Clinical trial NCT01868243: Dabigatran Versus Warfarin After Mitral and/or Aortic Bioprosthesis Replacement and Atrial Fibrillation Postoperatively
Official title: Dabigatran Versus Warfarin After Mitral and Aortic Bioprosthesis Replacement for the Management of Atrial Fibrillation Postoperatively: Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Primary Disease
Keywords: Atrial Fibrillation
Bioprosthesis
Stroke
Dabigatran
Warfarin
Lead sponsor: Hospital Ana Nery
Sponsor class: OTHER
First posted: 2013-06-04
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: DAWA is a phase 2, prospective, open-label, randomized, pilot study. The main variable to be observed in this study is intracardiac thrombus. There are no formal primary or secondary clinical efﬁcacy or safety outcomes because it is a pilot study.

Detailed description: Mortality and morbidity events (reversible ischemic neurological deficit, ischemic and hemorrhagic stroke, systemic embolism, any bleeding, prosthesis valve thrombosis and death) were evaluated in an exploratory manner. The details of the trial design have been previously described.8 The trial protocol was approved by the local ethics and research committee in the city of Salvador-Brazil, and written informed consent was obtained from all patients. An independent data and safety monitoring board closely monitored the trial. All the members contributed to the interpretation of the results, wrote the first version of the manuscript and approved all versions, made the decision to submit the manuscript for publication, and vouch for the accuracy and completeness of the data reported and the fidelity of this article to the study protocol.

Patients eligible for inclusion in the study were 18 to 64 years old, underwent mitral and/or aortic bioprosthesis valve replacement at least 3 months prior to entering the study and had documented AF postoperatively in addition to exclusion of atrial thrombus or valve prosthesis thrombosis by transesophageal echocardiography (TEE). Non-contrast brain computed tomography (CT) without hemorrhage or findings of acute cerebral infarction on the last 2 days of screening was also necessary.

Patients were randomly assigned to receive dabigatran or warfarin by a computer generated list of random numbers performed to 1:1 ratio between the groups. Following that, the allocation sequence was concealed from the researcher enrolling participants in sequentially numbered, opaque, black, sealed envelopes. After randomization, patients had study visits scheduled at 7 days (via telephone) and at 30 days (personally) with a monthly follow-up for 90 days. After this, non-contrast brain CT and TEE were repeated. The former was executed to document possible cerebral events with no clinical expression and the latter to analyze the incidence of intracardiac thrombi, new dense spontaneous echo contrast (SEC) or its resolution, in addition to thrombosis or dysfunction of valvular prosthesis.

Eligibility criteria: Inclusion Criteria:

1. Age from 18 to 64 years at entry
2. Patients with mitral and/or aorthic valve bioprosthesis for at least 3 months postoperatively
3. There is 12-lead electrocardiogram documented AF on the day of screening or randomization; or a 24-hour Holter electrocardiogram recording showing AF episodes postoperatively
4. Brain computed tomography scan without hemorrhage or findings of acute cerebral infarction on the last 2 days of screening
5. Exclusion of atrial thrombus or valve prosthesis thrombosis by transesophageal echocardiograph on the last 2 days of screening
6. Written, informed consent

Exclusion Criteria:

1. Previous hemorrhagic stroke
2. Ischemic stroke in the last 6 months
3. Severe renal impairment (creatinine clearance rates \< 30 ml/min)
4. Active liver disease (any etiology)
5. Concomitant use of any antiplatelet (aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, etc)
6. Increased risk of bleeding (congenital or acquired)
7. Uncontrolled hypertension
8. Gastrointestinal hemorrhage within the past year
9. Anemia (hemoglobin level \<10 g/dL) or thrombocytopenia (platelet count \< 100 × 109/L)
10. Active infective endocarditis
11. Pregnant or lactating women

Primary outcomes:
measure: Intracardiac Thrombus
timeFrame: 90 days
Secondary outcomes:
measure: Spontaneous Echo Contrast
timeFrame: 90 days
Other outcomes:
Locations:
city: Salvador
country: Brazil
facility: Hospital Ana Nery
state: Bahia
Study officials:
affiliation: Hospital Ana Nery
name: Andre R Duraes, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet. 2006 Sep 16;368(9540):1005-11. doi: 10.1016/S0140-6736(06)69208-8.
citation: Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005 Nov;5(11):685-94. doi: 10.1016/S1473-3099(05)70267-X.
citation: Sun JC, Davidson MJ, Lamy A, Eikelboom JW. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet. 2009 Aug 15;374(9689):565-76. doi: 10.1016/S0140-6736(09)60780-7.
citation: Heras M, Chesebro JH, Fuster V, Penny WJ, Grill DE, Bailey KR, Danielson GK, Orszulak TA, Pluth JR, Puga FJ, et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol. 1995 Apr;25(5):1111-9. doi: 10.1016/0735-1097(94)00563-6.
citation: Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.
citation: Duraes AR, de Souza Roriz P, de Almeida Nunes B, Albuquerque FP, de Bulhoes FV, de Souza Fernandes AM, Aras R. Dabigatran Versus Warfarin After Bioprosthesis Valve Replacement for the Management of Atrial Fibrillation Postoperatively: DAWA Pilot Study. Drugs R D. 2016 Jun;16(2):149-54. doi: 10.1007/s40268-016-0124-1.
citation: Duraes AR, Roriz PD, Bulhoes FV, Nunes BD, Muniz JQ, Neto IN, Fernandes AM, Reis FJ, Camara EJ, Junior ED, Segundo DTs, Silva FP, Aras R. Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: protocol. JMIR Res Protoc. 2014 Apr 1;3(2):e21. doi: 10.2196/resprot.3014.