have received 1.5 million sirolimus-eluting stents () worldwide despite a paucity of long-term follow-up data (1). For simple lesions, encouraging two-year results were reported by the first investigations in humans (2,3), as was the recent publication of the three-year results in the Randomized Study With the Sirolimus-Eluting Velocity Balloon-Expandable Stent in the Treatment of Patients With de Novo Native Coronary Artery Lesions (RAVEL), the first randomized trial on (4). However, fewer than 200 patients with simple lesions treated with a single 18-mm were studied in both trials combined. In porcine models, there have been some concerns regarding a late catch-up phenomenon whereby the initial benefits of disappear with time (5). Furthermore, From the Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands. Supported by the Erasmus Medical Center and by unrestricted institutional grants from Cordis, a Johnson & Johnson company. Manuscript received April 7, 2005; revised manuscript received May 12, 2005, accepted May 17, initial attempts at developing an antirestenosis device using a radioactive stent demonstrated that in humans restenosis and neointimal hyperplasia were delayed but not prevented (6). Late unpredictable events have been anecdotally reported with drug-eluting stents (7,8). In the treatment of unselected all-comer patients with complex disease, our group has previously reported on the intermediate results of the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry, demonstrating that the use of is associated with significantly lower incidence of major adverse cardiac events (MACE) and target vessel revascularization (TVR) when compared with bare-metal stents (BMS) at one year in patients with de novo coronary artery lesions (9). The purpose of this report is to investigate whether the beneficial effects of extend beyond one year and to detail the major adverse cardiac events that have occurred between one and two years. METHODS Study design and patient population. The methodology of the RESEARCH registry has been reported previously (10). Briefly, RESEARCH is a single-center registry conducted with the main purpose of evaluating the safety and efficacy of implantation for patients treated in daily practice. Since April 16, 2002, our institution adopted a

2 JACC Vol. 47, No. 7, 2006 April 4, 2006: Ong et al. Two-Year Results of the RESEARCH Registry 1357 Abbreviations and Acronyms BMS bare-metal stent CI confidence interval HR hazard ratio MACE major adverse cardiac event MI myocardial infarction RAVEL Randomized Study With the Sirolimus- Eluting Velocity Balloon-Expandable Stent in the Treatment of Patients With de Novo Native Coronary Artery Lesions RESEARCH Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital sirolimus-eluting stent TLR target lesion revascularization TVR target vessel revascularization policy of using (Cypher; Johnson & Johnson-Cordis unit, Cordis Europa, Roden, the Netherlands) as the default strategy for every percutaneous coronary intervention. In the first six months of enrollment, 508 patients with de novo lesions were treated exclusively with ( group) and compared with a group of 450 consecutive patients treated with bare stents for de novo lesions in the preceding six months (pre- group). The total study population thus comprised 958 patients divided into two sequential cohorts, primarily distinguished by the interventional strategy applied (BMS or implantation, respectively) (9). This protocol was approved by the hospital ethics committee and is in accordance with the Declaration of Helsinki. Written informed consent was obtained from every patient. Procedures and postintervention medications. All interventions were performed according to current standard guidelines with the final interventional strategy (including use of periprocedural glycoprotein IIb/IIIa inhibitors) at the operator s discretion. Angiographic success was defined as residual stenosis 30% by visual analysis in the presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. All patients were advised to maintain lifelong aspirin. At least one-month clopidogrel treatment (75 mg/day) was recommended for patients treated in the pre- phase. For patients treated with, clopidogrel was prescribed for at least three months, unless one of the following was present (in which case clopidogrel was maintained for at least 6 months): multiple implantation ( 3 stents), total stented length 36 mm, chronic total occlusion, and bifurcations. Definition of major adverse cardiac events. Major adverse cardiac events were defined as: 1) death; 2) nonfatal myocardial infarction (MI); or 3) TVR. Myocardial infarction was diagnosed by a rise in the creatine kinase-mb fraction of more than three times the upper limit of normal (11). Target lesion revascularization (TLR) was defined as a repeat intervention (surgical or percutaneous) to treat a luminal stenosis within the stent or in the 5-mm distal or proximal segments adjacent to the stent. Target vessel revascularization was defined as a re-intervention driven by any lesion located in the same epicardial vessel. Two-year follow-up data. For the two-year follow-up, survival data for all patients were obtained from municipal civil registries. A health questionnaire was sent to all living patients with specific questions on rehospitalization and major adverse cardiac events. As the principal referral center within the region, repeat procedures (percutaneous and surgical) are normally performed at our institution and recorded prospectively in our database. For patients who suffered an adverse event at another center, medical records or discharge summaries from the other institutions were systematically reviewed. General practitioners, referring cardiologists, and patients were contacted as necessary if further information was required. Statistical analysis. Continuous variables are presented as mean SD and were compared by means of the Student unpaired t test. Categorical variables are presented as counts and percentages and compared by means of the Fisher exact test. All statistical tests were two tailed. The cumulative incidence of adverse events was estimated according to the Kaplan-Meier method, and Cox proportional hazards models were used to assess risk reduction of adverse events. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored. Multivariate analyses were performed to identify independent predictors of adverse events, using all clinical, angiographic, and procedural variables included in Tables 1 and 2. Table 1. Baseline Characteristics of Patients Treated With Conventional Bare-Metal Stents Before the Introduction of ( ) and Patients Treated Exclusively With Implantation ( ) (n 508) p Value Male, % Age, yrs SD Diabetes, % Non insulin-dependent, % Insulin-dependent, % Hypertension, % Hypercholesterolemia, % Current smoking, % Previous myocardial infarction, % Previous angioplasty, % Previous coronary bypass surgery, % Single-vessel disease, % Multivessel disease, % Clinical presentation 0.7 Stable angina, % Unstable angina, % Acute myocardial infarction, % Cardiogenic shock, %* *Relative to patients with acute myocardial infarction. sirolimus-eluting stent.

3 1358 Ong et al. JACC Vol. 47, No. 7, 2006 Two-Year Results of the RESEARCH Registry April 4, 2006: Table 2. Angiographic and Procedural Characteristics of Patients Treated With Conventional Bare-Metal Stents Before the Introduction of ( ) and Patients Treated Exclusively With Implantation ( ) (n 508) p Value Treated vessel Left anterior descending, % Left circumflex, % Right coronary artery, % Left main coronary, % Bypass graft, % Lesion type A, % B1, % B2, % C, % Glycoprotein IIb/IIIa inhibitor, % Clopidogrel prescription, months SD Bifurcation stenting, % Number of stented segments SD Number of implanted stents SD Individual stent length 33 mm, % Total stented length per patient, mm SD Nominal stent diameter mm, % Post-dilation with a balloon mm larger, % Angiographic success of all lesions, % mainly due to a decrease in the need for TVR in the group (5.1% vs. 10.9% in the pre- group; HR 0.49, 95% CI 0.29 to 0.82; p 0.007). Two-year follow-up. Follow-up information was obtained in 97.7% of patients. At two years, there were no significant differences in mortality between the and pre- groups, (5.8% vs. 6.3%; HR 0.92, 95% CI 0.55 to 1.54; p 0.7) sirolimus-eluting stent. RESULTS Baseline and procedural characteristics. The baseline and procedural characteristics have been previously described and are included in Tables 1 and 2 for reference. Briefly, approximately half of the patients in both groups were admitted with acute coronary syndromes, and diabetes was present in 16% of cases. Patients treated with had significantly more multivessel disease, more type C lesions, more bifurcation stenting, more segments stented, and more stents used. Also, in the group, long stents and stents with smaller diameters were more frequently used. Periprocedural administration of glycoprotein IIb/IIIa inhibitors was more frequent in the pre- phase (33% vs. 19%; p 0.01). The angiographic success rate was similar in both groups. One-year follow-up. At one year, the cumulative incidence of death and death or myocardial infarction was similar between groups. Patients treated with had significantly less death, MI, or TLR at one year than patients treated in the pre- phase (8.8% vs. 12.6%, respectively; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.45 to 0.97; p 0.03). Similarly, the one-year cumulative risk of MACE (death, MI, or TVR) was significantly reduced in the group (9.7% vs. 14.8% in the pre- group; HR 0.62, 95% CI 0.44 to 0.89; p 0.008). The difference in outcomes between groups was Figure 1. Two-year adverse events in patients treated with bare stents before the introduction of sirolimus-eluting stents () (pre- group) and in patients treated exclusively with implantation ( group). (A) Cumulative risk of death. (B) Death or myocardial infarction. (C) Death, myocardial infarction, or target vessel revascularization.

4 JACC Vol. 47, No. 7, 2006 April 4, 2006: Ong et al. Two-Year Results of the RESEARCH Registry 1359 Figure 2. Two-year cumulative risk of target vessel revascularization in patients treated with bare stents before the introduction of sirolimuseluting stents () (pre- group) and in patients treated exclusively with implantation ( group). (Fig. 1A). The combined end point of death or MI were also similar (9.7% vs. 10.9%, respectively; HR 0.89, 95% CI 0.60 to 1.33; p 0.6) (Fig. 1B). The two-year incidence of the combined end point of MACE was lower in the group than in the pre- group (15.4% vs. 22.0%; HR 0.68, 95% CI 0.50 to 0.91; p 0.01) (Fig. 1C), driven by a significantly lower incidence of TVR in the group (8.2% vs. 14.8%, respectively; HR 0.53, 95% CI 0.36 to 0.79; p 0.002) (Fig. 2). Events from one to two years. Between one and two years, 53 events occurred (Table 3). There were 12 deaths in the group and 9 deaths in the pre- group. Two MIs occurred in the group compared with five in the pre- group (p 0.3). Target lesion revascularizations were infrequent in both the group (n 11) and the pre- group (n 14) (p 0.4). Including TLRs, there were 13 TVRs in the group versus 18 in the pre- group (p 0.3). Overall MACE occurred in 23 patients in the phase and 30 in the pre- phase (p 0.16). In this RESEARCH registry cohort of 958 patients, no patient in either group experienced late angiographic stent thrombosis out to 24 months. Between one and two years, a further five patients in the group and six in the pre- group required a repeat intervention for a lesion in a different vessel (p 1.0). Table 3. Number of Events Between One and Two Years Events Between 1 and 2 Years (n 508) p Value Death, n (%) 9 (2.0) 12 (2.4) 0.8 MI, n (%) 5 (1.1) 2 (0.4) 0.3 TLR, n (%) 14 (3.1) 11 (2.2) 0.4 TVR (includes TLR), n (%) 18 (4.0) 13 (2.6) 0.3 Non-TVR, n (%) 5 (1.1) 6 (1.2) 1.0 Total MACE, n (%) 30 (6.7) 23 (4.5) 0.16 MACE major adverse cardiac event; MI myocardial infarction; sirolimus-eluting stent; TLR target lesion revascularization; TVR target vessel revascularization. Table 4. Separate Cox Regression Analyses Performed to Determine Independent Predictors of MACE and TVR at Two-Year Follow-Up HR 95% CI p Value MACE* Use of Total stented length (per 10-mm increment) Previous PCI Diabetes mellitus Left main stenting Cardiogenic shock at entry TVR Use of Acute coronary syndrome at entry Total stented length (per 10-mm increment) Previous PCI Diabetes mellitus * Tested variables: age, gender, multivessel disease, hypertension, current smoking, right coronary artery stenting, type C lesion, number of stents, number of segments treated, use of 33-mm stent, total stent length, previous intervention, diabetes, left main stenting, cardiogenic shock, stent type. Tested variables: current smoking, bifurcation stenting, number of segments treated, number of stents, acute coronary syndrome at entry, total stented length, previous intervention, diabetes, stent type. Variables were included if significant on univariate analysis or if clinically relevant. CI confidence interval; HR hazard ratio; PCI percutaneous coronary intervention; other abbreviations as in Table 3. Multivariate predictors of outcomes. Cox regression analysis was performed to identify predictors of MACE at two years (Table 4). Cardiogenic shock at entry, stenting of the left main stem, diabetes, history of previous interventions, and longer stented lengths were all associated with adverse occurrences of MACE (Table 4). A separate Cox regression analysis was performed, and predictors of TVR were diabetes, previous interventions, and longer stented lengths, whereas acute coronary syndromes at entry was protective. When adjusted for independent predictors, the use of conferred a significant protective effect against both TVR (HR 0.45, 95% CI 0.29 to 0.68; p 0.001) and MACE (HR 0.58, 95% CI 0.43 to 0.80; p 0.001) at two-year follow-up. DISCUSSION This present paper reports that the beneficial effects of compared to BMS are maintained out to two years in a real-world population. At the end of two years, significantly less MACE occurred in the group compared to the pre- group. In the second year following stent implantation, a trend toward fewer repeat revascularizations occurred in the arm with no late catch-up seen. The reduction in the composite end point of MACE in the group was entirely driven by the component of TVR; the incidences of death and MI were similar in both groups in the follow-up period. This extends the finding of a large meta-analysis of drug-eluting trials that demonstrated no reduction in death or MI out to one year with drug-eluting stents (12). In this study, although there was a trend toward fewer events in -treated patients (p 0.16) between one and

5 1360 Ong et al. JACC Vol. 47, No. 7, 2006 Two-Year Results of the RESEARCH Registry April 4, 2006: two years, the beneficial effect seen with at two years was driven primarily by the reduction in events in the first year. Thus, once the important beneficial effect of neointimal suppression had occurred during the period after stenting, the next step was to detect whether a later rebound phenomenon (as seen in porcine models) occurred in humans. This first-in-man study with serial angiographic and intravascular ultrasound studies was encouraging, demonstrating in a small population that neointimal suppression was preserved out to two years. In the RAVEL study, however, some nonsignificant late catch-up effect was noted in the arm, with six TLR versus none in the bare group seen between one- and three-year follow-ups; however, the overall incidence of TLR in the arm of remained significantly less than the bare group at three years (4,13). In our registry, we did not observe any late catch-up phenomenon such as seen with radioactive stents and brachytherapy. In fact, during the second year, a trend toward a lower TVR rate was seen in the group compared with the pre- group (4.0% vs. 2.6%, respectively; p 0.3) (Table 3). In addition to the previously described events, approximately 1% of patients in each group required repeat intervention for progressive disease in a previously nontreated vessel (non-tvr revascularization). Because these lesions do not benefit from the beneficial local effects of, it is imperative that intensive risk factor reduction, both physical and pharmaceutical, are implemented to reduce the potential for progression of remote lesions (14). Although it was encouraging that no late angiographic stent thrombosis events were seen in either group out to two years, observation and interpretation of this rare and unexpected late complication requires a much larger sample size and longer term follow-up (15). Conclusions. The medium-term follow-up of the RESEARCH registry demonstrates that in the real world reduce the incidence of major adverse cardiac events at two years of follow-up, primarily by a smaller need for repeat revascularization of the target vessel compared to bare-metal stents, already evident during the first year. The reduction in events was maintained during the second year with no evidence of a late-catch up effect. No late angiographic stent thrombosis was seen out to two years in this cohort of patients studied. Reprint requests and correspondence: Prof. Patrick W. Serruys, Thoraxcenter, Ba-583, Dr. Molewaterplein 40, 3015-GD Rotterdam, the Netherlands. p.w.j.c.serruys@erasmusmc.nl. REFERENCES 1. 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