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 Methods
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 Results
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 Discussion
The present study involved a hospital-based cohort of Japanese patients with CAD who were treated with SES or BMS, often under IVUS guidance. The study revealed the following findings:
1. There were no significant differences in all-cause mortality and cardiac mortality between the two groups, but SES significantly reduced the incidence of MACE at long-term follow up, even after adjustment for patient backgrounds (53.2% of relative risk reduction).
2. Definite stent thrombosis per the ARC definition was not observed in either group during the follow-up period.
3. The incidence of cerebral hemorrhage and cerebral infarction was 0.5% and 0.5% in the SES group versus 1.2% and 0.6% in the BMS group, respectively, with no significant differences between the two groups.
Despite the important roles of race, medications and IVUS-guidance in the DES era, there has been limited information on the long-term outcomes of DES implanted under IVUS guidance (> 90% of cases) in Japanese patients.26,28–30,33–36 The present study suggests that SES are safe and reduce the incidence of post-PCI adverse events at long-term follow up. However, it should be noted that SES were chosen as the first-line stent, but BMS were used in the following cases: 1) AMI during the acute phase of increasing CK or CK-MB; 2) patients with poor medical compliance; 3) patients undergoing surgery within 1 year; 4) patients with aspirin intolerance; and 5) patients with bleeding complications such as gastrointestinal bleeding or cerebral hemorrhage. Also, the present results were obtained by performing follow-up angiography within 1 year. Routine follow-up angiography may contribute to the early detection of restenosis, which is not always a benign event, before the occurrence of a severe cardiac event.37 Furthermore, in the present study, most patients receiving SES continued to receive dual antiplatelet therapy for more than 1 year for the prevention not only of stent thrombosis, but new coronary lesions as well.28–30,38 We should note that it is possible that these strategies might influence the present findings.
In the Cleveland, Ontario and other studies, Type B2 and C lesions were common in real practice, and this tendency was applicable to the present study.15,16,20,22,36 Actually, the rate of AMI in the DES group was 7–9% in those registries, which is similar to the present study (6.7%). In contrast, in meta-analyses of randomized trials, Type B1 and B2 lesions were common.9 Furthermore, in most of the randomized trials, the average lesion length was rather short and the average reference vessel diameter was large, reflecting the outcomes of selected populations. These points should be kept in mind when comparing the present results with those of the randomized trials.
The rates of congestive heart failure on admission and decreased cardiac function were lower in the SES group, probably due to the lower frequency of acute coronary syndromes in this group. In contrast, patients with BMS restenosis lesions were included in the SES group, reflecting the higher rates of prior MI and prior PCI in the SES group. In addition, SES were implanted more frequently in patients with diabetes mellitus and more complex lesions, and the number of lesions treated was larger in the SES group than the BMS group, which indicates a higher risk of PCI. The background characteristics of the SES group, however, did not affect the increase in mortality and MACE, even after adjustment, but it cannot be denied that other unmeasured confounding factors may be involved.
The TVR curves separated and remained parallel for the follow-up period, which is consistent with other registries and confirms the durable benefit of SES in terms of restenosis prevention in this real-world setting. Furthermore, it is possible that a reduction in TVR could somewhat contribute to the reduction in MACE and to the tendency toward the reduction in restenosis-related cardiac deaths of patients receiving SES in the present study.7,37 In addition, patients with complex lesions appear to benefit the most from SES,13,14 and these patients were typical of those seen in real practice.
Randomized trials have raised concerns about stent thrombosis 1 year post implantation, but these findings were not confirmed in the present study. Stent thrombosis has been thought to occur frequently in cases of stent underexpansion and residual reference segment stenosis after implantation of SES.34 These procedure-related complications are reduced with the use of IVUS because it can help to select optimal stent size and is also useful in the detection of stent underexpansion and injury in the distal and proximal stent edges.33–35 In the present study, IVUS was frequently used even in the emergency at off-time. Furthermore, high-pressure balloon dilation also seems to be necessary to increase minimum lumen area and decrease incomplete stent expansion associated with stent thrombosis and revascularization.39 In our hospital, optimal stent deployment pressure for SES was 16 to 22 atm (mean 18.1 ± 2.2 atm), which might reduce the stent thrombosis and revascularization rate in this study. Generally, patients had not undergone implantation of SES for the lesions of pre-procedural reference vessel diameter of less than 2.5 mm or more than 4.0 mm confirmed by IVUS, and also in many cases we had performed predilatation prior to stent deployment for the prevention of stent underexpansion. It is possible that these very careful procedures in the stent deployment may decrease the stent thrombosis and revascularization rate. The characteristics of the Japanese race, long duration of dual antiplatelet therapy and low rate of AMI patients might also contribute the reduction in stent thrombosis.40
However, unexpectedly, the long duration of dual antiplatelet therapy did not lead to an increase in cerebral hemorrhage in the present study. Fukushima et al also showed that the mortality rate of Japanese patients receiving aspirin 100 mg once daily and ticlopidine 100 mg twice daily after SES implantation was 0.2 %, and the rate of bleeding side effects was zero.41 Therefore, the dual antiplatelet therapy of aspirin and ticlopidine seems to give rise to bleeding complications at a rather low rate, and the present study suggests that the long-term benefits of ticlopidine in terms of stent thrombosis and stroke appear to be well established in Japanese patients.
Study limitations. The present study has several limitations. First, this was a single-center cohort study, which may have led to selection bias and involved a relatively small number of study patients. Due to the relatively small sample size, the safety endpoints may be underpowered. Accordingly, more studies from other Japanese centers are needed involving larger populations and frequent use of IVUS, which could be combined with our database. However, a single-center registry allowed for a consistent PCI strategy and prospective collection of detailed clinical and angiographic PCI data by professional staff. Second, dual antiplatelet therapy with aspirin and ticlopidine was usually provided for more than 1 year post PCI. However, the actual duration varied according to the attending physician. Third, this was a nonrandomized, hospital-based cohort study, thus baseline and procedural characteristics varied between the patients receiving DES versus BMS, which renders it difficult to make a comparison between the two groups. For example, most patients with AMI received BMS; thus, the information on the safety and efficacy of DES for AMI remains unclear in the present study. Finally, our hospital is a teaching facility specializing in cardiovascular diseases; the results of this study may therefore not be easily generalized to all medical centers, but it is important to show an aspect of current therapy in a specialized hospital in Japan. We believe that the findings of our study represent accurate outcomes of SES and BMS, since we used a highly accurate method of diagnosis, consistent and thorough stent deployment techniques, and followed all cardiovascular events.
Conclusions
The present study involves a hospital-based cohort of Japanese patients with CAD who underwent implantation of SES or BMS, thus more extensively reflecting a real-world setting. The results revealed that implantation of SES appears to be safe and to significantly reduce the incidence of MACE at long-term follow up, particularly since we used thorough stent deployment techniques such as high-pressure balloon inflation and frequent IVUS guidance.
Acknowledgements. We thank Drs. Koichi Sagara, Akira Koike, Tokuhisa Uejima, Takayuki Otsuka, Ryuichi Funada and Shunsuke Matsuno of the Cardiovascular Institute and Dr. Shinya Suzuki of the University of Tokyo Hospital for their collection of data.
From the Cardiovascular Institute, Tokyo, Japan.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 3, 2009, provisional acceptance given May 18, 2009, final version accepted June 24, 2009.
Address for correspondence: Michinari Nakamura, MD, The Cardiovascular Institute, 7-3-10 Roppongi, Minato-ku, Tokyo, 106-0032, Japan. E-mail: nmichi-kyu@umin.ac.jp
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