1. To Bridge or Not to Bridge: Guide to Clinicians Hazem Elewa, RPh, PhD, BCPS Assistant Professor, College of Pharmacy, Qatar University

2. Disclosures I have no financial disclosures to report

3. Important concepts Bridging anticoagulation: To give a short-acting anticoagulant, usually low-molecular-weight heparin (LMWH) for 10 to 12 days around the periprocedural period, when warfarin is interrupted and its anticoagulant effect is not optimal Bridging aims to reduce patients’ thromboembolic (TE) risk, but may also increase patients’ risk for developing bleeding complications after surgery Bridging has become a common practice due to increased convenience and decreased cost of LMWH Douketis et al. Chest 2012;141;e326S-e350S The bridge study investigators. Circulation. 2012;125:e496-e498

4. 1. Perform patient anticoagulation assessment 7+ days prior to procedure 2. Categorize procedure-related bleeding risk 3. Categorize underlying thrombosis risk 4. Build bridging recommendation after weighing the risk of bleeding against the risk of thromboembolism 5. View specific guidance for novel oral anticoagulants (NOACs) and antiplatelets A stepwise guide Douketis et al. Chest 2012;141;e326S-e350S

5. High risk MVR; Caged-ball or tilting-disc AVR; Recent stroke or TIA AF with CHADS 2 of 5-6; Rheumatic valvular heart disease Recent VTE (within 3 months); Severe thrombophilia Moderate risk Bileaflet AVR + one more of the following: AF; Stroke or TIA; HTN; DM; CHF; older than 75 years AF with CHADS 2 of 3-4 VTE within 3-12 months; Recurrent VTE; Active cancer; Non- severe thrombophilia Low risk Bileaflet AVR without AF; No other risk factors for stroke AF with CHADS 2 of 1-2 assuming no history of stroke or TIA VTE more than 12 months and no other risk factors Risk of TE Douketis et al. Chest 2012;141;e326S-e350S

6. Risk of bleeding High bleeding risk proceduresLow bleeding risk proceduresMinimal bleeding risk procedures Cancer surgery Major orthopedic surgery Reconstructive plastic surgery Minor dental procedures simple dental extractions, restorations, prosthetics, endodontics Dental cleanings Dental filling Transurethral prostate resection, bladder resection or tumor ablation Nephrectomy, kidney biopsy Colonic polyp resection Bowel resection Percutaneous endoscopic gastrostomy (PEG) placement, endoscopic retrograde cholangiopancreatography Cutaneous/lymph node biopsies Shoulder/foot/hand surgery Coronary angiography Gastrointestinal endoscopy +/- biopsy Colonoscopy +/- biopsy Abdominal hysterectomy Minor dermatologic procedures (excision of basal and squamous cell skin cancers, actinic keratoses) Cardiac, intracranial, or spinal surgery Surgery in highly vascular organs (kidneys, liver, spleen) Any major operation (procedure duration >45 minutes) Pacemaker or cardioverter-defibrillator device implantation Laparoscopic cholecystectomy Abdominal hernia repair Hemorrhoidal surgery Bronchoscopy +/- biopsy Epidural injections with INR <1.2 Pacemaker battery change Arthroscopy Cataract procedures and other minor ophthalmologic procedures Douketis et al. Chest 2012;141;e326S-e350S

7. Decision to bridge Minimal bleeding risk No Yes What is the thromboembolic risk Continue warfarin Stop warfarin. No need to bridge Bridge Weigh benefits Vs.risks of warfarin interruption/ bridging

8. Decision to bridge High bleeding risk procedures Low bleeding risk procedures Minimal bleeding risk procedures Warfarin interruption: Yes Bridging with LMWH: Yes Warfarin interruption: Yes/No Bridging with LMWH: Yes/No Warfarin interruption: No Bridging with LMWH: No Warfarin interruption: Yes Bridging with LMWH: Yes/No Warfarin interruption: Yes/No Bridging with LMWH: Yes/No Warfarin interruption: No Bridging with LMWH: No Warfarin interruption: Yes Bridging with LMWH: No Warfarin interruption: Yes Bridging with LMWH: No Warfarin interruption: No Bridging with LMWH: No

9. Weigh benefits Vs.risks of warfarin interruption/ bridging Bridge No Bridge Patient preference Thromboembolic risks: Patient-related Procedure-related Cost Bleeding risks: Patient-related Procedure-related

10. How to bridge with LMWH Stop warfarin for five days before the procedure and restart in the evening of the procedure provided hemostasis is adequate. LMWH is started three days prior to the procedure and held 24 hours preoperatively, and resumed 24-72 hours post-procedure till reaching therapeutic INR with warfarin Douketis et al. Chest 2012;141;e326S-e350S

11. How to bridge Days prior or post procedure Management of Warfarin/ LMWH -7 to -10Assess need for bridging. Check baseline labs ( INR; Hgb, platelets, Cr.Cl) -6 to -5Begin to hold warfarin. No LMWH -3 to -4Start LMWH Last dose of LMWH (24hr prior to procedure). Recheck INR 0Continue to hold warfarin or resume in the evening. No LMWH +1Resume LMWH (or wait for 48-72hrs if at bleeding risk) +4 to +7Discontinue LMWH if INR is ≥ 1.9 Douketis et al. Chest 2012;141;e326S-e350S

12. Therapeutic dose: – Enoxaparin: 1mg/Kg SC Q12hrs or 1.5mg/Kg SC Q24hrs Reduce the dose to 1mg/Kg SC Q24hrs if Cr.Cl<30 ml/min – Dalteparin: 100 IU/Kg SC Q12hrs or 200 IU/Kg SC Q24hrs (Only if Cr.Cl≥30ml/min) Prophylactic dose: – Enoxaparin: 40mg SC Q24hrs or 30mg SC Q12hrs Reduce the dose to 30mg SC Q24hrs if Cr.Cl<30 ml/min – Dalteparin: 5000 IU SC Q24hrs (Only if Cr.Cl≥30ml/min) Intermediate dose: – Dose between prophylactic and therapeutic Dosing regimen of LMWH Siegal et al. Circulation. 2012;126:1630-1639

14. To evaluate the safety and efficacy of periprocedural bridging anticoagulation There was no reduction in the risk of TE events with the use of heparin bridging (OR, 0.80; 95% CI, 0.42–1.54) There was an increased risk of overall bleeding (OR, 5.40; 95% CI, 3.00 –9.74) in bridged Vs.non- bridged Review of bridging studies Siegal et al. Circulation. 2012;126:1630-1639

15. Risk of TE events in bridged Vs non- bridged patients Siegal et al. Circulation. 2012;126:1630-1639

16. Risk of bleeding events in bridged Vs. non-bridged patients Siegal et al. Circulation. 2012;126:1630-1639

17. 20 studies (57%) reported use of therapeutic dose LMWH 13 studies (37%) reported use of prophylactic/ intermediate dose LMWH for bridging There was no difference in TE events but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27– 4.08) with therapeutic versus prophylactic/intermediate dose LMWH bridging Review of bridging studies Siegal et al. Circulation. 2012;126:1630-1639

18. Majority of the studies included were observational (only 1 RCT) Significant heterogeneity for the analyses of bleeding events Lack of systematic report of bleeding events according to the type of procedure Review of bridging studies Siegal et al. Circulation. 2012;126:1630-1639 Possibly, majority of bridged patients were at high TE risk whereas non-bridged patients were at low TE risk which explains the lack of difference in TE events between groups

19. The BRIDGE study The bridge study investigators. Circulation. 2012;125:e496-e498www.clinicaltrials.gov/ct2/show/NCT00432796 Includes only AF patients with at least 1 risk factor Dalteparin daily 3 days prior to the procedure to be stopped 24hrs prior to the procedure and resumed the day after Matching placebo with the same regimen TE and bleeding events

20. PERIOP 2 study www.clinicaltrials.gov/ct2/show/NCT00432796 Include AF or mechanical heart valve Stop warfarin 5 days before and start dalteparin(200 IU/Kg/day) 3 days before Surgery Dalteparin daily the day after the procedure If low risk of bleeding 200 IU/Kg daily Matching placebo the day after the procedure If high risk of bleeding 5000 IU daily

21. Periprocedural management with NOACs

22. Clinical case An 71 year-old female on chronic warfarin therapy for a mitral valve replacement is having a dental extraction in 10 days. Which of the following is the best approach: – A) Interrupt warfarin for the procedure with no bridging – B) Bridge using prophylactic LMWH before and after the procedure – C) Bridge using therapeutic LMWH before and after the procedure – D) Continue warfarin with co-administration of local prohemostatic agent

23. Periprocedural management of patients on long-term anticoagulation remains a common but difficult problem Decision to interrupt, bridge and resume anticoagulants MUST BE CLEARLY COMMUNICATED among providers and patients American College of Chest Physicians (ACCP) recommendations in regards to periprocedural management have weak grade (2C), reflecting the lack of high-quality evidence There may be an overuse of bridging which can lead to increase in bleeding risk with theoretical benefit Conclusion