Comparison of Outcomes and Costs Associated With Aspirin ± Clopidogrel After Coronary Artery Bypass Grafting

Accepted Manuscript Title: Comparison of Outcomes and Costs Associated with Aspirin +/Clopidogrel after Coronary Artery Bypass Grafting Author: Ramin Ebrahimi, Sandeep Gupta, Brendan M. Carr, Muath Bishawi, Faisal G. Bakaeen, G. Hossein Almassi, Joseph Collins, Frederick L. Grover, Jacquelyn A. Quin, Todd H. Wagner, A. Laurie W. Shroyer, Brack Hattler PII: DOI: Reference:

S0002-9149(17)31926-4 https://doi.org/10.1016/j.amjcard.2017.12.010 AJC 23039

To appear in:

The American Journal of Cardiology

Received date: Accepted date:

23-6-2017 11-12-2017

Please cite this article as: Ramin Ebrahimi, Sandeep Gupta, Brendan M. Carr, Muath Bishawi, Faisal G. Bakaeen, G. Hossein Almassi, Joseph Collins, Frederick L. Grover, Jacquelyn A. Quin, Todd H. Wagner, A. Laurie W. Shroyer, Brack Hattler, Comparison of Outcomes and Costs Associated with Aspirin +/- Clopidogrel after Coronary Artery Bypass Grafting, The American Journal of Cardiology (2018), https://doi.org/10.1016/j.amjcard.2017.12.010. 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.

Comparison of Outcomes and Costs Associated with Aspirin +/- Clopidogrel after Coronary Artery Bypass Grafting Ramin Ebrahimi, MDa,b, Sandeep Gupta, MDc, Brendan M. Carr, MD, MSc,d, Muath Bishawi, MD, MPHc,e, Faisal G. Bakaeen, MDf, G. Hossein Almassi, MDg,h, Joseph Collins, ScDi, Frederick L. Grover, MDj,k, Jacquelyn A. Quin, MD, MPHl, Todd H. Wagner, PhDm,n, A. Laurie W. Shroyer, PhD, MSHAc,j, and Brack Hattler, MDo,p a

Department of Cardiology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; bDepartment of Medicine, University of California Los Angeles, Los Angeles, CA, USA; cResearch Service, Northport VA Medical Center, Northport, NY, USA; d Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA; eCardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, USA; fDepartment of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH, USA; gMilwaukee VA Medical Center, Milwaukee, WI, USA; hCardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; iCooperative Studies Program Coordinating Center and VA Medical Center, Perry Point, MD, USA; jResearch Service, VA Eastern Colorado Healthcare System, Denver, CO, USA; kCardiothoracic Surgery, the University of Colorado School of Medicine at the Anschutz Medical Campus, Aurora, CO, USA; lCardiac Surgery, VA Boston Healthcare System, West Roxbury, MA, USA; mVA Palo Alto Health Economics Resource Center, Menlo Park, CA, USA; nDepartment of Health Research and Policy, Stanford University, Stanford, CA, USA; oCardiology, VA Eastern Colorado Health Care System, Denver, CO, USA, pUniversity of Colorado School of Medicine at the Anschutz Medical Campus, Aurora, CO, USA *Contributed equally to this work. Running Title: Clopidogrel Post-CABG and Clinical Outcomes Financial Support: This study was supported by the Department of Veterans Affairs Cooperative Studies Program (CSP #517) located in Washington, D.C. Acknowledgements: This study was supported by the Cooperative Studies Program of the Department of Veterans Affairs (CSP #517), and in part by the Offices of Research and Development located at the Northport, Greater Los Angeles and Denver Veterans Affairs Medical Centers(VAMC). A special thanks go to Ms. Janet Baltz and Ms. Shirley Lu for their extraordinary support. Corresponding Author: Ramin Ebrahimi, MD, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd. (Mail code: 111E), Los Angeles, CA 90073, USA, Phone: 310-268-3109, Fax: 310-268-4178, E-mail: [email protected] Declaration of Conflict of Interest: Ramin Ebrahimi, MD is a Speaker for Sanofi-Aventis, Bristol Myers, Pfizer and Janssen, Regeneron

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Abstract: Optimal antiplatelet therapy after coronary artery bypass graft (CABG) surgery remains controversial. This study evaluated the role of aspirin and clopidogrel (DAPT) versus aspirin only (ASA) on post-CABG clinical outcomes and costs. In the VA Randomized On/Off Bypass (ROOBY) trial, clopidogrel use post-CABG was prospectively collected beginning in year two of this study to include 1,525 of the 2,203 original ROOBY patients who received aspirin post-CABG. Discretionarily, surgeons post-CABG administered either DAPT or ASA treatments. The ROOBY trial’s primary 30-day composite (mortality or perioperative morbidity), 1-year composite (all-cause death, repeat revascularization or non-fatal myocardial infarction), and costs were compared for these two strategies. Of the 1,525 subjects, 511 received DAPT and 1,014 ASA. DAPT subjects, compared to ASA subjects, had lower rates of preoperative left ventricular ejection fraction ≥ 45% (78.8% vs. 85.7%, p < 0.001), on-pump CABG (36.6% vs. 57.1%, p = 0.001) and endoscopic vein harvesting (30.0% vs. 42.8%, p < 0.001). ASA patients were more likely to have earlier aspirin administration and receive 325 versus 81 mg dosages. The 30-day composite outcome rate was significantly lower for DAPT patients compared to ASA patients (3.3% vs. 7.1%, p = 0.003), but the 1-year composite outcome was equal between the two groups (12.0% vs.12.0%, p = 1.0). At 1-year, there were no cost differences between the groups. Propensity analyses did not significantly alter the results. In conclusion, DAPT appeared safe and was associated with fewer 30-day adverse outcomes than aspirin only and with no 1year outcome or cost differences. Key Words: Clopidogrel, Aspirin, Coronary Artery Bypass Surgery, Clinical outcomes

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Optimal antiplatelet therapy after coronary artery bypass graft (CABG) surgery remains controversial.1 The 2011 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines recommend daily aspirin therapy as a class I recommendation after CABG.2This recommendation is based on data from approximately 30 years ago that demonstrated superior outcomes in CABG patients who received aspirin therapy postoperatively. In the past two decades, newer oral antiplatelet agents have been utilized in the care of patients with coronary artery disease. More recently, limited data from observational studies, sub-group analyses of large clinical trials, and single-center studies have provided inconsistent conclusions regarding the addition of a second antiplatelet agent to aspirin post-CABG to improve graft patency or clinical outcomes.3-7The goal of this study was to evaluate the role of dual antiplatelet therapy using aspirin with clopidogrel (DAPT) versus aspirin only (ASA) after CABG surgery in improving short-term and 1-year clinical outcomes. Differences in costs between these two strategies were also evaluated. Methods The detailed methods for the Department of Veterans Affairs (VA) Randomized On/Off Bypass (ROOBY) trial have been previously published.8 The ROOBY trial protocol (including this sub-study) was approved by participating VA Medical Centers’ Institutional Review Boards (IRB) and Research and Development Office Committees; informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization were obtained for each subject. In brief, ROOBY was a randomized, single-blinded, multi-center VA Cooperative Study conducted at 18 VA medical centers between February 2002 and May 2008.In the ROOBY trial 2,203 patients scheduled for elective or urgent CABG-only procedures were randomized to

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either an on-pump (n = 1,099) or off-pump (n = 1,104) approach to compare short-term and 1year outcomes. ROOBY patient data pertaining to demographics, co-morbidities, laboratory testing, pharmacotherapy, and clinical outcomes were gathered. In July of 2003, the ROOBY trial’s data collection forms were expanded to add new data elements including the preoperative and postoperative use of clopidogrel. At each site, the clinical use of DAPT or ASA was left to the discretion of the surgeon. The ROOBY trial’s primary 30-day endpoint was a composite of death or major complications (reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure) before discharge or within 30 days after CABG. The primary 1-year composite included death, repeat coronary revascularization, or non-fatal myocardial infarction. The ROOBY trial’s post-CABG costs incurred during the index hospitalization and cumulatively through one year were also compared between the two groups. Costs were obtained from VA Managerial Cost Accounting files, which tracked resources using activity based cost accounting methods. Following discharge, ROOBY patient assessments were coordinated every two months. These phone call activity logs were used to identify each participant’s use of nonVA services, with non-VA costs estimated based upon the average service costs. Based on the estimated distance traveled from each patient’s home to the medical center, travel costs were estimated based upon standardized transportation costs per mile using the 2010 United States Internal Revenue Service health care reimbursement rates. Baseline characteristic were compared using student’s t-test or analysis of variance for continuous variables and two-tailed Fisher’s exact test or Chi-squared test for categorical variables. The primary endpoints were compared using continuity-corrected chi-square tests.

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As DAPT versus ASA therapy was not randomized, both sensitivity and propensity analysis were performed to make sure the conclusions were robust. As physicians may have been biased against giving patients with post-CABG bleeding clopidogrel, a sensitivity analysis was performed excluding subjects who had reoperations for bleeding. A propensity analysis was run using selected variables based on clinical expertise and literature review. Variables included were: off-pump versus on-pump surgery approach, age, chronic obstructive pulmonary disease, renal dysfunction, diabetes, prior myocardial infarction, preoperative use of clopidogrel, preoperative use of aspirin, endoscopic versus open saphenous vein graft harvest, preoperative unstable angina, any target vessel characterized as “poor quality”, any conduit characterized as “poor quality”, red blood cell transfusion (intra- or perioperative), any transfusion,(intra- or perioperative), early postoperative aspirin use within first postoperative day, and early postoperative clopidogrel use within first postoperative day. Finally, multivariate logistic regression analysis was also used to identify risk factors associated with both of the primary 30day and 1-year composite outcomes. Similar to previously published ROOBY sub-studies, a pvalue of < 0.01 was established a priori to identify statistically significant associations to address potential concerns related to the multiple comparisons. All analyses were performed using SAS© version 9.0, Cary, N.C. Results Overall, 2,203 ROOBY patients were randomized to off-pump or on-pump CABG-only procedures. Data collection regarding post-CABG clopidogrel therapy was prospectively initiated in July 2003 with 1,525 (69.2%) of all ROOBY trial patients included in this subanalysis (Figure 1). Of these, 1,014 patients received ASA (435 off-pump and 579 on-pump) and

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511 patients received DAPT (324 off-pump and 187 on-pump) post-CABG and prior to discharge. Detailed comparison of patient’s baseline risks and post-CABG medical therapy between DAPT and ASA groups are shown in Table 1. In general, the baseline characteristics were similar between groups except that DAPT patients were more likely to have been on clopidogrel therapy before surgery, were less likely to have left ventricular ejection fraction ≥45%, were less frequently revascularized on pump, and had a lower rate of endoscopic vein harvesting. PostCABG, ASA patients had higher rates of early administration of aspirin and were more likely to receive aspirin 325 mg instead of 81mg compared to DAPT patients. Furthermore, DAPT patients were more likely to be discharged on lipid lowering medications. The 30-day composite adverse outcome rate was significantly reduced in the DAPT group versus the ASA group (p = 0.003) (Table 2). However, no difference in the 1-year composite outcome was seen between groups (p = 1.00). The 30-day composite outcome difference favoring DAPT over ASA was highly significant in the on-pump group of patients (p = 0.002); while there was a non-significant trend favoring DAPT in the off-pump group (p = 0.20). Propensity analyses did not alter the findings for 30-day or 1-year outcomes. Review of the individual components of the early composite outcome (Table 3) revealed a general trend favoring DAPT in all sub-components of the short-term outcome with the exception of stroke. Counterintuitively, the reoperation rate for bleeding trended lower in patients who received DAPT as compared to ASA (1.0% vs. 3.0% respectively, p = 0.02). Potential explanations for this unexpected finding include the fact that there were significantly higher rates of aspirin administration early post-CABG in the ASA group vs. the DAPT group (p < 0.001) as well as increased rates of high aspirin dosages at 325 mg (p < 0.001) administered in the ASA

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group versus the DAPT group (Table 1). Alternatively, this finding may represent a potential selection bias; namely, subjects who were taken to the operating room for bleeding were less likely to subsequently receive clopidogrel. A sensitivity analysis excluding the 35 subjects who had reoperation for bleeding revealed the same trend for better 30-day outcomes in those who received DAPT (2.4%) than ASA only (4.3%, p = 0.08). Propensity score matching using logistic regression identified the factors associated with a clinician’s choice to use dual antiplatelet therapy. These factors included an off-pump approach (p < 0.0001), lack of early administration of postoperative aspirin (p < 0.0001), and an endoscopic approach for harvesting saphenous vein grafts (p = 0.0032). Logistic regression analysis found being in the ASA group (p = 0.0056) and administration of aspirin after postoperative day one (p = 0.0015) were associated with increased risk of an adverse short-term composite event. Only pre-operative unstable angina (p = 0.0029) was associated with increased risk for the 1-year composite outcome. Total index hospitalization costs (with nursing, pharmacy, radiology, and surgery cost details provided) and total 1-year costs (with inpatient versus outpatient cost details provided) were not significantly different between groups (Table 4). Post-discharge pharmacy costs also were not significantly different. Discussion The utility of aspirin for prevention of coronary artery thrombosis dates back to 1950.9 Although the initial study to investigate the beneficial effects of aspirin on graft patency evaluated treatment with aspirin and dipyridamole or warfarin versus placebo post-CABG and failed to reveal any improvement in graft patency in either arm compared to placebo,10 subsequent studies showed improved graft patency associated with post-CABG aspirin

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use.11While other trials over the ensuing years questioned the value of aspirin use post-CABG,1214

more definitive studies in the following decade supported the early use of aspirin post-CABG

to improve graft patency and survival.15-17Aspirin therapy early post-CABG to improve graft patency is now the “standard of care” and advocated by national guidelines.3 Clopidogrel, an antiplatelet agent inhibiting the platelet P2Y12 receptor and belonging to the thienopyridine class, has been in use for approximately two decades in patients with established coronary artery disease and has been shown to be effective in reducing adverse clinical events in patients with acute coronary syndromes and those who receive coronary artery stenting.18-19However, the utility of routine clopidogrel use in patients undergoing CABG remains unknown. The data to support use of clopidogrel post-CABG to improve graft patency and clinical outcomes is primarily based on retrospective analyses and is inconsistent.5-7, 20-21As a result, there is insufficient and divergent data to guide physicians on choice of post-CABG antiplatelet therapy, timing of delivery, optimal dosage and duration of therapy. Additional limitations of the post-CABG anti-platelet literature include not differentiating between patients referred to CABG for acute coronary syndromes versus stable coronary disease, not mentioning the method of vein harvesting (standard versus endoscopic), and inconsistently providing data on the dosing and timing of both pre- and post-CABG clopidogrel and aspirin use. Many studies do not distinguish between on-pump and off-pump approaches nor do they report standard cardiac medication use or the use of oral anticoagulants. In this study, short-term outcomes were better with DAPT compared to ASA after CABG, and these findings persisted even after excluding patients who were taken back to the operating room for bleeding. One possible explanation for this finding may be the fact that a higher percentage of the patients who received postoperative clopidogrel received this therapy

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preoperatively as well. In these patients, the operation may have been delayed allowing the subjects to have a more complete preoperative evaluation and be better optimized prior to surgery. This potential explanation is supported by the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial sub-analysis where pre-CABG clopidogrel use in patients with acute coronary syndrome resulted in delayed timing of CABG but significantly improved 30-day outcomes.22 Other potential mechanisms for improved 30 day outcomes include reduction in thromboembolic events. The 1-year clinical outcomes were not significantly different between DAPT versus ASA. Although DAPT subjects were discharged on clopidogrel, the duration of clopidogrel therapy and adherence up to 1-year were unknown. Lack of post-discharge clopidogrel adherence may be responsible, in part, for the lack of documented 1-year DAPT benefits. These 1-year clinical outcomes are consistent with a prior ROOBY sub-analysis revealing no difference in graft patency at 1-year post-CABG between DAPT and aspirin only treatments.3 A key strength of this ROOBY trial sub-study was the prospectively collected clopidogrel and aspirin use data, as well as prospectively captured clinical outcomes. As with any observational study, however, this ROOBY trial sub-study has several limitations including the potential for a selection bias and for confounding. Given the unique characteristics of the ROOBY trial participants, these findings may have limited generalizability to non-Veteran patient populations and women. While DAPT versus ASA post-CABG is associated with better short-term outcomes, the data presented herein suggests that this potential benefit does not translate to a 1-year clinical benefit. Future studies are needed to further examine the role of dual antiplatelet therapy post-

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CABG and to assess the potential benefits of individualizing therapy based upon measurements of platelet inhibition.

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References 1. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O'Gara PT, Sabatine MS, Smith PK, Smith SC Jr. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68:1082-1115 2. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, Cigarroa JE, Disesa VJ,Hiratzka LF, Hutter AM Jr, Jessen ME, Keeley EC, Lahey SJ, Lange RA, London MJ, Mack MJ, Patel MR, Puskas JD, Sabik JF, Selnes O, Shahian DM, Trost JC, Winniford MD. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124:e652-e735 3. Ebrahimi R, Bakaeen FG, Uberoi A, Ardehali A, Baltz JH, Hattler B, Almassi GH, Wagner TH, Collins JF, Grover FL, Shroyer AL. Effect of Clopidogrel use post coronary artery bypass surgery on graft patency. Ann ThoracSurg 2014; 97:15-21 4. Mannacio VA, Di Tommaso L, Antignan A, De Amicis V, Vosa C. Aspirin plus Clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study. Heart 2012; 98:1710-1715 5. Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative Clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study. Eur J Cardiothorac Surg 2006; 29:190-195

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6. Lopez J, Morales C, Avanzas P, Callejo F, Hernandez-Vaquero D, Llosa JC. Long-term effect of dual antiplatelet treatment after off-pump coronary artery bypass grafting. J Cardiac Surg 2013; 28:366-372 7. Sun JC, Teoh KH, Lamy A, Sheth T, Ellins ML, Jung H, Yusuf S, Anand S, Connolly S, Whitlock RP, Eikelboom JW. Randomized trial of aspirin and Clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study. Am Heart J 2010; 160:1178-1184 8. Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E, Lucke JC, Baltz JH, Novitzky D. On-pump versus off-pump coronary-artery bypass surgery. New Engk J Med 2009; 361:1827-1837 9. Craven LL. Acetylsalicylic acid, possible preventive of coronary thrombosis. Ann West Med Surg 1950; 4:95 10. Pantely GA, Goodnight SH Jr, Rahimtoola SH, Harlan BJ, DeMots H, Calvin L, Rösch J. Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass: a controlled, randomized study. N Engl J Med 1979; 301:962966 11. Chesebro JH, Clements IP, Fuster V, Elveback LR, Smith HC, Bardsley WT, Frye RL, Holmes DR Jr, Vlietstra RE, Pluth JR, Wallace RB, Puga FJ, Orszulak TA, Piehler JM, Schaff HV, Danielson GK. A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency. N Engl J Med 1982; 307:73-78

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12. McEnany MT, Salzman EW, Mundth ED, DeSanctis RW, Harthorne JW, Weintraub RM, Gates S, Austen WG.The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts. J Thorac Cardiov Sur 1982; 83:81-89 13. Sharma GV, Khuri SF, Josa M, Folland ED, Parisi AF. The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency. Circulation 1983; 68:II218II221 14. Brown BG, Cukingnan RA, DeRouen T, Goede LV, Wong M, Fee HJ, Roth JA, Carey JS.Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 1985; 72:138-146 15. Chesebro JH, Fuster V, Elveback LR, Clements IP, Smith HC, Holmes DR Jr, Bardsley WT, Pluth JR, Wallace RB, Puga FJ, et al. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984; 310:209-214 16. Johnson WD, Kayser KL, Hartz AJ, Saedi SF. Aspirin use and survival after coronary bypass surgery. AM Heart J 1992; 123:603-608 17. Mangano DT, Multicenter Study of Perioperative Ischemia Research G. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002; 347:1309-1317 18. Committee CS. A randomised, blinded, trial of Clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329-1339 19. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494-502

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20. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706-1717 21. Gundry SR, Romano MA, Shattuck OH, Razzouk AJ, Bailey LL. Seven-year follow-up of coronary artery bypasses performed with and without cardiopulmonary bypass. J Thorac Cardiov Sur 1998; 115:1273-1277 22. Ebrahimi R, Dyke C, Mehran R, Manoukian SV, Feit F, Cox DA, Gersh BJ, Ohman EM, White HD, Moses JW, Ware JH, Lincoff AM, Stone GW. Outcomes following preoperative Clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2009; 53:1965-1972

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Figure 1. Study Flow Diagram

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Table 1 Patient characteristics and process of care details by post-operative clopidogrel use DAPT ASA n = 511* n = 1014† Age (mean ± SD) 62.4 ± 8.3 62.7 ± 8.3 Men 507 (99.2%) 1008 (99.4%) Current smoker 164 (32.1%) 345/1012 (34.1%) Diabetes Mellitus 239 (46.8%) 443 (43.7%) Peripheral arterial disease 74 (14.5%) 152 (15.0%) Hyperlipidemia 447/505 (88.5%) 882/1007 (87.6%) Hypertension 435 (85.1%) 901 (88.9%) Cerebrovascular accident 44 (8.6%) 66 (6.5%) Creatinine >1.5 mg/dL 45 (8.8%) 74 (7.3%) Previous heart surgery 0 (0%) 6 (0.6%) Previous myocardial infarction 145/497 (29.2%) 277/1010 (27.4%) Urgent CABG for acute 6 (1.2%) 17 (1.7%) myocardial infarction LVEF > 45% at baseline 395/501 (78.8%) 844/985 (85.7%) Sinus rhythm at baseline 492/507 (97.0%) 991/1013 (97.8%) Preoperative aspirin 422/508 (83.1%) 866/1007 (86.0%) Preoperative clopidogrel 112/509 (22.0%) 139/1007 (13.8%) Treatment arm On-pump 187 (36.6%) 579 (57.1%) Off-pump 324 (63.4%) 435 (42.9%) Endoscopic vein harvest 149/496 (30.0%) 410/957 (42.8%) Day of Aspirin initiation 0 or 1 236 (67.2%) 578 (78.7%) 3 43 (12.3%) 71 (9.7%) 3 20 (5.7%) 38 (5.2%) >3 52 (14.8%) 47 (6.4%) Day of clopidogrel initiation 0-1 185 (52.3%) 2 48 (13.6%) 3 30 (8.5%) >3 91 (25.7%) Aspirin dose 81 mg 222 (62.2%) 357 (47.9%) 325 mg 121 (33.9%) 379 (50.9%) All other 14 (3.9%) 9 (1.2%) Discharge Medications ACE inhibitor 264 (51.7%) 476/1012 (47.0%) Lipid lowering medications 446 (87.3%) 827/1012 (81.7%) Beta-blocker 472 (92.4%) 941/1012 (93.0%)

P value 0.47 0.74 0.45 0.28 0.82 0.62 0.04 0.14 0.31 0.19 0.50 0.45 < 0.001 0.35 0.15 < 0.001 < 0.001 < 0.001

< 0.001

< 0.001

0.09 0.005 0.68

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*N = 511 unless otherwise specified †N = 1014 unless otherwise specified

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Table 2 Comparison of 30-day and 1-year outcomes for patients by post-operative clopidogrel use DAPT ASA All Patients n = 511 n = 1014 30-day composite* 17 (3.3%) 72 (7.1%) 1-year composite†‡ 58/485 (12.0%) 118/981 (12.0%) 1-year repeat revascularization 24/485 (4.9%) 42/981 (4.3%) 1-year non-fatal MI 29/485 (6.0%) 64/981 (6.5%) 1-year death 13 (2.5%) 28 (2.8%) On-Pump 30-day composite 1-year composite 1-year repeat revascularization 1-year non-fatal MI 1-year death Off-Pump 30-day composite 1-year composite 1-year repeat revascularization 1-year non-fatal MI 1-year death

n = 187 3 (1.6%) 20/178 (11.2%) 10/178 (5.6%) 11/178 (6.2%) 3 (1.6%) n = 324 14 (4.3%) 38/307 (12.4%) 14/307 (4.6%) 18/307 (5.9%) 10 (3.1%)

P-value 0.003 1.00 0.59 0.73 0.87

n = 579 43 (7.4%) 50/554 (9.0%) 16/554 (2.9%) 27/554 (4.9%) 15 (2.6%)

0.002 0.38 0.10 0.56 0.58

n = 435 29 (6.7%) 68/427 (15.9%) 26/427 (6.1%) 37/427 (8.7%) 13 (3.0%)

0.20 0.20 0.41 0.20 1.00

* 30-day composite endpoint included death or major complications (reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure requiring dialysis) within 30 days of surgery or prior to discharge † 1-year composite endpoint included death from any cause, nonfatal myocardial infarction and repeat revascularization from surgery to 1 year. ‡ 1-year composite outcomes only include patients who completed 1-year follow-up with exception of death which was known for all patients.

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Table 3 Comparison of individual components of the 30-day composite outcome by post-operative clopidogrel use DAPT All Patients Reoperation -Reoperation for bleeding Cardiac arrest Coma >24 hrs New mechanical support Stroke Renal failure Operative death On-pump Reoperation Reoperation for bleeding Cardiac arrest Coma >24 hrs New mechanical support Stroke Renal failure Operative death Off-pump Reoperation -Reoperation for bleeding Cardiac arrest Coma >24 hrs New mechanical support Stroke Renal failure Operative death

n = 511

ASA

P-value

n = 1014

7 (1.4%) 5 (1.0%) 3 (0.6%) 0 (0.0%) 4 (0.8%) 5 (1.0%) 1 (0.2%) 1 (0.2%) n = 187 n = 579 2 (1.1%) 2 (1.1%) 1 (0.5%) 0 (0.0%) 1 (0.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) n = 324

38 (3.7%) 30 (3.0%) 16 (1.6%) 3 (0.3%) 12 (1.2%) 8 (0.8%) 10 (1.0%) 10 (1.0%)

0.01 0.02 0.14 0.56 0.60 0.77 0.11 0.11

23 (4.0%) 16 (2.8%) 8 (1.4%) 1 (0.2%) 6 (1.0%) 5 (0.9%) 5 (0.9%) 5 (0.9%)

0.06 0.27 0.70 1.00 1.00 0.34 0.34 0.34

15 (3.4%) 14 (3.2%) 8 (1.8%) 2 (0.5%) 6 (1.4%) 3 (0.7%) 5 (1.1%) 5 (1.1%)

0.11 0.05 0.20 0.74 0.74 0.30 0.25 0.25

n = 435 5 (1.5%) 3 (0.9%) 2 (0.6%) 0 (0.0%) 3 (0.9%) 5 (1.5%) 1 (0.3%) 1 (0.3%)

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Table 4 Costs incurred during index hospitalization and through 1-year DAPT ASA mean ± SD ($) mean ± SD ($) n = 509 n = 1012 Index CABG hospitalization costs Lab costs 1674 ± 1567 1604 ± 2551 Nursing costs 13237 ± 13275 12095 ± 23205 Pharmacy costs 1612 ± 1870 2058 ± 9090 Radiology costs 1094 ± 1319 1032 ± 2834 Surgery costs 11815 ± 11479 16244 ± 7515 All other costs 5462 ± 4840 5154 ± 11222 Total cost 34892 ± 25363 38186 ± 44655 Post discharge through 1-year costs Inpatient costs 10371 ± 29288 7467 ± 23081 Outpatient costs 15923 ± 19238 9638 ± 9667 Pharmacy costs 451 ± 1031 324 ± 1060 Total costs through 1-year Non-VA costs 2179 ± 15830 1893 ± 9723 VA costs 61186 ± 46733 55292 ± 52331 Total cost 63365 ± 49733 57185 ± 54013

99% CI of difference ($)

P-value

(-204 – 343) (-1275 – 3559) (-1214 – 321) (-213 – 337) (-5878 – -2981) (-757 – 1373) (-7932 – 1344)

0.51 0.22 0.13 0.56 <0.001 0.46 0.07

(-935 – 6744) (3946 – 8623) (-21 – 274)

0.05 <0.001 0.03

(-1691 – 2262) (-930 – 12720) (-999 – 13360)

0.71 0.03 0.03

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