Therapeutics
Dabigatran increased bleeding and stroke compared with warfarin after mechanical heart valve implantation
Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-14.
Clinical impact rating: C ★★★★★★★ Question
Conclusion
Does dabigatran prevent thromboembolic complications compared with warfarin after implantation of mechanical heart valves?
Dabigatran increased bleeding and stroke compared with warfarin in patients with mechanical heart valves.
Methods
*See Glossary.
Design: Randomized controlled trial (Randomized Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement [RE-ALIGN]). ClinicalTrials.gov NCT01452347 and NCT01505881. Allocation: Concealed.* Blinding: Blinded* (event adjudication committee and echocardiogram analysis). Follow-up period: {Mean 26 weeks; maximum 55 weeks}†. The trial was stopped early for harm. Setting: 39 centers in 10 countries. Patients: 252 patients 18 to 75 years of age (mean age 56 y, 65% men) who were having a mechanical bileaflet valve implanted in the aortic and/or mitral valve position (n = 199) or who had a mechanical bileaflet mitral valve implanted, with or without aortic valve replacement, > 3 months before randomization (n = 53). Exclusion criteria included uncontrolled hypertension, high risk for bleeding, severe renal impairment, or active liver disease. Intervention: Dabigatran, initial dose 150 to 300 mg twice daily based on renal function, targeted to a trough plasma level ≥ 50 ng/ mL (n = 168); or warfarin, targeted to an international normalized ratio of 2 to 3 in patients at low thromboembolic risk and 2.5 to 3.5 in those at intermediate or high risk (n = 84). After 12 weeks, patients could enroll in a trial extension and continue assigned drugs, or switch from the study drug to a nonstudy vitamin K antagonist. Outcomes: Included death, stroke, transient ischemic attack (TIA), systemic embolism, valve thrombosis, myocardial infarction (MI), and bleeding. Patient follow-up: {90%}† (100% were included in the intentionto-treat analysis).
Main results Dabigatran increased bleeding compared with warfarin; groups did not differ for death or TIA (Table). Dabigatran increased risk for stroke compared with warfarin (5.4% vs 0%, {P = 0.024}‡); groups did not differ for valve thrombosis without symptoms (3.0% vs 0%, {P = 0.13}‡) or MI (1.8% vs 0%, {P = 0.29}‡). No patients had systemic embolism. Dabigatran vs warfarin in patients with mechanical heart valves§ Outcomes
Dabigatran
Warfarin
Death
0.60%
2.4%
75% (−166 to 98)
Not significant
TIA
1.8%
2.4%
25% (−331 to 87)
Not significant
RRI (CI)
NNH (CI)
124% (21 to 286)
7 (3 to 40)
Bleeding
27%
12%
At a mean 26 wk of follow-up RRR (95% CI) NNT (CI)
†Information provided by author. ‡P values calculated from event rates in article using the Fisher exact test.
Source of funding: Boehringer Ingelheim. For correspondence: Dr. F. Van de Werf, University Hospitals Leuven, Leuven, Belgium. E-mail [email protected]. ■
Commentary In the RE-LY trial, dabigatran, 150 mg twice daily, decreased the risk for stroke or systemic embolism compared with warfarin in patients with nonvalvular atrial fibrillation (1). Because of the known drawbacks of warfarin, including the need for frequent blood draws and dose adjustments, as well as food–drug and drug–drug interactions, there has been an impetus to find a better way to anticoagulate patients with mechanical heart valves. Based on this, the investigators undertook the RE-ALIGN trial. The results unexpectedly found an increase in stroke and bleeding in patients randomized to dabigatran compared with warfarin, necessitating early termination of the study. Why did dabigatran work in RE-LY (1) but not in RE-ALIGN? The reasons are unclear but may be related, in part, to the different mechanisms of thrombus formation in patients with mechanical valves. In such patients, a prosthetic nidus activates the coagulation cascade, whereas in patients with nonvalvular atrial fibrillation, thrombus largely results from stagnant flow in the left atrial appendage. As such, this may be a class effect of novel oral anticoagulants, rather than limited to dabigatran, although data are lacking. Since both stroke and bleeding risk were higher with dabigatran, it is unlikely that a lower or higher dose would have led to a better outcome. Are these findings limited to mechanical valves or could dabigatran be considered in other scenarios? There is currently no evidence showing the safety or efficacy of dabigatran in patients with valvular heart disease or bioprosthetic valves; therefore, use of dabigatran in these patients is not recommended. The RE-ALIGN study serves as a caution about off-label drug use in unstudied populations. The RE-ALIGN study found increased risk for harm with dabigatran compared with warfarin in patients with mechanical heart valves. Therefore, off-label use of dabigatran in these patients remains contraindicated. Theodore J. Kolias, MD University of Michigan Ann Arbor, Michigan, USA Reference 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
§TIA = transient ischemic attack; other abbreviations defined in Glossary. RRR, RRI, NNH, and CI calculated from hazard ratios and control event rates in article.
JC6
© 2013 American College of Physicians
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a NYU Medical Center Library User on 03/10/2017
Dabigatran increased bleeding and stroke compared with warfarin after mechanical heart valve implantation
Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-14.
Clinical impact rating: C ★★★★★★★ Question
Conclusion
Does dabigatran prevent thromboembolic complications compared with warfarin after implantation of mechanical heart valves?
Dabigatran increased bleeding and stroke compared with warfarin in patients with mechanical heart valves.
Methods
*See Glossary.
Design: Randomized controlled trial (Randomized Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement [RE-ALIGN]). ClinicalTrials.gov NCT01452347 and NCT01505881. Allocation: Concealed.* Blinding: Blinded* (event adjudication committee and echocardiogram analysis). Follow-up period: {Mean 26 weeks; maximum 55 weeks}†. The trial was stopped early for harm. Setting: 39 centers in 10 countries. Patients: 252 patients 18 to 75 years of age (mean age 56 y, 65% men) who were having a mechanical bileaflet valve implanted in the aortic and/or mitral valve position (n = 199) or who had a mechanical bileaflet mitral valve implanted, with or without aortic valve replacement, > 3 months before randomization (n = 53). Exclusion criteria included uncontrolled hypertension, high risk for bleeding, severe renal impairment, or active liver disease. Intervention: Dabigatran, initial dose 150 to 300 mg twice daily based on renal function, targeted to a trough plasma level ≥ 50 ng/ mL (n = 168); or warfarin, targeted to an international normalized ratio of 2 to 3 in patients at low thromboembolic risk and 2.5 to 3.5 in those at intermediate or high risk (n = 84). After 12 weeks, patients could enroll in a trial extension and continue assigned drugs, or switch from the study drug to a nonstudy vitamin K antagonist. Outcomes: Included death, stroke, transient ischemic attack (TIA), systemic embolism, valve thrombosis, myocardial infarction (MI), and bleeding. Patient follow-up: {90%}† (100% were included in the intentionto-treat analysis).
Main results Dabigatran increased bleeding compared with warfarin; groups did not differ for death or TIA (Table). Dabigatran increased risk for stroke compared with warfarin (5.4% vs 0%, {P = 0.024}‡); groups did not differ for valve thrombosis without symptoms (3.0% vs 0%, {P = 0.13}‡) or MI (1.8% vs 0%, {P = 0.29}‡). No patients had systemic embolism. Dabigatran vs warfarin in patients with mechanical heart valves§ Outcomes
Dabigatran
Warfarin
Death
0.60%
2.4%
75% (−166 to 98)
Not significant
TIA
1.8%
2.4%
25% (−331 to 87)
Not significant
RRI (CI)
NNH (CI)
124% (21 to 286)
7 (3 to 40)
Bleeding
27%
12%
At a mean 26 wk of follow-up RRR (95% CI) NNT (CI)
†Information provided by author. ‡P values calculated from event rates in article using the Fisher exact test.
Source of funding: Boehringer Ingelheim. For correspondence: Dr. F. Van de Werf, University Hospitals Leuven, Leuven, Belgium. E-mail [email protected]. ■
Commentary In the RE-LY trial, dabigatran, 150 mg twice daily, decreased the risk for stroke or systemic embolism compared with warfarin in patients with nonvalvular atrial fibrillation (1). Because of the known drawbacks of warfarin, including the need for frequent blood draws and dose adjustments, as well as food–drug and drug–drug interactions, there has been an impetus to find a better way to anticoagulate patients with mechanical heart valves. Based on this, the investigators undertook the RE-ALIGN trial. The results unexpectedly found an increase in stroke and bleeding in patients randomized to dabigatran compared with warfarin, necessitating early termination of the study. Why did dabigatran work in RE-LY (1) but not in RE-ALIGN? The reasons are unclear but may be related, in part, to the different mechanisms of thrombus formation in patients with mechanical valves. In such patients, a prosthetic nidus activates the coagulation cascade, whereas in patients with nonvalvular atrial fibrillation, thrombus largely results from stagnant flow in the left atrial appendage. As such, this may be a class effect of novel oral anticoagulants, rather than limited to dabigatran, although data are lacking. Since both stroke and bleeding risk were higher with dabigatran, it is unlikely that a lower or higher dose would have led to a better outcome. Are these findings limited to mechanical valves or could dabigatran be considered in other scenarios? There is currently no evidence showing the safety or efficacy of dabigatran in patients with valvular heart disease or bioprosthetic valves; therefore, use of dabigatran in these patients is not recommended. The RE-ALIGN study serves as a caution about off-label drug use in unstudied populations. The RE-ALIGN study found increased risk for harm with dabigatran compared with warfarin in patients with mechanical heart valves. Therefore, off-label use of dabigatran in these patients remains contraindicated. Theodore J. Kolias, MD University of Michigan Ann Arbor, Michigan, USA Reference 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
§TIA = transient ischemic attack; other abbreviations defined in Glossary. RRR, RRI, NNH, and CI calculated from hazard ratios and control event rates in article.
JC6
© 2013 American College of Physicians
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a NYU Medical Center Library User on 03/10/2017
