Clayton Jensen, PharmD Candidate 2018

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves

Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. N Engl J Med. 2013 Sep 26; 369 (13): 1206-14.
BACKGROUND
Background Prosthetic heart valve-replacement is performed in several hundred thousand patients worldwide each year 1
Mechanical valves are more durable than bioprosthetic valves but typically require lifelong anticoagulant therapy 2
Vitamin K antagonists provide excellent protection against thromboembolic complications (TCs) in patients with
mechanical heart valves3 but require restrictions on food, alcohol, and drugs and life-long coagulation monitoring
Due to limitations of vitamin K antagonist, many patients opt for bioprosthesis rather than a mechanical valve,
despite higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprosthesis
STUDY OVERVIEW
Funding Boehringer Ingelheim sponsored this study
Steering committee was responsible for study design/protocols/study oversight/analysis (authors)
Trial design Prospective, randomized, phase 2, open-label trial with blinded end-point adjudication
Purpose To validate a new regimen for the administration of dabigatran to prevent thromboembolic complications in patients
with mechanical heart valves
Objectives To compare the efficacy and safety of dabigatran to warfarin for prevention of thromboembolic complications in
patients with mechanical heart valves
METHODS
Duration Study Occurred from November 2011 to November 2012
Population A ended study in October 2012; Population B ended study in November 2012
Location Multicenter, international study: 39 centers in 10 countries
Eligibility Inclusion criteria Exclusion criteria
Criteria 18-75 years of age Previous prosthetic heart valve replacement
Undergoing implantation Aortic root replacement, replacement of ascending aorta, concomitant
of a mechanical bileaflet bioprosthetic valve replacement or mechanical tricuspid or pulmonary valve
valve in the aortic or replacement at the time of the index valve replacement surgery (defined as the
mitral position or both surgery that had been conducted within 7 days of randomization for population
(population A) A or at least three months ago, for population B)
Had undergone Clinically relevant paravalvular leaks, endocarditis, complex congenital heart
implantation of a abnormality, acute coronary syndrome with one month, uncontrolled
mechanical bileaflet hypertension, recent emergency surgery, planned surgery or intervention within
mitral valve (with or one month after randomization, any history of hemorrhagic stroke, at high risk
without mechanical of bleeding, active hepatitis or abnormal liver function with persistently elevated
bileaflet aortic-valve ALT, AST or alkaline phosphatase more than 3x the upper limit of normal,
replacement) more than 3 creatinine clearance <40 mL/min, patients with a clear indication for long-term
months prior to dual antiplatelet therapy or oral anticoagulant therapy for other indications for
randomization which dabigatran in not approved, recent malignancy or radiation therapy,
(population B) treatment with selected drugs that may interact with dabigatran, at risk of
pregnancy or with known allergy to dabigatran or warfarin.
Intervention Patients assigned in a 2:1 ratio to receive either dabigatran or warfarin.
o Dabigatran was adjusted to goal trough 50 ng/mL (primarily based on data from the RE-Ly trial, in which
dabigatran at a dose of 150 mg BID, as compared to warfarin, had superior efficacy and similar safety in
patients with atrial fibrillation).
The selection of initial dabigatran dose was based on kidney function.
CrCl < 70 mL/min = 150 mg BID
CrCl 70 109 mL/min = 220 mg BID
CrCl > 109 mL/min = 300 mg BID
If Dabigatran trough remained < 50 ng/mL, the patient was switched to nonstudy vitamin K
antagonist therapy.
If CrCl worsened to < 30 mL/min or decreased from baseline 50%, the patient was switched to
nonstudy vitamin K antagonist therapy.
o Warfarin dose adjusted to achieve:
INR 2 3 in those deemed to be at low thromboembolic risk (patients with a mechanical aortic valve with
no additional risk factors).
INR 2.5 3.5 in those deemed to be at intermediate or high thromboembolic risk (patients with a
mechanical aortic valve with additional risk factors or a mechanical mitral valve).
Designed as a 12-week trial. At the end of 12 weeks, trial participants could choose to stop the study drug and
switch to a nonstudy vitamin K antagonist or they choose to enroll in an extension trail.
o Participants in the extension trial continued to receive the assigned study drug for a planned interval of up to
84 months.
Outcomes Primary outcome
o Trough plasma level of Dabigatran.
Secondary Efficacy outcomes
o Death, Stroke, Myocardial infarction, Systemic embolism, TIA
Secondary Safety outcomes
o Bleeding (major and any)
Trial was designed to test a dosing regimen that would result in less than 10% of patients having a dabigatran
Statistical trough level below 50 ng/mL.
Analysis o Required a sample of 405 patients randomly assigned to receive dabigatran or warfarin in a ratio of 2:1.
Clinical outcomes were analyzed per an intention-to-treat principle, with all patients who underwent
randomization included in the analysis
Events that occurred after randomization and up until November 28, 2012 were included in the primary analysis
of clinical outcomes.
A P value of 0.05 or less was considered to indicate statistical significance.
 Clayton Jensen, PharmD Candidate 2018
RESULTS
Study Based on an interim unblinded review of safety data, the data and safety monitoring board recommended
Discontinuation discontinuation of the study for population A on October 11, 2012, and for population B on November 28, 2012,
because of excess thromboembolic and bleeding events among patients in the dabigatran group.4
Study 252 patients underwent randomization (2:1)
Population o 168 = dabigatran; 84 = warfarin
o 199 = population A; 53 = population B
o 172 = Aortic valve; 71 = Mitral valve; 9 = both
243 patients received treatment
o 162 = dabigatran; 81 = warfarin
158 patients participated in the extension trial
o 99 = dabigatran; 59 = warfarin
Baseline characteristics were similar
o Mean age: 56.0 = dabigatran; 55.7 = warfarin
o Male: 64% = dabigatran; 67% = warfarin
Primary
Endpoint

Secondary
Endpoints

DISCUSSION
Authors The use of dabigatran in patients with mechanical heart valves was associated with increased rates of
Conclusions4 thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess
risk.
At the doses tested, dabigatran was not as effective as warfarin for the prevention of thromboembolic
complications in patients with mechanical heart valves and was associated with an increased risk of bleeding.
Strengths4 Clinical outcomes were prespecified, objectively defined, and independently adjudicated by experts who were
unaware of the study-group assignments, all factors that minimize the potential for bias
Limitations4 Open label trial, thus subject to bias
Choice of 50 ng/mL trough level of dabigatran may not have been appropriate
Application to Dabigatran is now contraindicated in patients with mechanical prosthetic heart valve.
Practice5

1. Sun JC, Davidson MJ, Lamy A, Eikelboom JW. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 2009;374:565-76.
2. Stassano P, Di Tommaso L, Monaco M, et al. Aortic valve replacement: a prospective randomized evaluation of mechanical versus biological valves in patients ages 55 to 70 years.
J Am Coll Cardiol 2009;54: 1862-8.
3. Cannegieter SC, Rosendaal FR, Brit E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994;89:635-41.
4. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. N Engl J Med. 2013 Sep 26; 369 (13): 1206-14.
5. Product Information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield , CT, 2014.