The risk of internal bleeding is an acknowledged risk with any blood thinner. However, in the case of Pradaxa, it is the leading cause of death.
According to the Food and Drug Administration (FDA), the drug is linked to thousands of adverse events, including 542 that were fatal. In addition, the Institute of Safe Medication Practices reported that Pradaxa was linked to more deaths and injuries in 2011 than any of the 800 other drugs it reviewed.
Pradaxa is prescribed for people with atrial fibrillation (AF) in order to reduce the risk of stroke. AF is a condition in which the top two chambers of the heart called the atria beat erratically and quickly, sometimes as many as 200-300 times a minute. These irregular beats are too weak to push the blood out of the heart. This allows the blood to pool in the heart, and this stagnant blood can eventually clot. If these clots leave the heart and travel to the brain, they can block blood flow to the brain and cause a stroke. People with AF are four to six times more likely to suffer a stroke than others.
One of the most dangerous side effects of Pradaxa (dabigatran etexilate) is uncontrolled bleeding, which can be fatal.
No Blood Clotting Leads to Excessive Bleeding
By inhibiting a clotting enzyme called thrombin, Pradaxa reduces the body's ability to form clots and greatly lessens the risk of stroke. While the drug is highly effective at stopping naturally occurring clots from forming, it also disables the body's ability to stop bleeding after an injury. The same mechanism that makes this drug so effective at reducing strokes is what may also cause hemorrhaging in people who take it. Normally when people suffer an internal injury, the body stops the bleeding by forming a clot.
For instance, the most common form of an internal bleeding injury is a bruise. The tissues and blood vessels under the skin are damaged and bleed, forming the bruise. The body forms blood clots to stop the bleeding. People who take blood thinners do not have the same ability to form blood clots to heal minor bumps and bruises.
Internal hemorrhaging caused by Pradaxa is so dangerous because doctors do not have a way to stop it. Prior to the release of Pradaxa, Warfarin was the drug of choice to reduce the incidence of blood clots and prevent strokes in people with irregular heartbeats, and it has been used since the 1950s. Warfarin thins the blood by decreasing the amount of vitamin K – an essential vitamin for the blood clotting process. As an anticoagulant, Warfarin also carries a bleeding risk. However, Warfarin bleeds can be stopped by administering an antidote derived from vitamin K.
Because Boehringer released the drug without an antidote, a number of individuals and families filed lawsuits against the drugmaker after suffering from uncontrolled and sometimes fatal bleeding. Plaintiffs and their families also accuse Boehringer of failing to provide adequate dosing information and misrepresenting the safety and effectiveness of the drug compared with warfarin.
In late May 2014, the manufacturer announced it would pay $650 million in settlements to cover 4,000 state and federal claims.
Treatment for Pradaxa Bleeding
One of the greatest concerns facing the medical community in effectively treating Pradaxa bleeds is the lack of an antidote. Bleeding is the No. 1 cause of death and injury related to Pradaxa, though the drug is also responsible for a number of other serious complications. People who suffer from severe bleeding are seen by ER doctors who must work quickly to reverse internal bleeding.
Because Pradaxa works by directly inhibiting the blood-clotting enzyme thrombin, doctors cannot inject clotting factors into the body to reverse the effects of the drug. This leaves doctors with very few options to treat a patient suffering from a Pradaxa-induced bleed, and often doctors are forced to simply monitor the patient until the drug is expelled by the body. This can take several hours, however, and in patients with poor kidney function it may take over 24 hours for the drug to leave the body.
Because Pradaxa is cleared from the body through the kidneys, some doctors recommend kidney dialysis to remove the drug from the body. However, patients already in a weakened state have a difficult time tolerating dialysis. In addition, it is only effective at removing 60 percent of the drug from the body. Also, there are no published studies that support this method of treatment.
In the absence of an antidote or more effective means of hemorrhage control, supportive care is usually administered in the form of fluids, blood and monitoring. For minor bleeds, delaying the next one or two doses of the drug is the only treatment available.
Who Is Most At Risk?
While there is a risk of bleeding for anyone who takes Pradaxa, certain groups of people are more at risk than others.
|You are at higher risk of suffering from Pradaxa bleeding if you:
|Are older than 75
||Have kidney problems
|Have a stomach ulcer
||Have a low body weight
|Have recent or recurrent stomach or intestinal bleeding
|You are also at risk if you take other medicines that increase bleeding risk, such as:
|Aspirin or products that contain aspirin
||Non-steroidal anti-inflammatory drugs (NSAIDs)
||Clopidogrel bisulfate (Plavix)
FDA Reviews Pradaxa Bleeding Cases
In 2011, the highest number of drug-related adverse events reported to the FDA was attributed to the two anticoagulants: Pradaxa (ranked No. 1) and Warfarin (ranked No. 2). A number of doctors, patients and their families are questioning why Pradaxa was approved without an antidote, when the drug's manufacturer knew that uncontrollable bleeding was a serious side effect. In December 2011, the FDA responded to the high incidence of bleeding injuries and deaths by beginning a reevaluation of Pradaxa's bleeding risks in comparison to warfarin.
In November 2012, the agency completed its review and stated that "bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial)." However, the FDA failed to acknowledge the lack of an antidote for Pradaxa.
Furthermore, its methods for analyzing the bleeding risk were based on insurance claim forms, administrative data and non-adjusted incidence ratios as a part of the Sentinel Initiative – a program created by the FDA to monitor the safety of drugs and devices. Critics of the Sentinel Initiative come from the agency's own ranks: The nonprofit group Observations Medical Outcomes Project (OMOP) – formed by the FDA, Pharmaceutical Research and Manufacturers of America (PhRMA) and the National Institutes of Health (NIH) – questions the accuracy of the Sentinel Initiative.
OMOP recommended that the FDA rethink its analysis. The FDA responded by claiming that it is "continuing to evaluate multiple sources of data in the ongoing safety review of this issue."
Clinical Trial Results vs. Real-World Experience
A study in the New England Journal of Medicine (NEJM) published in March 2012 revealed a discrepancy between the results of the Boehringer-sponsored RE-LY trial and results of Pradaxa in real-world clinical practice. The RE-LY trial showed that Pradaxa was safer and more effective reportedly because the patients in the study were younger, had perfect kidney function and were at a healthy weight.
Dr. Paul Harper, one of the authors of the NEJM review, wrote: "Our audit illustrates the difficulty in extrapolating trial data into clinical practice and emphasizes the need for post-marketing surveillance and adverse-event reporting to detect groups whose risk factors may not be apparent in a clinical-trial setting."
According to the study, many patients who present for treatment in actual clinical practice are older than 80, have poor kidney performance and are underweight – putting them at increased risk for bleeding events. The NEJM study also showed that a reduction in drug dosage did not lessen the occurrence of bleeds and that "the serious consequences of the lack of an effective reversal agent should not be underestimated."
In November 2012, Boehringer released the results of the RELY-ABLE study, a two-year follow-up of patients from the original RELY study. Not surprisingly, the follow-up study posted the same positive results as the initial trial. However, the extension study did not contain a warfarin group for comparison.