RE-CIRCUITing Anticoagulants for Catheter Ablation

Sandy Liu, Mercer University College of Pharmacy

Catheter ablation of atrial fibrillation is typically performed with uninterrupted anticoagulation with warfarin or interrupted non-vitamin K antagonist (NVKA) oral anticoagulant therapy.  Due to the lack of controlled data, it is unknown whether uninterrupted anticoagulation with a NVKA agent, such as dabigatran, is a safer option than warfarin. [1]

Warfarin is a vitamin K antagonist that competitively inhibits the subunit 1 of the multi-unit vitamin K epoxide reductase (VKOR) complex, thus depleting functional K reserves and reducing synthesis of active clotting factors. [2]  Conversely, dabigatran is a reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin, thereby preventing thrombin-mediated effects, including cleavage of fibrinogen to fibrin monomers, inhibition of thrombin-induced platelet aggregation and activation of factors V, VIII, XI and XIII. [3]

Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation [1]
Design Prospective, randomized, open-label, blinded end point; N= 678
Objective To assess the safety and efficacy of differing dabigatran and warfarin regimens in the setting of atrial fibrillation (AF) catheter ablation
Study Groups Treatment set: Dabigatran (n= 339); Warfarin (n = 339)

Ablation set: Dabigatran (n= 317); Warfarin (n= 318)

Methods Patients received either dabigatran (150 mg twice daily) or warfarin (combination of 1, 3, and 5 mg, with dose adjustment for a target international normalized ratio [INR] of 2.0 to 3.0), with no stratification. The trial consisted of four sequential periods: a screening period of 0 to 2 weeks; a pre-ablation treatment period of 4 to 8 weeks to achieve the desired stable anticoagulation range in patients receiving warfarin; a post-ablation treatment period of 8 weeks (starting with the ablation procedure); and a follow-up period of 1 week (9 weeks after ablation procedure).  The morning dose of dabigatran was taken on the day of ablation at the patient’s scheduled time.  Ablation was performed with uninterrupted anticoagulation treatment, and anticoagulation was continued for 8 weeks after the procedure.

From time of randomization to catheter ablation, 21 patients in the dabigatran group and 20 patients in the warfarin group prematurely discontinued treatment due to adverse events, nonadherence to study protocol or other reasons.

Duration April 2015 to November 2016
Primary Outcome Measure Incidence of major bleeding events during and up to 2 months post- ablation
Baseline Characteristics
Dabigatran Warfarin
Mean age, years ± SD 59.1 ± 10.4 59.3 ± 10.3
Male, n (%) 230 (72.6) 245 (77.0)
Mean body-mass index 28.5 28.8
Mean CHA2DS2VASc score 2.0 2.2
Activated clotting time, n (sec.) 312 (330) 308 (342)
Medical history, n (%)
Congestive heart failure 31 (9.8) 34 (10.7)
    Left ventricular dysfunction 25 (7.9) 23 (7.2)
Coronary artery disease 32 (10.1) 48 (15.1)
        Hypertension 166 (52.4) 177 (55.7)
        Previous stroke 10 (3.2) 9 (2.8)
        Diabetes mellitus 30 (9.5) 34 (10.7)
Atrial fibrillation, n (%)
       Paroxysmal 213 (67.2) 219 (68.9)
       Persistent 86 (27.1) 81 (25.5)
Long-standing persistent 18 (5.7) 18 (5.7)
Medication use, n (%)
       Vitamin K antagonists 95 (28.1) 86 (25.4)
       Dabigatran 45 (13.3) 36 (10.7)
       Rivaroxaban 29 (8.6) 29 (8.6)
       Apixaban 21 (6.2) 30 (8.9)
       Edoxaban 3 (0.9) 0
       NSAIDs 66 (19.5) 78 (23.1)
       Proton-pump inhibitors 73 (21.6) 79 (23.4)
       Statins 106 (31.4) 101 (29.9)
        Beta-blockers 195 (57.7) 204 (60.4)
Results
Incidence of Major Bleeding Events
Dabigatran, n (%) Warfarin, n (%) Absolute risk difference

(95% CI)

p-value
5 (1.6) 22 (6.9) -5.3 (-8.4 to -2.2) < 0.001
Adverse Events Common Adverse Events: N/A
Serious Adverse Events* (dabigatran vs warfarin): event that required hospitalization (7.7% vs 10.1%); event that prolonged hospitalization (3.8% vs 6.5%)
*defined as an incapacitating event or inability to perform usual activities)
Percentage that Discontinued due to Adverse Events (dabigatran vs warfarin): 5.6% vs 2.4%
Study Author Conclusions In patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin

Warfarin is a highly monitored anticoagulant with a wide array of drug-drug interactions, contraindications, and adverse drug events.  Having an alternative agent, such as dabigatran, provides both patients and physicians peace of mind.  The benefits of warfarin and dabigatran is the availability of their reversal agents, phytonadione and idarucizumab, respectively.  A complete reversal of the anticoagulant effect reduces the incidence of bleeding and other serious hemorrhagic complications.  Compared to the 66% of warfarin users who remained in the defined INR range, mean adherence with dabigatran was 97.6%.  This may have negatively impacted the bleeding outcomes of the warfarin cohort.

References

[1] Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med. 2017.

[2] Warfarin. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://www.online.lexi.com. Accessed March 21, 2017.

[3] Dabigatran etexilate. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://www.online.lexi.com. Accessed March 21, 2017.

 

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