Clinical case scenarios on perioperative management of anticoagulants

Eleni M Arnaoutoglou, MD, PhD

Professor of Anesthesiology

University of Thessaly

Chief of Anesthesiology Department

University Hospital of Larissa

• VKA patients: who to bridge?

• DOAC patients: when to stop and resume?

• Urgent procedure: how to reverse?

Learning Objectives

• A 78-year-old man is scheduled for EVAR

• He is receiving acenocoumarol (Sintrom) for stroke prevention in paroxysmal AF, Hx of DM

• No Hx of stroke, or HF

• Metoprolol for hypertension

One doctor told he needs to be assessed for heparin bridging

Another doctor told he does not need bridging

What is the thromboembolic risk?

CHADS2Cardiac failure, Hypertension, Age ≥75, Diabetes, Stroke (Doubled)

Bridging in Patients with AF: Evidence

• 1 RCT of no bridging vs. bridging (BRIDGE)

– non-inferior for ATE: 0.4% vs. 0.3%

– superior for major bleeding: 1.3% vs. 3.2%

(17% with prior stroke/TIA, <5% with CHADS2 5-6)

• >10 non-randomized observational studies

– low rates of ATE (<0.5%)

– higher rates of major bleeding with bridging (4-7%)

Douketis J, et al. Arch Intern Med 2004 Dunn AS, et al. J Thromb Haemost 2006 Kovacs MJ, et al. Circulation 2004 Douketis J, et al. Thromb Haemost 2004 Spyropoulos A, et al. J Thromb Haemost 2006 Schulman S, et al. J Thromb Haemost 2014Douketis J, et al. N Engl J Med 2015

Bridging in Patients on VKAs with MHV

• 1 RCT of no bridging vs. bridging: PERIOP-2

– post-op bridging vs. no bridging (all bridged pre-op)

– study complete (~1,300 patients)

Bridging in Patients on VKAs with VTE

• No RCTs of no bridging vs. bridging

• 2 non-randomized studies of bridging vs. no bridging– most patients with VTE >3 months ago– low rates of recurrent VTE (<0.5%) without

bridging

Clark NP, et al. JAMA Intern Med 2015Skeith L, et al. J Thromb Haemost 2012

We recommend that for low–moderate thrombotic risk patients:

• VKA should be stopped 3 before surgery (acenocoumarol)

• No bridging therapy is needed

• Measure INR on the day before surgery and give 5 mg oral vitamin K if INR exceeds 1.5 1C

• We recommend bridging therapy for high thrombotic risk patients;acenocoumarol: 3 days before surgery, last dose; 2 and 1 day before surgery, LMWH (last dose 24 h before surgery) 1C

• We suggest that the therapeutic dose of LMWH or UFH should be tailored for each patient, depending on the respective thrombotic and bleeding risk. 2C

• We recommend that for moderate to high thrombotic risk patients, prophylactic doses of heparin (UFH or LMWH) should be started during the evening or the day after the procedure (at least 6 h after) and given for up to 48 to 72 h, and then therapeutic anticoagulation should be resumed

• VKA can restart at that time or later, only when surgical haemostasis is achieved. 1C

•75-yr, 65-kg old female, with AF on

apixaban, 5 mg BID

–hypertension, diabetes

–CrCl = 59 mL/min

•Scheduled for EVAR Monday 9AM, for incidentally found AAA…

She needs to be off apixaban for 2 days

…NO, she needs to be off apixaban for 5 days and needs heparin bridging

• Lack of high quality data(perioperative management,laboratory monitoring of anticoagulation, urgent surgery)

• Individualized management after communication.....

• Need for a consensus of the surgeon, anesthesiologist, cardiologist, hematologist whoshould weigh the relative risk of bleeding versus prevention of thrombosis

• Development of institutional guidelines and hospital policies for the perioperative management of DOACs

Practice Guidelines: Perioperative Anticoagulation

1) When is it safe to interrupt?2) When is it safe to resume?3) Is heparin bridging needed?4) Is coagulation function testing needed?

How to manage DOAC-treated patients perioperatively?

Pause study• Design: Multi-centre prospective cohort

study

• Patients: 2,961 patients with atrial fibrillation (987 per DOAC – dabigatran, rivaroxaban, apixaban)

Secondary: to demonstrate that a high proportion of patients (>90%) have a minimal pre-procedure residual anticoagulant level (<50 ng/mL)

Pre-procedure blood sample to measure:-dilute thrombin time (dabigatran patients)-anti-factor Xa (rivaroxaban, apixabanpatients)-PT, aPTT, TT (all patients)

Primary: to demonstrate that this protocol is safe, defined by low rates of major bleeding (1.0%) and arterial thromboembolism (0.5%)

Methods: Patient Eligibility and Intervention

Consecutive adults (≥18 years) with atrial fibrillation:- receiving DOAC (apixaban, dabigatran, rivaroxaban)- require DOAC interruption for elective surgery/procedure- can adhere to planned DOAC interruption

Excluded if:- CrCl<30 mL/min (dabigatran, rivaroxaban)- CrCl<25 mL/min (apixaban)- cognitive impairment/psychiatric Illness- non-consenting- previous participation in study

Blood sample: day of (just before) surgery/procedureFollow-up: weekly for 4 weeks post-procedureNo heparin bridging (low-dose heparin as VTE prophylaxis OK)

Surg./proced.classified as

HIGH or LOW bleeding risk

Pause study

Outcome (%, 95% CI)(expected)

Cohort

Apixabann=1257

Dabigatrann=668

Rivaroxabann=1082

*Arterialthromboembolism (0.5%)

0.16 (0-0.48)n=2

0.60 (0-1.33)n=4

0.37 (0-0.82)n=4

**Majorbleeding (1.0%)

1.35 (0-2.00)n=17

0.90 (0-1.73)n=6

1.85 (0-2.65)n=20

Results: Primary Outcomes (ITT Analysis)

0

50

100

150

200

250

300

350

400

apixaban dabigatran rivaroxaban

<30 ng/mL 30-49.9 ng/mL ≥50 ng/mL

93.1% <30 ng/mL

98.9% <30 ng/mL

85.3% <30 ng/mL

98.9% (823/832) with DOAC level <50 ng/mL

High-Bleed-Risk: 2 days off pre-op

This strategy with no bridging was associated with low rates of major bleeding and arterial thromboembolism

98.8% had a residual anticoagulant level <50 ng/mL

The bleeding risk of the vascular procedure

Renal function

Renal function

High-bleed risk surgery/procedure

TIME Thursday

Friday Saturday Sunday Monday 8 AM

8 AM Ø

8 PM Ø Ø

Ø

Low-bleed risk surgery/procedure

When to stop DOACs? (dabigatran/apixaban)

High-bleed risk surgery/procedure

Low-bleed risk surgery/procedure

When to stop DOACs? (rivaroxaban)

Managing an urgent surgery(DOACs)

• Time since the last dose is an important

consideration in someone who requires urgent

surgery with high risk of bleeding

• A delay of 8–12 h is likely to be sufficient to

enable major surgery

Available Reversal Agents

J Am Coll Cardiol. 2017 Dec 19;70(24):3042-3067

Take home message…

• VKA patients: who to bridge?– selected atrial fibrillation

– mechanical mitral (and most aortic) valves, VTE <3 mts

• DOAC patients: when to stop and resume?– omit 1 day before/after low bleed risk procedure

– omit 2 days before/after high bleed risk procedure

– no bridging, no testing

• Urgent procedure: how to reverse?– Dabigatran can be reversed selectively with idarucizumab

– 4F-PCC first line for the reversal of factor Xa inhibitors

– 4F-PCC first line for the reversal of VKAs plus 5 to 10 mg IV vitamin K