Author + information
- Received April 7, 2005
- Revision received May 12, 2005
- Accepted May 17, 2005
- Published online April 4, 2006.
- Andrew T.L. Ong, MBBS, FRACP,
- Ron T. van Domburg, PhD,
- Jiro Aoki, MD,
- Karel Sonnenschein,
- Pedro A. Lemos, MD, PhD and
- Patrick W. Serruys, MD, PhD, FACC⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Patrick W. Serruys, Thoraxcenter, Ba-583, Dr. Molewaterplein 40, 3015-GD Rotterdam, the Netherlands.
Objectives The purpose of this study was to investigate the medium-term (two year) outcome of the unrestricted utilization of sirolimus-eluting stents (SES) in an all-comer population.
Background Despite the implantation of SES in over a million patients to date, limited data exist on long-term outcomes.
Methods 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 SES were compared with 450 patients who received bare stents in the immediately preceding period (pre-SES group).
Results Patients in the SES 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 SES group and 22.0% in the pre-SES 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 SES group and in the pre-SES group was 8.2% and 14.8%, respectively (HR 0.53, 95% CI 0.36 to 0.79; p = 0.002).
Conclusions 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.
In the two years since the introduction of drug-eluting stents worldwide, the take-up has been astounding. Drug-eluting stents now comprise at least 70% of the stent market in the U.S. and 40% in Europe, and they are increasing with time. To date, over 1 million patients have received 1.5 million sirolimus-eluting stents (SES) 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 SES (4). However, fewer than 200 patients with simple lesions treated with a single 18-mm SES 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 SES disappear with time (5). Furthermore, 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 SES 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 SES extend beyond one year and to detail the major adverse cardiac events that have occurred between one and two years.
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 SES implantation for patients treated in daily practice. Since April 16, 2002, our institution adopted a policy of using SES (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 SES (SES group) and compared with a group of 450 consecutive patients treated with bare stents for de novo lesions in the preceding six months (pre-SES group). The total study population thus comprised 958 patients divided into two sequential cohorts, primarily distinguished by the interventional strategy applied (BMS or SES 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-SES phase. For patients treated with SES, 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 SES 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.
Continuous variables are presented as mean ± SD and were compared by means of the Student unpaired ttest. 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.⇓⇓
Baseline and procedural characteristics
The baseline and procedural characteristics have been previously described and are included in Tables 1 and 2for 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 SES had significantly more multivessel disease, more type C lesions, more bifurcation stenting, more segments stented, and more stents used. Also, in the SES 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-SES phase (33% vs. 19%; p < 0.01). The angiographic success rate was similar in both groups.
At one year, the cumulative incidence of death and death or myocardial infarction was similar between groups. Patients treated with SES had significantly less death, MI, or TLR at one year than patients treated in the pre-SES 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 SES group (9.7% vs. 14.8% in the pre-SES group; HR 0.62, 95% CI 0.44 to 0.89; p = 0.008). The difference in outcomes between groups was mainly due to a decrease in the need for TVR in the SES group (5.1% vs. 10.9% in the pre-SES group; HR 0.49, 95% CI 0.29 to 0.82; p = 0.007).
Follow-up information was obtained in 97.7% of patients. At two years, there were no significant differences in mortality between the SES and pre-SES groups, (5.8% vs. 6.3%; HR 0.92, 95% CI 0.55 to 1.54; p = 0.7) (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 SES group than in the pre-SES 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 SES 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 SES group and 9 deaths in the pre-SES group. Two MIs occurred in the SES group compared with five in the pre-SES group (p = 0.3). Target lesion revascularizations were infrequent in both the SES group (n = 11) and the pre-SES group (n = 14) (p = 0.4). Including TLRs, there were 13 TVRs in the SES group versus 18 in the pre-SES group (p = 0.3). Overall MACE occurred in 23 patients in the SES phase and 30 in the pre-SES 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 SES group and six in the pre-SES group required a repeat intervention for a lesion in a different vessel (p = 1.0).
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 SES 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.
This present paper reports that the beneficial effects of SES 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 SES group compared to the pre-SES group. In the second year following stent implantation, a trend toward fewer repeat revascularizations occurred in the SES arm with no late catch-up seen.
The reduction in the composite end point of MACE in the SES 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 SES-treated patients (p = 0.16) between one and two years, the beneficial effect seen with SES 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 SES 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 SES 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 SES group compared with the pre-SES 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 SES, 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).
The medium-term follow-up of the RESEARCH registry demonstrates that in the real world SES 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.
Supported by the Erasmus Medical Center and by unrestricted institutional grants from Cordis, a Johnson & Johnson company.
- Abbreviations and Acronyms
- bare-metal stent
- confidence interval
- hazard ratio
- major adverse cardiac event
- myocardial infarction
- Randomized Study With the Sirolimus-Eluting Velocity Balloon-Expandable Stent in the Treatment of Patients With de Novo Native Coronary Artery Lesions
- Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital
- sirolimus-eluting stent
- target lesion revascularization
- target vessel revascularization
- Received April 7, 2005.
- Revision received May 12, 2005.
- Accepted May 17, 2005.
- American College of Cardiology Foundation
- ↵(2005) Stories of Survival and Hope Mark the One Million Patient Milestone for the Cypher Sirolimus-Eluting Coronary Stent, February 14, Available at: http://www.jnj.com/news/jnj_news/20050214_094141.htm. Accessed February 16, 2005.
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