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RE-LY: A Clinical Study of Pradaxa


Pradaxa (also known as Dabigatran Etexilate) is an inactive “parent” drug that relies on the body’s metabolism to eventually manufacture a form of the drug that the body can use as an anti-coagulant, a process that occurs after the drug has been ingested by a patient.

Anti-coagulants such as Warfarin (also known as Coumadin) and Pradaxa work in different ways.  Warfarin has been the “blood thinner” of choice for several decades.  It works by decreasing the quantity of a few key proteins in blood that causes the blood to clot.  However, many common medications and even some foods containing vitamin K can interact adversely with Warfarin.  In particular, Warfarin works by inhibiting vitamin K and reducing the presence of clotting factors.  As a result, patients taking Warfarin need regular blood tests called International Normalized Ratio (INR) and Prothrombin Time (PT), which measure the amount of time it takes for blood to clot and therefore monitor the effectiveness of the blood thinning drugs being ingested.

More recently, scientists undertook research on a set of “late stage” anticoagulants that patients could take and not have to worry about the interfering effects of common drugs or certain foods high in Vitamin K (such as kale, spinach, collard greens, parsley, broccoli, and brussel sprouts).  This recent anticoagulant drug research has resulted in the development of late stage anticoagulants, including:

  • ELIQUIS (also known as Apixaban), is in the investigational stage and being developed by Bristol-Meyers Squibb;
  •  Betrixaban (which does not yet have a brand name), is now ready for Phase III clinical trials and is being developed by  Merck and Portola Pharmaceuticals
  •  Xarelto (also known as Rivaroxaban), is manufactured and marketed by Janssen; and
  •  Pradaxa (also known as Dabigatran Etexilate), has been approved by the FDA for a little more than a year and has been under a cloud of suspicion for most of the time that it has been marketed by Boehringer Ingelheim.

Boehringer Ingelheim, the manufacturer of Pradaxa, conducted a clinical trial known as RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy).  This manufacturer sponsored study was intended to evaluate the efficacy and safety of two different doses of Pradaxa compared to Warfarin in over 18,000 patients with atrial fibrillation.  The goals of the study were to determine which anti-coagulant medication and dose was the most effective in reducing strokes (both hemorrhagic and ischemic) and embolism in these patients.  In this study, 182 patients who took the 110 mg regimen of Pradaxa sustained a stroke (1.53% per year) versus 134 patients who received the 150 mg regimen of Pradaxa (1.11% per year).  The data also revealed that 199 patients who were taking Warfarin (1.69% per year) sustained a stroke.  There was also an incidental finding that both groups of Pradaxa subjects had a higher incidence of myocardial infarctions or heart attacks than the Warfarin group, while the study participants who took Warfarin experienced a higher rate of major or life-threatening bleeding episodes and the Pradaxa subjects exhibited a higher rate of major gastrointestinal bleeding events.  The study also noted several safety concerns relative to Pradaxa, including excess dyspepsia, gastrointestinal bleeding, myocardial infarction, a potential for abnormally higher accumulation of the drug in patients who had pre-existing kidney and liver dysfunction.

On January 9, 2012, a meta-analysis (a review of all available research) was published in the Archives of Internal Medicine, which analyzed the results of the RE-LY trial as well as further data on the risks of heart attacks, myocardial infarction (MI), or acute coronary syndrome (ACS) associated with use of this anti-coagulant.  This meta-analysis included data from 7 clinical trials (which were designed to determine whether Pradaxa was effective in preventing strokes, acute venous thromboembolism, ACS, or deep vein thrombosis (DVT).  The authors of this latest study concluded that Pradaxa (Dabigatran Etexilate) use was associated with a significantly higher risk of heart attacks or ACS than had been seen in the control groups, and that the increased risk noted in these other trials was consistent with the increased risk that had been noted in the RE-LY clinical trial as well.  The authors of this meta-analysis concluded:  “Dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls.  Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.”  This latest study also notes that while the authors of the RE-LY study initially reported that the study documented a significant decrease in the risks of stroke and systemic embolism, that those positive results were outweighed once the data were further analyzed and actually showed a higher incidence of serious adverse events than initially reported, including patients who suffered serious harm due to heart attacks, strokes, and excessive bleeding.

This is just the latest in a long history of safety concerns relating to Pradaxa, which was first approved for use in Europe for the prevention of venous thromboembolism following knee and hip implant surgeries in 2008 and approved by the FDA in 2010 for use to prevent strokes and blood clots in patients with atrial fibrillation.  Pradaxa’s safety and efficacy can become compromised due to a need for twice daily dosing and creating potential compliance problems.  Pradaxa is also influenced by humidity and moisture; thus, it has a short, 60-day shelf life after opening the bottle, which can cause problems with its effectiveness.

Finally, while physicians can control an overdose or accumulation of Warfarin by administering vitamin K, which interferes with Warfarin’s effectiveness, no such “antidote” is available to counteract runaway Pradaxa levels.  Also, patients who require emergency surgery or who have suffered trauma need to have the anti-clotting properties of their drugs quickly reversed, and patients who are taking Pradaxa do not have this option, which has led to a number of patient deaths that could likely have been avoided if the patients had instead been taking Coumadin.

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