Comparison of Three-Year Clinical Outcomes After Sirolimus-Eluting Stent Implantation Among Insulin-Treated Diabetic, Non–Insulin-Treated Diabetic, and Non-Diabetic Patients from j-Cypher Registry




The purpose of the present study was to evaluate the 3-year clinical outcomes after percutaneous coronary intervention with sirolimus-eluting stents in patients with insulin-treated diabetes mellitus (DM-insulin) and those with non–insulin-treated DM (DM–non-insulin) compared to patients without DM. Of 10,778 consecutive patients treated exclusively with sirolimus-eluting stents in the j-Cypher registry, we identified 996 patients with DM-insulin, 3,404 with DM–non-insulin, and 6,378 without DM. Compared to the non-DM group, the adjusted risk of a serious cardiovascular event (composite of all-cause death, myocardial infarction, and stroke) was significantly greater in the DM-insulin group (hazard ratio 1.12, 95% confidence interval [CI] 1.03 to 1.23; p = 0.01), but not in the DM–non-insulin group (hazard ratio 1.02, 95% CI 0.96 to 1.09; p = 0.47). The adjusted risk of target lesion revascularization was significantly greater in both the DM-insulin group (odds ratio 1.52, 95% CI 1.19 to 1.92; p = 0.0006) and the DM–non-insulin group (odds ratio 1.24, 95% CI 1.05 to 1.45; p = 0.009). In conclusion, a diabetes-associated excess risk of target lesion revascularization was found, regardless of insulin use in this large, real-world study of Japanese patients with sirolimus-eluting stent implantation. However, regarding serious cardiovascular events, an excess risk was seen only in the DM-insulin group. The risk of serious cardiovascular events was similar between the DM–non-insulin and non-DM groups.


The present study evaluated the effect of the presence of insulin-treated and non–insulin-treated diabetes mellitus (DM) on the incidence of serious cardiovascular events and repeated coronary revascularization after sirolimus-eluting stent (SES) implantation. We evaluated the 3-year clinical outcomes of patients with insulin-treated DM (DM-insulin) and non–insulin-treated DM (DM–non-insulin) relative to patients without DM in a large cohort who had undergone percutaneous coronary intervention (PCI) using SESs in a real-world clinical practice in Japan.


Methods


The design and patient enrollment of the j-Cypher registry has been previously published. In brief, the j-Cypher registry is a physician-initiated prospective, multicenter, prospective cohort study in Japan enrolling consecutive patients who have undergone SES implantation at 37 centers in Japan (see Supplemental Appendix A). The institutional review boards of all 37 participating centers approved the present study, and all patients provided written informed consent.


After SES implantation, dual antiplatelet treatment with aspirin plus a thienopyridine derivative (ticlopidine 200 mg/day or clopidogrel 75 mg/day) was to be maintained for ≥3 months. Thereafter, the decision regarding the duration of dual antiplatelet therapy was left to the discretion of each attending physician. Lifelong use of aspirin was recommended after the procedure.


Although the 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 or referring physicians at 30 days, 6 months, and 1 year after the procedure and yearly thereafter. When death, myocardial infarction, and stent thrombosis were reported, the events were adjudicated using the original source documents by a clinical events committee (Supplemental Appendix C). Adjudication of target lesion revascularization (TLR) events was left to the judgment of the local investigators.


From August 2004 to November 2006, 12,824 patients (19,675 lesions) were enrolled in the j-Cypher registry, and 10,778 patients (14,811 lesions) who had been treated exclusively with SES implantation constituted the study population for the present analysis. Of these patients, 4,400 had DM and 6,378 did not (non-DM group). The patients with DM were stratified by DM treatment. The DM–non-insulin group included 3,404 patients without insulin therapy, and the DM-insulin group included 996 patients who required insulin ( Figure 1 ). Of the 3,404 patients with DM-non-insulin, 2,330 were treated with oral glucose-lowering drugs and 1,074 patients were treated without medication. In the present post hoc subanalysis of the j-Cypher registry, the baseline characteristics and clinical outcomes in the DM-insulin group and DM–non-insulin group were compared to those in the non-DM group. The primary outcome measure for the present analysis was serious cardiac events (a composite of all-cause death, myocardial infarction, and stroke) assessed at 3 years after SES implantation. The secondary outcome measure included the individual components of the primary outcome events, definite stent thrombosis, TLR, non-TLR, and any coronary revascularization.




Figure 1


Study flow chart. BMS = bare metal stent; DES = drug-eluting stent.


DM was considered present if the fasting plasma glucose level was ≥126 mg/dl, the glucose level was >200 mg/dl at 2 hours after a 75-g oral glucose tolerance test, the casual plasma glucose level was >200 mg/dl, or the patient was taking antidiabetic medication. The diagnosis of DM and the use of insulin at the index SES implantation were reported by the site investigators.


Death was regarded as cardiac in origin unless obviously noncardiac causes could be identified. Any death during the index hospitalization was regarded as a cardiac death. Sudden death was defined as an unexplained death in a previously stable patient. Myocardial infarction was adjudicated according to the definition in the Arterial Revascularization Therapy Study. Within 1 week of the index procedure, only Q-wave myocardial infarction was adjudicated as myocardial infarction. TLR was defined as either PCI or coronary artery bypass grafting (CABG) because of restenosis or thrombosis of the target lesion, including the proximal and distal edge segments and the ostium of the side branches. Non-TLR was defined as coronary revascularization procedures, either PCI or CABG, other than TLR. Stent thrombosis was defined according to the Academic Research Consortium definition. Unless otherwise noted, definite stent thrombosis assessed on a patient-level basis was used as the end point for stent thrombosis.


Continuous variables are presented as the mean ± SD and categorical variables as numbers and percentages. Categorical variables were compared using the chi-square test. Continuous variables were compared using the t test or Wilcoxon rank-sum test based on the distribution. The incidence of the primary and secondary outcome measures was estimated using the Kaplan-Meier method, and differences were assessed using the log-rank test.


The adjusted risk of the primary outcome measure for the DM-insulin versus non-DM and DM–non-insulin versus non-DM groups was estimated using a multivariate Cox proportional hazard model by incorporating the variable DM-insulin or DM–non-insulin into the multivariate models with the 23 risk-adjustment variables listed in Supplemental Tables 1 and 2 . Continuous risk-adjustment variables were dichotomized according to the clinically meaningful reference values. The results are expressed as adjusted hazard ratios and their 95% confidence intervals (CIs). For the evaluation of the adjusted risk of TLR, a multivariate logistic regression model, instead of a Cox proportional hazard model, was used, because restenosis has been well known to be a time-related phenomenon. Also, the timing of TLR could have been highly influenced by the physicians’ and patients’ decisions. Using a logistic regression model, we could minimize the influence of the timing of TLR on the adjusted analysis for TLR. The patients included in the multivariate logistic regression model were the 1,882 patients who had undergone TLR within 3 years and the 2,415 patients who had completed 3 years of follow-up without TLR. The same independent variables used in the Cox proportional hazard model were incorporated into the multivariate logistic regression model. The results are expressed as the adjusted odds ratio and their 95% CIs. All analyses were conducted using JMP, version 7.1 (SAS Institute, Cary, North Carolina). All reported p values were 2-sided, and p <0.05 was considered significant.




Results


Compared to the patients without DM, the patients with DM-insulin and DM–non-insulin were younger, had a greater body mass index, and more often had hypertension, end-stage renal disease (including hemodialysis), heart failure, previous stroke, multivessel disease, and previous coronary revascularization procedures. Furthermore, those with DM-insulin were more often women, more often had peripheral vascular disease, and less often had a smoking habit or acute coronary syndrome than those without DM ( Table 1 ).



Table 1

Baseline characteristics
















































































































































































































































































































































































Characteristic Non-DM DM-Non-Insulin p Value DM-Insulin p Value
Patients (n) 6,378 3,404 996
Age (years) 68.8 ± 10.6 67.9 ± 9.4 <0.0001 66.7 ± 9.4 <0.0001
Age >80 years 952 (15%) 347 (10%) <0.0001 63 (6%) <0.0001
Men 4,867 (76%) 2,585 (76%) 0.68 671 (67%) <0.0001
Body mass index (%) 23.7 ± 4.0 24.3 ± 3.7 <0.0001 24.1 ± 3.4 0.0007
Hypertension 4,670 (73%) 2,638 (78%) <0.0001 761 (76%) 0.03
Current smoking 1265 (20%) 696 (21%) 0.47 158 (16%) 0.003
Estimated glomerular filtration rate <30 ml/min/1.73 m 2
Without hemodialysis 229 (3.7%) 192 (6.0%) <0.0001 101 (12%) <0.0001
With hemodialysis 238 (3.7%) 191 (5.6%) <0.0001 165 (17%) <0.0001
Peripheral vascular disease 697 (11%) 409 (12%) 0.11 170 (17%) <0.0001
Previous myocardial infarction 1713 (27%) 1,026 (30%) 0.0006 285 (29%) 0.25
Previous stroke 523 (8.2%) 354 (10%) 0.0003 130 (13%) <0.0001
Previous percutaneous coronary intervention 2,962 (46%) 1704 (50%) 0.0006 513 (52%) 0.003
Previous coronary artery bypass grafting 401 (6.3%) 274 (8.1%) 0.001 112 (11%) <0.0001
Heart failure 718 (11%) 511 (15%) <0.0001 231 (23%) <0.0001
Acute coronary syndrome 1403 (25%) 734 (22%) 0.62 171 (17%) 0.0004
ST-segment elevation myocardial infarction 455 (7.1%) 225 (6.6%) 0.33 53 (5.3%) 0.03
Multivessel disease 2,911 (46%) 1884 (55%) <0.0001 597 (60%) <0.0001
Triple-vessel disease 594 (9.3%) 498 (15%) <0.0001 164 (17%) <0.0001
Unprotected left main 356 (5.6%) 206 (6.1%) 0.34 73 (7.3%) 0.03
Lesions treated (n) 1.34 ± 0.63 1.40 ± 0.68 <0.0001 1.47 ± 0.76 <0.0001
Total stents (n) 1.69 ± 0.98 1.81 ± 1.06 <0.0001 1.95 ± 1.21 <0.0001
Total stent length (mm) 37.3 ± 24.3 40.5 ± 26.4 <0.0001 43.9 ± 29.6 <0.0001
Diabetes mellitus treatment
Oral hypoglycemic agent 2,330 (69%) 92 (9%)
Insulin 996 (100%)
Baseline medications
Cilostazol 207 (3.3%) 100 (3.0%) 0.43 44 (4.5%) 0.07
Statins 3,057 (48%) 1,687 (50%) 0.08 474 (48%) 0.87
Angiotensin-converting enzyme inhibitors 965 (15%) 597 (18%) 0.002 169 (17%) 0.14
Angiotensin II receptor blockers 2,283 (36%) 1,336 (40%) 0.0004 407 (41%) 0.002
β Blockers 1,692 (27%) 1,012 (30%) 0.0004 304 (31%) 0.009
Lesion characteristics
Lesions (n) 8,574 4,774 1,463
Target lesion location <0.0001 <0.0001
Left anterior descending 3,673 (43%) 1,944 (41%) 521 (36%)
Left circumflex 1,801 (21%) 1,010 (21%) 319 (22%)
Right 2,758 (32%) 1,610 (34%) 545 (37%)
Left main 278 (3.2%) 160 (3.4%) 61 (4.2%)
Saphenous vein graft 51 (0.6%) 43 (0.9%) 15 (1.0%)
Lesion length ≥30 mm 1,135 (13%) 741 (16%) 0.0004 270 (19%) 0.0001
Reference diameter <2.5 mm 2,268 (27%) 1438 (30%) <0.0001 490 (34%) <0.0001
In-stent restenosis 1,074 (13%) 625 (13%) 0.36 196 (13%) 0.36
Chronic total occlusion 734 (8.6%) 478 (10%) 0.006 136 (9.3%) 0.36
Severe calcium 656 (7.7%) 454 (9.5%) 0.0002 201 (14%) 0.0001
Bifurcation lesion 1743 (20%) 848 (18%) 0.0003 266 (18%) 0.054
Total stent length per lesion (mm) 28.1 ± 14.8 29.2 ± 15.8 <0.0001 30.3 ± 16.5 0.0001
Minimal stent size (mm) 2.91 ± 0.37 2.87 ± 0.37 <0.0001 2.83 ± 0.36 0.0001
Postdilation 3,755 (44%) 2048 (43%) 0.29 688 (48%) 0.01
Maximum inflation pressure (atm) 17.9 ± 4.4 18.3 ± 4.2 0.006 18.6 ± 4.4 0.0004

Data are presented as n (%) or mean ± SD (continuous variables).

Versus non-DM group.



The patients with DM-insulin and DM–non-insulin had more complex lesion and procedural characteristics, such as long lesions, small vessel size, severe calcification, longer total stent length, and greater final inflation pressure, than the patients without DM.


The cumulative incidence of the clinical events through 3 years is listed in Table 2 ( Supplemental Table 3 ). The crude incidence of serious cardiovascular events (i.e., all-cause death, myocardial infarction, and stroke) was significantly greater in the DM-insulin group than in the non-DM group. However, although the cumulative incidence of serious cardiovascular events in the DM–non-insulin group tended to be greater than that in the non-DM group, the difference did not reach statistical significance ( Figure 2 ). After adjusting for the confounders using the multivariate Cox proportional hazard model, the risk of DM-insulin versus non-DM for serious cardiovascular events remained significant (hazard ratio 1.12, 95% CI 1.03 to 1.23; p = 0.01). However, after adjusting for the confounders, a trend was no longer seen for the excess risk of DM–non-insulin versus non-DM for serious cardiovascular events (hazard ratio 1.02, 95% CI 0.96 to 1.09; p = 0.47; Supplemental Table 1 ).



Table 2

Clinical event rates through 3 years



























































































































Event Non-DM (n = 6,378) DM-Non-Insulin (n = 3,404) p Value DM-Insulin (n = 996) p Value
Death/myocardial infarction/stroke 649 (12.7%) 392 (13.8%) 0.057 185 (22.3%) <0.0001
All-cause death 412 (8.2%) 267 (9.3%) 0.01 132 (16.2%) <0.0001
Cardiac death 203 (3.8%) 135 (4.6%) 0.046 62 (8.1%) <0.0001
Associated with heart failure 58 (1.1%) 44 (1.5%) 0.08 19 (2.7%) 0.003
Associated with myocardial infarction 17 (0.3%) 19 (0.7%) 0.02 6 (0.6%) 0.07
Sudden death 76 (1.5%) 39 (1.4%) 0.85 25 (3.5%) 0.0007
Myocardial infarction 124 (2.7%) 61 (2.5%) 0.57 26 (2.9%) 0.14
Stroke 193 (3.7%) 110 (4.0%) 0.57 51 (6.6%) <0.0001
Stent thrombosis
Definite 57 (1.2%) 32 (1.2%) 0.84 12 (1.3%) 0.33
Definite/probable 65 (1.4%) 38 (1.4%) 0.67 13 (1.4%) 0.39
Definite/probable/possible 153 (3.1%) 84 (3.1%) 0.84 41 (5.1%) 0.001
Target lesion revascularization 535 (10.2%) 394 (13.8%) <0.0001 168 (19.3%) <0.0001
Coronary artery bypass graft 85 (1.8%) 57 (2.0%) 0.17 19 (2.4%) 0.13
Nontarget lesion revascularization 1,199 (22.1%) 815 (28.1%) <0.0001 274 (32.8%) <0.0001
Any revascularization 1,481 (27.2%) 999 (34.0%) <0.0001 346 (40.1%) <0.0001

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Dec 22, 2016 | Posted by in CARDIOLOGY | Comments Off on Comparison of Three-Year Clinical Outcomes After Sirolimus-Eluting Stent Implantation Among Insulin-Treated Diabetic, Non–Insulin-Treated Diabetic, and Non-Diabetic Patients from j-Cypher Registry

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