ACCP Cardiology PRN Journal Club March 29 th , 2016
Announcements • Thank you attending the ACCP Cardiology PRN Journal Club – Thank you if you attended before or have been attending • We have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/ • If there are any suggestions, please let us know.
Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial: Stopping vs. Continuing Aspirin before Coronary Artery Surgery Zachary Noel, PharmD, BCPS PGY2 Cardiology Resident University of Kentucky Healthcare Danielle Blais, PharmD, BCPS Cardiology Specialty Pharmacist Ohio State University Medical Center
Background: Effect of Aspirin on Platelets • Average platelet lifespan 7-10 days • Aspirin (ASA) prevents formation of thromboxane A2 via cyclooxygenase (COX) inhibition – Single 100mg dose provides maximal COX inhibition in 60 minutes – Effect persists for lifespan of platelet • Discontinuation of aspirin for ~3-5 days restores 50% of the active platelet pool Aspirin. Circulation . 2000;101:1206-1218
Background: Aspirin Use in Coronary Artery Disease • Aspirin is one of the cornerstone therapies for secondary prevention of coronary artery disease (CAD) • Interventional therapies for CAD include percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) • Optimal perioperative ASA dose and timing prior to CABG is not known – Risk of thrombotic events with discontinuation vs. risk of bleeding complications with continuation is not well defined
Perioperative Use of Aspirin in Coronary Artery Surgery Aspirin Use Perioperatively Restarting ASA within 24-48 hours post-op Delayed ASA Unknown whether continuing aspirin during associated Discontinuing initiation this period reduces thrombotic events, but with improved +2 -5 -4 0 likely associated associated may be associated with modest increases in graft patency, with greater with worse blood loss fewer ischemic thrombotic risk outcomes events, and mortality benefit
Background: Current Guidelines on Aspirin Use Prior to Coronary Surgery Guideline Year Recommendation Strength of Evidence Canadian 2011 Patients who are receiving ASA and require IB Cardiovascular CABG should continue ASA up to the time of Society Guidelines surgery ACCF/AHA Guidelines 2011 Aspirin should be administered preoperatively IB Society of Thoracic 2012 The interval between discontinuation of IIA Surgeons Guidelines antiplatelet drugs and operation is uncertain and depends on multiple factors related to patient drug responsiveness and thrombotic risk American College of 2012 Continue ASA around the time of surgery 2C Chest Physicians instead of stopping ASA 7 to 10 days before Guidelines surgery The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol. 2011; 27. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary. J Thorac Cardiovasc Surg . 2012; 143: 4-34. Antiplatelet Drugs in Cardiac and Noncardiac Operations. Ann Thorac Surg. 2012;94:1761 – 81. Douketis JD, et al. The perioperative management of antithrombotic therapy: Chest 2012; 133: Suppl: 299S-339S.
Background Trials Study Methods ASA Dose Results Preoperative Aspirin Retrospective cohort 81-325mg Reduction in in-hospital mortality Therapy Is Associated of patients receiving with no difference in bleeding With Improved ASA within 5 days of Postoperative Outcomes surgery in CABG Effect of Timing of Chronic Retrospective review Unknown No difference in mortality or Preoperative Aspirin of those taking ASA >6 thrombotic events but more Discontinuation in CABG days or ≤5 days before transfusions in the late use group CABG Aspirin and coronary Systematic review and 81-325mg Lower incidence of MI but higher artery surgery: a meta-analysis of pre- blood loss and surgical re-exploration systematic review and operative ASA use in those taking ASA before surgery meta-analysis prior to CABG Circulation . 2005;112 [suppl I]:I-286 – I-292. Circulation . 2011;123:577-583. British Journal of Anaesthesia . 2015, 376 – 85
ATACAS Trial • Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial • Designed to evaluate patients at risk for thrombotic complications undergoing elective CABG to determine whether: 1. ASA should be continued up until the day of CABG 2. TXA should be routinely used in CABG
Trial Design • Randomized, double-blind, multicenter, placebo-controlled trial • 2 x 2 factorial design with patient allocated in a 1:1:1:1 fashion Tranexamic Acid (TXA) + - Aspirin (ASA) + ASA ASA TXA Placebo - Placebo Placebo TXA Placebo
Methods • Inclusion criteria 1. Elective CABG (on- or off-pump) AND 2. Identified as elevated risk for major complications: • Age ≥ 70 years old • Left ventricular (LV) impairment • Concomitant valvular or aortic surgery • Chronic obstructive pulmonary disease • Repeat cardiac surgery • Renal impairment (SCr >2.0 mg/dl; CrCl<45 ml/min.) • BMI >25 kg/m 2 • Mean pulmonary arterial pressure >25 mm Hg • Peripheral vascular disease
Methods • Exclusion Criteria – ASA use within 5 days of surgery – Warfarin or clopidogrel use within 7 days of surgery – Glycoprotein IIb/IIIa antagonists within 24 hours of surgery – History of bleeding disorder – Thrombocytopenia – Severe renal impairment (serum creatinine >3.3 mg/dl; creatinine clearance <25 ml/min.) – Poor English language comprehension – Clinician preference towards antifibrinolytic therapy – Thromboembolic disease – Urgent CABG – Allergy of contraindication to ASA or TXA – Pregnancy
Procedures • Randomized in a 1:1 fashion to: – ASA 100mg 1-2 hours preoperatively OR - Placebo - Postoperative antiplatelet therapy was administered in accordance with local practices - Patients followed for 30 days
Standardization • Standardized protocols for heparinization, ACT goal, protamine reversal, and red blood cell transfusions were employed • Stepwise algorithm for excessive bleeding: 1. Protamine 50-100mg 2. Consider aprotinin 3. 5U platelet transfusion if platelets < 100,000/L 4. 5U fresh frozen plasma if INR >1.4 or fibrinogen <150 g/L 5. Cryoprecipitate if fibrinogen <100 g/L 6. Recombinant factor VIIa 90ug/kg, aprotinin, or desmopressin if above strategies ineffective
Endpoints Endpoints Criteria Primary Composite all-cause mortality Major ischemic complications defined as: • MI, stroke, PE, renal failure, bowel and major ischemic complications within 30 days infarction of operation Secondary All-cause mortality Ischemic complications Defined as: • MI, stroke, PE, renal failure, bowel infarction Bleeding complications and Bleeding complications defined as: • Major hemorrhage requiring blood transfusions reoperation for bleeding • Cardiac tamponade MI – myocardial infarction; PE – pulmonary embolism
Prespecified Subgroup Populations • Age • Sex • Diabetes • Prior MI • Unstable angina • European System for Cardiac Operative Risk Evaluation (EuroSCORE) • LV function • Bleeding risk during surgery • On-pump/off-pump procedure • Aortic total ischemic time
Statistical Analysis • Intent-to-treat analysis • Power calculations – 4484 patients needed to detect a 30% difference in the primary outcome (alpha 0.05; beta 0.1) – Prespecified goal to enroll 4600 patients
Results • Over 11,000 were screened but only 5700 were eligible • 2127 patients were enrolled between 2006 to 2013 TXA (1053) + - ASA (1047) + 517 523 - 525 524
Myles PS et al. N Engl J Med 2016;374:728-737
Results • Due to lower than expected enrollment rates but higher than anticipated primary outcome rates, the trial was stopped in July 2013 • Revised power analysis based on enrollment at that time could detect with 96% power a 30% relative risk reduction – Minimal between group difference that could be detected with 80% power was 24% lower relative risk
Baseline Characteristics
Characteristic ASA Placebo (N=1047) N=1053) Age (years) 66 66 Male (%) 872 (83) 858 (82) NYHA Classification (%) I 163 (16) 184 (17) II 580 (55) 578 (55) III 276 (26) 271 (26) IV 28 (3) 19 (2) EuroSCORE (% risk) 4.1 4.1 Comorbidities (%) Diabetes 347 (33) 368 (35) Hypertension 847 (80) 845 (80) Angina 744 (71) 756 (72) Heart failure 136 (13) 133 (13) MI within 90 days 75 (7) 83 (8) Previous cardiac surgery 17 (2) 14 (1)
Baseline Characteristics (cont.) Characteristic ASA Placebo (N=1047) (N=1053) Surgery Status (%) Non-elective 120 (12) 111 (11) On-pump surgery 1013 (97) 1022 (97) Off-pump surgery 34 (3) 29 (3) Isolated CABG surgery 775 (74) 801 (76) Combined CABG-valve surgery 233 (22) 209 (20) Surgical Characteristics Median number of grafts 3 3 Median cross clamp time (min.) 67 66 Duration of surgery (hrs) 3.8 3.8 Postoperative ASA use within 24 hours (%) 819 (78) 799 (76)
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