Real World Studies Compares Dabigatran with Rivaroxaban or Apixaban in Nonvalvular AFib

MedicalResearch.com Interview with:

Todd C. Villines, M.D. FSCCT Professor of Medicine Uniformed Services University School of Medicine Director of Cardiovascular Research and Cardiac CT Cardiology Fellowship Program Director Walter Reed National Military Medical Center Bethesda, Maryland Assistant Professor of Medicine Georgetown School of Medicine

Dr. Villines

Todd C. Villines, M.D. FSCCT
Professor of Medicine
Uniformed Services University School of Medicine
Director of Cardiovascular Research and Cardiac CT
Cardiology Fellowship Program Director
Walter Reed National Military Medical Center
Bethesda, Maryland
Assistant Professor of Medicine
Georgetown School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study was a retrospective, observational real-world analysis assessing the safety and effectiveness of novel oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) treated through the U.S. Department of Defense Military Health System. The study examined major bleeding and stroke rates in NVAF patients who had initiated treatment with dabigatran compared to those treated with rivaroxaban or apixaban.

The study examined two cohorts: one that resulted in 12,763 propensity score matched dabigatran (150 mg bid) and rivaroxaban (20 mg daily) patients, and another that resulted in 4,802 propensity score matched dabigatran (150 mg bid) and apixaban (5 mg bid) patients. Dabigatran patients demonstrated lower rates of major bleeding compared to rivaroxaban patients (2.08 percent vs 2.53) percent and similar rates of stroke (0.60 percent vs 0.78 percent). In the exploratory analysis, dabigatran and apixaban patients showed similar rates of major bleeding (1.60 percent vs 1.21 percent) and stroke (0.44 percent vs 0.35 percent). Continue reading

Association Between Statin Use and Ischemic Stroke or Hemorrhage in Patients Taking Dabigatran for A Fib

MedicalResearch.com Interview with:

Dr-Tony-Antoniou.jpg

Dr. Tony Antoniou

Dr. Tony Antoniou, PhD Research Scholar
Department of Family and Community Medicine and a Scientist
Keenan Research Centre of the Li Ka Shing Knowledge Institute
St. Michael’s Hospital
Assistant Professor in the Department of Family and Community Medicine and
Leslie Dan Faculty of Pharmacy
University of Toronto, Toronto, Ontario

MedicalResearch.com: What is the background for this study?
What are the main findings?

Response: Dabigatran etexilate is an anticoagulant that is commonly used for stroke prevention in patients with atrial fibrillation. Absorption of dabigatran etexilate is opposed by intestinal P-glycoprotein, an efflux transporter. Once absorbed, dabigatran etexilate is converted to its active form by carboxylesterase enzymes. Unlike other statins, simvastatin and lovastatin can inhibit P-glycoprotein and carboxylesterase. This may result in increased absorption of dabigatran etexilate, thereby increasing the risk of bleeding. Conversely, inhibition of carboxylesterase may decrease the effectiveness of dabigatran etexilate.

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Dabigatran Carries Risk of GI Bleeding; Risk Greater in Kidney Disease, Black Patients

Inmaculada Hernandez, PharmD PhD Student, Health Services Research and Policy Deparment of Health Policy and Management Graduate School of Public Health University of Pittsburgh Pittsburgh, PA 15261MedicalResearch.com Interview with:
Inmaculada Hernandez, PharmD

PhD Student, Health Services Research and Policy
Deparment of Health Policy and Management
Graduate School of Public Health
University of Pittsburgh Pittsburgh, PA 15261

Medical Research: What is the background for this study? What are the main findings?

Response: The approval of dabigatran was considered a major contribution to the therapeutic arsenal of anticoagulants since warfarin, whose therapeutic management is complicated, was the only oral anticoagulant approved before 2011. Clinicians therefore considered dabigatran a very promising drug; however, the safety warnings released by the regulatory agencies and the reports of bleeding published in 2011 raised concerns about the safety profile of dabigatran. By the time we initiated our study, the FDA had concluded that dabigatran was associated with similar rates of bleeding than warfarin. However, the results of this observational study were not adjusted by patient characteristics. We therefore compared the risks of bleeding with dabigatran and warfarin adjusting for patient characteristics and using propensity score methods to mitigate selection biases, which observational studies are sensitive to.

We found that dabigatran was associated with a higher risk of major bleeding and gastrointestinal bleeding than warfarin. However, the risk of intracranial bleeding was lower with dabigatran. In addition, we found that the increased risk of bleeding with dabigatran was specially higher for African Americans and for patients with chronic kidney disease.

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Monoclonal Idarucizumab Antibody May Reverse Dabigatran Anticoagulation

MedicalResearch.com Interview with:
Dr. Joanne van Ryn, PhD
Department of CardioMetabolic Disease Research
Boehringer Ingelheim GmbH & Co., Germany

MedicalResearch: What is the background for this study? What are the main findings?

Response: Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific antidote to reverse the anticoagulant effect of dabigatran. Currently, there are no specific antidotes available for any of the newer oral anticoagulants, or NOACs, to complement the existing range of bleed management options during critical care situations. Idarucizumab is being developed to provide physicians with an additional therapeutic option they could consider should a patient require emergency intervention or if a patient experiences uncontrolled bleeding.

Pre-clinical studies indicated idarucizumab binds specifically to and inhibits dabigatran. Phase I data with idarucizumab in healthy volunteers demonstrated the potential of idarucizumab to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation. In that placebo-controlled study, idarucizumab did not cause any clinically relevant side effects.

This phase I sub-study in 35 healthy volunteers showed that idarucizumab restores dabigatran-induced inhibition of fibrin formation at a small wound site. Fibrin, the main component of a blood clot, was assessed by measuring levels of fibrinopeptide A (FPA), a substance that is released when fibrin is formed. Fibrin formation was assessed after a small scratch, similar to a paper cut, was made. Measurements were conducted at baseline, after administration of dabigatran, and after subsequent administration of idarucizumab or placebo. The results showed that dabigatran almost completely inhibited the production of FPA at the wound site, and that idarucizumab restored FPA production:

  • At baseline, before the volunteers took dabigatran, the average level of FPA was 3981 ng/mL.
  • On day three, 2.5 hours after the volunteers took dabigatran, the average level of FPA was 208 ng/mL, an approximate 95 percent decrease compared to baseline.
  • On day four, 2.5 hours after the volunteers took dabigatran and 30 minutes after they were infused with 1 g, 2 g or 4 g of idarucizumab, FPA levels were 24 percent, 45 percent and 95 percent, respectively, of the average baseline level.

The restored fibrin production at the wound site after idarucizumab dosing with 2g or 4g also correlated with reversal of the dabigatran-anticoagulation activity in circulating blood.

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Atrial Fibrillation: More Bleeding With Dabigatran Than Warfarin

Yuting Zhang, Ph.D. Associate Professor and Director Pharmaceutical Economics Research Group University of Pittsburgh Graduate School of Public Health Department of Health Policy and Management.MedicalResearch.com Interview with:
Yuting Zhang, Ph.D.

Associate Professor and Director
Pharmaceutical Economics Research Group
University of Pittsburgh Graduate School of Public Health
Department of Health Policy and Management.

Medical Research: What are the main findings of the study?

Dr. Zhang: Patients with atrial fibrillation who take the blood thinner dabigatran are at greater risk for major bleeding and gastrointestinal bleeding than those who take warfarin, indicating that greater caution is needed when prescribing dabigatran to certain high-risk patients. High-risk groups include those who are 75 and older; African Americans; those with chronic kidney disease; and those with seven or more co-existing medical problems.

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Dabigatran: Comparison Mini-Sentinel Clinical Trials and GI Bleeding

Ilke Sipahi, MD Department of Cardiology Acibadem University Medical School, Istanbul, Turkey Harrington Heart and Vascular Institute, University Hospitals Case Medical Cente  Case Western Reserve University School of Medicine, Cleveland, OhioMedicalResearch.com Interview with:
Ilke Sipahi, MD
Department of Cardiology
Acibadem University Medical School, Istanbul, Turkey
Harrington Heart and Vascular Institute, University Hospitals Case Medical Cente, Case Western Reserve University School of Medicine, Cleveland, Ohio

MedicalResearch.com: Were you surprised at the extreme difference between these 2 analyses?

Answer: I was surprised. However, it is not unusual to find completely
contradictory results in medical studies. I was more surprised at the
fact that FDA paid more attention to it administrative observational
dataset rather than the huge large randomized clinical trials, all
showing excess GI bleeds with dabigatran (Pradaxa). Anyone who is even
slightly familiar with the medical literature knows that randomized trials are the gold standard in medical studies.
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Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism

 Author Interview: Sam Schulman M.D., FRCPC(C) Professor, Division of Hematology and Thromboembolism, Department of Medicine Associate Professor, Medicine, Karolinska Institute, Stockholm, Sweden Director, Clinical Thromboembolism Program Hamilton Health Sciences, Hamilton General Hospital, Hamilton, OntarioMedicalResearch.com  Author Interview: Sam Schulman M.D., FRCPC(C)
Professor, Division of Hematology and Thromboembolism, Department of Medicine
Associate Professor, Medicine, Karolinska Institute, Stockholm, Sweden
Director, Clinical Thromboembolism Program Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario

MedicalResearch.com: What are the main findings of the study?

Response: Similar effect of dabigatran  as warfarin, 92% risk reduction compared to placebo. The risk of bleeding is reduced by almost 50% compared to warfarin but in comparison with placebo there is an increased risk of minor bleeding. No routine coagulation monitoring or dose adjustments are required, making the treatment convenient for patients and physicians.
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