This study assesses demographic and clinical variables associated with perioperative and late stroke in diabetes mellitus patients after multivessel coronary artery bypass grafting (CABG). Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) is the largest randomized trial of diabetic patients undergoing multivessel CABG. FREEDOM patients had improved survival free of death, myocardial infarction, or stroke and increased overall survival after CABG compared to percutaneous intervention. However, the stroke rate was greater following CABG than percutaneous intervention. We studied predictors of stroke in CABG-treated patients analyzing separately overall, perioperative (≤30 days after surgery), and late (>30 days after surgery) stroke. For long-term outcomes (overall stroke and late stroke), Cox proportional hazards regression was used, accounting for time to event, and logistic regression was used for perioperative stroke. Independent perioperative stroke predictors were previous stroke (odds ratio [OR] 6.96, 95% confidence interval [CI] 1.43 to 33.96; p = 0.02), warfarin use (OR 10.26, 95% CI 1.10 to 96.03; p = 0.02), and surgery outside the United States or Canada (OR 9.81, 95% CI 1.28 to 75.40; p = 0.03). Independent late stroke predictors: renal insufficiency (hazard ratio [HR] 3.57, 95% CI 1.01 to 12.64; p = 0.048), baseline low-density lipoprotein ≥105 mg/dl (HR 3.28, 95% CI 1.19 to 9.02; p = 0.02), and baseline diastolic blood pressure (each 1 mm Hg increase reduces stroke hazard by 5%; HR 0.95, 95% CI 0.91 to 0.99; p = 0.03). There was no overlap between predictors of perioperative versus late stroke. In conclusion, late post-CABG strokes were associated with well-described risk factors. Nearly half of the strokes were perioperative. Independent risk factors for perioperative stroke: previous stroke, previous warfarin use, and CABG performed outside the United States or Canada.
The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) Trial investigated revascularization with coronary artery bypass grafting (CABG) versus percutaneous intervention (PCI) in patients with diabetes mellitus and multivessel coronary artery disease (CAD). In these patients, CABG was superior to PCI with respect to survival free of the composite end point of death, myocardial infarction (MI), or stroke and in overall survival. However, stroke was more common in the patients who underwent CABG, mitigating somewhat, although not eliminating, the benefit of CABG over PCI. If alterable risk factors for stroke could be found, the advantage of CABG could be enhanced. This report examines CABG-related strokes in patients with diabetes mellitus and multivessel CAD in the FREEDOM trial. This analysis is unique in 3 ways: (1) an exclusively diabetic population is studied; (2) the median follow-up is almost 4 years; and (3) patients were enrolled at over 100 high-volume centers.
Methods
This analysis is based on the data collected during the FREEDOM trial (FREEDOM ClinicalTrials.Gov number, NCT00086450 ) conducted from 2005 to 2010 at 140 international centers (funded by the National Heart, Lung, and Blood Institute). The design and results of the FREEDOM trial have been reported in detail. The study enrolled 1,900 patients with diabetes mellitus and multivessel CAD confirmed by angiography who had diameter stenosis of >70% in ≥2 major epicardial arteries involving at least 2 separate coronary artery territories but without significant left main coronary artery stenosis. Minimum follow-up for all patients was 2 years, and the first enrolled patients were followed for 6.75 years (median in survivors, 3.8 years). All critical cardiovascular (CV) outcomes (stroke, MI, CV death) were adjudicated by an independent medical clinical events committee.
Overall stroke was the primary outcome of this study. In addition to modeling overall stroke, we also separately analyzed 2 other outcomes: “perioperative” (≤30 days from surgery) and “late” (>30 days after surgery) strokes.
Stroke was defined as the presence of at least 1 of the following factors: a focal neurologic deficit of central origin lasting >72 hours or lasting >24 hours with imaging evidence of cerebral infarction or intracerebral hemorrhage, a nonfocal encephalopathy lasting >24 hours with imaging evidence of cerebral infarction or hemorrhage adequate to account for the clinical state, or retinal arterial ischemia or hemorrhage.
Independent predictors examined included demographic, baseline medical history and perioperative characteristics ( Table 1 ). The original focus of the report was on post-CABG strokes. However, after results suggested that a prespecified geographical region was an important predictor of a perioperative stroke, additional analyses were performed to corroborate this finding by comparing CV death and all-cause death by region.
| Variable | All subjects (n=898) | Stroke | ||
|---|---|---|---|---|
| No (n=862) | Yes (n=36) | P-value ∗ | ||
| Death | 82 (9%) | 68 (8%) | 14 (39%) | <0.001 |
| All strokes | 36 (4%) | NA | 36 (100%) | |
| Death at any time after stroke (N=36) | 14 (39%) | NA | 14 (39%) | |
| Perioperative stroke (≤ 30 days post-procedure) | 16 (2%) | NA | 16 (44%) | |
| Death at any time after perioperative stroke (N=36) | 9 (56%) | NA | 9 (56%) | |
| Clinical Site | 0.159 | |||
| US or Canada | 334 (37%) | 325 (38%) | 9 (25%) | |
| Other | 564 (63%) | 537 (62%) | 27 (75%) | |
| Age at procedure, years | ||||
| Mean±SD | 62.9±9.1 | 62.8±9.0 | 64.2±11.3 | 0.389 |
| Median (IQR) | 63.0 (56.2-70.0) | 63.0 (56.2-69.7) | 62.6 (55.7-74.9) | 0.595 |
| Women | 271 (30%) | 258 (30%) | 13 (36%) | 0.460 |
| Race | 0.660 | |||
| White | 692 (77%) | 665 (77%) | 27 (75%) | |
| Black | 54 (6%) | 52 (6%) | 2 (6%) | |
| Asian | 75 (8%) | 73 (8%) | 2 (6%) | |
| Other | 77 (9%) | 72 (8%) | 5 (14%) | |
| Systolic blood pressure (mmHg) (N=897) | (N=861) | (N=36) | ||
| Mean±SD | 133±19 | 134±19 | 128±19 | 0.099 |
| Median (IQR) | 130 (120-142) | 130 (120-142) | 127 (115-140) | 0.110 |
| Systolic blood pressure categories (mmHg) (N=897) | (N=861) | (N=36) | 0.049 | |
| <120 | 160 (18%) | 148 (17%) | 12 (33%) | |
| 120-159 | 641 (71%) | 621 (72%) | 20 (56%) | |
| ≥160 | 96 (11%) | 92 (11%) | 4 (11%) | |
| Diastolic blood pressure (mmHg) (N=897) | (N=861) | (N=36) | ||
| Mean±SD | 76.0±11.3 | 76±11 | 73±12 | 0.123 |
| Median (IQR) | 78.0 (70.0-80.0) | 78 (70-80) | 75 (68-80) | 0.290 |
| Diastolic blood pressure categories (mmHg) (N=897) | (N=861) | (N=36) | 1.000 | |
| <80 | 473 (53%) | 454 (53%) | 19 (53%) | |
| 80-99 | 394 (44%) | 378 (44%) | 16 (44%) | |
| ≥100 | 30 (3%) | 29 (3%) | 1 (3%) | |
| Low Density Lipoprotein (mg/dL) (N=826) | (N=794) | (N=32) | ||
| Mean±SD | 92.9±36.3 | 92.5±36.1 | 103.7±41.5 | 0.086 |
| Median (IQR) | 88.4 (66.0-114.0) | 88.0 (66.0-113.0) | 102.0 (71.5-131.6) | 0.115 |
| Low Density Lipoprotein ≥105mg/dL (N=826) | 274 (33%) | 258 (32%) | 16 (50%) | 0.054 |
| High Density Lipoprotein (mg/dL) (N=842) | (N=809) | (N=33) | ||
| Mean±SD | 39.5±11.6 | 39.6±11.6 | 38.6±11.3 | 0.871 |
| Median (IQR) | 38.0 (31.0-45.0) | 38.0 (31.0-45.0) | 38.0 (30.9-45.0) | 0.918 |
| Body Mass Index ( kg/m 2 ) (N=897) | (N=861) | (N=36) | ||
| Mean±SD | 29.8±5.3 | 29.9±5.4 | 28.0±4.2 | 0.035 |
| Median (IQR) | 29.1 (26.3-32.3) | 29.2 (26.3-32.3) | 27.6 (25.9-30.8) | 0.066 |
| Left Ventricle EF ( %) (N=630) | (N=606) | (N=24) | ||
| Mean±SD | 66.6±10.5 | 66.6±10.5 | 65.5±10.5 | 0.5907 |
| 1 Median (IQR) | 67.5 (60.6-74.0) | 67.5 (60.7-74.0) | 65.7 (60.3-72.2) | 0.441 |
| Syntax score (N=891) | (N=855) | (N=36) | ||
| Mean±SD | 26.0±8.8 | 26.0±8.8 | 26.1±7.9 | 0.420 |
| Median (IQR) | 26.0 (19.0-31.5) | 26.0 (19.0-31.5) | 25.5 (20.0-31.8) | 0.820 |
| Prior stroke | 26 (3%) | 21 (2%) | 5 (14%) | 0.003 |
| Current smoker | 150 (17%) | 142 (16%) | 8 (22%) | 0.362 |
| Previous Myocardial Infarction | 230 (26%) | 222 (26%) | 8 (22%) | 0.702 |
| Prior renal insufficiency | 52 (6%) | 46 (5%) | 6 (17%) | 0.014 |
| Prior peripheral vascular disease | 93 (10%) | 89 (10%) | 4 (11%) | 0.782 |
| Prior hypertension (history) | 762 (85%) | 731 (85%) | 31 (86%) | 1.000 |
| Prior arrhythmia (history) | 35 (4%) | 32 (4%) | 3 (8%) | 0.161 |
| Warfarin use | 7 (1%) | 5 (1%) | 2 (6%) | 0.029 |
| On cross-clamp during CABG | 685 (76%) | 654 (76%) | 31 (86%) | 0.228 |
| Cross-clamp time during CABG ( minutes) (N=685) | (N=654) | (N=31) | ||
| Mean±SD | 61.7±26.9 | 62.0±27.2 | 55.3±20.3 | 0.174 |
| Median (IQR) | 59.0 (41.0-78.0) | 59.0 (41.0-79.0) | 25.5 (20.0-70.0) | 0.239 |
| On cardiopulmonary bypass | 733 (82%) | 700 (81%) | 33 (92%) | 0.128 |
| Cardiopulmonary bypass time (minutes) (N=733) | (N=700) | (N=33) | ||
| Mean±SD | 90.0±34.7 | 90.2±35.1 | 84.2±22.6 | 0.327 |
| Median (IQR) | 85.0 (65.0-108.0) | 85.0 (65.0-109.0) | 51.0 (38.0-101.0) | 0.570 |
| Circulatory support, %on-pump | 732 (82%) | 698 (81%) | 34 (94%) | 0.046 |
| Number of grafts used | 0.437 | |||
| 1 | 12 (1%) | 11 (1%) | 1 (3%) | |
| 2 | 260 (29%) | 252 (29 %) | 8 (22%) | |
| 3 | 451 (50%) | 433 (50%) | 18 (50%) | |
| 4 | 150 (17%) | 141 (16%) | 9 (25%) | |
| 5 | 23 (3%) | 23 (3%) | 0 (0%) | |
| 6 | 1 (0%) | 1 (0.1%) | 0 (0%) | |
| 7 | 1 (0%) | 1 (0.1%) | 0 (0%) | |
| Bilateral mammary artery usage (N=893) | 110 (12%) | 104 (12%) | 6 (17%) | 0.434 |
| During CABG and Postoperative | ||||
| Atrial fibrillation † | 57 (6%) | 55 (6%) | 2 (6%) | 1.000 |
| Postoperative | ||||
| Myocardial infarction ‡ | 45 (5%) | 44 (5%) | 1 (3%) | 1.000 |
| Baseline or Postoperative | ||||
| Myocardial infarction ‡ | 264 (29%) | 255 (30%) | 9 (25%) | 0.709 |
∗ For continuous variables t-test for means, Wilcoxon test for test of medians; for frequency variables Fisher exact test used.
† Two subjects with atrial fibrillation suffered strokes. One occurred prior to hospital discharge while the other occurred after discharge.
The actual index procedure was used in all analyses. Follow-up time was defined as the time from the index procedure until the first stroke (some subjects experienced 1 postprocedural stroke). Subjects who did not have a stroke were censored at the last date of contact or death.
The relation between perioperative stroke (as well other CV outcomes and mortality) and covariates was examined using logistic regression; goodness of fit was assessed with calibration (calculated with the Hosmer–Lemeshow test) and discrimination. For long-term outcomes (i.e., overall stroke and late stroke), Cox proportional-hazards regression was used, accounting for time to event. Regression analyses were performed with and without covariates, including key demographic, baseline, and perioperative patient characteristics. Odds ratios (ORs) for short-term outcomes and hazard ratios (HRs) for longer-terms outcomes with 95% confidence intervals and p values associated with the Wald chi-square test were reported. Statistical significance was defined using a 2-sided critical value of p = 0.05. The proportional hazards assumption was evaluated using a test for nonproportionality based on Martingale residuals and interaction with time terms was used where appropriate. Stepwise regressions (with p = 0.15 as entry significance level and p = 0.05 as stay significance level) were used to inform selection of final models. Associations between geographical region and postprocedural stroke (and other key outcomes) were examined for regions defined as US and Canada versus the rest of the world. These regions were specified before analysis in this study and were motivated by the regional groupings in the recently reported PLATO and FREEDOM trials. All analyses were conducted with the use of SAS software version 9.3 (SAS Institute).
Results
A total of 1,900 subjects were randomized into the FREEDOM Trial of whom 898 underwent CABG as their index procedure (mean 62.9 ± 9.1 years, aged 34.3 to 85.6 years) including 627 men (70%, mean 62.4 ± 9.0 years, aged 34.3 to 82.1 years) and 271 women (30%, mean 63.9 ± 9.5 years, aged 36.7 to 85.6 years); 692 (77%) were white, 75 (8%) were Asian, and 54 (6%) were black.
Thirty-six patients had a postprocedural stroke (including 2 subjects who suffered 2 consecutive strokes). The time of stroke varied from the first month after procedure (n = 16; all perioperative strokes actually happened within the first 15 days) to 4.6 years after procedure. Of 82 subjects who died after procedure, 14 had a postprocedural stroke. Most (92%, n = 33) of the strokes were ischemic; 8% (n = 3) were hemorrhagic. Additionally, of the 36 strokes, 20 (56%) occurred with the patient on aspirin alone, 9 (25%) occurred with the patient on aspirin and clopidogrel, 1 (3%) with the patient on clopidogrel alone, and 1 (3%) with the patient on warfarin, whereas 6 (16%) occurred with the patient on no antiplatelet therapy.
The covariates examined in this study ( Table 1 ) included baseline demographic data and clinical history, perioperative characteristics, and pertinent postoperative variables. Univariate analyses of associations with stroke for all 3 outcomes (perioperative stroke, late stroke, and any stroke) are provided in Table 2 , which reports associations significant (p <0.05) for at least 1 of the 3 outcomes used in the multivariable models. Variables with a univariate p value ≤0.20 were examined in multivariable analysis.
| Perioperative stroke (≤30 days) | Late stroke (>30 days) | All strokes combined | ||||
|---|---|---|---|---|---|---|
| N | 898 | 864 | 898 | |||
| # of strokes | 16 | 20 | 36 | |||
| Variables | OR | P ∗ | HR | P † | HR | P † |
| Region § | 0.03 | 0.99 | 0.01 | |||
| US or Canada | Reference | Reference | Reference | |||
| Other | 9.10 | 0.99 | 9.05 | |||
| Region-Time interaction | NA | NA | 0.44 | 0.01 | ||
| Prior stroke at baseline | 5.11 | 0.04 | 5.65 | 0.006 | 5.33 | <0.001 |
| Baseline warfarin use | 9.73 | 0.04 | 8.36 | 0.04 | 8.72 | 0.003 |
| Baseline history of renal insufficiency | 3.92 | 0.04 | 3.23 | 0.06 | 3.50 | 0.005 |
| On cross-clamp during CABG | NA ‡ | 0.95 | 1.04 | 0.94 | 2.06 | 0.13 |
| Baseline highest tertile of Low Density Lipoprotein (≥105mg/dL) | 1.58 (0.58-4.29) | 0.37 | 2.96 | 0.03 | 2.16 | 0.03 |
| Baseline systolic blood pressure (mmHg) | 0.35 | 0.14 | 0.09 | |||
| <120 | 2.27 | 2.74 | 2.52 | |||
| 120-159 | Reference | Reference | Reference | |||
| ≥160 | 1.49 | 1.53 | 1.52 | |||
| Baseline diastolic blood pressure (mmHg) | 1.01 | 0.54 | 0.95 | 0.007 | 0.98 | 0.13 |
| Body Mass Index, (kg/m 2 ) | 0.91 | 0.11 | 0.93 | 0.13 | 0.92 | 0.03 |
| Circulatory support, on-pump | NA ‡ | 0.96 | 2.32 | 0.26 | 4.17 | 0.049 |
| Current smoker | 0.33 | 0.28 | 2.83 | 0.03 | 1.46 | 0.35 |
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