Antithrombotic therapy and oral surgery Michael B Streiff, MD FACP Professor of Medicine and Pathology Medical Director, Johns Hopkins Anticoagulation Service Chairman, VTE Guideline Committee ,National Comprehensive Cancer Network President, Medical and Scientific Advisory Board, National Blood Clot Alliance

Disclosures- Michael B. Streiff, MD Consulting Bayer CSL Behring Daiichi-Sankyo Janssen Pfizer Portola Educational Grants Covidien Research support AHRQ Boehringer-Ingelheim Janssen NIH/NHLBI PCORI Portola Roche

Scope of the Problem In 2009 548 million dental procedures performed annually Over 50% of Americans take daily aspirin Over 2 million MI and stroke annually in US More than 30 million warfarin prescriptions each year Manski, R.J. and Brown, E. AHRQ Statistical Brief #368. April 2012.. Williams CD et al Am J Prev Med 2015; AHA/ASA Annual stats 2018; Wysowski DK et al Arch Intern Med 2007

Plan for Procedures: Thromboembolism Risk Stratification Mechanical Heart Valve Atrial Fibrillation Venous Thromboembolism High (> 10% per year ATE or 10% per month VTE) Mitral valve, Caged-ball or tilting disk valve, recent stroke, systemic embolism CHADS2 score 5 or 6, Recent stroke, systemic embolism, rheumatic valve disease Recent VTE (< 3 months) High risk thrombophilia (protein C,S, AT deficiency, APS, etc.) Intermediate (4-10%) Bileaflet aortic valve with stroke risk factors CHADS2 score 3 or 4 VTE within past 3-12 months, recurrent VTE, active cancer, Low risk thrombophilia Low (< 4%) Bileaflet aortic valve without stroke risk factors CHADS2 score of 0-2 (no prior stroke or systemic embolism) VTE > 12 months ago Spyropoulos AC et al. J Thromb Haemost 2016

Plan for Procedures: Procedural Bleeding Risk Stratification Perioperative Bleeding Risk Surgery/Procedure Very high Neurosurgery (intracranial/spinal) Urologic or cardiac surgery High Major cancer surgery Renal biopsy Large polyp resection Orthopedic surgery Head and neck surgery Major intra-abdominal or thoracic surgery Low Laparoscopic cholecystectomy Coronary angiography Arthroscopy Bronchoscopy with biopsy Very Low Minor dermatologic procedure Cataract removal NCCN Guidelines 2018

A Systematic Review of Peri-procedural Anticoagulation Review of 34 studies (21 prospective, 1 RCT) Therapeutic AC in 20 studies (57%) Last pre-op LMWH dose 24+ hrs. before surgery (36%), 12-23 hrs. (36%) LMWH restart within 24 hrs (55%), > 24 hrs (16%) Bridging increases bleeding complications Siegal D et al. Circulation 2012

The Bridge Trial (Standard Risk AF) Warfarin Warfarin- restart POD 1 Dalteparin 100 units/kg q12h N=950 Low risk-within 24 hrs. R High Risk-with 48-72 hrs. Day - 5 Placebo N=934 Procedure Follow up 30 days Pre-op Bridge Day -3 Randomized double-blind placebo controlled trial 6445 AF pts screened, 1884 (29%) enrolled Mean age 72 yrs. , Male 1382 (73%) Mean CHADS2 score 2.35 Low bleeding risk procedures N=1539 (81.7%) Douketis JD et al. NEJM 2015

Bridging did not improve outcomes Douketis JD et al. NEJM 2015

Perioperative Management of AC for VTE Retrospective cohort of 1178 pts. and 1812 procedures VTE risk: Low 79%, Med 18%, High 3% Therapeutic bridge 73% Conclusion: Bridge therapy associated with excess bleed risk, no benefit Outcome Bridge (N=555) No Bridge (N=1257) P Value Recurrent VTE High 0/36 0/21 1.0 Med 0/109 1/215 (0.5%) 0.48 Low 0/410 2/1021 (0.2%) 0.37 Bleed 2/36 (5.6%) 1/21 (4.8%) 0.90 5/109 (4.6%) 0/215 0.004 8/410 (2.0%) 1/1021 (0.1%) < 0.001 Clark NP et al. JAMA Internal Med 2015

Who should be considered for perioperative bridging? Mechanical mitral valve Afib with stroke (especially within 3 months) Afib with CHADS2 score 5 or 6 Venous thromboembolism with 3 months Active cancer with unprovoked VTE Recurrent unprovoked VTE Previous thromboembolism with therapy interruption or subtherapeutic AC High risk thrombophilia (Antiphospholipid syndrome, protein C or S or antithrombin deficiency)

When to stop warfarin and apixaban Warfarin (INR 2-3): at least 5 days prior to procedure Apixaban (Half-life): CrCl > 80 ml/min (12 hrs.) CrCl 50-79 ml/min (15 hrs.) CrCl 30-49 ml/min (18 hrs.) Low risk surgery (4 half-lives = 6.3% drug left) Stop 2-3 days before surgery CrCl > 80 = 48 h, CrCl 50-79 = 60 h, CrCl 30-49 = 72 h High risk surgery (6 half-lives = 1.6% drug left) Stop 3-4.5 days before surgery CrCl > 80 = 72 h, CrCl 50-79 = 90 h, CrCl = 30-49 = 108 h University of Washington Anticoagulation Service; NCCN Guideline 2018

When to stop dabigatran Half-life CrCl > 80 ml/min (14 h) CrCl 50-79 ml/min (17 h) CrCl 30-49 ml/min (19 h) Low risk surgery (4 half-lives = 6.3% drug left) Stop 2.5-3 days before surgery CrCl > 80 = 56 h, CrCl 50-79 = 68 h, CrCl 30-49 = 76 h High risk surgery (6 half-lives = 1.6% drug left) Stop 4-5 days before surgery CrCl > 80 = 84 h, CrCl 50-79 = 102 h, CrCl = 30-49 = 114 h Van Ryn J et al. Thromb Haemost 2010; NCCN Guideline 2018;

When to stop edoxaban Half-life 10-14 hours Low risk surgery (4 half-lives = 6.3% drug left) Stop 2 days before surgery High risk surgery (6 half-lives = 1.6% drug left) Stop 4 days before surgery NCCN Guideline 2018; Edoxaban PI

When to stop rivaroxaban Half Life CrCl > 80 ml/min (8 hrs.) CrCl 50-79 ml/min (9 hrs.) CrCl 30-49 ml/min (9 hrs.) Age 60+ (11-13 hrs.) Low risk surgery (4 half-lives = 6.3% drug left) (about 2 days) Stop 2 days before surgery CrCl > 80 = 32 h, CrCl 50-79 = 36 h, CrCl 30-49 = 36 h, Age 60+ = 52 hours High risk surgery (6 half-lives = 1.6% drug left)(about 2-3 days) Stop 3 days before surgery CrCl > 80 = 48 h, CrCl 50-79 = 54 h, CrCl = 30-49 = 54 h), Age 60+ = 78 hours University of Washington Anticoagulation Service; NCCN Guideline 2018; Rivaroxaban PI

When to restart AC Tentative based upon post-op course Collaborative decision with surgeon VTE prophylaxis dosing prior to therapeutic Low risk surgery Restart no sooner than 24-48 hours High risk surgery Restart no sooner than 72 hours Very high risk surgery Restart no sooner than 5-7 days

Perioperative Management of AC Step 1: Assess the bleeding risk of the procedure Step 2: Assess the risk of recurrent thromboembolism Step 3: Determine the elimination half-life of the anticoagulants and review the list of medication and supplements Step 4: Review the pre-op labs (CBC, CMP, PT) Step 5: Design a tentative perioperative AC management plan and discuss with surgeon

Pre-operative AC Time line Pre-op day 10-14 CBC, CMP (Calculate creatinine clearance!), PT/INR Assess thromboembolic and bleeding risk Discuss tentative bridging plan with patient and surgeon and disseminate plan Pre-op day 5-6 stop warfarin and start enoxaparin 1mg/kg q12h 36-48 hrs. after last dose of warfarin Pre-op day 3-5 stop DOAC and start enoxaparin 12-24 hours after last dose of DOAC Last dose of enoxaparin 24-48 hours pre-operation Very high thrombotic risk consider UFH IV

Warfarin and Oral Surgery Literature review ( Wahl MJ JADA 2000) 950 pts. with >2400 surgeries (extractions, alveolar or gingival surgery) Only 12 pts. (1.3%) required more than local measures for hemostasis Nine (75%) had supra-therapeutic INR; 5 of 526 pts (0.95%) who held AC had thrombotic event,4 died Single-center Retrospective study (Eichhorn W et al. Clin Oral Invest 2012) 637 pts., 934 procedures (osteotomy, extractions) continued warfarin (INR 2.44) Local hemostasis with collagen fleece, suture, compression, fibrin glue 47 pts. (7.4%) had bleeding treated with local measures vs. 2 of 285 (0.7%) control pts.

Warfarin and Oral Surgery Prospective single center study of warfarin (INR 2-3) plus aspirin (N=71) versus warfarin (N=71) or aspirin alone (N=71) (Bajkin BV JADA 2012) Risk of bleeding tended to be more with combined warfarin INR 2-3 and aspirin therapy (4.2%) than warfarin INR 2-3 (2.8%) or aspirin (0%) Bleeding manageable with local measures Prospective open randomized study of warfarin (N=109) v. warfarin-LMWH bridge (N=105) (Bajkin B J Oral Maxillofac Surg 67:990-995, 2009) No difference in bleeding (7.3% v. 4.8%) , all treated with local measures, No thromboembolism

Warfarin and LMWH bridging Prospective randomized study of simple extractions with or without LMWH bridging Warfarin INR 2.45 (N=109) vs. LMWH bridging (INR 1.26) Post-op bleeding: 8 warfarin (7.3%) vs. 5 LMWH (4.8%). Treated with local measures, no transfusions Conclusion- Bridging unnecessary for simple extractions Bajkin BV et al J Oral Maxilofac Surg 2009

DOACs and Dental Surgery Prospective observational study of 367 pts. (119 DOACs, 248 warfarin) DOAC held morning of the procedure; warfarin continued Bleeding: 4 DOAC (3.1%) vs. 23 warfarin (8.8%). Bleeding controlled with local measures or holding AC dose Yoshikawa H et al. J Oral Maxillofac Surg 2019

Plan for Procedures: Procedural Bleeding Risk Stratification for Oral Surgery Estimated Bleeding Risk Low Bleeding Risk Moderate Bleeding Risk High Bleeding Risk Procedure Supragingival scaling (standard cleaning) Simple restorations Anesthetic injections Subgingival scaling Restorations with subgingival prep Standard root canal Simple extraction Regional injection of anesthestics Multiple extractions Apicoectomy (root removal) Alveolar surgery (bone removal) Management Continue AC Use local hemostatic measures May continue AC Consult dentist May need to interrupt AC University of Washington Anticoagulation Service

Oral Surgery Recommendations Discussion between oral surgeon, physician and patient prior to procedure to outline management For routine oral surgery (simple extractions < 3, 3 implants, etc.) warfarin (INR < 3.5 on day prior to surgery), single or dual APA or DOAC may be continued with local hemostatic measures (collagen, TXA rinse, topical fibrin, sutures) For DOACs do not take daily dose morning of surgery For AC + dual APA or warfarin INR >3.5 or more extensive surgery individualized management Aframian DJ, et al Oral Surg Oral Med 2007; van Diermen DE et al. Oral Surg Oral Med 2013

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