Race/Ethnic Differences in the Risk of Hemorrhagic Complications Among Patients With Ischemic Stroke Receiving Thrombolytic Therapy

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1 Race/Ethnic Differences in the Risk of Hemorrhagic Complications Among Patients With Ischemic Stroke Receiving Thrombolytic Therapy Rajendra H. Mehta, MD, MS; Margueritte Cox, MS; Eric E. Smith, MD, MPH; Ying Xian, MD, PhD; Deepak L. Bhatt, MD, MPH; Gregg C. Fonarow, MD; Eric D. Peterson, MD, MPH; for the Get With The Guidelines-Stroke Program Background and Purpose Race/ethnic-related differences in safety of intravenous thrombolytic therapy have been shown in patients with myocardial infarction, but not studied in ischemic stroke. Methods Using data from the Get With The Guidelines (GWTG)-Stroke program (n=54 334), we evaluated differences in risk-adjusted bleeding rates (any, symptomatic intracerebral hemorrhage [sich], serious life-threatening [excluding sich], or other) and mortality in white (n=40 411), black (n=8243), Hispanic (n=4257), and Asian (n=1523) patients receiving intravenous tissue-type plasminogen activator (tpa) for acute ischemic stroke. Results Compared with white patients, overall adjusted hemorrhagic complications after tpa were higher in black (odds ratio, 1.14, 95% confidence interval, ) and Asian (odds ratio, 1.36, 95% confidence interval, ) patients. Overall adjusted bleeding complications in Hispanics were similar to those of whites. Increased risk of overall bleeding in Asians was related to higher risk of adjusted sich (odds ratio, 1.47, 95% confidence interval, ), whereas in blacks, it was related to higher risk of other bleeding. No significant race-related difference was noted in risk of serious or life-threatening bleeding or in overall mortality or death in patients with sich or any hemorrhagic complications. Conclusions In patients with stroke receiving tpa, hemorrhagic complications were slightly higher in blacks and Asians, but not in Hispanics compared with whites. Asians also faced significantly higher risk for sich relative to other race/ ethnic groups. Future studies are needed to evaluate whether reduction in tpa dose similar to that used in many Asian countries could improve the safety of tpa therapy in Asians in the United States with acute ischemic strokes while maintaining efficacy. (Stroke. 2014;45: ) Key Words: outcome race and ethnicity stroke thrombolysis Large, multicenter, randomized placebo-controlled clinical trials have demonstrated that early use of intravenous thrombolysis <4.5 hours of symptom onset reduces morbidity and mortality in selected patients with ischemic stroke. 1 5 However, these pivotal trials were conducted in largely white populations with low representation of racial or ethnic minorities. Yet, observational studies have raised concerns that the efficacy and safety of thrombolytic therapy may vary among racial and ethnic groups. For example, blacks treated with intravenous thrombolytic therapy for acute ST segment elevation myocardial infarction (STEMI) have higher bleeding risk and mortality relative to their white counterparts. 6,7 In contrast, Asians or Hispanics with STEMI have had similar responses as whites treated with fibrinolysis. 8,9 However, race-related differences in efficacy and safety of intravenous thrombolytic therapy have not been studied among patients with ischemic stroke. Using data on patients enrolled in the Get With The Guidelines (GWTG)-Stroke program, the goals of the current study were: (1) to determine comparative bleeding rates in whites, blacks, Asians, and Hispanics among those receiving intravenous tissue-type plasminogen activator (tpa) for acute ischemic stroke; (2) to investigate whether any differences in bleeding risk persist after adjusting for baseline clinical features; and (3) to evaluate relationships between race/ethnicity, bleeding events, and overall and cause-specific mortality. Methods GWTG-Stroke Program, Patient Population, and Definitions Details of the GWTG-Stroke program, including the methods of data collection and data definitions used, have been described previously Data from patients hospitalized with ischemic stroke at Received February 11, 2014; final revision received May 27, 2014; accepted May 28, From the Department of Internal Medicine/Division of Cardiology, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC (R.H.M., M.C., Y.X., E.D.P.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (E.E.S.); Department of Internal Medicine/ Division of Cardiology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA (D.L.B.); and Department of Internal Medicine/ Division of Cardiology, University of California, Los Angeles (G.C.F.). Correspondence to Rajendra H. Mehta, MD, Department of Internal Medicine/Division of Cardiology, Duke Clinical Research Institute, Box 17969, 2400 Pratt St, Durham, NC raj.mehta@dm.duke.edu 2014 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 2264 Stroke August 2014 GWTG-Stroke participating hospitals between April 1, 2009, and April 30, 2013 (n= ; 1922 sites) were included in this analysis. Patients were excluded if they were enrolled before April 1, 2009 (n= ), nonischemic stroke (n= ), in-hospital stroke (n=20 946), did not receive intravenous tpa (n= ), received intra-arterial tpa (n=3127), received tpa under experimental protocol (n=120), or >4.5 hours of symptom onset (n=1322), those with missing values of either race (n=136) or tpa complications (n=957), and those belonging to race/ethnic group other than white, black, Hispanic, or Asian (n=2248). The remaining patients formed the basis of this analysis. Information on race and ethnicity was obtained from patient selfdesignation as recorded by administrative personnel during the registration process, admitting providers in the medical record, or nurses in nursing intake forms. Race and ethnicity were collected as separate questions as recommended by the Office of Minority Health. We then classified the responses into the categories reported. Thus, white race/ethnicity are non-hispanic white patients, blacks are non- Hispanic blacks, Asians are non-hispanic Asians, and Hispanic patients are those of Hispanic ethnicity irrespective of race. Bleeding was collected in GWTG-Stroke program as complication of thrombolytic therapy and included symptomatic intracranial hemorrhage 36 hours (sich) and life-threatening serious systemic hemorrhage 36 hours (other than sich), and other serious bleeding. sich within the first 36 hours of treatment was defined as any neurological deterioration with evidence of ICH on repeat brain imaging (National Institute of Neurological Disorders and Stroke definition). 5 Serious systemic hemorrhage was defined as bleeding <36 hours of intravenous tpa (not including sich) and >3 U of packed RBC transfusion <7 days or before discharge (whichever was earlier), with a physician note attributing the bleeding problem as the reason for transfusion. Other serious bleeding was defined as any bleeding besides above that required additional medical intervention(s) or prolonged hospital stay. Outcomes of Interests Primary outcomes of interests were any complication of tpa (sich, serious systemic life-threatening hemorrhage, and other bleeding) as well as individual component of this composite end point, and all cause in-hospital mortality (total and in patients with tpa complication). Statistical Analyses Patients were categorized into 4 race/ethnicity-based groups: white, black, Hispanic, and Asian. Other demographic (besides race/ethnicity) and clinical variables, as well as hospital-level characteristics, were displayed. Continuous variables are reported as medians with 25th and 75th percentiles, and categorical variables as frequencies and percentages. Univariate comparisons were performed using Pearson χ 2 test for categorical variables and Wilcoxon rank-sum test for continuous variables. Multivariable logistic regression analysis using generalized estimating equation (exchangeable correlation structure) to account for within-hospital correlation was used to adjust for the confounding effect of the differences in baseline patient and hospital characteristics between the different race/ethnic groups on outcomes of interests. White race was used as a reference group for comparisons. Baseline factors in addition to race/ethnicity used to account for baseline differences included age, sex, arrival mode, medical history (smoking, diabetes mellitus, coronary artery disease or myocardial infarction, stroke/tia, atrial fibrillation/flutter, carotid stenosis, peripheral vascular disease, hypertension, and dyslipidemia) and findings on physical examination (time to treatment, systolic blood pressure, heart rate, and weight). In addition, hospital-level characteristics associated with outcomes were also included (geographic region, number of beds, academic versus not, annual stroke volume, and percentage of minority treated). Spline transformations were generated to assess whether continuous variables were related to outcomes in nonlinear fashion. Imputations for missing variables were imputed as the most frequent category for categorical variables and as median value for continuous variables with the exception of medical history variables, which were imputed as no. Most variables had missing rates <2%; notable exceptions included baseline features (body mass index, 27.7%; heart rate, 17.1%; systolic blood pressure, 15.1%; insurance type, 12.1%; arrival mode, 9.5%) and laboratory data (fasting blood glucose, 22.0%; prothrombin time, 18.6%; serum creatinine, 17.3%). We also performed a sensitivity analysis evaluating risk-adjusted outcomes of interest (adjusting for baseline patient and hospital characteristics and National Institutes of Health Stroke Scale [NIHSS]) among patients who had the NIHSS score available (n=50 231; 92.4%). Finally, we evaluated risk-adjusted mortality in patients who had any complication and in those who had sich after intravenous tpa. Odds ratios and 95% confidence intervals were generated (reference whites). For all analyses, a 2-tailed P value <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.3 software (SAS Institute, Cary, NC). Results Patient Demographics, History, and Presentation Among patients receiving tpa, whites were oldest relative to the other race/ethnic group. Although statistically significantly different because of large sample size, the door to needle time or the symptom onset to treatment time was not clinically significantly different among the 4 groups (Table 1). Compared with other race/ethnic groups, the prevalence of history of atrial fibrillation, prosthetic heart valves, coronary artery disease, peripheral vascular disease, carotid stenosis, and dyslipidemia was highest in whites; that of prior stroke, hypertension, congestive heart failure, or current smoking highest in blacks; and that of diabetes mellitus highest in Hispanics. In contrast, the prevalence of diabetes mellitus and hypertension was lowest in whites; atrial fibrillation lowest in blacks; and history of prosthetic heart valve, previous stroke, coronary artery disease, carotid stenosis, peripheral vascular disease, smoking, and heart failure lowest in Asians. Blacks were likely to present with the highest heart rate and systolic and diastolic blood pressures and, although they had the highest presenting serum creatinine, their presenting estimated glomerular filtration rate was highest given their younger age and highest body mass index. The NIHSS was highest among Asians compared with other race/ethnic groups. Blacks were more likely to be treated in large teaching hospitals but were least likely to be treated at certified primary stroke centers. In-Hospital Hemorrhagic Complications Any observed hemorrhagic complications after tpa were higher in Asians compared with whites and remained significantly higher even after adjustment for baseline confounding. Similarly, adjusted odds of sich was 1.5-fold and significantly higher among Asians compared with whites, whereas the adjusted odds for serious or life-threatening hemorrhage and other hemorrhagic complications was not statistically significantly different compared with whites (Tables 2 and 3). Blacks too had significantly higher adjusted odds of any hemorrhagic complications as well as other serious hemorrhagic complications compared with whites after tpa. Adjusted odds for sich or serious systemic life-threatening

3 Mehta et al Race, Stroke, Thrombolysis, and Outcomes 2265 Table 1. Baseline Characteristics Variable Overall White Black Hispanic Asian P Value n Demographics Age, y* 72 (59, 82) 74 (62, 83) 62 (52, 74) 68 (56, 79) 72, 61, 81) < Female sex Arrival mode and timelines Ambulance Arrival during nonregular hours < Onset to arrival time, min* 59 (39, 90) 59 (40, 90) 59 (39, 90) 58 (38, 90) 57 (40, 90) Door to needle time, min* 73 (55, 96) 73 (55, 95) 75 (56, 99) 73 (55, 97) 70 (55, 94) < Onset to treatment time, min* 142 (112, 174) 142 (112, 174) 145 (114, 175) 142 ( ) 140 (108, 172) Medical history Atrial fibrillation/flutter < Prosthetic heart valve Previous stroke/tia < Coronary artery disease < Carotid stenosis < Diabetes mellitus < Peripheral vascular disease < Hypertension < Current smoker < Dyslipidemia < Congestive heart failure < Presenting features and laboratory NIHSS score* 10 (6, 17) 10 (6, 17) 10 (6, 16) 11 (6, 17) 11 (6, 18) < Heart rate, bpm* 80 (69, 92) 79 (69, 91) 82 (71, 95) 81 (70, 94) 79 (69, 92) < Systolic blood pressure, mm Hg* 154 (137, 175) 154 (137, 174) 156 (138, 179) 155 (137, 177) 155 (138, 177) < Diastolic blood pressure, mm Hg* 83 (72, 96) 82 (71, 94) 88 (77, 102) 84 (73, 97) 84 (72, 96) < Body mass index, kg/m 2 * 27 (24, 32) 27 (24, 31) 29 (25, 34) 28 (25, 33) 25 (22, 28) < Fasting blood glucose, mg/dl* 119 (102, 148) 118 (102, 145) 119 (101, 154) 128 (106, 172) 129 (109, 164) < Prothrombin time, INR* 1.0 (1.0, 1.1) 1.0 (1.0, 1.1) 1.0 (1.0, 1.1) 1.0 (1.0, 1.1) 1.0 (1.0, 1,1) < Serum creatinine, mg/dl* 1.0 (0.8, 1,30) 1.0 (0.8, 1,2) 1.1 (0.9, 1.4) 1.0 (0.8, 1.20) 1.0 (0.8, 1.20) < Estimated GFR, ml/min* 71 (54, 88) 69 (52, 86) 78 (58, 98) 74 (56, 94) 73 (56, 89) < Hospital characteristics Teaching/academic < Rural < Number of beds* 379 (265, 561) 370 (258, 548) 445 (319, 701) 390 (280, 595) 349 (228, 489) < Number of stroke discharges < Ischemic stroke admissions/y* 212 (147, 318) 210 (144, 319) 230 (160, 319) 192 (140, 292) 212 (148, 305) < Volume of tpa administration/y* 18 (10, 27) 17 (10, 26) 19 (11, 29) 19 (11, 29) 18 (12, 25) < Primary stroke center certification < GFR indicates glomerular filtration rate; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; and tpa, tissue-type plasminogen activator. *Median (25th, 75th percentile). hemorrhagic complications were similar for blacks and whites. In contrast, there were no differences in the adjusted odds for any complication in Hispanics compared with whites treated with tpa. Sensitivity analyses restricting the patient population to that with information on NIHSS demonstrated results directionally similar to that of overall results for all race/ethnic comparisons relative to their white counterparts.

4 2266 Stroke August 2014 Table 2. Outcomes Variable Overall White Black Hispanic Asian P Value n tpa complications Any complication Symptomatic intracranial hemorrhage < Serious/life-threatening hemorrhage Other In-hospital mortality* Overall < Patients with intracranial hemorrhage Patients with any tpa complication Patients without any tpa complications < Length of stay >4 d < Discharge status Discharged home < Discharge ambulatory status < Unable to ambulate Ambulate with assistance Ambulate independently tpa indicates tissue-type plasminogen activator. *Excludes transfer outs. Discharge Status and Mortality After tpa Blacks were most likely whereas Asians least likely to be ambulating independently at discharge compared with other groups. Asians were least likely whereas Hispanics most likely to be discharged home compared with other groups (Tables 2 and 3). Overall observed in-hospital mortality was lower for blacks and Hispanics compared with whites, whereas Asians had similar observed in-hospital death compared with whites. However, once adjusted for baseline confounding, there were no significant racial differences in in-hospital mortality compared with whites. These results were changed slightly once accounted for NIHSS score (in addition to baseline and hospital characteristics), where blacks had lower adjusted odds for death relative to whites. Among those with ICH or any hemorrhagic complications, there were no differences in adjusted (for baseline and hospital characteristics and NIHSS) in-hospital mortality by race. Discussion Our study represents the largest study to date of race/ethnic differences in the risks of hemorrhagic complications after tpa therapy in acute ischemic stroke. Our data indicated that adjusted overall complications after tpa were higher in both Asian and blacks compared with white patients with stroke. In Asians, this increase was because of higher adjusted sich with similar risks of life-threatening serious or other complications compared with whites. In blacks, this increased risk of any complication after tpa was because of higher adjusted rates of other tpa complications compared with whites. The observed incidence of sich was significantly lower in blacks than in whites after tpa therapy. However, given their younger age and lower prevalence of comorbid conditions, once adjusted for baseline confounding, there was no significant difference in the odds of sich in blacks compared with whites, whereas serious or life-threatening hemorrhagic complications remained similar to that in whites. Hispanics had similar adjusted odds of tpa complications compared with whites. Overall adjusted in-hospital mortality was similar by race. Adjusted mortality in patients with sich (or any complications) after tpa for stroke was higher than in their counterparts without sich (or any complications). However, in patients with sich (or any complications), adjusted mortality for blacks, Hispanics, and Asians was similar to that in whites. One prior study used the National Inpatient Sample hospital discharge database for the period of 2001 to 2008 obtained from the Healthcare Cost and Utilization Project of the Agency of Healthcare Research and Quality and evaluated the race/ethnic disparities in the use and outcomes of patients with stroke receiving tpa. 13 This study found that the use of tpa in patients with stroke was higher for whites (2.3%) compared with blacks (1.8%; P<0.001) and Hispanics (2.0%; P<0.001), whereas it was similar for whites and Asians (2.3% versus 2.2%; P=0.07). Furthermore, they found that ICH rates were significantly higher in Asians compared with whites (odds ratio, 2.01; 95% confidence interval, ; P<0.001). In-hospital mortality was also significantly higher among Asians compared with whites (odds ratio, 1.22; 95% confidence interval, ; P=0.02). In contrast, the rates of ICH or in-hospital mortality did not differ significantly in blacks and Hispanics compared with whites. Similarly, a previous study from the GWTG registry evaluating the predictors of sich in patients receiving tpa for acute stroke has shown

5 Mehta et al Race, Stroke, Thrombolysis, and Outcomes 2267 Table 3. Adjusted Outcomes and Results of Sensitivity Analyses Variables Adjusted Odds Ratio* 95% Confidence Interval P Value Overall patients (n=54 334) Any tpa complications Blacks , Hispanics , Asians , 1.61 <0.001 Intracranial hemorrhage Blacks , Hispanics , Asians , 1.82 <0.001 Serious/life-threatening hemorrhage Blacks , Hispanics , Asians , Other complications of tpa Blacks , 1.47 <0.001 Hispanics , Asians , In-hospital mortality Blacks , Hispanics , Asians , Patients with NIHSS data (n=50 231) Any tpa complications Blacks , Hispanics , Asians , Intracranial hemorrhage Blacks , Hispanics , Asians , Serious/life-threatening hemorrhage Blacks , Hispanics , Asians , Other complications of tpa Blacks , Hispanics , Asians , In-hospital mortality Blacks , Hispanics , Asians , Death among patients with any tpa complications (n=4767) Blacks , Hispanics , Asians , Death in patients with intracranial hemorrhage after tpa (n=2576) Blacks , Hispanics , Asians , NIHSS indicates National Institutes of Health Stroke Scale; and tpa, tissue-type plasminogen activator. *Whites for all comparisons.

6 2268 Stroke August 2014 Asian race (compared with non-asian) to be associated with an independent risk of sich (odds ratio, 2.12; 95% confidence interval, ). 14 Although some of the findings of our study were consistent with other studies, our study allows more accurate identification of potential clinical confounders. Specifically, unlike in study by Nasr et al, 13 data on baseline prognostic clinical, presenting, and laboratory features (smoking status, body mass index, baseline heart rate and blood pressure, time to treatment, NIHSS) were available in GTWG-Stroke initiative, thus allowing for a relatively more robust risk adjustment in our study compared with that by Nasr et al. 13 The study evaluating independent predictors of sich from GWTG did not focus specifically on the racial differences in bleeding, but rather just reported increased odds of sich among Asians after tpa for acute stroke. 14 Finally, our study provided additional information on race/ethnic disparities in other serious systemic hemorrhagic complications among patients receiving tpa (besides sich) and in-hospital mortality associated with these complications that were not reported in the prior studies. The reasons for the increased risk of sich in Asians compared with whites with strokes receiving intravenous tpa are not known. Differences in measured confounders (including NIHSS) explained part, but failed to account fully for the increased risk of sich in Asians compared with whites treated with tpa for stroke in our study. Previous studies have suggested that a lower dose of tpa than the dose routinely used in the United States in Asians with stroke was associated with similar efficacy but with a lower risk of intracranial bleeding Alternatively, given that studies in acute STEMI population have failed to show higher risk of intracranial bleeding among Asians compared with whites despite higher dose of front-loaded regimen of tpa and concomitant intravenous anticoagulation, 8 this may suggest that perhaps rather than increased sensitivity to thrombolysis, weakening in the blood vessel wall or surrounding milieu potentially related to diffuse atherosclerosis, which increases the permeability of RBCs across the damaged blood vessels, may account for the higher risk of bleeding in Asian patients with stroke (who typically are older with higher comorbid conditions) after tpa. Our findings of no increased risk of sich among blacks compared with whites were also at odds with those reported in patients with acute STEMI. 6,7,19 Among patients with acute STEMI treated with front-loaded tpa, blacks have been consistently shown to be at an increased risk of ICH as well as other bleeding events compared with whites despite their younger age and higher body weight. Genetically inherent enhanced sensitivity to thrombolysis has been speculated by some as the mechanism underlying the increased risk of ICH among blacks. 6 However, given that no such increased risk was observed among more elderly black patients with stroke raises the possibility that perhaps other factors including front-loading of tpa in patients with acute STEMI (compared with a slower infusion of tpa over a longer period in stroke patients) or the routine concomitant intravenous anticoagulation in these patients may explain this disparate finding in the 2 ethnic populations. Our findings may have some implications. First, our data suggest that as in many Asian countries where the use of lower dose of tpa (0.6 mg/kg) <3 hours of stroke onset is a norm, this regimen may perhaps also be equally efficacious and likely safer for Asians compared with higher dose routinely used among white patients with stroke in the United States. This hypothesis needs to be tested in future study. Second, efficacy and safety of tpa for acute stroke tested and proven in large randomized trials consisting mostly of white patients should not be presumed to be true in other race/ethnic groups because these may vary. Enrollment of a large number of patients of diverse race/ethnic groups in clinical trials or comparative effectiveness studies through well-designed registries would allow better understanding of the efficacy/effectiveness and safety of tpa in the treatment of acute stroke in various race/ethnic groups. Limitations Patients and hospitals may not be entirely representative because hospital participation in GWTG-Stroke is voluntary. Nonetheless, the demographics of the GWTG-Stroke fee-forservice Medicare patient population are similar to the overall demographics of fee-for service Medicare patients with stroke. 20 Our study was observational and retrospective, and we are unable to account for the influence of missing or unmeasured confounders on study findings. Therefore, we recommend caution when inferring causal relationships from our data. We used a definition of sich based on the 1995 National Institute of Neurological Disorders and Stroke trial that attributes clinical worsening to ICH documented on computerized tomography or magnetic resonance imaging based on the investigator s judgment. This definition is different from the European Cooperative Acute Stroke Study (ECASS) II definition, in which clinical deterioration is defined as a 4-point increase in NIHSS, or the Safe Implementation of Thrombolysis in Stroke: A Multinational Multicentre Monitoring Study of Safety and Efficacy of Thrombolysis in Stroke (SITS-MOST) definition, in which, in addition, only parenchymal hemorrhages type 2 can be considered symptomatic. sich events were determined by the treating physicians, and neuroimaging data were not centrally reviewed. Thus, although we are unable to provide information on the rates of bleeds and outcomes in area of index stroke compared with those in the remote areas of the brain, the large difference in mortality between patients with and without sich suggests that the sich events were clinically relevant. Asians were categorized as one group, but in fact represent a heterogeneous population. Given that there was no systematic validation that all race/ethnicity were self-reported, it is possible that race/ethnicity group could be misclassified including that Hispanic patients were misclassified by sites as being non-hispanic white or non-hispanic black patients. Conclusions In patients with stroke receiving tpa, complications were slightly higher in blacks and Asians, but not in Hispanics compared with whites. Asian patients also faced higher risk for sich relative to other race/ethnic groups. Future studies are needed to evaluate whether reduction in tpa dose similar to that used in many Asian countries could improve the safety of tpa therapy in Asians in the United States with acute ischemic strokes while maintaining efficacy.

7 Mehta et al Race, Stroke, Thrombolysis, and Outcomes 2269 Sources of Funding The Get With The Guidelines (GTWG)-Stroke program is provided by the American Heart Association (AHA)/American Stroke Association. GTWG-Stroke has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol Myers Squibb/ Sanofi Pharmaceutical Partnership, Janseen Pharmaceuticals, and AHA Pharmaceutical Round. Disclosures Dr Bhatt discloses the following relationships advisory board: Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; chair: American Heart Association Get With The Guidelines Steering Committee; honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today s Intervention), WebMD (CME steering committees); other: Senior Associate Editor, Journal of Invasive Cardiology; data monitoring committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; research grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; unfunded research: FlowCo, PLx Pharma, Takeda. 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