Unrestricted Utilization of Sirolimus-Eluting Stents Compared With Conventional Bare Stent Implantation in the “Real World”
The Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry
Background— The effectiveness of sirolimus-eluting stents in unselected patients treated in the daily practice is currently unknown.
Methods and Results— Sirolimus-eluting stent implantation has been used as the default strategy for all percutaneous procedures in our hospital as part of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Consecutive patients with de novo lesions (n=508) treated exclusively with sirolimus-eluting stents (SES group) were compared with 450 patients who received bare stents in the period just before (pre-SES group). Patients in the SES group more frequently had multivessel disease, more type C lesions, received more stents, and had more bifurcation stenting. At 1 year, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was 9.7% in the SES group and 14.8% in the pre-SES group (hazard ratio [HR], 0.62 [95% CI, 0.44 to 0.89]; P=0.008). The 1-year risk of clinically driven target vessel revascularization in the SES group and in the pre-SES group was 3.7% versus 10.9%, respectively (HR, 0.35 [95% CI, 0.21 to 0.57]; P<0.001).
Conclusions— Unrestricted utilization of sirolimus-eluting stents in the “real world” is safe and effective in reducing both repeat revascularization and major adverse cardiac events at 1 year compared with bare stent implantation.
Received July 28, 2003; revision received October 2, 2003; accepted October 6, 2003.
In-stent restenosis has long been recognized as the main limitation of coronary stenting, with rates of as high as 50% in more complex subsets. Recently, sirolimus-eluting stent (SES) implantation has been proven to markedly reduce the incidence of angiographic restenosis and repeat revascularization in selected patients.1–3 In the First-In-Man study, no cases of restenosis were detected in a series of 45 patients, with persistent neointimal inhibition demonstrated up to 2 years.4 These findings have been further confirmed in randomized trials comparing SES with conventional bare stents.2,3 In the RAndomized study with the sirolimus-eluting Bx VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions (RAVEL),2 there were no cases of binary angiographic restenosis in patients treated with SES implantation. Similarly, in the SIRolImUS-eluting Bx velocity balloon expandable stent trial (SIRIUS),3 restenosis occurred in 9% of cases in the SES group compared with 36% of patients treated with conventional stents (P<0.001).
See p 140
Based on these findings, since the first half of 2002, SES have progressively received clinical approval by official regulatory agencies and are currently available for routine use in Europe, Asia, South America, and more recently the United States. However, all clinical trials completed so far have included elective patients with relatively noncomplex lesions. The effects of SES implantation in complex, un-selected patients, such as those treated in daily practice, remains largely unknown. Notably, the occurrence of restenosis in a small but relevant proportion of patients in the SIRIUS trial occurred mainly in patients with diabetes, small vessels, and long lesions,3 characteristics frequently found in most series. Moreover, restenosis after SES implantation has been recently shown to occur in association with procedures with increased complexity.5 The present study was therefore conducted to investigate the impact of SES on the outcomes of patients treated in the “real world” of interventional cardiology, as compared with a strategy using conventional bare stent implantation.
Study Design and Patient Population
The study protocol of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) has been described elsewhere.6 Briefly, the 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. To include a patient population representative of the “real world,” we have adopted since April 16, 2002, a policy of using SES (Cypher; Johnson & Johnson-Cordis unit, Cordis Europa NV) as the default strategy for every percutaneous coronary intervention.
In the first 6 months enrollment, a total of 508 patients with de novo lesions were treated exclusively with SES and were included in the present report (SES group) (72% of the 710 patients treated with stents in during the period). Patients treated with bare stents and SES in the same procedure (66 patients) and those treated only with bare stents (136 patients) were not included in the present report. At the initiation of the RESEARCH registry, SES were available in lengths of 8, 18, and 33mm and diameters from 2.25 to 3.00 mm, but postdilation with larger balloons was allowed (0.5-mm larger balloons were used in 55% of cases in which a 3.0-mm SES was used). However, unavailability of an appropriate SES size was still the reason for nonutilization of SES in 77% of cases. Moreover, 5% of cases were included in the other study and were not enrolled in the RESEARCH. In the remaining patients not included, SES were not used for a variety of reasons, predominantly operator’s personal choice.
Patients treated solely with SES were compared with a group of consecutive patients treated with bare stents for de novo lesions in the preceding 6 months (pre-SES group). To better match the vessel sizes treated in the two study groups, patients receiving bare metal stents larger than 3.5-mm were excluded from this analysis (n=176). This cutoff value (instead of 3.0-mm diameter stents) was chosen because of the postdilation policy applied in the SES group, which extended the use of SES to patients with 3.5-mm vessels by visual estimation. In addition, patients treated with bare stents smaller than 2.25 mm were not included (n=30). In total, 450 consecutive patients thereby comprise the pre-SES group (69% of all patients with de novo lesions treated with stents during the period). The present study population was consequently composed of a total of 958 patients divided into two sequential cohorts, primarily distinguished by the interventional strategy applied (bare stent or SES implantation, respectively). 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,7 and the final interventional strategy was entirely left to the discretion of the operator. Angiographic success was defined as residual stenosis <30% by visual analysis in the presence of TIMI 3 grade flow. Periprocedural glycoprotein IIbIIIa inhibitors and antithrombotic medications were used according to the operator’s decision. All patients were advised to maintain lifelong aspirin. At least 1-month clopidogrel treatment (75 mg/d) was recommended for patients treated in the pre-SES phase. For patients treated with SES, clopidogrel was prescribed for at least 3 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.
End Point Definitions and Clinical Follow-Up
The primary outcome was the occurrence of major adverse cardiac events, defined as (1) death, (2) nonfatal myocardial infarction, or (3) target vessel revascularization. Myocardial infarction was diagnosed by a rise in the creatine kinase level to more than twice the upper normal limit with an increased creatine kinase-MB. Target lesion revascularization 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 reintervention driven by any lesion located in the same epicardial vessel. Thrombotic stent occlusion was angiographically documented as a complete occlusion (TIMI flow 0 or 1) or a flow-limiting thrombus (TIMI flow 1 or 2) of a previously successfully treated artery.
Information about the in-hospital outcomes was obtained from an electronic clinical database for patients maintained in our institution and by review of the hospital records for those discharged to referring hospitals (patients were referred from a total of 14 local hospitals). Postdischarge survival status was obtained from the Municipal Civil Registries. All repeat interventions (surgical and percutaneous) and rehospitalizations were prospectively collected during the follow-up. Questionnaires with information about anginal status and medication usage were sent to all living patients. The referring physicians and institutions were contacted whenever necessary for additional information.
During follow-up, coronary angiography was obtained as clinically indicated by symptoms or documentation of myocardial ischemia. Additionally, late angiographic evaluation was eventually obtained from “complex” patients in the SES group, typically with SES implanted in bifurcations, left main coronary, chronic total occlusions, very small vessels, long stented length (>36 mm), and acute myocardial infarction (in total, 38% patients in the SES group had angiographic follow-up between 6 and 8 months). No angiographic re-study was performed in the pre-SES group. Because of the well-known effect of angiographic reevaluation in increasing the incidence of repeat revascularization,8 all reinterventions were retrospectively adjudicated and classified as clinically driven or nonclinically driven by a group of clinicians not involved in the treatment of the particular patient analyzed. Clinically driven repeat revascularization was defined as any intervention motivated by a significant luminal stenosis (>50% diameter stenosis) in the presence of anginal symptoms and/or proven myocardial ischemia in the target vessel territory by noninvasive testing.
Continuous variables were presented as mean±SD and were compared by means of the Student unpaired t test. Categorical variables were presented as counts and percentages and compared by means of the Fisher exact test. All statistical tests were 2-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
Baseline and procedural characteristics are shown in Table 1 and Table 2. Overall, 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 IIbIIIa inhibitors was more frequent in the pre-SES phase (33% versus 19%; P<0.01). The angiographic success rate was similar in both groups.
Complete follow-up information was available for 99.1% of patients (mean follow-up period, 405 days). There were no significant differences between the SES group and the pre-SES group in the incidence of major adverse cardiac events during the first month (3.0% versus 4.2% respectively; P=0.3) (Table 3). Target vessel revascularization at 30 days was 1.0% (n=5) in the SES group and 2.2% (n=10) in the pre-SES group (P=0.2), which included emergency bypass surgery in 2 patients (0.4%) in the SES group and in 2 cases (0.4%) in the pre-SES group (P=1.0) and early “redo” target vessel revascularization (eg, residual dissection or compromised side branch in patients with continuing symptoms) in 1 patient (0.2%) in the SES group and in 1 patient (0.2%) in the pre-SES group (P=1.0). In the remaining cases, 30-day repeat intervention was performed for angiographically documented stent thrombosis in 2 patients (0.4%) in the SES group and in 7 patients (1.6%) in the pre-SES group (P=0.1). No further thrombotic stent occlusion was observed in the late follow-up.
At 1 year, the cumulative incidence of death and death or myocardial infarction was similar between both groups (Figure 1, A and B). Patients treated with SES had significantly less death, myocardial infarction, or target lesion revascularization at 1 year than patients treated in the pre-SES phase (8.8% versus 12.6%, respectively; hazard ratio [HR] 0.66 [95% CI, 0.45 to 0.97]; P=0.03) (Figure 1C). Similarly, the 1-year cumulative risk of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was significantly reduced in the SES group (9.7% versus 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 both groups was mainly due to a decrease in the need for target vessel revascularization in the SES group (5.1% versus 10.9% in the pre-SES group; HR, 0.49 [95% CI, 0.29 to 0.82]; P=0.007). Specifically, treatment with SES was associated with a marked reduction in clinically driven repeat interventions at 1 year (3.7% versus 10.9% in the pre-SES group; HR, 0.35 [95% CI, 0.21 to 0.57]; P<0.001) (Figure 2).
Predictors of Adverse Events
The impact of SES implantation on the risk of subsequent clinically driven target vessel revascularization in specific subsets is shown in Figure 3. SES implantation was associated with a risk reduction that ranged from 28% to 79% across the subgroups evaluated. However, the benefit of SES did not reach statistical significance in women (HR, 0.59 [95% CI, 0.24 to 1.45]; P=0.25) and diabetics (HR, 0.72 [95% CI, 0.30 to 1.77]; P=0.50). Patients treated with bifurcation stenting (HR, 0.38 [95% CI, 0.13 to 1.13]; P=0.08) and patients receiving 33-mm or longer stents (HR, 0.41 [95% CI, 0.16 to 1.03]; P=0.06) presented a strong trend to have better outcomes with SES implantation. In the other subgroups, SES use significantly decreased the need of repeat intervention (Figure 3). Importantly, the postdilation strategy applied in the present study did not influence the clinical benefit of SES implantation. The magnitude of the risk reduction was similar between patients treated with postdilation (HR, 0.28 [95% CI, 0.13 to 0.62]; P=0.002) or without postdilation (HR, 0.35 [95% CI, 0.18 to 0.70]; P=0.003) procedures.
Multivariate Cox proportional hazards analysis identified SES utilization to be independently associated with a reduced risk of adverse clinical events (Table 4). After adjustment for other independent variables, SES significantly decreased the risk of clinically driven target vessel revascularization (adjusted HR, 0.33 [95% CI, 0.20 to 0.56]; P<0.01) and the risk of major adverse cardiac events (adjusted HR, 0.55 [95% CI, 0.38 to 0.80]; P<0.01).
SES implantation has been shown to markedly decrease the incidence of in-stent restenosis in the context of randomized trials.2,3 However, these studies have enrolled relatively noncomplex patient populations referred for elective intervention. As a consequence, the findings from these studies cannot be directly extrapolated to many patients treated in the everyday practice, where complex, nonelective cases are the rule rather than the exception. In the present study, SES implantation was associated with a reduction in the rates of repeat revascularization and major adverse cardiac events at 1 year in a consecutive, unselected cohort of patients. SES implantation resulted in a relative reduction of 51% in the overall rate of target vessel revascularization and of 65% in the rate of clinically driven target vessel revascularization.
Our series compared a strategy of unrestricted usage of SES with conventional approaches that used bare stents in the pre-SES era. Although the two study groups were consecutively included over a total period of only 1 year, some important differences were noted in the interventional strategy applied. Patients in the SES phase were treated with a less restrictive interventional approach, with a significant increase in the number and length of stents implanted, number of coronary segments dilated, bifurcation stenting, and decrease in the diameter of the stents. Possibly, this change in practice may reflect the early recognition by the operators that the acute results, even in this complex population, were maintained in the medium term. Also, it may reflect an attempt to accomplish more complete lesion coverage and ensure uniform drug delivery over the entire diseased segment, since stent discontinuity and edge injury have been recently shown by our group to be associated with post-SES restenosis.5 Moreover, the higher complex profile of patients treated with SES (eg, high rates of multivessel disease, type C lesions, bifurcations) may translate a change in the decision-making process promoted by the availability of SES in our institution. Although both study groups differed in some baseline and procedural characteristics, which may somewhat limit an unbiased comparison between them, it is worth noting that most if not all differences would be traditionally expected to increase the incidence of late complications in the SES-treated patients. Nevertheless, the treatment effect of SES was significantly higher than bare stents, remaining virtually unaffected after adjustment for procedural characteristics.
The reduction of adverse events after SES implantation in our series is lower than that observed in the RAVEL trial, in which no binary angiographic restenosis was diagnosed.2 The present findings more closely resemble those seen in the SIRIUS trial (75% reduction in clinically driven target lesion revascularization), in which patients with higher risk profiles were included.3 Compared with the RAVEL study, the relative decline in effectiveness in the SIRIUS trial and in the RESEARCH study may have been related to the complexity of the procedures included. Although SES implantation markedly reduced the risk of subsequent revascularization in most subsets, the benefit of the new treatment did not reach statistical significance in some subgroups in our series. Indeed, the presence of diabetes and treatment of long lesions were shown to independently increase the incidence of complications. These findings highlight the need of further analyses with larger numbers of patients to fully estimate the clinical impact of SES in these patients. Also, whether the outcomes of higher-risk subgroups can be improved with refinements in the procedural techniques remains to be established.
Importantly, the reduction of late complications was accomplished without any increase in unexpected sudden events. Our results extend the findings observed in an early report6 and show that SES implantation in complex patients is safe, with no increase in acute device-related adverse events. The incidence (0.4%) and timing (within the first month) of documented thrombotic stent occlusion in the SES group was compatible with the current results with conventional bare metal stents. The utilization of IIbIIIa inhibitors and clopidogrel differed between both study groups. However, these differences did not significantly influence the clinical outcome in our study. Nevertheless, it should be noted that these agents were not uniformly used across the various patient subsets, being mainly used in cases at a higher risk of complications, which may have blunted the overall positive effect of these drugs.
Although restenotic lesions have been shown to be amenable to treatment by SES,9,10 the treatment of de novo lesions may be considered as the main field of application of the new device. In this regard, this study was conducted to evaluate the use of SES as a prophylactic strategy in preventing rather than treating in-stent restenosis in the “real world.”
Some patients were not treated with the SES during the time period of the study. However, in most instances, this was due to unavailability of large-diameter SES. As large vessels have been shown to present a lower risk of restenosis,3 it is quite possible that the noninclusion of patients with larger vessels may have resulted in an underestimation of the overall treatment effect in the present report. The present study is a single-center experience from a tertiary referral center and lacks the obvious advantages of a multicenter, multinational randomized study. Furthermore, it is unlikely that a randomized study will be conducted in the context in which this study was performed, with virtually no exclusion criteria.
This study demonstrates that unrestricted utilization of SES in the “real world” is safe and effective in reducing the need of further revascularization and the incidence of major adverse cardiac events after 1 year, as compared with patients treated with bare stent implantation in the period immediately before.
This study was supported by the Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands, and by an unrestricted institutional grant from Cordis, a Johnson & Johnson Company, Miami Lakes, Fla.
Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation. 2001; 104: 2007–2011.
Degertekin M, Serruys PW, Foley DP, et al. Persistent inhibition of neointimal hyperplasia after sirolimus-eluting stent implantation: long-term (up to 2 years) clinical, angiographic, and intravascular ultrasound follow-up. Circulation. 2002; 106: 1610–1613.
Lemos PA, Saia F, Ligthart JMR, et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation. 2003; 108: 257–260.
Lemos PA, Lee C, Degertekin M, et al. Early outcome after sirolimus-eluting stent implantation in patients with acute coronary syndromes: insights from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. J Am Coll Cardiol. 2003; 41: 2093–2099.
Smith SC Jr, Dove JT, Jacobs AK, et al. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001; 37: 2239i–lxvi.
Sousa JE, Costa MA, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation. 2003; 107: 24–27.