1. 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

2. 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

3. Scope of the Problem
In 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
Williams CD et al Am J Prev Med 2015; AHA/ASA Annual stats 2018; Wysowski DK et al Arch Intern Med 2007

4. 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

5. 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

6. 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%), hrs. (36%)
LMWH restart within 24 hrs (55%), > 24 hrs (16%)
Bridging increases bleeding complications
Siegal D et al. Circulation 2012

7. 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 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

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

9. 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

10. 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)

11. 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 ml/min (15 hrs.)
CrCl 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 = 60 h, CrCl = 72 h
High risk surgery (6 half-lives = 1.6% drug left)
Stop days before surgery
CrCl > 80 = 72 h, CrCl = 90 h, CrCl = = 108 h
University of Washington Anticoagulation Service; NCCN Guideline 2018

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

13. 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

14. When to stop rivaroxaban
Half Life
CrCl > 80 ml/min (8 hrs.)
CrCl ml/min (9 hrs.)
CrCl 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 = 36 h, CrCl = 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 = 54 h, CrCl = = 54 h), Age 60+ = 78 hours
University of Washington Anticoagulation Service; NCCN Guideline 2018; Rivaroxaban PI

15. 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 hours
High risk surgery
Restart no sooner than 72 hours
Very high risk surgery
Restart no sooner than 5-7 days

16. 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

17. 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 hrs. after last dose of warfarin
Pre-op day 3-5 stop DOAC and start enoxaparin hours after last dose of DOAC
Last dose of enoxaparin hours pre-operation
Very high thrombotic risk consider UFH IV

18. 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.

19. 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: , 2009)
No difference in bleeding (7.3% v. 4.8%) , all treated with local measures, No thromboembolism

20. 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

21. 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

22. 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

23. 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

24. Questions ?