RE-ALIGN

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Eikelboom JW, et al. "Dabigatran versus warfarin in patients with mechanical heart valves". The New England Journal of Medicine. 2013. 369(13):1206-1214.
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Clinical Question

In patients with mechanical heart valves, what dose of dabigatran best achieves therapeutic trough levels, and how do these doses compare to warfarin in terms of efficacy and safety?

Bottom Line

In this phase II study, patients receiving dabigatran had more thromboembolic events and bleeding than those receiving standard therapy with warfarin.

Major Points

Dabigatran is an oral direct thrombin inhibitor with several benefits compared to warfarin, and growing evidence supports its use in various thrombotic conditions. For example, among patients with atrial fibrillation, RE-LY (2009) demonstrated the superior efficacy of dabigatran for stroke prevention without increasing rates of bleeding compared to warfarin. For patients with acute VTE, RE-COVER (2009) demonstrated similar efficacy and safety with dabigatran compared to warfarin. However, among patients with mechanical heart valves, no large randomized trial had compared dabigatran to the standard of care warfarin.

The 2013 Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN) randomized 252 patients with recently placed mechanical heart valves in a 2:1 unblinded fashion to either dabigatran or warfarin, with patients stratified according to interval since replacement (within 3-7 days in population A; ≤3 months in population B). As a dose-finding trial, the primary endpoint was time above target dabigatran trough level, but the major secondary endpoints included thromboembolism and bleeding. The Re-ALIGN study aimed to study outcomes at 12 weeks of follow-up, with extended follow-up done as a separate study termed RE-ALIGN-EX. However, the trial was terminated early when an interim analysis revealed more thromboembolic events and bleeding with dabigatran compared to warfarin.

Attempts to explain the excess in thromboembolic events center on the selection of the dabigatran trough level, extrapolation of studies of dabigatran for different indications, and the potential decreased efficacy of dabigatran in the postoperative hypercoagulable state. The selection of 50ng/mL as the target dabigatran trough level was based on data from RE-LY, which enrolled older patients (mean age 71 years). Patients in RE-ALIGN, however, were considerably younger (mean age 56 years) with better renal function than the older cohort, and therefore may have more rapidly cleared the drug leading to more time below the target dabigatran trough level.[1] In addition, dabigatran may have downstream effects on the coagulation cascade that impair its ability to blunt the postoperative hypercoagulable state relative to warfarin.

Following RE-ALIGN, the FDA notified clinicians that dabigatran was contraindicated in patients with mechanical heart valves, and that such patients treated with off-label dabigatran should be immediately transitioned to a vitamin K antagonist such as warfarin.[2]

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[3]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)

Design

  • Multicenter, phase 2, open-label, randomized controlled trial
  • N=252
    • Dabigatran (n=168)
    • Warfarin (n=84)
  • Setting: 39 centers in 10 countries
  • Enrollment: 2011-2012
  • Follow-up: 12 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Plasma dabigatran trough level

Population

Inclusion Criteria

  • Age 18-75 years
  • One of the following:
  • Undergoing aortic and/or mitral valve replacement (population A) or prior mitral and/or aortic valve replacement ≥3 months prior

Exclusion Criteria

  • Prior prosthetic heart valve replacement
  • Replacement of ascending aorta or aortic root
  • Bioprosthetic valve replacement, mechanical tricuspid valve replacement, or mechanical pulmonary valve replacement concomitantly with the index surgery
  • Complex congenital heart abnormality
  • Clinically relevant paravalvular leaks
  • Endocarditis
  • ACS within one month
  • Uncontrolled hypertension
  • History of hemorrhagic stroke
  • High risk for bleeding
  • Recent malignancy or radiation therapy
  • Recent emergency surgery
  • Planned surgery or intervention within one month after randomization
  • Hepatitis or abnormal liver function (persistently elevated ALT, AST or alkaline phosphatase >3x ULN)
  • CrCl <40 mL/min
  • Clear indication for long-term dual antiplatelet therapy
  • Oral anticoagulant therapy for indications for which dabigatran is not approved except mechanical valves
  • Treatment with selected drugs that may interact with dabigatran
  • Risk of pregnancy or with known allergy to dabigatran or warfarin

Baseline Characteristics

From the dabigatran group.

  • Demographics: male 64%, age 56 years, Canada 9%, W. Europe 58%, Central Europe 33%
  • Valve: aortic 67%, mitral 29%, both 4%
  • Baseline health data: CrCl 107.8 mL/min
  • Thromboembolic risk: low 30%, intermediate or high 70%
  • Surgery timing: same hospitalization 79% (population A), ≥3 months prior 21% (population B)
  • ASA or clopidogrel after surgery: Either or both 30%, both 2%
  • PMH: CAD 23%, MI 5%, AF 22%, A-flutter 4%, NYHA class ≥2 37%, LVEF ≤40% 7%, HTN 60%, DM 16%, HLD 45%, CVA 3%, TIA 2%, hypercoaguability 2%
  • PSH: CABG 3%
  • Surgical risk by EuroSCORE: 2.3 (≥10 is very high risk)

Interventions

  • 2:1 randomization to dabigatran or warfarin
    • Dabigatran group: Dabigatran was adjusted to goal trough ≥50 ng/mL, starting doses at 150mg PO BID if CrCl <70 mL/min, 200mg PO BID if 70-109 mL/min, 300mg PO BID for CrCl ≥110 mL/min
      • If dabigatran trough remained <50ng/mL at the highest dose, the patient was switched to VKA therapy
      • If CrCl worsened to <30mL/min or decrease from baseline ≥50%, the patient was switched to VKA therapy
    • Warfarin group: Target INR 2-3 if mechanical aortic valve and no additional thromboembolism risk factors or 2.5-3.5 for all others, including those with mechanical mitral valve

Outcomes

Primary Outcome

Comparisons are population A vs. population B vs. all patients.

Trough dabigatran level
Week 1: 66 vs. 123 vs. 75 ng/mL
Week 2: 69 vs. 115 vs. 79 ng/mL
Week 4: 98 vs. 125 vs. 103 ng/mL
End of treatment: 107 vs. 125 vs. 110 ng/mL

Secondary Outcomes

Comparisons are dabigatran vs. warfarin.

Safety outcomes
Death: 1% vs. 2% (HR 0.25; 95% CI 0.02-2.72; P=0.26)
Stroke: 5% vs. 0%
MI: 3% vs. 0%
Systemic embolism: 0% vs. 0%
TIA: 2% vs. 2% (HR 0.75; 95% CI 0.13-4.49; P=0.75)
Bleeding: (any) 45% vs. 10% (HR 2.45; 95% CI 1.23-4.86; P=0.01)
Bleeding: (major) 7% vs. 2% (HR 1.76; 95% CI 0.37-8.46; P=0.48)
All patients had pericardial bleeding.

Criticisms

  • Open-label design may have introduced bias.
  • Choice of 50ng/mL trough level may not have been appropriate.

Funding

Boehringer Ingelheim

Further Reading

  1. Hylek EM. "Dabigatran and mechanical heart valves -- Not as easy as we hoped." The New England Journal of Medicine. 2013;369:1264-1266.
  2. FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves
  3. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.