Challenging Anticoagulation Case Studies. Earl J. Hope, M.D. Tower Health Cardiology

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2 Challenging Anticoagulation Case Studies Earl J. Hope, M.D. Tower Health Cardiology

3 Financial Disclosures Nothing to disclose

4 Objectives: 1. Understand indications for heparin bridging. 2. Recognize the role of anticoagulation reversal agents Focus of this talk is on stopping anticoagulation (Decisions about starting anticoagulation are much easier)

5 Oral Anticoagulants Vitamin K Antagonists (VKA) Effective Clearance Reversal Agents Warfarin (Coumadin) 2-3 days for INR <2.0 Vitamin K, FFP, 4-6 days to normalize INR Prothrombin Complex Concentrates (PCC) Direct Oral Anticoagulants (DOAC formerly NOAC) Direct Thrombin Inhibitor (DTI) Renal Clearance Reversal Agents Dabigitran (Pradaxa) 80% Idarucizumab (Praxbind) Dialysis Factor Xa Inhibitors Rivoroxaban (Xarelto) 35% Apixaban (Eliquis) 25% Adexanet alfa (FDA approval 5/3/18) Edoxaban (Savaysa) 35%

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7 Bleeding Risk versus Thromboembolic Risk Reassess need for and timing of surgery Reassess need for anticoagulant

8 Guidelines

9 John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

10 John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

11 Bleeding Risk Assessment Patient Factors HAS-BLED ( 3 denotes high bleeding risk) Hypertension (>160mmHg systolic) Abnormal Renal Function (Cr > 2.2) Abnormal Liver Function H/O bleeding Labile INR Elderly (>65 years) Antiplatelet or NSAID Rx ETOH/Drug use (>8 drinks/wk) Bleeding within 3 months Abnormal platelets INR > therapeutic range at time of procedure H/O bleeding with previous bridging H/O bleeding with previous similar procedure Procedural Factors (examples) Not Clinically Relevant Local anesthesia, soft tissue injection Low Risk Right Heart Cath, EGD, cataract, carpal tunnel release, breast biopsy, simple dental extraction, cystoscopy Uncertain Risk Cardiac cath (femoral), laparoscopy Intermediate/high Risk ORIF, TKR, Neuro/Spinal surgery Potential consequences of bleeding Intracranial/spinal procedures Spinal/epidural anesthesia

12 Take Home Message #1 Continue warfarin for patients with no significant bleeding risks undergoing low bleeding risk procedures.

13 BRUISE CONTROL Trial *681 patients (mostly in Canada) scheduled for elective pacemaker or ICD *Moderate to high risk of arterial thromboembolism or high risk of venous thromboembolism Examples: Mechanical mitral valve, bileaflet aortic valve and additional risk factor, Afib with CHADS2 2, Afib with stroke/tia within 3 months, DVT/PE within 3 months Continued warfarin Heparin Bridging Device Hematoma 3.5% 16% P<0.001 Patient Satisfaction P<0.001 (1-7 scale) David H. Birnie, et. Al. (2013) Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation. N Engl J Med 368:

14 John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

15 Low Procedural Bleeding Risk Uncertain, Intermediate, or High Procedural Bleeding Risk Increased Patient Bleeding Risk John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

16 Take Home Message #2 Generally hold DOAC s before procedures. Timing depends on specific drug, renal function, and procedural bleeding risk.

17 John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

18 Bridging Increases Risk of Perioperative Bleeding! BRIDGE Trial 1884 patients with Atrial Fibrillation who required cessation of warfarin Randomized to LMWH bridging or no bridging Excluded patient with mechanical heart valve or stroke/tia/systemic embolism within 3 months LMWH Bridging No bridging Thromboembolic Events 0.3% 0.4% Major Bleeding 3.2% 1.3% James D. Douketis, et. Al. Perioperative Bridging Anticoagulation in patients with Atrial Fibrillation. (2015) N Engl J Med. 373;

19 ORBIT-AF Trial Atrial fibrillation registry of over 7000 patients 2200 required cessation of oral anticoagulant RX for procedures Bridging used in 24% LMWH Bridging No Bridging Bleeding Events 5.0% 1.3% Composite endpoint* 13% 6.3% *Major bleeding, MI, Stroke, Systemic Embolism, Hospitalization, or death within 30 days Benjamin A. Steinberg, et.al. Use and Outcomes Associated with Bridging During Anticoagulation Interruptions in Patients with Atrial Fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). (2014) CirculationAHA

20 Take Home Message #3 Bridging with LMWH increases bleeding risk and should be reserved for patients at high risk for thromboembolism.

21 Stephen J. Rechenmacher, and James C. Fang JACC 2015;66: American College of Cardiology Foundation

22 John U. Doherty, et.al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of Cardiology Feb 2017, 69 (7)

23 Summary: Molecular Weight Heparin (LMWH - enoxaparin/lovenox) Bridging Check INR 7 days before procedure Stop Warfarin 5 days before procedure Start LMWH 3 days before procedure Stop LMWH 24 hours before procedure Check INR 24 hours before procedure, give vitamin K, 1-2 mg po if INR >1.5 Use Bridging Anticoagulation. In patients with high thromboembolic risk without major bleed or ICH within 3 mos. Atrial fibrillation with CHA2DS2-VASC score 7-8 Mechanical Heart valve Embolic stroke or PE within 3 months Consider Bridging Anticoagulation In patients with moderate thromboembolic risk and previous stroke or PE *Unfractionated heparin used inpatients with significant renal insufficiency *Generally no need for bridging with DOAC s, unless postoperative resumption of RX is delayed.

24 Take Home Message #4 For patients taking warfarin with life threatening or critical site bleeding, 4F-PCC provides the most immediate reversal of anticoagulation.

25 2017 by American College of Cardiology Writing Committee et al. JACC 2017;j.jacc

26 ANNEXA -4 Study Open-label study of patients with acute major bleeding while on factor Xa inhibitor minute bolus followed by 2 hour infusion. Interim analysis of 228 patients reported at ACC 2018 *Anti-Factor Xa activity reduced and sustained by 90% after bolus. *83% achieved effective hemostasis Stuart J. Connolly, et.al. N Engl J Med 2016; 375:

27 Take Home Message #5 DOAC Reversal agents are approved, but are specific to Direct Thrombin Inhibitors or Factor Xa Inhibitors.

28 Take Home Messages 1. Continue warfarin for patients with no significant bleeding risks undergoing low bleeding risk procedures. 2. Generally hold DOAC s before procedures. Timing depends on specific drug, renal function, and procedural bleeding risk. 3. Bridging with LMWH increases bleeding risk and should be reserved for patients at high risk for thromboembolism. 4. For patients taking warfarin with life threatening or critical site bleeding, 4F-PCC provides the most immediate reversal. 5. DOAC Reversal agents are approved, but are specific to Direct Thrombin Inhibitors or Factor Xa Inhibitors.