Methods

The study design and main results for the j-Cypher registry have been previously reported in detail. In brief, the j-Cypher registry is a physician-directed, prospective, multicenter registry enrolling unselected consecutive patients undergoing sirolimus-eluting stent implantation at 37 Japanese centers ( Supplemental Appendix A ). Although data entry was basically left to the individual sites, the clinical research coordinators ( Supplemental Appendix B ) at the Data Management Center (Department of Cardiology, Kyoto University Hospital) supported the data entry when necessary. Logical inconsistencies were resolved by inquiries to the site investigators and/or by audits against the original data sources. Follow-up data were obtained from the hospital charts or by interviewing the patients and/or referring physicians. When death, myocardial infarction (MI), or stent thrombosis (ST) was reported, the events were adjudicated using the original source documents by a clinical events committee ( Supplemental Appendix C ).

The present post hoc subanalysis of the j-Cypher registry data was intended to evaluate the safety and efficacy of sirolimus-eluting stent use in patients presenting with ACS. From August 2004 to November 2006, 12,824 patients were enrolled in the j-Cypher registry, and 10,778 patients were treated exclusively with sirolimus-eluting stents. Of these 10,778 patients, 2,308 had ACS and 8,470 did not. The patients with ACS were further subdivided by the presence of acute myocardial infarction (AMI) (n = 953) and unstable angina pectoris (UAP) (n = 1,355). The primary outcome measures for safety in the present analysis included ST (definite or probable) and the composite of death or MI. Target lesion revascularization was selected as the primary outcome measure for efficacy. The incidence of these events was compared between those with and without ACS within the total cohort treated exclusively with sirolimus-eluting stents and between those with AMI and those with UAP within the cohort of patients with ACS. The median follow-up interval of the surviving patients was 867 days (interquartile range 658 to 1,095) in the ACS group and 936 days (interquartile range 732 to 1095) in the non-ACS group.

The ethics committee at each participating institution approved the study protocol. All patients gave written informed consent before enrollment. A glycoprotein IIb/IIIa inhibitor was not used because it is unavailable in Japan. The recommended antiplatelet regimen was aspirin (≥81 mg/day) to be given indefinitely and thienopyridine (200 mg/day ticlopidine or 75 mg/day clopidogrel) for ≥3 months. The duration of antiplatelet therapy was left to the discretion of each attending physician. Persistent discontinuation was defined as withdrawal lasting ≥2 months.

ACS was diagnosed according to clinical symptoms, electrocardiographic changes compatible with acute myocardial ischemia, and elevation of cardiac biomarkers. AMI (ST-segment elevation AMI and non–ST-segment elevation AMI) and UAP were discriminated according to the presence or absence of cardiac biomarker elevation. Death was regarded as cardiac in origin unless obvious noncardiac causes could be identified. MI was adjudicated according to the definition used by the Arterial Revascularization Therapy Study. Definite and probable ST using the Academic Research Consortium definition was considered ST in the present study. Target lesion revascularization was defined as either percutaneous coronary intervention or coronary artery bypass grafting because of restenosis or ST of the target lesion that included the proximal and distal edge segments and the ostium of the side branches.

Categorical variables are expressed as the number and percentages and were compared using the chi-square test. Continuous variables are expressed as the mean ± SD, unless indicated otherwise. Continuous variables were compared using Student’s t test or the Wilcoxon rank-sum test on the basis of their distribution. The cumulative incidence of adverse events was estimated using the Kaplan-Meier method, and the curves were compared using the log-rank test. In an attempt to evaluate the incidence of the primary and secondary outcome measures beyond 1 year, a landmark analysis was also conducted of patients who had not had end point events within the first year. A multivariate Cox proportional hazard model was developed to adjust for the differences in baseline characteristics. In the multivariate model, we incorporated ACS versus non-ACS or AMI versus UAP, together with 22 risk factors used in the previous report. Proportional hazard assumptions for the variables of ACS versus non-ACS or AMI versus UAP were assessed on the plots of log (time) versus log [−log (survival)] stratified by the variable and were found to be justified.

All statistical analyses were performed using the JMP, version 7.0, software (SAS Institute, Cary, North Carolina). p Values <0.05 were considered statistically significant.

Results

The patients in the ACS group were significantly older and more ill than those in the non-ACS group ( Table 1 ). The cumulative incidence of persistent thienopyridine discontinuation at 3 years in the ACS group was significantly greater than that in the non-ACS group ( Figure 1 ). The cumulative 3-year incidence of all-cause death, cardiac death, and ST (definite and definite/probable) were significantly greater in the ACS group than in the non-ACS group ( Table 2 ). Within the first year after sirolimus-eluting stent implantation, the incidence of death or MI in the ACS group was significantly greater than that in the non-ACS group (7.0% vs 3.8%, p <0.0001). However, beyond 1 year after sirolimus-eluting stent implantation, the incidence of death or MI was not different between the ACS group and the non-ACS group (7.7% vs 6.9%, p = 0.37; Figure 2 ). The adjusted hazard ratios for the patients with ACS versus those without ACS for death or MI were 1.24 (95% confidence interval [CI] 1.12 to 1.37, p <0.0001) within the first year and 1.01 (95% CI 0.90 to 1.13, p = 0.87) after 1 year ( Table 3 ). Similarly, although the incidence of definite or probable ST within the first year was significantly greater in the ACS group than in the non-ACS group (1.3% vs 0.5%, p <0.0001), the statistical significance of the difference in the incidence of ST had disappeared beyond 1 year after sirolimus-eluting stent implantation (1.0% vs 0.6%, p = 0.06; Figure 3 ). The adjusted hazard ratios of those with ACS versus those without ACS for definite or probable ST were 1.43 (95% CI 1.11 to 1.82, p = 0.006) within the first year and 1.32 (95% CI 0.92 to 1.86, p = 0.13) beyond the first year ( Table 3 ). The incidence of target lesion revascularization at 3 years after stent implantation in the ACS group (12.1%) was similar to that in the non-ACS group (12.2%; Table 2 and Figure 4 ).

Incidence of persistent thienopyridine discontinuation. (A) ACS versus non-ACS groups and (B) AMI versus UAP groups.

Incidence of death or MI for those with and without ACS. ( A ) Event rate within 1 year and ( B ) event rate beyond 1 year.

Incidence of ST in those with and without ACS. ( A ) Event rate within 1 year and ( B ) event rate beyond 1 year.

Incidence of target lesion revascularization for those with and without ACS.

The comparison of baseline characteristics between the UAP and AMI groups are listed in Table 4 . The cumulative incidence of persistent thienopyridine discontinuation at 3 years was not different between the AMI and UAP groups ( Figure 1 ). The cumulative 3-year incidence of cardiac death was significantly greater in the AMI group than in the UAP group ( Table 5 ). However, the cumulative incidence of ST (definite and definite/probable) at 3 years was similar between the 2 groups. Within the first year after sirolimus-eluting stent implantation, the incidence of death or MI in the AMI group was significantly greater than that in the UAP group (8.9% vs 5.8%, p <0.004). However, >1 year after sirolimus-eluting stent implantation, the rate of death or MI was not different between the AMI and the UAP groups (7.6% vs 7.8%, p = 0.45; Figure 5 ). The adjusted hazard ratios for those with AMI versus those with UAP for death or MI were 1.33 (95% CI 1.12 to 1.60, p = 0.001) within the first year and 1.00 (95% CI 0.78 to 1.22, p = 0.83) beyond the first year ( Table 6 ). The incidence of definite or probable ST was not different between the AMI and UAP groups both within the first year and >1 year after sirolimus-eluting stent implantation ( Figure 6 ). After adjusting for confounding factors, the patients with AMI had a greater risk of definite or probable ST than did the patients with UAP within the first year but not beyond 1 year after sirolimus-eluting stent implantation. The adjusted hazard ratios for the patients with AMI versus those with UAP for definite or probable ST were 1.57 (95% CI 1.05 to 2.39, p = 0.03) within the first year and 0.83 (95% CI 0.38 to 1.60, p = 0.59) beyond the first year ( Table 6 ). The incidence of target lesion revascularization at 3 years after stent implantation in the AMI group was similar to that in the UAP group ( Table 5 and Figure 7 ).

Table 4

Baseline patient characteristics stratified by acute myocardial infarction (AMI) and unstable angina pectoris (UAP)

Variable	AMI	UAP	p Value
Patient characteristics
Patients	953	1,355
Age (years)	68.4 ± 11.6	69.0 ± 10.8	0.25
Age ≥80 years	172 (18%)	224 (17%)	0.34
Men	707 (74%)	972 (72%)	0.19
ST-segment elevation myocardial infarction	733 (77%)	0
Non–ST-segment elevation myocardial infarction	220 (23%)	0
Body mass index (kg/m 2 )	23.5 ± 3.4	23.8 ± 3.4	0.045
Body mass index <25.0 kg/m 2	673 (70%)	908 (67%)	0.06
Hypertension	644 (68%)	1,044 (77%)	<0.0001
Diabetes mellitus	362 (38%)	543 (40%)	0.31
Diabetes mellitus requiring insulin	66 (6.9%)	105 (7.8%)	0.46
Current smoker	343 (36%)	328 (24%)	<0.0001
Estimated glomerular filtration rate <30 ml/min/1.73 m 2
Without hemodialysis	50 (5.3%)	93 (6.9%)	0.11
With hemodialysis	26 (2.7%)	98 (7.2%)	<0.0001
Previous myocardial infarction	120 (13%)	276 (20%)	<0.0001
Previous stroke	98 (10%)	155 (11%)	0.38
Peripheral vascular disease	66 (6.9%)	154 (11%)	0.0003
Previous heart failure	60 (6.3%)	122 (9.0%)	0.02
Previous percutaneous coronary intervention	137 (14%)	511 (38%)	<0.0001
Previous coronary artery bypass grafting	20 (2.1%)	110 (8.1%)	<0.0001
Multivessel disease	494 (52%)	754 (56%)	0.07
Target of unprotected left main coronary artery	44 (4.6%)	79 (5.8%)	0.20
Ejection fraction (%)	50.8 ± 12.7	58.5 ± 12.8	<0.0001
Number of coronary arteries treated	1.27 ± 0.54	1.25 ± 0.54	0.46
Total number of stents	1.8 ± 1.0	1.8 ± 1.1	0.84
Total stent length (mm)	40.1 ± 15.6	39.4 ± 26.5	0.53
Shock state at procedure	46 (4.8%)	18 (1.3%)	<0.0001
Emergent procedure	680 (71%)	384 (28%)	<0.0001
Lesion and procedural characteristics
Number of lesions	1357	1957
Lesion location			<0.0001
Left anterior descending	641 (47%)	866 (44%)
Left circumflex	255 (19%)	393 (20%)
Right	404 (30%)	583 (30%)
Left main	47 (3.5%)	1,957 (4.8%)
Saphenous vein graft	8 (0.6%)	21 (1.1%)
In-stent restenosis	27 (2.0%)	163 (8.3%)	<0.0001
Severe calcium	87 (6.4%)	204 (10%)	<0.0001
Bifurcation lesion	222 (16%)	389 (20%)	0.01
Lesion length ≥30 mm	197 (15%)	239 (12%)	0.05
Preprocedural reference diameter <2.5 mm	316 (24%)	554 (29%)	0.001
Use of intravascular ultrasonography	629 (47%)	882 (45%)	0.45
Direct stenting	356 (27%)	469 (24%)	0.14
Maximum inflation pressure (atm)	17.9 ± 3.4	17.9 ± 3.3	0.31
Length of stents used (mm)	28.6 ± 14.1	27.7 ± 14.4	0.04
Average size of stents used (mm)	2.9 ± 0.4	2.9 ± 0.4	0.99
Initial Thrombolysis In Myocardial Infarction grade flow			<0.0001
0	424 (31%)	137 (7.0%)
1	57 (4.2%)	54 (2.8%)
2	197 (15%)	258 (13%)
3	671 (50%)	1,499 (77%)
Final Thrombolysis In Myocardial Infarction grade flow			0.004
0	14 (1.0%)	13 (0.8%)
1	3 (0.2%)	3 (0.2%)
2	26 (2.2%)	14 (0.7%)
3	1,303 (97%)	1,914 (98%)
Thrombus present	522 (38%)	111 (5.7%)	<0.0001
Thrombectomy	349 (31%)	75 (4.8%)	<0.0001
Use of distal protection device	59 (5.2%)	38 (2.4%)	<0.0001
Persistent slow flow after stent implantation	10 (0.9%)	7 (0.5%)	0.16

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