Long-Term Safety and Efficacy of Sirolimus-Eluting Stents in Japanese Patients: A Single-Center Cohort Study
- Volume 21 - Issue 10 - October, 2009
- Posted on: 10/9/09
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ABSTRACT: Background. The long-term safety and efficacy of sirolimus-eluting stents (SES) remain uncertain in real practice in Japan. Methods. We used a hospital-based cohort (n = 6,562) comprising all the new patients who had visited our hospital between 2004 and 2007 to investigate the mortality and morbidity after SES or bare-metal stent (BMS) implantation. Results. Of the total, coronary artery disease was observed in 822 patients (12.5%), and SES or BMS were implanted in 208 and 167 patients, respectively. Patients receiving SES more often had diabetes but less often presented with acute myocardial infarction (MI). Median follow-up periods were 815 and 894 days for SES and BMS, respectively (p = 0.305). Intravascular ultrasound (IVUS) was used at a high rate (> 90%) in both groups, and maximum pressure inflation for SES was high at approximately 18 atm. The unadjusted cumulative incidence of all-cause death and major adverse cardiac events (MACE) (cardiac death, MI or target vessel revascularization) at 2 years was 4.3% versus 7.2% (p = 0.233) and 16.3% versus 32.9% (p < 0.001), respectively. In multivariate analysis, all-cause mortality was similar between SES (hazard ratio [HR] 0.981, 95% confidence interval [CI] 0.366–2.632) and BMS, but SES significantly reduced MACE (HR 0.468, 95% CI 0.280–0.784). Definite stent thrombosis set by the Academic Research Consortium was not observed in either group, and the incidence of cerebral hemorrhage was 0.5% in SES and 1.2% in BMS, respectively (p = 0.588). Conclusions. SES used in real-world settings appeared to be safe and significantly associated with a lower risk of adverse events at long-term follow up in Japan, especially utilizing a careful stent deployment technique including high-pressure inflation and IVUS use.
J INVASIVE CARDIOL 2009;21:526–531
Key words: sirolimus-eluting stents; intravascular ultrasound;
cohort study; Japanese
After the BASKET-LATE trial,1 drug-eluting stents (DES) have been believed to be associated with an increased risk of cardiac mortality and non-fatal myocardial infarction (MI), especially after the discontinuation of thienopyridines. Time-dependent increase of stent thrombosis, a significant complication associated with poor clinical outcomes, remains a concern in the DES era.1–5 Several meta-analyses of randomized trials indicated that DES had no significant effect on long-term survival and survival free of MI.5–10 Also, some registries including short-term (< 1 year) clinical outcomes reported that the incidence of death and MI was not significantly lower with the use of DES compared with that of bare-metal stents (BMS).11–14 In contrast, reports on current real-world settings have shown that DES reduced mortality, MI and repeat revascularization rates compared with BMS at long-term follow up in Western countries.15–18 Furthermore, stent thrombosis appears to be very infrequent in Asian countries (0–0.8%) compared to Western countries (0.6–3.2% at 1 year).19–24 Therefore, long-term outcomes of DES may be different according to the percutaneous coronary intervention (PCI) procedure performed, the patient’s race, the rate of off-label use, the follow-up period and the medical treatments employed after PCI.14,22,23,25–30 Thus, the influence of DES on long-term mortality and morbidity needs to be determined in real-world clinical practice in Japan.
A prospective, observational cohort study conducted at our hospital was designed to investigate the prognosis of Japanese patients with cardiovascular disease.31 The purpose of the present study with this database was to identify the outcomes of sirolimus-eluting stents (SES) and BMS in Japanese patients.
Study population. We conducted a hospital-based cohort study since 2004 to assess the clinical variables, mortality and morbidity of Japanese patients with cardiovascular disease. The study population comprised all the new patients who had visited our hospital in Tokyo between June 2004 and March 2007 and did not meet the exclusion criteria including patients with cancer under no treatment, patients living abroad and patients visiting just one time without undergoing examination. The institute is a teaching hospital with a cardiac catheterization laboratory and a cardiac surgery facility.
When written informed consent for entering the Shinken database was obtained from the patients, all data were transmitted to the database center at the hospital, and all their clinical outcomes were monitored by medical records, mail and/or telephone contact with the patients. The institute’s ethical committee granted permission for this study.
Analysis cohort. Among the database population, all patients undergoing PCI with stenting between June 2004 and March 2007 were identified. Study subjects were assigned to either the DES group or the BMS group according to the stent type used during the index PCI procedure. Individuals receiving both DES and BMS during the index procedure were excluded from the analysis.
Definitions. Coronary artery disease encompasses stable angina pectoris, unstable angina, acute myocardial infarction (AMI) and vasospastic angina. In the present study, the confirmed and discharge diagnoses of unstable angina and AMI were made according to the following definitions: unstable angina was defined according to the Braunwald Classification with creatine-kinase (CK) and CK-MB isozyme values not exceeding twice the respective upper limits of normal, and had one or more of the following three historical features: 1) new-onset exertional angina of < 1 month’s duration; 2) a changing pattern; and 3) new-onset angina at rest. A diagnosis of AMI was made if the CK and CK-MB values exceeded twice the upper limit of normal and the time from onset to admission was within 7 days. The time of the onset of AMI was determined by the attending physicians on the basis of patient self-reports, electrocardiograms (ECGs) and blood tests.
The present study included information on baseline characteristics of patients and their cardiac history, risk factors, lesion characteristics, cardiac procedures and medications. Angiographically significant stenosis was defined as ≥ 50% stenosis. Target vessel revascularization (TVR) was defined as PCI in a vessel treated during the index procedure or any coronary artery bypass graft surgery (CABG) after the index procedure.
PCI procedure. Of the DES, sirolimus-eluting stents (SES) were used during the study period in Japan. Among the thienopyridines, ticlopidine was usually administered in Japan due to the off-label indications for clopidogrel after DES implantation in Japan, and dual antiplatelet therapy with aspirin and a thienopyridine were provided for ≥ 1 year after PCI. In our hospital, SES were selected as the first-line stent unless patients met the exclusion criteria as follow: 1) AMI during the acute phase of increasing CK or CK-MB; 2) poor medication compliance; 3) undergoing the surgery within 1 year; 4) aspirin intolerance; and 5) bleeding complication disease such as gastrointestinal bleeding or cerebral hemorrhage. Intravascular ultrasound (IVUS) was routinely used whether SES or BMS were implanted and whether the PCI procedure was emergent or elective; also, follow-up angiography was performed within 1 year. When we performed implantation of SES, optimal stent deployment pressure was high (16–22 atm).
Follow up and data collection. The following clinical outcomes were evaluated: all-cause mortality, cardiac mortality, target vessel revascularization (TVR), readmission for heart failure and major adverse cardiac events (MACE), defined as cardiac death, nonfatal MI and TVR.
Statistical analysis. Continuous variables between groups were compared using the unpaired t-test. Categorical variables were compared using the chi-square test. Results for continuous data were expressed as mean ± standard deviation. Cumulative event curves were plotted by the Kaplan-Meier method, and the difference was tested by the log-rank test. Covariates of stent types, presence or absence of acute coronary syndrome, age, gender, estimated glomerular filtration rate, diabetes, congestive heart failure on admission and number of diseased vessels were used to construct a multivariate Cox proportional hazards model of MACE by a stepwise procedure. Covariates of stent types, presence or absence of acute coronary syndrome, age and gender were for all-cause death and cardiac death. Data were analyzed using statistical SPSS software, version 14.0 (SPSS Japan, Inc., Tokyo). For all analyses, significance was defined as p < 0.05.
Patient population. A total of 6,562 patients were enrolled in the Shinken Database 2004–2007 and underwent follow up. Of the total, 822 patients presented with coronary artery disease (CAD) (12.5%) at the initial visit and were treated by PCI, CABG or a conservative, noninvasive strategy. As the first-line treatment for CAD, PCI was performed in 426 patients, and SES or BMS alone were implanted in 208 and 167 patients, respectively. The others underwent one of the following: directional coronary atherectomy alone, percutaneous transluminal rotational ablation alone, percutaneous plain-old balloon angioplasty, or received both stent types. The median follow-up periods of the present study for the SES and BMS groups were 815 and 894 days, respectively (p = 0.305).
Patient characteristics and therapeutic strategies. Tables 1 and 2 compare the clinical characteristics, echocardiographic and angiographic findings and procedural characteristics between the SES and BMS groups. Patients treated with SES presented with AMI less often than patients who received BMS (6.7% and 57.5%, respectively, p < 0.001), and more patients receiving BMS had congestive heart failure on admission (p = 0.001). Comorbidities were similar in both groups except for diabetes mellitus. SES were implanted more frequently in patients with diabetes mellitus (42.5% in SES and 31.7% in BMS; p = 0.041). Furthermore, patients receiving SES more frequently had prior MI and prior PCI. Decreased left ventricular ejection fraction and larger ventricular dimensions were more frequently observed in the BMS group than the SES group. There were no significant differences in the number of males, age, body mass index, estimated glomerular filtration rate, presence of left main CAD, number of diseased coronary arteries and the use of debulking. However, the number of lesions treated was greater in the SES group than the BMS group (1.3 ± 0.6 vs. 1.1 ± 0.4, respectively; p < 0.001). IVUS was used in both groups at a relatively high rate, but patients who received SES were treated more frequently with IVUS than those who received BMS (99.5% and 91.6%, respectively; p < 0.001). The maximum pressure inflation was 18.1 ± 2.2 atm in the SES group and 14.7 ± 1.9 atm in the BMS group. SES were more likely to be implanted in left anterior descending artery lesions. In terms of lesion and stent characteristics, the rates of chronic total occlusion and American College of Cardiology (ACC) Type-C lesions were significantly higher in the SES group than in the BMS group. The average lesion length was longer in the SES group than in the BMS group (26.3 ± 12.6 mm vs. 20.0 ± 11.7 mm, respectively; p < 0.001). Patients receiving SES had a significantly larger number of stents, longer stent lengths, larger stent diameters and smaller reference vessel diameters than those receiving BMS (2.0 ± 1.0, 22.8 ± 4.89 mm, 2.99 ± 0.25 mm and 2.93 ± 0.56 mm versus 1.5 ± 0.7, 20.9 ± 5.52 mm, 3.29 ± 0.48 mm and 3.09 ± 0.60 mm, respectively).