Perioperative Anticoagulation

Wendy Lim, MD, MSc, FRCPCProfessor, Department of Medicine, Division of Hematology & ThromboembolismMcMaster University

DisclosuresResearch support None

Employee None

Consultant Pfizer Canada

Major stockholder None

Speaker’s bureau None

Honoraria BMS-Pfizer, Pfizer Canada, Novartis, Portola Pharmaceuticals(CME presentations)

Scientific advisory board None

Objectives

By the end of the session you should be able to:

1. Describe the key trials and new data outlining use of perioperative heparin bridging

2. Outline an approach to the perioperative use of DOACs

Perioperative anticoagulation• Management of anticoagulation around the time of surgery or invasive

procedures is common • ~3 million people in North America take vitamin K antagonists (VKA) or direct oral

anticoagulants (DOACs) for atrial fibrillation (AF) 1, ~1 in 6 will require perioperative management2

• ~75,000 diagnosed with venous thromboembolism (VTE) annually1

• Stopping anticoagulation increases thrombotic risk but surgery/invasive procedures are associated with bleeding which can be increased with anticoagulants

• Estimate risk of thromboembolic event when anticoagulant is discontinued vs. risk of bleeding when anticoagulant is given close to procedure

1-Barnes et al. Am J Med 2015;128;1300; 2-Zulikifly et al. Int J Clin Pract 2018;72:e13070

Perioperative anticoagulation: Key questions

1. Does the anticoagulant therapy need to be temporarily stopped in the perioperative period?

2. If VKAs are interrupted, is bridging anticoagulation needed?

3. If DOACs are interrupted, what is the optimal time to stop and re-introduce post surgery/procedure?

1. Does the anticoagulant need to be temporarily stopped in the perioperative period?

• Systematic reviews, observational studies of continued anticoagulation in minimal bleed risk procedures associated with procedure site bleeding ~2.0-3.0%1,2

• Minimal bleed risk procedures: minor dental and skin procedures (e.g., dental cleaning, limited extraction, removal of skin lesions), cataract (eye) surgery, diagnostic procedures (e.g., thoracentesis, paracentesis, endoscopy without biopsy)

• RCTs in patients with AF on VKA or DOAC undergoing pacemaker/defibrillator placement and AF ablation have incidence of pocket hematoma ~2.1-3.5% at 30 d if anticoagulants continued3,4

1-Spyropoulos et al. J Thromb Haemost 2019 July, 2-Nazha et al. Circulation 2018:138:1402. 3-Birnie et al. N Engl J Med 2013;368:2084. 4-Birnie et al. Eur Heart J, 2019;39:3973

2. If VKAs are interrupted, is bridging needed?• BRIDGE trial demonstrated in patients with AF that no bridging was

noninferior to LMWH bridging in preventing arterial TE and decreased risk of major bleeding*

• Mean CHADS2 in patients with TE event = 2.6 (range, 1-4)

What about mechanical heart valves or VTE?

*Douketis et al. N Engl J Med 2015;373:823

PERIOP 2 trial: Double blind randomized control trial of postoperative low molecular weight bridging therapy for patients who are at high risk for arterial thromboembolism

• Multicentre randomized double blind trial of postoperative LMWH bridging in patients with AF or mechanical heart valve requiring interruption for procedure

• Excluded patients with active bleeding, platelets <100, spinal/cardiac/ neuro surgery, life expectancy <3m, CrCl<30, multiple mechanical or Starr-Edwards valve, valve w/history of stroke/TIA, history of HIT

• Procedure• Day -6: Last dose of warfarin• Day -3, -2: Dalteparin 200 IU/kg (max 18,000)• Day -1: Dalteparin 100 IU/kg (max 18,000)• Day 0, 1: Resume 2x baseline dose warfarin post-procedure• Day 0, 1: Randomized to dalteparin vs placebo x 4d and until INR >1.9

Kovacs et al. Blood 2018 (abstract);373:823

D +1 D +2 D +3 D +4

D -6 D -5 D -4 D -3 D -2 D -1D 0Sx

Preoperatively

LMWH Bridging (control)Last dose warfarin Dalteparin

(IU/kg/day)Max 18000 IU

200 200 100 warfarin

200 IU/kg or 5,000 IULow or High Risk Bleeding*

Placebo (experimental)

D +1 D +2 D +3 D +4

Randomized D +1

*examples of high risk bleeding: cancer surgery, vascular surgery, TURP/prostate biopsy, liver biopsy

Kovacs et al. Blood 2018 (abstract);373:823

PERIOP 2 trial

• Randomization stratified by presence of mechanical valve, post-procedure risk of major bleeding, and by centre

• High post-op bleeding risk: Dalteparin 5000 IU OD (fixed dose)• Low post-op bleeding risk: Dalteparin 200 IU/kg (max 18,000 IU)

• 1o analysis: proportion of patients with major TE (stroke, proximal DVT, PE, MI, SE) over 90 days

• 2o outcomes: major bleeding, all cause mortality, composite major TE and major bleeding

Kovacs et al. Blood 2018 (abstract);373:823

Results: Baseline characteristicsTotal

(N=1471)No Bridging

(N=650)*Bridging(N=821)*

Age – yr Mean (SD) 69.7 (12.3) 69.2 (12.9) 70.1 (11.9)

Male sex –No. (%) 946 (64.3) 428 (65.9) 518 (63.1)

Sub-Group: Atrial Fibrillation - No. (%) 1167 (79.3) 497 (76.5)* 670 (81.6)*

Sub-Group: Mechanical Valves –No. (%) 304 (20.7) 153 (23.5) 151 (18.4)

With Atrial Fibrillation – No. (%) 99 (32.6), N=304 46 (30.1), N=153 53 (35.1), N=151

Mitral – No. (%) 132 (43.4), N=304 67 (43.8), N=153 65 (43.1). N=151

Aortic – No. (%) 172 (56.6), N=304 86 (56.2), N=153 86 (57.0), N=151

*Difference in the numbers due to an initial randomization error

Kovacs et al. Blood 2018 (abstract);373:823

Results: Outcomes• N=1471; n=1167 AF, n=304 mechanical valve (99 with concurrent AF)

Dalteparin vs placebo• Major TE: 0.7% vs 1.1%• Major bleed: 1.5% vs 2.5%• Similar findings between AF

and valve patients• No benefit to post

procedure LMWH bridging

Kovacs et al. Blood 2018 (abstract);373:823

Perioperative anticoagulation: Key questions

1. Does the anticoagulant therapy need to be temporarily stopped in the perioperative period?

2. If VKAs are interrupted, is bridging anticoagulation needed?

3. If DOACs are interrupted, what is the optimal time to stop and re-introduce post surgery/procedure?

Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

• Prospective multicentre study, 3 parallel DOAC cohorts of patients with AF requiring interruption for surgery/procedure

• Standardized perioperative strategy based on DOAC PK properties and procedure-associated bleeding risk

• Patients classified based on bleeding risk (high/low) and CrCl for dabigatran• DOACs stopped 1d before and after surgery for low bleed risk and 2d for high

bleed risk surgery with longer interruption for dabigatran & CrCl <50 ml/min• No heparin bridging or coagulation testing to guide management• 1o clinical outcomes: major bleeding & arterial TE (ischemic stroke, systemic

embolism, TIA)• Measured proportion of patients with an undetectable or minimal residual anticoagulant

level (<50 ng/mL) at time of the surgery/procedure• Follow up for 30d post-procedure

Douketis et al. JAMA Intern Med 2019 Aug 5

PAUSE study

• N=3007• Mean age 72.5y, 66.1% male, 33.5% high bleed risk surgery• Apixaban n=1257, Dabigatran n=668, Rivaroxaban n=1082

Results• Residual anticoagulant level <50 ng/mL at time of surgery/procedure

seen in >90% of patients• Apixaban 90.5%• Dabigatran 95.1%• Rivaroxaban 96.8%

Douketis et al. JAMA Intern Med 2019 Aug 5

Perioperative management protocol

Douketis et al. JAMA Intern Med 2019 Aug 5

Low-dose LMWH prophylaxis allowed

Research sample drawn (not for clinical use) +30d follow-up

Results: Baseline characteristicsPatient Characteristics Cohort

Apixabann=1257

Dabigatrann=668

Rivaroxabann=1082

Age – mean 73.1 72.4 72.0

Male sex, % 64.0 68.6 67.0

CHADS2 score – mean 2.1 2.2 2.0

Modified HASBLED score – mean 2.0 1.9 1.8

CrCl – mean, in mL/min 77.9 85.9 82.2

Lower-dose DOAC, % 20.0 37.1 16.7

ASA use, % 12.4 14.7 9.1

High bleed risk surgery/procedure, % 32.3 34.1 34.5

N=3007

Douketis et al. JAMA Intern Med 2019 Aug 5

Results: Major bleeding

• Apixaban 1.35%, Dabigatran 0.90%, Rivaroxaban 1.85%; All patients 1.43%

Douketis et al. JAMA Intern Med 2019 Aug 5

Results: Arterial thromboembolism

• Apixaban 0.16%, Dabigatran 0.60%, Rivaroxaban 0.37%; All patients 0.33%• Low rates of bleeding and thromboembolism using this strategy

Douketis et al. JAMA Intern Med 2019 Aug 5

Summary: Perioperative anticoagulation1. Does the anticoagulant therapy need to be temporarily stopped in the

perioperative period?• No need to stop for procedures associated with minimal bleeding risk (dental, skin, eye),

cardiac devices (pacemaker/ICD)

2. If VKAs are interrupted, is bridging anticoagulation needed?• Consider no bridging for low-(moderate) risk AF, no post-procedure bridging for

mechanical valves (PERIOP 2)• Unclear for higher risk AF, VTE, pre-procedure valves

3. If DOACs are interrupted, what is the optimal time to stop and re-introduce post surgery/procedure?• Consider using the PAUSE protocol; omit 1 day before/after low bleed risk procedure and

omit 2 days before/after high bleed risk procedure

Thank you!