We investigated the impact of diabetes mellitus on long-term outcomes of percutaneous coronary intervention (PCI) in the drug-eluting stent era versus coronary artery bypass grafting (CABG) in a real-world population with advanced coronary disease. We identified 3,982 patients with 3-vessel and/or left main disease of 15,939 patients with first coronary revascularization enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2 (patients without diabetes: n = 1,984 [PCI: n = 1,123 and CABG: n = 861], and patients with diabetes: n = 1,998 [PCI: n = 1,065 and CABG: n = 933]). Cumulative 5-year incidence of all-cause death after PCI was significantly higher than after CABG both in patients without and with diabetes (19.8% vs 16.2%, p = 0.01, and 22.9% vs 19.0%, p = 0.046, respectively). After adjusting confounders, the excess mortality risk of PCI relative to CABG was no longer significant (hazard ratio [HR] 1.16; 95% confidence interval [CI] 0.88 to 1.54; p = 0.29) in patients without diabetes, whereas it remained significant (HR 1.31; 95% CI 1.01 to 1.70; p = 0.04) in patients with diabetes. The excess adjusted risks of PCI relative to CABG for cardiac death, myocardial infarction (MI), and any coronary revascularization were significant in both patients without (HR 1.59, 95% CI 1.01 to 2.51, p = 0.047; HR 2.16, 95% CI 1.20 to 3.87, p = 0.01; and HR 3.30, 95% CI 2.55 to 4.25, p <0.001, respectively) and with diabetes (HR 1.45, 95% CI 1.00 to 2.51, p = 0.047; HR 2.31, 95% CI 1.31 to 4.08, p = 0.004; and HR 3.70, 95% CI 2.91 to 4.69, p <0.001, respectively). There was no interaction between diabetic status and the effect of PCI relative to CABG for all-cause death, cardiac death, MI, and any revascularization. In conclusion, in both patients without and with diabetes with 3-vessel and/or left main disease, CABG compared with PCI was associated with better 5-year outcomes in terms of cardiac death, MI, and any coronary revascularization. There was no difference in the direction and magnitude of treatment effect of CABG relative to PCI regardless of diabetic status.
Coronary artery disease is a major cause of morbidity and mortality in patients with diabetes mellitus. In addition, diabetes has been shown to be a predictor for poor outcomes after both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Although several randomized controlled trials (RCTs) have compared the outcomes of PCI with CABG in patients with diabetes, these studies included less complex coronary lesions suitable for PCI. Thus, it is also important to compare the outcomes in a real-world population with more complex coronary lesions who were often excluded from RCTs. Furthermore, limited data have been available that compared the outcomes of PCI with CABG in the era of drug-eluting stent (DES). In the present study, we evaluated the 5-year outcomes of PCI compared with CABG stratified by diabetic status in patients with 3-vessel and/or left main coronary artery disease using a large observational database of patients with first coronary revascularization in Japan.
Methods
The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2 is a physician-initiated, non–company-sponsored, multicenter registry that enrolled consecutive patients who underwent first coronary revascularization in 26 centers in Japan from January 2005 to December 2007. The relevant ethics committees in all 26 participating centers (see Supplementary Data A ) approved the research protocol. Because of retrospective enrollment, written informed consent from the patients was waived. However, patients who refused participation in the study when contacted for follow-up were excluded.
The study design and patient enrollment in the registry have been previously described in detail. Of 15,939 patients enrolled in the registry, the study population for the present subanalysis of the CREDO-Kyoto PCI/CABG Registry Cohort-2 consisted of 3,982 patients with 3-vessel and/or left main coronary artery disease excluding those patients who refused study participation (n = 99), had concomitant noncoronary surgery (n = 609), had acute myocardial infarction (MI) (n = 4,892), and single- or double-vessel disease (n = 6,267). Of the 3,982 study patients, there were 1,984 patients without diabetes (PCI: n = 1,123, and CABG: n = 861) and 1,998 patients with diabetes (PCI: n = 1,065 and CABG: n = 933).
Diabetes mellitus (type 1 or type 2) was defined according to the American Diabetes Association as (a) history of either presence of classic symptoms of diabetes mellitus with elevation of plasma glucose (random of >200 mg/dl) or elevation of hemoglobin A1c of >6.5% or (b) currently on pharmacologic treatment (oral drugs and insulin).
Demographic, angiographic, and procedural data were collected from hospital charts according to the prespecified definitions by experienced research co-ordinators in an independent research organization (Research Institute for Production Development, Kyoto, Japan; see Supplementary Data B ). Definitions for clinical characteristics are described in the Supplementary Data C .
The Synergy between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) scores were available in 2,147 patients: 98% for PCI and 89% for CABG, respectively. The SYNTAX score was calculated using the SYNTAX score calculator (available at http://www.syntaxscore.com ) by a dedicated SYNTAX score committee (see Supplementary Data D ) in a blinded fashion to the clinical data. Intraobserver and interobserver variabilities of the SYNTAX score calculation in our group were previously reported. Cut-off values for SYNTAX score tertiles (low <23, intermediate 23 to 33, and high ≥33) were defined according to the analysis in the SYNTAX trial.
Collection of follow-up information was conducted mainly through review of inpatient and outpatient hospital charts by clinical research co-ordinators in the independent research organization. Additional follow-up information was collected through contact with patients, relatives, and/or referring physicians by sending mail with questions on vital status, additional hospitalizations, and antiplatelet medications. Death, MI, and stroke were adjudicated by the clinical event committee (see Supplementary Data E ).
The outcome measures evaluated in the present analysis included all-cause death, cardiac death, sudden death, stroke, MI, and any coronary revascularization. Death was regarded as cardiac in origin unless obvious noncardiac causes could be identified. Any death during the index hospitalization for coronary revascularization was regarded as cardiac death. Sudden death was defined as unexpected death in previously stable patients. MI was defined according to the definition in the Arterial Revascularization Therapy Study. Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 hours. Scheduled staged coronary revascularization procedures performed within 3 months of the initial procedure were not regarded as follow-up events but were included in the index procedure.
All continuous variables are expressed as the mean ± SD. Differences in baseline characteristics between the 2 groups were examined by unpaired t test and Fisher’s exact test. Cumulative probabilities for the outcomes were estimated by the Kaplan-Meier method, and the Kaplan-Meier curves of the PCI and CABG groups were compared using the log-rank test. The effects of PCI relative to CABG expressed as hazard ratio (HR) with 95% confidence intervals (CIs) were estimated by the stratified Cox proportional hazard models. The models include PCI or CABG as the covariate and quartiles of propensity scores and the 26 participating centers as the stratification variables. The propensity scores, which were the probabilities that a patient would undergo PCI, were estimated with multivariable logistic regression analyses including age, gender, body mass index, hypertension, dyslipidemia, current smoker, heart failure, mitral regurgitation grade 3/4, previous MI, previous stroke, peripheral arterial disease, atrial fibrillation, chronic kidney disease, hemodialysis, anemia, platelet count, chronic obstructive lung disease, liver cirrhosis, malignancy, emergency procedure, number of diseased vessel, left main disease, target chronic total occlusion, and target proximal left anterior descending coronary artery. These variables were consistent with the previous reports from the current registry. Continuous variables except age were dichotomized using clinically meaningful reference values or median values. All reported p values were 2 sided, and p values <0.05 were regarded as statistically significant.
All analyses were conducted by a statistician (ST) using SAS software, version 9.2 (SAS Institute Inc., Cary, North Carolina) and S-Plus, version 7.0 (Insightful Corp., Seattle, Washington). The investigators had full access to the data and take responsibility for its integrity and have read and agreed to the manuscript as written.
Results
CABG was more often chosen in patients with diabetes than without diabetes. SYNTAX score was significantly higher in patients with diabetes than without diabetes ( Table 1 ). The differences in baseline clinical and angiographic characteristics between the CABG and PCI groups were consistent regardless of diabetic status ( Tables 2 and 3 ). Hemoglobin A1c level was not different between the PCI and CABG groups in patients without diabetes. In patients with diabetes, hemoglobin A1c level was higher in the PCI group than in the CABG group. However, patients on insulin therapy were more common in the CABG group than in the PCI group.
| Variable | Diabetes mellitus | P value | |||
|---|---|---|---|---|---|
| No (N=1984) | Yes (N=1998) | ||||
| Age (years) | 70.3±9.2 | 68.3±9.3 | <0.001 | ||
| Age>75 | 763 | (38%) | 543 | (27%) | <0.001 |
| Men | 1482 | (75%) | 1406 | (70%) | 0.002 |
| Body mass index (kg/m 2 ) | 23.4±3.4 | 23.8±3.4 | <0.001 | ||
| Body mass index>25 | 584 | (29%) | 654 | (33%) | 0.02 |
| Diabetes treatment | |||||
| on oral drugs | 1180 | (59%) | |||
| on insulin therapy | 594 | (30%) | |||
| Hemoglobin A1c ∗ | 5.4±0.4 | 7.2±1.5 | <0.001 | ||
| Hypertension | 1693 | (85%) | 1724 | (86%) | 0.39 |
| Current smoker | 477 | (24%) | 499 | (25%) | 0.49 |
| Ejection fraction (%) † | 59.6±13.6 | 57.2±14.3 | <0.001 | ||
| Mitral regurgitation grade 3-4 + /4 + | 91 | (5%) | 95 | (5%) | 0.80 |
| Previous myocardial infarction | 394 | (20%) | 417 | (21%) | 0.43 |
| Heart failure | 323 | (16%) | 516 | (26%) | <0.001 |
| Atrial fibrillation | 265 | (13%) | 218 | (11%) | 0.02 |
| Previous stroke | 275 | (14%) | 319 | (16%) | 0.06 |
| Peripheral artery disease | 224 | (11%) | 291 | (15%) | 0.002 |
| eGFR (ml/min/1.73m 2 ) | 58.9±21.9 | 57.3±25.7 | 0.03 | ||
| eGFR <30 ml/min/1.73m 2 without dialysis | 101 | (5%) | 160 | (8%) | <0.001 |
| Hemodialysis | 94 | (5%) | 146 | (7%) | <0.001 |
| Anemia (hemoglobin <11.0 g/dl) | 290 | (15%) | 411 | (21%) | <0.001 |
| Platelet count < 100 x 10 9 /L) | 32 | (2%) | 42 | (2%) | 0.25 |
| Chronic obstructive pulmonary disease | 69 | (3%) | 45 | (2%) | 0.02 |
| Liver cirrhosis | 55 | (3%) | 69 | (3%) | 0.22 |
| Malignancy | 219 | (11%) | 218 | (11%) | 0.90 |
| Number of narrowed coronary arteries: | |||||
| 3 | 1425 | (72%) | 1553 | (78%) | <0.001 |
| Left main | 559 | (28%) | 445 | (22%) | <0.001 |
| descending artery | 1396 | (70%) | 1519 | (76%) | <0.001 |
| Chronic total occlusion | 609 | (31%) | 610 | (31%) | 0.92 |
| SYNTAX score ‡ | 26.5±10.5 | 27.4±11.2 | 0.02 | ||
| Low (< 23) | 713 | (38%) | 693 | (37%) | 0.21 |
| Intermediate (23-32) | 678 | (36%) | 656 | (35%) | |
| High (≥33) | 475 | (25%) | 526 | (28%) | |
| Number of target lesions or anastomoses | 2.5±1.2 | 2.7±1.2 | <0.001 | ||
| Percutaneous coronary intervention | 1123 | (57%) | 1065 | (53%) | 0.04 |
| Stent use | 1067 | (95%) | 1014 | (95%) | 0.83 |
| Drug-eluting stent use | 790 | (70%) | 812 | (76%) | 0.002 |
| Left internal thoracic artery use | 828 | (96%) | 905 | (97%) | 0.33 |
| Off-pump coronary bypass | 550 | (64%) | 589 | (63%) | 0.74 |
| Emergency procedure | 117 | (6%) | 107 | (5%) | 0.46 |
∗ Hemoglobin A1c levels were available in 1225 patients for non-diabetes (62%) and in 1691 patients for diabetes (85%), respectively.
† Ejection fractions were available in 1784 patients for non-diabetes (90%) and in 1800 patients for diabetes (90%), respectively.
‡ SYNTAX scores were available in 1864 patients for non-diabetes (94%) and in 1875 patients for diabetes (94%), respectively.
| Variable | Non-Diabetes | P value | |||
|---|---|---|---|---|---|
| PCI (N=1123) | CABG (N=861) | ||||
| Age (years) | 71.2±10.3 | 69.2±9.2 | <0.001 | ||
| >75 years | 477 | (42%) | 286 | (33%) | <0.001 |
| Men | 826 | (74%) | 656 | (76%) | 0.18 |
| Body mass index (kg/m 2 ) | 23.6±3.6 | 23.2±3.2 | 0.03 | ||
| Body mass index>25 | 346 | (31%) | 238 | (28%) | 0.21 |
| Hemoglobin A1c ∗ | 5.4±0.4 | 5.3±0.4 | 0.09 | ||
| Hypertension | 967 | (86%) | 726 | (84%) | 0.26 |
| Current smoker | 276 | (25%) | 201 | (23%) | 0.52 |
| Ejection fraction † (%) | 59.8±13.5 | 59.4±13.7 | 0.54 | ||
| Mitral regurgitation grade 3-4 + /4 + | 70 | (6%) | 21 | (2%) | <0.001 |
| Previous myocardial infarction | 202 | (18%) | 192 | (22%) | 0.02 |
| Heart failure | 176 | (16%) | 147 | (17%) | 0.40 |
| Atrial fibrillation | 101 | (9%) | 164 | (19%) | <0.001 |
| Previous stroke | 157 | (14%) | 118 | (14%) | 0.86 |
| Peripheral artery disease | 114 | (10%) | 110 | (13%) | 0.07 |
| eGFR (ml/min/1.73m 2 ) | 60.3±21.1 | 57.1±22.8 | 0.002 | ||
| eGFR <30 ml/min/1.73m 2 without dialysis | 52 | (5%) | 49 | (6%) | 0.16 |
| Hemodialysis | 44 | (4%) | 50 | (6%) | 0.29 |
| Anemia (hemoglobin <11.0 g/dl) | 154 | (14%) | 136 | (16%) | 0.19 |
| Platelet count <100 x 10 9 /L) | 15 | (1%) | 17 | (2%) | 0.26 |
| Chronic obstructive pulmonary disease | 40 | (4%) | 29 | (3%) | 0.82 |
| Liver cirrhosis | 32 | (3%) | 23 | (3%) | 0.81 |
| Malignancy | 130 | (12%) | 89 | (10%) | 0.38 |
| Number of narrowed coronary arteries: | |||||
| 3 | 913 | (81%) | 512 | (59%) | <0.001 |
| Left main | 210 | (19%) | 349 | (41%) | <0.001 |
| Proximal left anterior descending artery | 667 | (59%) | 729 | (85%) | <0.001 |
| Chronic total occlusion | 235 | (21%) | 374 | (43%) | <0.001 |
| SYNTAX score ‡ | 24.2±9.6 | 29.7±10.9 | <0.001 | ||
| Low (<23) | 510 | (46%) | 203 | (26%) | <0.001 |
| Intermediate (23-32) | 391 | (36%) | 285 | (37%) | |
| High (≥33) | 196 | (18%) | 279 | (36%) | |
| Number of target lesions or anastomoses | 2.0±1.0 | 3.2±1.0 | <0.001 | ||
| Stent use | 1067 | (95%) | |||
| Drug-eluting stent use | 790 | (70%) | |||
| Left internal thoracic artery use | 828 | (96%) | |||
| Off-pump coronary bypass | 550 | (64%) | |||
| Emergency procedure | 79 | (7%) | 38 | (4%) | 0.01 |
∗ Hemoglobin A1c levels were available in 625 patients for non-diabetes (56%) and in 600 patients for diabetes (70%), respectively.
† Ejection fractions were available in 972 patients for non-diabetes (87%) and in 812 patients for diabetes (94%), respectively.
‡ SYNTAX scores were available in 1097 patients for PCI (98%) and in 767 patients for CABG (89%), respectively.
| Variable | Diabetes mellitus | P value | |||
|---|---|---|---|---|---|
| PCI (N=1065) | CABG (N=933) | ||||
| Age (years) | 68.7±9.6 | 67.8±8.8 | 0.04 | ||
| >75 years | 316 | (30%) | 227 | (24%) | 0.007 |
| Male gender | 728 | (68%) | 678 | (73%) | 0.04 |
| Body mass index (kg/m 2 ) | 24.0±3.5 | 23.6±3.2 | 0.002 | ||
| Body mass index>25 | 374 | (35%) | 280 | (30%) | 0.02 |
| Diabetes treatment | |||||
| on oral drugs | 648 | (61%) | 532 | (57%) | 0.08 |
| on insulin therapy | 285 | (27%) | 309 | (33%) | 0.002 |
| Hemoglobin A1c ∗ | 7.3±1.5 | 7.1±1.4 | 0.02 | ||
| Hypertension | 938 | (88%) | 786 | (84%) | 0.01 |
| Current smoker | 264 | (25%) | 235 | (25%) | 0.84 |
| Ejection fraction † (%) | 57.3±14.1 | 57.1±14.4 | 0.74 | ||
| Mitral regurgitation grade 3-4 + /4 + | 63 | (6%) | 32 | (3%) | 0.01 |
| Previous myocardial infarction | 213 | (20%) | 204 | (22%) | 0.31 |
| Heart failure | 276 | (26%) | 240 | (26%) | 0.92 |
| Atrial fibrillation | 66 | (6%) | 152 | (16%) | <0.001 |
| Previous stroke | 189 | (18%) | 130 | (14%) | 0.02 |
| Peripheral artery disease | 162 | (15%) | 129 | (14%) | 0.38 |
| eGFR (ml/min/1.73m 2 ) | 58.5±25.8 | 55.5±25.4 | 0.005 | ||
| eGFR <30 ml/min/1.73m 2 without dialysis | 70 | (7%) | 90 | (10%) | 0.01 |
| Hemodialysis | 78 | (7%) | 68 | (7%) | 0.98 |
| Anemia (hemoglobin <11.0 g/dl) | 201 | (19%) | 210 | (23%) | 0.04 |
| Platelet count <100 x 10 9 /L) | 18 | (2%) | 24 | (3%) | 0.17 |
| Chronic obstructive pulmonary disease | 32 | (3%) | 13 | (1%) | 0.02 |
| Liver cirrhosis | 39 | (4%) | 30 | (3%) | 0.59 |
| Malignancy | 120 | (11%) | 98 | (11%) | 0.58 |
| Number of narrowed coronary arteries: | |||||
| 3 | 911 | (86%) | 642 | (69%) | <0.001 |
| Left main | 154 | (14%) | 291 | (31%) | <0.001 |
| Proximal left anterior descending artery | 679 | (64%) | 840 | (90%) | <0.001 |
| Chronic total occlusion | 225 | (21%) | 385 | (41%) | <0.001 |
| SYNTAX score ‡ | 24.4±9.6 | 31.2±11.9 | <0.001 | ||
| Low (<23) | 485 | (46%) | 208 | (25%) | <0.001 |
| Intermediate (23-32) | 377 | (36%) | 279 | (34%) | |
| High (≥33) | 188 | (18%) | 338 | (41%) | |
| Number of target lesions or anastomoses | 2.1±1.0 | 3.4±1.1 | <0.001 | ||
| Stent use | 1014 | (95%) | |||
| Drug-eluting stent use | 812 | (76%) | |||
| Left internal thoracic artery use | 905 | (97%) | |||
| Off-pump coronary bypass | 589 | (63%) | |||
| Emergency procedure | 58 | (5%) | 49 | (5%) | 0.85 |
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