Management of Bleeding with NOACS in Era of Specific Reversal Agents Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA 1 1

RE-LY: Bleeding with Antiplatelet Therapy Major Bleeding* 2.8 4.6 6.3 None ASA ASA + Clopidogrel HR=1.50 (95%CI: 1.22, 1.86) HR=2.34 (95%CI: 1.53, 3.57) HR=1.81 (95%CI: 1.46, 2.24) HR=2.16 (95%CI: 1.34, 3.47) HR=1.53 (95%CI: 1.21, 1.92) HR=2.39 (95%CI: 1.53, 3.74) WARFARIN 2.6 4.3 5.5 Dabi 150 2.2 3.8 5.4 Dabi 110 0 5 10 *Adjusted for age, gender, warfarin experience, SBP, CAD, CHF, TIA, HTN, DM, CrCl, Statins Dans AL, et al. Circulation. 2013; 127:634-640

How to Approach Combination Antithrombotic Therapy 3 Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of print]

Discontinuing NOACs Prior to Procedures Minor Bleeding Risk Endoscopy with biopsy, prostate or bladder biopsy, EPS/RFA for SVT, angiography, pacemaker or implantable cardioverter defibrillator (unless complex anatomic setting, such as congenital heart disease) Major Bleeding Risk Complex left-sided ablation (AF, VT), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, TURP, kidney biopsy Heidbuchel H, et al. Europace. 2015; 17(10):1467-1507

Practical Suggestions NOACs in CKD: Practical Suggestions Yearly CrCl ≥60 ml/min Every 6 mo. Elderly (≥75 yrs) or frail patients (especially if on dabigatran or edoxaban) Every X mo. CrCl ≤60 ml/min: recheck interval=CrCl/10 (Example: CrCl=30 ml/min; recheck every 3 months) 5 Heidbuchel H, et al. Europace. 2015; 17(10):1467-1507 5

Coagulation Tests Test Apixaban/Rivaroxaban/Edoxaban Dabigatran Qualitative Present / Absent PT rivaroxaban>edoxaban>apixaban [sensitivity depends on reagents] TT>aPTT Quantitative test Chromogenic anti-FXa [requires specific calibration to drug] Dilute TT, chromogenic anti-FIIa [requires specific calibration] Normal PT or aPTT does not guarantee absence of anticoagulant effect Quantitative tests are not standardized or approved Tripodi A, et al. Thromb Haemost 2011; 105:735-736 Barrett YC, et al. Thromb Haemost 2010; 104:1263-1271 van Ryn J, et al. Thromb Haemost 2010; 103:1116-1127 Stangier J, et al. Br J Clin Pharmacol 2007; 64:292-303 Cuker A, et al. JACC 2014; 64(11):1128-1139 6 6 6

Non-Specific Reversal Agents Only After D/C drug and Supportive Care (fluids / transfusions) Agent Clotting Factors Replaced Dose 4 Factor-PCC Factors II, VII, IX, X 25-50 units/kg 3 Factor-PCC Factors II, IX, X aPCC Factors II, VIIa, IX, X 80 units/kg rFVIIa FVIIa 90 ug/kg 7 7 7

Specific NOAC Reversal Agents Ruff CT, et al. Circulation. 2016 ; 134(3):248-261

REVERSE-AD: Idarucizumab Group A: Uncontrolled bleeding + dabigatran-treated Group B: Emergency surgery or procedure + dabigatran-treated N=300 0–15 minutes 90 days follow-up 0–24 hours Hospital arrival 5 g idarucizumab (two separate infusions of 2.5 g) Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 d Pre-1st vial 1 h Blood samples ~20 min Pollack CV, et al. Thromb Haemost 2015;114(1):198-205

Reversal of Dabigatran with Idarucizumab Median maximum reversal within 4 hours was 100% for both dTT and ECT (95% CI, 100–100), evident after first vial of idarucizumab dTT normalized in 98% and 93% of Group A and B patients, respectively* ECT normalized in 89% and 88% of Group A and B patients, respectively* Similar results with central laboratory aPTT and TT Pollack CV, et al. N Engl J Med 2015;373:511-20

Poor Outcomes Regardless of Reversal Pollack CV, et al. N Engl J Med 2015;373:511-20

ANNEXA - A & R: Andexanet Alpha Part I: Andexanet Bolus Only apixaban ________ rivaroxaban apixaban- 400mg andexanet rivaroxaban- 800mg andexanet R n ~ 35 per Xa Anti-fXa levels (Biomarker endpoint) Placebo Andexanet Bolus + Infusion (x 2hrs) Part 2: apixaban ________ rivaroxaban apixaban- 400mg + 480mg (4mg/min) andexanet rivaroxaban- 800mg + 960mg (8mg/min) andexanet R n ~ 35 per Xa Placebo Crowther M, ISTH 2015

Anti–FXa Activity before and after Andexanet Figure 1. Time Courses of Anti–Factor Xa Activity before and after Administration of Andexanet. Anti–factor Xa activity among persons who had received anticoagulation treatment with apixaban or rivaroxaban was measured before and after the administration of andexanet or placebo on study day 4. Dashed lines indicate the end of administration of the bolus or infusion. Panel A shows data from participants in the apixaban study (ANNEXA-A) who received andexanet, as a 400-mg intravenous bolus, or placebo; Panel B participants in the rivaroxaban study (ANNEXA-R) who received andexanet, as an 800-mg intravenous bolus, or placebo; Panel C participants in the apixaban study who received andexanet, as a 400-mg intravenous bolus plus a 4-mg-per-minute infusion for 120 minutes, or placebo; and Panel D participants in the rivaroxaban study who received andexanet, as an 800-mg intravenous bolus plus a 8-mg-per-minute infusion for 120 minutes, or placebo. Different scales along the x axis in each graph are used to enable visualization of the immediate, short-term dynamics as well as the longer-term dynamics of anti–factor Xa activity after andexanet treatment. The points on the graph represent the mean anti–factor Xa activity level, and I bars indicate the standard error. There was a significant difference (P<0.05) in the percent change in anti–factor Xa activity (relative to the pre-bolus activity level) between andexanet and placebo until 2 hours after administration of the bolus or infusion. Siegal DM et al. N Engl J Med 2015 Nov 11 [Epub ahead of prin]

Pre-PER977, 2.75 hrs post 60 mg p.o. edoxaban Ciraparantag Scale Bar: 1 inch BASELINE (Pre-edoxaban) ANTICOAGULATED (Pre-PER977, 2.75 hrs 60 mg edoxaban p.o.) REVERSED (1 hr post 100 mg i.v. bolus PER977) *** ** * Pre-edoxaban baseline Pre-PER977, 2.75 hrs post 60 mg p.o. edoxaban 1 hr post 100 mg i.v. PER977 Visual examination of blood clots from WBCT (whole-blood clotting time) assay pre- and postPER977. Top, clot fibrin structure pre- and post- PER977 (upper and lower photos represent lower and higher magnification). Bottom, computer algorithm-based quantification of clot fibrin diameter. 15 Ansell JE, et al. NEJM. 2014; 371(22):2141-2142

Management of NOAC-Related Bleeding Ruff CT, et al. Circulation. 2016 ; 134(3):248-261

Management of NOAC Treated Patients who Require Invasive Procedures Ruff CT, et al. Circulation. 2016 ; 134(3):248-261

Conclusions Serious bleeding is uncommon with NOACs 50% less compared to warfarin Many bleeds are preventable Stop unnecessary antiplatelet agents and NSAIDs For most bleeds: temporarily stopping anticoagulation and supportive measures are all that is needed Laboratory coagulation tests have limited utility PCCs are the preferred non-specific reversal agent Specific antidotes available for dabigatran and likely soon to be available for Fxa inhibitors: trauma, urgent surgery/procedures, stroke requiring lysis Anticoagulation should be restarted in the majority of patients who experience a bleed once stabilized 18 18 18