1. Cardiovascular Complications After Joint Replacement Surgery: A Crossroad in Anticoagulation Vincent D. Pellegrini Jr, MD Professor and Chair Department of Orthopedic Surgery Medical University of South Carolina Charleston, South Carolina Moderator: Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Director Venous Thromboembolism Research Group Staff Cardiologist Brigham and Women's Hospital Boston, Massachusetts Panelists: Kevin J. Bozic, MD, MBA William R. Murray Professor Vice Chair Department of Orthopaedic Surgery University of California, San Francisco

2. .. Timing of MI Following THR/TKR Surgery: A Nationwide Cohort Study Cumulative incidence rates of AMI: A: Patients undergoing THR B: Patients undergoing TKR 66,524 patients with THR, 28,703 patients with TKR, and 286,165 matched controls 99.1% had received thromboprophylaxis; 93%, LMWH. Study done in Denmark. Risk of AMI is substantially increased in the first 2 weeks after THR (25-fold) and TKR (31- fold) surgery compared with controls. Lalmohamed A, et al. [1] IMAGES NO LONGER AVAILABLE

3. ASA Physical Status Classification System American Society of Anesthesiologists. [2] ASA Physical Status Description 1A normal healthy patient 2A patient with mild systemic disease 3A patient with severe systemic disease 4A patient with severe systemic disease that is a constant threat to life 5A moribund patient who is not expected to survive without the operation 6A patient declared brain-dead whose organs are being removed for donor purposes

4. Minimizing CV Risk Principal advancement in joint replacement surgery has been improvement in anesthetic techniques, especially the use of regional anesthesia Stratify perioperative risk and ensure all modifiable risk factors have been optimized

5. VTE Prevalence After Major Orthopaedic Surgery Without Prophylaxis ProcedureDVT (Total, %) PE (Total, %) Fatal PE (%) Total hip replacement42-570.9-280.1-2.0 Total knee replacement 41-851.5-10 0.1-1.7 Geerts, WH, et al. [3]

6. … Types of VTE Prophylaxis: 2008 Survey Anderson FA, et al. [5]

7. Rivaroxaban (FDA-approved) RECORD1: Rivaroxaban 10 mg vs enoxaparin 40 mg for 5 weeks, THR a RECORD2: Rivaroxaban 10 mg for 5 weeks vs enoxaparin 40 mg for 10-14 days, THR b RECORD3: Rivaroxaban 10 mg vs enoxaparin 40 mg for 13-17 days, TKR c RECORD4: Rivaroxaban 10 mg vs enoxaparin 30 mg every 12 hours for 17 days, TKR d a. Eriksson BI, et al. [6] b. Kakkar AK, et al. [7] c. Lassen MR, et al. [8] d. Turpie AG, et al. [9] Novel Oral Anticoagulants: Trials in Major Orthopaedic Surgery

8. Apixaban: Pooled Results of ADVANCE-2 and ADVANCE-3 N = 8464 patients undergoing TKR (ADVANCE-2) and THR (ADVANCE-3) Not FDA approved for use in major orthopaedic surgery Raskob GE, et al. [10] ApixabanEnoxaparin Risk Difference (95% CI)P Value Efficacy Major VTE, %0.71.5 -0.8 (-1.2 to -0.3).001 Safety Major bleeding, %0.70.8 -0.02 (-0.4 to 0.4) -- Clinically relevant nonmajor bleeding, % 3.64.2 -0.6 (-1.4 to 0.3) --

9. Dabigatran: RE-MOBILIZE, RE-MODEL, RE-NOVATE: Pooled Analysis Not FDA approved for use in major orthopaedic surgery Enoxaparin Dabigatran 150 mg Dabigatran 220 mg EfficacyP Value Major VTE and VTE-related Mortality, % 3.33.8.913.0.20 Safety Major bleeding, %1.41.10.161.4.61 Major + clinically relevant nonmajor bleeding 5.05.6.585.6.56 Friedman RJ, et al. [11]

10. N = 12,729RivaroxabanEnoxaparin Hazard Ratio (95% CI)P Value Efficacy Composite of symptomatic VTE + all-cause mortality, % 0.51 0.48 (0.30-0.76).001 Safety: Bleeding Events Major bleeding, %0.30.2 1.62 (0.77-1.53).23 Major + clinically relevant nonmajor bleeding, % 2.82.5 1.17 (0.93-1.46).19 Turpie AGG, et al. [12] RECORD 1-4: Pooled Analysis

11. RivaroxabanEnoxaparin Hazard Ratio (95% CI) P Value Bleeding Events* Major bleeding0.3%0.2% 1.62 (0.77-1.53).23 Major + non-major clinically relevant bleeding 2.8%2.5% 1.17 (0.93-1.46).19 Any bleeding6.6%6.2% 1.07 (0.92-1.24).38 Turpie AG, et al. [12] *Day 12 ± 2 active treatment pool. RECORD 1-4: Pooled Analysis - Safety

12. Enoxaparin Rivaroxaban RECORD Study Design Mandatory bilateral venography R S U R G E R Y F O L L O W U P Evening before surgery Day 1 Double blind Last dose, day before venography 6-8 hours postsurgery Turpie AGG, et al. [12]

13. Summary Patients undergoing major orthopaedic surgery are at high risk for developing VTE/PE. Effective prophylaxis reduces this risk considerably. As new agents become more widely used, the use of the older oral anticoagulants, including LMWH and warfarin, is declining.

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