Management of Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

By Dr. Christopher Cheung (biography and no disclosures) and Dr. Kenneth Gin (biography and disclosures, disclosures: Research for Bayer, Ad board Bayer, BI, Pfizer). Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with current practice patterns.

What I did before

Atrial fibrillation (AF) affects approximately 350,000 Canadians including more than 5% of patients aged 80 years and older, and is an important cause of stroke with significant morbidity and mortality.(1) Novel or direct oral anticoagulants (NOACs, DOACs) can markedly reduce the risk of stroke and systemic embolism in non-valvular AF by up to 80%. The Canadian Cardiovascular Society (CCS) AF Guidelines recommend oral anticoagulant therapy (OAC) in all non-valvular AF patients aged ≥ 65 years or with a history of congestive heart failure, hypertension, diabetes, stroke, or systemic embolism (“CHADS-65”), with a preference towards NOACs.(2) In North America, contemporary data suggests that 80% of patients are receiving OACs, including 52% of patients receiving NOACs (GLORIA-AF and SPRINT-AF registries).(3,4)

Perioperative management of anticoagulation is challenging as physicians must consider the risks of stroke, systemic embolism, and perioperative bleeding. The 2014 CCS guidelines have recommended balancing the risks of a thromboembolic event (using CHADS₂ score, mechanical heart valve, or rheumatic heart disease) with the bleeding risk (using HASBLED risk score), but with no specific thresholds for bridging non-valvular AF.(5) Similarly, in the 2014 AHA/ACC/HRS Guidelines, management of bridging anticoagulation in patients without mechanical valves is equally vague, with clinicians to “balance the risks of stroke and bleeding and duration of time a patient will not be anticoagulated” (Level of Evidence: C).(6)

In patients receiving pacemaker or defibrillator surgery, the BRUISE-CONTROL study randomized 681 patients to received continued warfarin anticoagulation or heparin bridging. The study was terminated early due to a significant reduction in pocket hematoma with uninterrupted anticoagulation, compared to bridging.(7) Thus, recent guidelines have recommended that procedures with a low or very low probability of major bleeding (i.e. dental procedures, cardiac device implantation) can be safety performed without interruption of anticoagulation.(2) However, prior to the BRIDGE trial, perioperative bridging anticoagulation in patients requiring interruption of warfarin therapy remained unclear.

What changed my practice

In the BRIDGE trial published in the New England Journal of Medicine, 1884 patients with AF receiving warfarin therapy undergoing elective surgery requiring interruption of warfarin therapy were randomized to receive bridging anticoagulation with low-molecular-weight heparin (LMWH) or matching placebo.(8) Warfarin therapy was stopped 5 days prior to the procedure, and resumed 24 hours afterwards. Patients randomized to LMWH received dalteparin (100 IU per kg subcutaneously twice daily), beginning 3 days prior to procedure until 24 hours prior, and resumed LWMH 24-72 hours after the procedure (12-24 hours after low-bleeding risk procedures, 48-72 hours after high-bleeding risk procedures). The inclusion criteria consisted of patients with permanent or paroxysmal AF (valvular and non-valvular), received warfarin therapy for 3 months or longer, and at least one CHADS₂ risk factor (i.e. congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, or prior stroke/transient ischemic attack (TIA). Patients with a mechanical heart valve, recent stroke/embolism/TIA within 12 weeks, recent major bleed within 6 weeks, and planned high-risk surgery (i.e. cardiac, intracranial, intraspinal) were excluded. The study was performed at 108 sites across Canada and the United States.(8)

The mean age of the population was 71.7 ± 8.8 years (73% male) with a mean CHADS₂ score was 2.3 ± 1.0.(8) There were relatively few patients with a high CHADS₂ score (13.8% with CHADS₂ score 4-6), and most patients (89.4%) underwent a surgical procedure classified as low bleeding risk. At 30 days, the thromboembolism rate of bridging (0.3%) was non-inferior to placebo (0.4%, primary efficacy outcome), with a median time to thromboembolic event of 19.0 days (IQR 6-23).(8) Major bleeding at 30 days, defined as symptomatic or clinically overt bleeding (transfusion of ≥2 units packed red blood cells, decrease in hemoglobin >20 g/L, or need for reoperation or intervention), bleeding at a critical site, or fatal bleeding, met the superiority threshold with more bleeding with bridging (3.2%) compared to placebo (1.3%, primary safety outcome). This translates into a relative risk of 0.41 (95% CI 0.20-0.78) for major bleeding with placebo compared to bridging anticoagulation.(8)

What I do now

The BRIDGE trial demonstrated that patients with AF undergoing elective surgery can safely discontinue warfarin treatment without bridging anticoagulation.(8) Bridging anticoagulation was non-inferior to placebo in preventing arterial thromboembolism (ischemic and hemorrhagic stroke, TIA, and systemic embolism), but was associated with an increased rate of major bleeding. Based on the BRIDGE results, we do not routinely provide bridging anticoagulation for patients with AF and a low risk of thromboembolism (CHADS₂ score 0-3). The 2016 CCS AF Guidelines have incorporated these findings into their recommendations (Table 1).(2) In patients receiving warfarin therapy requiring interruption prior to surgery, bridging therapy should be instituted only in patients at high risk for thromboembolic events (CHADS₂ score ≥ 4, mechanical heart valve, stroke/TIA within 3 months, rheumatic mitral stenosis [MS]).(2) Apart from the lack of a significant effect on thromboembolic event rates, bridging anticoagulation significantly increases the risk of major bleeding. A recent meta-analysis of observational and randomized studies also reported a significant increase in overall bleeding and major bleeding, consistent with the findings of the BRIDGE trial.(9)

Notable limitations in the BRIDGE study include the relatively small population of high risk (13.8% with CHADS₂ score 4-6) and very high risk individuals (3.1% with CHADS₂ score 5-6). Furthermore, although patients with AF associated with valvular disease were eligible, only a small proportion of patients had MS (2%) and thus, the results do not apply to these high-risk populations (i.e. severe rheumatic MS, MS with prior stroke). Other exclusions included high risk surgery (i.e. carotid endarterectomy, cardiac surgery), mechanical heart valves, and patients with a recent stroke/TIA within 12 weeks.(8)

The 2016 CCS AF Guidelines also make several additional recommendations for anticoagulation in the perioperative setting (summarized in Table 1). Patients with AF or atrial flutter (AFL) do not require interruption of anticoagulation for procedures with a low-risk of bleeding, including cardiac device implantation and dental procedures (based on the BRUISE-CONTROL study).(7) Most patients with AF receiving NOACs do not require perioperative bridging, due to the short half-lives of these agents (based on the Perioperative Dabigatran Study, OPTIC-AF, and Dresden NOAC Registries).(10-12) The Thrombosis Canada Perioperative Management Algorithm is a readily accessible, helpful tool to aid clinicians in the decision and management of peri-procedural anticoagulation (http://thrombosiscanada.ca/?page_id=502&calc=perioperativeAnticoagulantAlgorithm, mobile app available). The Thrombosis Canada Clinical Guide for perioperative warfarin management mirrors the BRIDGE trial and CCS Guidelines, with the notable exception of high-risk defined as CHADS₂ score 5-6 (rather than CHADS₂ score 4-6 in CCS Guidelines).(2)

Conclusion

Perioperative bridging anticoagulation should only be considered in patients with the highest thromboembolic risk (CHADS₂ 4-6, mechanical heart valves, recent stroke/TIA).(2) In patients at lower thromboembolic risk (i.e. participants in the BRIDGE trial), perioperative bridging anticoagulation was non-inferior and did not reduce thromboembolic events, and was associated with more major bleeding events compared to placebo. Thromboembolic events occurred in both groups at similar frequency and relatively remotely from the procedure (19 days) and may be unrelated to bridging anticoagulation entirely.

Table 1. CCS 2016 Periprocedural Anticoagulation Recommendations

References

1. Healey J, Brambatti M. Periprocedural management of oral anticoagulation in patients with atrial fibrillation: Approach in the era of new oral anticoagulants. J. Cardiol. 2013;29:S54-S59. (View with CPSBC or UBC) DOI: 10.1016/j.cjca.2013.02.021
2. Macle L, Cairns J, Leblanc K, et al. 2016 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. J. Cardiol. 2016;32:1170-1185. (View with CPSBC or UBC) DOI: 10.1016/j.cjca.2016.07.591
3. Huisman M, Rothman K, Paquette M, et al. The changing landscape for stroke prevention in AF: Findings from the GLORIA-AF registry phase 2. Am. Coll. Cardiol. 2017;69:777-785. (View with CPSBC or UBC) DOI: 10.1016/j.jacc.2016.11.061
4. Ha A, Singh N, Cox J, et al. Oral anticoagulation for stroke prevention in Canadian practice: Stroke prevention and rhythm interventions in atrial fibrillation (SPRINT-AF) registry. J. Cardiol. 2016;32:204-210. (View with CPSBC or UBC) DOI: 10.1016/j.cjca.2015.04.028
5. Verma A, Cairns J, Mitchell L, et al. 2014 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. J. Cardiol. 2014;30:1114-1130. (View with CPSBC or UBC) DOI: 10.1016/j.cjca.2014.08.001
6. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):2071-104. (View)
7. Birnie D, Healey J, Wells G, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. Engl. J. Med. 2013;368:2084-2093. (View) DOI: 10.1056/NEJMoa1302946
8. Douketis J, Spyropoulos A, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. Engl. J. Med. 2015;373:823-833. (View) DOI: 10.1056/NEJMoa1501035
9. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: Systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation. 2012;126(13):1630-9. (View)
10. Schulman S, Carrier M, Lee AY, et al. Perioperative management of dabigatran: A prospective cohort study. Circulation. 2015;132:167-73. (View)
11. Steinberg BA. Interruption of all anticoagulation is non-inferior to the use of short-term parenteral bridging in patients with atrial fibrillation undergoing invasive procedures.   Based. Med. 2015;20:200-200. (Request with CPSBC or view UBC) DOI: 10.1136/ebmed-2015-110263
12. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Heart. J. 2014;35:1888-1896. (Request with CPSBC or view UBC) DOI: 10.1093/eurheartj/eht557

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Management of Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

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