Accepted Manuscript Predictors of Stroke Associated with Coronary Artery Bypass Grafting in Patients with Diabetes Mellitus and Multivessel Coronary Artery Disease Michael J. Domanski, MD, Michael E. Farkouh, MD, Victor Zak, PhD, Steven Feske, MD, Donald Easton, MD, Jesse Weinberger, MD, Martial Hamon, MD, Jorge Escobedo, MD, MSc, Peter Shrader, MA, Flora S. Siami, MPH, Valentin Fuster, MD, PhD PII:

S0002-9149(15)00729-8

DOI:

10.1016/j.amjcard.2015.02.033

Reference:

AJC 21002

To appear in:

The American Journal of Cardiology

Received Date: 31 October 2014 Revised Date:

9 February 2015

Accepted Date: 11 February 2015

Please cite this article as: Domanski MJ, Farkouh ME, Zak V, Feske S, Easton D, Weinberger J, Hamon M, Escobedo J, Shrader P, Siami FS, Fuster V, Predictors of Stroke Associated with Coronary Artery Bypass Grafting in Patients with Diabetes Mellitus and Multivessel Coronary Artery Disease, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.02.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Predictors of Stroke Associated with Coronary Artery Bypass Grafting in Patients with Diabetes Mellitus and Multivessel Coronary Artery Disease Michael J. Domanski, MDa, Michael E. Farkouh, MDa,b, Victor Zak, PhDc, Steven Feske, MDd, Donald Easton, MDe, Jesse Weinberger, MDa, Martial Hamon, MDf, Jorge Escobedo, MD, MScg, Peter Shrader, MAc, Flora S Siami, MPH c, Valentin Fuster, MD, PhDa,h

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From: aCardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, bPeter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada, cthe New England Research Institutes, Boston, MA, dBrigham and Women’s Hospital, Boston, MA, eUniversity of California at San Francisco School of Medicine, San Francisco, CA, f University Hospital of Caen, Normandy, France, gUnidad de Investigación en Epidemiología Clínica, Instituto Mexicano del Seguro Social, Mexico, and hCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

Address for Correspondence: Michael Domanski, MD Icahn School of Medicine at Mount Sinai One Gustav L. Levy Place

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New York, New York 10029

[email protected]

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Office Telephone: 212-241-4619; Cell 646-438-2019

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Abstract This study assesses demographic and clinical variables associated with perioperative and late stroke in diabetes mellitus patients following multivessel coronary artery bypass grafting (CABG). FREEDOM is

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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 following CABG compared to percutaneous intervention (PCI). However, the stroke rate was greater following

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CABG than PCI. We studied predictors of stroke in CABG-treated patients analyzing separately overall, perioperative (≤30 days post-surgery), and late (>30 days post-surgery) stroke. For long–term outcomes

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(overall stroke and late stroke), Cox proportional-hazards regression was used, accounting for time to event, and logistic regression was used for perioperative stroke. Results: independent perioperative stroke predictors were prior stroke (OR = 6.96 [1.43-33.96.03]; p = 0.02), warfarin use (OR = 10.26 [1.1033.96]; p = 0.02), and surgery outside the United States or Canada (OR = 9.81 [1.28-75.40]; p = 0.03). Independent late stroke predictors: renal insufficiency (HR = 3.57 [1.01-12.64]; p = 0.048), baseline

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LDL≥105 mg/dL (HR = 3.28 [1.19-9.02]; p= 0.02); and baseline diastolic blood pressure (each one mmHg increase reduces stroke hazard by 5%; HR = 0.95 [0.91-0.99]; p = 0.03). There was no overlap between predictors of perioperative versus late stroke. In conclusion, late post-CABG strokes were

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associated with well described risk factors. Nearly half of the strokes were perioperative. Independent risk factors for perioperative stroke: prior stroke, prior warfarin use and CABG performed outside the

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United States or Canada.

Keywords: coronary artery disease, CABG, FREEDOM, stroke

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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

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multivessel coronary artery disease (CAD).1,2 In these patients, CABG was superior to PCI with respect to survival free of the composite endpoint of death, myocardial infarction (MI) or stroke and in overall survival.1,2 However, stroke was more common in the CABG patients, mitigating somewhat, though not

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eliminating, the benefit of CABG over PCI. If alterable risk factors for stroke could be found, the

advantage of CABG could be enhanced. This article examines CABG-related strokes in patients with

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diabetes mellitus and multivessel CAD in the FREEDOM trial. This analysis is unique in three 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

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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

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have been reported in detail.1,2 The study enrolled 1900 patients with diabetes mellitus and multivessel CAD confirmed by angiography who had diameter stenosis of >70% in ≥2 major epicardial arteries

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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 among survivors, 3.8 years). All critical cardiovascular (CV) outcomes (stroke, myocardial infarction, 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.

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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

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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

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characteristics (Table 1). The original focus of the article was on post-CABG strokes. However, after results suggested that a pre-specified geographical region was an important predictor of a perioperative

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stroke, additional analyses were performed to corroborate this finding by comparing cardiovascular death and all cause death by region.

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 more than one post-procedure stroke). Subjects who did not have a stroke were censored at the last date of contact or death.

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The relationship 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

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stroke and late stroke) Cox proportional-hazards regression was used, accounting for time to event.3 Regression analyses were performed with and without covariates, including key demographic, baseline

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and perioperative patient characteristics. Odds ratios (ORs) for short-term outcomes and hazard ratios (HR) 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 non-proportionality based on Martingale residuals4 and interaction with time terms were 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 post-procedure stroke (and other

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key outcomes) were examined for regions defined as US and Canada versus the rest of the world. These regions were specified prior to analysis in this study and were motivated by the regional groupings in the recently reported PLATO5 and FREEDOM trials. All analyses were conducted with the use of SAS

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software version 9.3 (SAS Institute). RESULTS

A total of 1900 subjects were randomized into the FREEDOM Trial of whom 898 underwent CABG

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as their index procedure (mean 62.9 ± 9.1 years, aged 34.3 to 85.6) including 627 men (70%, mean 62.4 ± 9.0 years, aged 34.3 to 82.1) and 271 women (30%, mean 63.9 ± 9.5 years, aged 36.7 to 85.6); 692

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(77%) were white, 75 (8%) Asian and 54 (6%) were black.

Thirty-six patients had a post-procedure stroke (including 2 subjects who suffered 2 consecutive strokes). The time of stroke varied from the first month post-procedure (n = 16; all perioperative strokes actually happened within the first 15 days) to 4.6 years post-procedure. Of 82 subjects who died postprocedure, 14 had a post-procedure stroke. Most (92%, n = 33) of the strokes were ischemic; 8% (n = 3)

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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, one (3%) with the patient on clopidogrel alone, and one (3%) with the patient on warfarin, while 6 (16%) occurred with the patient on no

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antiplatelet therapy.

The covariates examined in this study (Table 1) included baseline demographic data and clinical

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history, perioperative characteristics and pertinent postoperative variables. Univariate analyses of associations with stroke for all three outcomes (perioperative stroke (second column), late stroke (third column) and any stroke (fourth column) are shown in Table 2, which reports associations significant (P

Predictors of stroke associated with coronary artery bypass grafting in patients with diabetes mellitus and multivessel coronary artery disease.

This study assesses demographic and clinical variables associated with perioperative and late stroke in diabetes mellitus patients after multivessel c...
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