Antiplatelet Therapy and Stent Thrombosis After Sirolimus-Eluting Stent Implantation
Background— The influences of antiplatelet therapy discontinuation on the risk of stent thrombosis and long-term clinical outcomes after drug-eluting stent implantation have not yet been addressed adequately.
Methods and Results— In an observational study in Japan, 2-year outcomes were assessed in 10 778 patients undergoing sirolimus-eluting stent implantation. Data on status of antiplatelet therapy during follow-up were collected prospectively. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, P<0.001; 0.72% versus 0.07%, P=0.02; and 2.1% versus 0.14%, P=0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Adjusted rates of death or myocardial infarction at 24 months were 4.1% for patients taking thienopyridine and 4.1% for patients not taking thienopyridine (P=0.99) in the 6-month landmark analysis.
Conclusions— Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.
Received July 18, 2008; accepted November 30, 2008.
Concerns have been raised about the safety of drug-eluting stents (DES), and certain issues remain unresolved.1,2 First, although premature discontinuation of antiplatelet therapy is reported to be the most powerful predictor of stent thrombosis (ST) and adverse cardiovascular outcomes,3–5 the relative contribution of discontinuation of either aspirin or thienopyridine on ST rates has not been addressed adequately. Furthermore, the optimal duration of dual-antiplatelet therapy has not been well established, although dual-antiplatelet therapy beyond 1 year has become commonplace in clinical practice. To address these issues, a large-scale, multicenter registry of patients undergoing sirolimus-eluting stent (SES) implantation was designed with prospective data collection on the status of antiplatelet therapy during follow-up.
Clinical Perspective p 995
The j-Cypher registry is a physician-initiated prospective, multicenter observational study in Japan enrolling consecutive patients undergoing SES implantation. The relevant review boards in all 37 participating centers (online-only Data Supplement, Appendix I) approved the study protocol. Written informed consent was obtained from all patients.
In an attempt to evaluate penetration of SES and to secure enrollment of truly consecutive patients, all patients undergoing percutaneous coronary intervention (PCI) in each center during the study interval were recorded on the PCI screening list by the technical staff in the catheterization laboratories. When SES implantation was undertaken, each patient was invited to participate in the j-Cypher registry. Although data entry was basically left to the individual sites, the clinical research coordinators (online-only Data Supplement, Appendix II) in the data management center (Kyoto University Hospital, Department of Cardiology) supported data entry when necessary. Obvious inconsistencies were resolved by inquiries to the site investigators and/or by audits against the original data sources. Follow-up data were obtained from hospital charts or by contacting patients and/or referring physicians at 30 days, 6 months, and 1 year and yearly thereafter. When death, myocardial infarction (MI), and ST were reported, the events were adjudicated with use of the original source documents by a clinical events committee (online-only Data Supplement, Appendix II).
Between August 2004 and November 2006, 15 155 patients were enrolled in the registry from among 29 555 consecutive patients recorded on the PCI screening list. SES penetration varied markedly across centers, with a median penetration rate of 53% (range 16% to 92%). After the exclusion of 2331 patients who were registered repeatedly because of PCI for restenosis or new lesions, 12 824 patients were enrolled in the registry for the first time. Of 19 675 target lesions, 17 050 were treated exclusively with SES. Treatment for the remaining 2625 lesions included bare-metal stent (BMS; 1259 lesions), combination of SES and other stent types (495 lesions), other DES (60 lesions), nonstent PCI (672 lesions), and failed procedure (139 lesions). Ultimately, 10 778 patients (84%) treated with SES exclusively constituted the study population for the present analysis.
Complete 1-year follow-up (median of 491 days; interquartile range 387 to 730 days) was achieved in 96% of patients. At 1-year follow-up, information was collected from the hospital charts (75% of cases) or by contacting patients (25% of cases). Additional information was obtained from the referring physicians in 6% of cases.
Coronary angiographic parameters were assessed in each participating center either by visual assessment or by quantitative angiographic measurement. Bifurcation lesion was defined as that involving a side branch of ≥2.2 mm in diameter.
Death was regarded as cardiac in origin unless obvious noncardiac causes could be identified. Any death during the index hospitalization was regarded as cardiac death. Sudden death was defined as unexplained death in previously stable patients. MI was adjudicated according to the definition in the Arterial Revascularization Therapy Study.6 Within 1 week of the index procedure, only Q-wave MI was adjudicated as MI.
ST was defined according to the Academic Research Consortium definition.7 Not only sudden death but also those deaths without enough information to exclude sudden death were regarded as possible ST. Unless otherwise noted, definite ST assessed on an individual patient basis was used as the end point for ST, because this was the end point used in a recent large-scale registry for DES.8
The recommended antiplatelet regimen was aspirin (≥81 mg daily) indefinitely and thienopyridine (200 mg of ticlopidine or 75 mg of clopidogrel daily) for at least 3 months. Duration of antiplatelet therapy was left to the discretion of each attending physician.
Dates of discontinuation of aspirin and thienopyridine were reported separately on the follow-up forms. When discontinuation was intended to be temporary, the dates the medications were restarted were also reported. When the attending physician intended to discontinue medications permanently, dates related to the restarting of medications after discontinuation were not systematically reported. Persistent discontinuation was defined as withdrawal that lasted at least 2 months.
ST incidences were evaluated according to the status of aspirin therapy and thienopyridine therapy. Analyses were made by time intervals after index PCI (ie, within 30 days, 31 to 180 days, 181 to 365 days, 366 to 548 days, and 549 to 730 days) in accordance with a previous report.4 Those patients in whom occurrence of ST could be evaluated throughout the given intervals of interest were eligible for the analysis. Patients with known discontinuation of therapy for any duration until the end of the given intervals were assigned to the discontinuation group of patients without ST. In patients with ST, only discontinuation before the onset of ST was evaluated. Patients with acute ST and those with ST during the prior intervals were excluded from the analysis.
The influence of prolonged dual-antiplatelet therapy on clinical outcome was assessed with the so-called landmark analysis reported previously, which is a form of survival analysis that classifies patients on the basis of some nonoutcome event that occurs during follow-up (eg, discontinuation of thienopyridine at 6 months).9 Eligible patients were those patients who continued taking aspirin and were free from death, MI, stroke, or ST at the 6-month landmark point.
Categorical variables were compared with the χ2 test. Continuous variables are expressed as mean±SD unless otherwise indicated. Continuous variables were compared with the Student t test or Wilcoxon rank sum test based on the distribution. Cumulative incidence was estimated by the Kaplan–Meier method, and differences were assessed with the log-rank test.
A Cox proportional hazard model was used to identify independent risk factors of ST. We used the variables listed in supplemental Table I as potential independent variables. The continuous variables were dichotomized by clinically meaningful reference values or median values. To determine the independent risk factors, we first selected variables with P values <0.05 in the univariable Cox models and for which proportional hazard assumptions were acceptable on the plots of log (time) versus log [−log (survival)] stratified by the variable. We then included them simultaneously in the multivariable models. Patients with missing values for any selected variable were excluded from the multivariable analysis. The robustness of independent risk factors for ST that were identified by the full model without selection of variables was confirmed by both forward and backward selection procedures.
Landmark analysis was conducted as described previously.9 We computed the propensity score using logistic regression, with the dependent variable being continued thienopyridine use at 6 months and with the 23 independent variables listed in supplemental Table I. Next, we computed the adjusted survival curves of groups with and without thienopyridine use at the 6-month landmark using the Cox proportional hazard model in conjunction with methods described by Ghali et al,10 adjusting for the propensity score and the above-mentioned 23 covariates.
All analyses were conducted by a physician (Takeshi Kimura) and an independent statistician (Takeshi Morimoto) with the use of SAS software version 9.1 (SAS Institute Inc, Cary, NC) and S-Plus version 7.0 (Insightful Corp, Seattle, Wash). All reported P values are 2-sided.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
It was common for patients in the present study to have high-risk features, such as age ≥80 years, diabetes mellitus, renal failure, or unprotected left main disease (Table 1). Complex lesions such as chronic total occlusion, long lesions, and small vessels were also common. However, only 21% of patients presented with acute coronary syndrome (ACS). Procedures were characterized by use of high inflation pressure and a high rate of intravascular ultrasound guidance.
Cumulative incidences of death, cardiac death, and sudden death at 2 years were 7.2%, 3.7%, and 1.4%, respectively (Table 2). Incidence of MI was 1.5% at 2 years. MI related to ST constituted 45% of all MIs, or 0.7% at 2 years. Incidence of target-lesion revascularization was 10.2% at 2 years.
Incidence, Clinical Sequelae, and Predictors of ST
Cumulative incidences of ST at 2 years were 0.77% for definite ST, 0.91% for definite or probable ST, and 2.48% for all ST (Table 2). Incidences of definite ST were 0.34% (95% confidence interval [CI] 0.23% to 0.45%) at 30 days, 0.54% (95% CI 0.4% to 0.68%) at 1 year, and 0.77% (95% CI 0.58% to 0.96%) at 2 years (Figure 1A). The slope of the linear portion of the cumulative incidence curve of ST between 30 days and 2 years was 0.2% per year. Clinical sequelae within 30 days of ST were MI in 85% to 95% of cases and death in 11% to 38% of cases, depending on ST timing (Table 3).
Univariable predictors for ST are shown in supplemental Table I. Multivariable analysis identified ACS (hazard ratio [HR] 2.53, 95% CI 1.3 to 4.92, P=0.006) and heart failure (HR 2.33, 95% CI 1.12 to 4.84, P=0.02) as independent predictors of early ST. Independent predictors of late or very late ST included hemodialysis (HR 6.86, 95% CI 3.05 to 15.45, P<0.001), end-stage renal disease (estimated glomerular filtration rate <30 mL · min−1 · 1.73 m−2) without hemodialysis (HR 5.33, 95% CI 2.0 to 14.15, P<0.001), side-branch stenting (HR 3.5, 95% CI 1.36 to 9.03, P=0.01), and smoking (HR 2.36, 95% CI 1.17 to 4.76, P=0.02).
Discontinuation of Antiplatelet Therapy and ST
During the index hospitalization, aspirin and thienopyridine were administered in 98.9% and 99.5% (ticlopidine 96.9% and clopidogrel 2.6%) of patients, respectively. Cilostazol was administered in 3.2% of patients at the time of hospital discharge.
The status of antiplatelet therapy immediately before the onset of ST was known for the vast majority of patients with ST, except for 1 patient who presented with cardiogenic shock. The majority of patients (86%) with early ST were taking dual-antiplatelet therapy at the time of ST. The prevalence of dual therapy was 57% for late ST and 36% for very late ST, respectively (Table 3). Among 18 patients who had ST after any antiplatelet therapy discontinuation, the majority of ST events occurred >1 week after discontinuation (Figure 1B and 1C).
Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. A steep rise was found at ≈3 months in the cumulative incidence curve of persistent discontinuation of thienopyridine (Figure 1D); however, a corresponding steep rise was not observed in the cumulative ST incidence curve (Figure 1A).
With regard to the relation between aspirin and/or thienopyridine discontinuation and ST, patients who discontinued both aspirin and thienopyridine had a significantly higher ST rate than those who continued both agents in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, P<0.001; 0.72% versus 0.07%, P=0.02; and 2.1% versus 0.14%, P=0.004, respectively; Figure 2). When discontinuation of aspirin was considered, discontinuation of thienopyridine therapy only was not associated with increased ST risk in any of the time intervals.
Landmark Analysis Based on Thienopyridine Use
At 6 months, thienopyridine use was maintained in 7247 (73%) of 9875 patients eligible for the landmark analysis. Patients taking thienopyridine had significantly more complex characteristics, although some of these statistically significant differences might not be clinically relevant (Table 4). After adjustment for differences in baseline characteristics, the rates of death, MI, death or MI, and a combined end point of cardiac death, MI, or stroke at 24 months were not different between the 2 groups with or without thienopyridine therapy in the 6-month landmark analysis (Figure 3; Table 5).
The influence of ACS on the 6-month landmark analysis was evaluated. The cumulative rate of death or MI was significantly higher in patients with ACS than in those without ACS (Figure 4A); however, rates of death or MI beyond 6 months were similar in both groups (Figure 4B). Adjusted rates of death or MI at 24 months in the 2 groups either taking or not taking thienopyridine therapy at 6 months were similar in patients with or without ACS (Figure 4C and 4D).
The main findings of the present study are that discontinuation of both aspirin and thienopyridine, but not discontinuation of thienopyridine therapy only, is associated with an increased ST risk and that no apparent clinical benefit is received from thienopyridine use beyond 6 months after SES implantation. More than 2 years ago, concerns were raised about DES safety.1,2 Although more recent reports from registries and meta-analyses of randomized, controlled trials provided data supporting the relative safety of DES compared with BMS,11,12 a cohort study conducted in Bern, Switzerland, and Rotterdam, Netherlands, demonstrated that definite ST continues to occur at the constant rate of 0.6% per year from 30 days to 3 years after DES implantation.8 The present ongoing analysis using the same ST end point also showed that ST remained a continuous hazard up to 2 years after SES implantation, although the cumulative incidence of ST appeared to be considerably lower than that in the Bern and Rotterdam cohorts.8
We can suggest several potential reasons for the markedly lower rate of early ST in the present registry. First, there might be ethnic differences in the propensity for ST. We reported a 0.9% rate of early ST in 320 Japanese patients undergoing planned BMS implantation with an antithrombotic regimen that included aspirin and warfarin.13 This early ST rate appears to be markedly lower than the 2.7% in 550 US patients reported in the Stent Anticoagulation Restenosis Study using the same antithrombotic regimen and the same BMS.14 Second, the incidence of ACS presentation, which is an established risk factor for early ST, was lower in the present study population than in the Bern and Rotterdam cohorts9 (21% and 59%, respectively). Third, only 3% of patients in the present study discontinued thienopyridine within 30 days of SES implantation compared with the 14% discontinuation rate reported in the PREMIER registry (Prospective Registry Evaluating Myocardial Infarction: Events and Recovery).5 We cannot provide a clear explanation for the lower rate of late and very late ST in the present study population compared with that in the Bern and Rotterdam cohorts,8 because the mechanisms of late and very late ST have not yet been well clarified.
Although no randomized study has evaluated the role of dual-antiplatelet therapy in DES, the benefit of dual-antiplatelet therapy in preventing ST within 1 month after BMS implantation has been well established from randomized trials.14,15 The TRITON-TIMI 38 trial (Trial to Assess Improvements in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction) also demonstrated that more intensive antiplatelet therapy with prasugrel was associated with a marked reduction in ST rate compared with standard antiplatelet therapy with clopidogrel.16 Reduction of the ST rate in the prasugrel group was predominantly seen within 30 days after stent implantation, although the reduction in the rate of late ST was also of borderline significance. Therefore, the role of intensive antiplatelet therapy in reducing early ST appears to be firmly established.
However, the role of thienopyridine therapy in reducing late ST beyond 1 month after stent implantation has not been well addressed. Although premature discontinuation of antiplatelet therapy has been reported to be the most powerful predictor of ST and/or adverse outcome,3–5 these previous reports did not discriminate the relative impact of discontinuation of either aspirin, thienopyridine, or both agents. The present analysis demonstrated that withdrawal of both thienopyridine and aspirin, but not of thienopyridine therapy alone, was associated with increased ST risk beyond 1 month after SES implantation. Aspirin withdrawal was reported to be responsible for admission with an ACS in 51 (4%) of 1236 patients, with a mean delay between aspirin cessation and hospitalization of 10±2 days.17 It is noteworthy that late and very late ST at a mean of 16±7 months after BMS implantation was responsible for ACS in 10 (20%) of these 51 patients.
Furthermore, only one third of ST events after discontinuation of antiplatelet therapy (mostly thienopyridine) occurred within the first 28 days after discontinuation. This might lead to a discussion about whether or not a direct link in fact exists between discontinuation of antiplatelet therapy and ST, particularly very late ST.
Previous prospective studies demonstrated a clinical benefit of the prolonged use of thienopyridine for up to 1 year in patients undergoing PCI with BMS,18,19 primarily in the setting of ACS. Extrapolation of these findings to DES might make it appear reasonable to advocate adherence to dual-antiplatelet therapy for 1 year after DES implantation; however, the present study results suggest that it is also reasonable to discontinue thienopyridine and adhere to aspirin monotherapy in situations in which continuation of dual-antiplatelet therapy appears to be otherwise clinically irrelevant. Furthermore, because the majority of ST events occurred >1 week after discontinuation of antiplatelet therapy, it appears important to make the duration of discontinuation as short as possible if discontinuation is unavoidable.
The optimal duration of dual-antiplatelet therapy has not been well established. A single-center observational study of 1216 DES patients and 2393 BMS patients reported that use of clopidogrel at 6 and 12 months was associated with a lower incidence of death or MI at 24 months in patients with DES but not in patients with BMS.9 On the other hand, a similar analysis in 671 diabetic patients reported that use of clopidogrel at 6 months was associated with a significantly lower incidence of death or MI at 18 months in patients with BMS but not in those with DES.20 Relatively small sample sizes in these subgroup analyses to evaluate hard clinical end points might be 1 of the reasons for the discrepancy. The present analysis of a larger number of patients by the same method demonstrated a similar long-term clinical outcome regardless of thienopyridine use at 6 months in SES patients. Given the increased risk of bleeding and the huge economic burden with prolonged dual-antiplatelet therapy,18,19,21 the optimal duration of dual-antiplatelet therapy should be defined by prospective randomized trials evaluating the net clinical benefit after considering both ischemic events and bleeding complications.
The present study has several important limitations. First, baseline characteristics and procedural characteristics such as the high rate of intravascular ultrasound guidance in the present cohort might be markedly different from practices outside Japan. Also, ticlopidine was used as a thienopyridine antiplatelet agent in the vast majority of patients, in contrast to the use of clopidogrel in most other studies. These and other ethnic differences might make it difficult to apply the findings in the present study outside of Japan. Second, although data on antiplatelet therapy use were collected prospectively, no attempt was made to verify compliance with antiplatelet medications for patients in whom discontinuation was not reported; this might well have led to overestimation of compliance. In addition, we did not systematically evaluate the restarting of antiplatelet therapy after persistent discontinuation, which could have resulted in the potential underestimation of medication use. In fact, in the 6-month landmark analysis, 13% of patients who underwent repeated revascularization >6 months after the first procedure were likely to have restarted thienopyridine. The limitation of a landmark analysis is that it only examines specific points in time. A Cox proportional hazards model with a time-dependent covariate (thienopyridine discontinuation) might be able to examine the continuous risk of thienopyridine discontinuation. Furthermore, when follow-up information was obtained by contact with patients, dates of discontinuation of aspirin and thienopyridine were based on retrospective recall by the patients or relatives, which suggests a potential for recall bias. Third, unmeasured confounders related to thienopyridine discontinuation might be present because of the observational study design. Fourth, the number of patients at risk at 2-year follow-up was limited. Therefore, the results of the present study might be valid only during the first year after SES implantation. Finally, bleeding complications were not evaluated, which made it impossible to evaluate the net clinical efficacy of dual-antiplatelet therapy.
Despite these limitations, we would conclude that discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy alone, was associated with an increased risk of ST. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after SES implantation.
The authors are indebted to Yoko Kasakura for secretarial assistance.
Sources of Funding
This study was supported by Cordis Cardiology Japan, a Johnson & Johnson company. The study sponsor was not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Dr Kimura serves as an advisory board member and member of the speakers’ bureau for Cordis Cardiology and has received honoraria from Cordis Cardiology. Dr Nakagawa is a member of the speakers’ bureau and has received honoraria from Cordis Cardiology. Dr Miyazaki is an advisory board member and receives honoraria from Cordis Cardiology. Drs Shiode and Mitsudo both report receipt of honoraria from Cordis Cardiology. The remaining authors report no conflicts.
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Randomized data are lacking on the optimal duration of dual-antiplatelet therapy after drug-eluting stent implantation and on the risks associated with discontinuation of dual-antiplatelet therapy. Despite the absence of randomized data, the use of dual-antiplatelet therapy beyond 1 year has become commonplace in clinical practice. In the j-Cypher registry, 10 778 Japanese patients treated exclusively by sirolimus-eluting stents were followed up for up to 2 years with prospective data collection on the status of antiplatelet therapy during follow-up. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. The main findings of the present study were that discontinuation of both aspirin and thienopyridine, but not discontinuation of thienopyridine therapy only, was associated with an increased stent thrombosis risk and that no apparent clinical benefit of thienopyridine use could be seen beyond 6 months after sirolimus-eluting stent implantation, according to the 6-month landmark analysis. Given the increased risk of bleeding and huge economic burden associated with prolonged dual-antiplatelet therapy, the optimal duration of dual-antiplatelet therapy should be defined by prospective randomized trials evaluating its net clinical benefit after consideration of both ischemic events and bleeding complications.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.808311/DC1.