In its first year on the market, Pradaxa was the most frequently mentioned drug in the U.S. Food and Drug Administration (FDA) database of adverse event reports. The FDA received 817 reports of adverse events involving Pradaxa in 2011 alone. Additional reports from manufacturers, databases and health professionals brought the number of serious adverse events associated with Pradaxa in 2011 to 3,781— 542 of which were fatal. Nearly 2,400 cases involved hemorrhage, 291 cases involved acute kidney failure, 644 cases involved stroke and 15 cases involved suspected liver failure.
The number of adverse events associated with Pradaxa reached 3,781 in 2011.
Another blood-thinner, warfarin, ranked second in 2011, with 490 direct reports to the FDA and 1,106 cases overall, including 72 deaths. In the past, warfarin consistently had one of the largest numbers of direct reports to the FDA. The nonprofit Institute of Safe Medication Practices (ISMP) gathered and published the data in its publication QuarterWatch.
“Within weeks of approval, the new drug surged to near the top of the adverse event rankings with reports of hemorrhage and blood clots,” ISMP said of Pradaxa. “Hemorrhages reported for [Pradaxa] were more likely to result in a fatal outcome than cases for two other anticoagulants, warfarin and [Xarelto].”
According to a 2015 report in QuarterWatch, Pradaxa continued to have the largest number in overall serious reports in the U.S. as well as the largest total of reported severe hemorrhages and the most patient deaths. Of the 3,592 total Pradaxa adverse event reports for 2014, 188 were direct reports to the FDA, 752 involved deaths, 721 involved strokes and 2,709 — or 75 percent — involved hemorrhage. Xarelto had the second-most overall serious reports at 3,331.
Lack of Blood Clotting Can Lead to Excessive Bleeding
Normally when a person suffers an internal injury, the body stops the bleeding by forming a clot. By inhibiting a clotting enzyme called thrombin, Pradaxa reduces the body’s ability to form clots, in turn lessening 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 Pradaxa so effective at reducing strokes is what may also cause hemorrhaging in people who take it.
Internal bleeding is the most frequently reported side effect of Pradaxa, and the risk of major gastrointestinal bleeding is higher for users of the drug. Bleeding can cause death, and hemorrhages in the brain and central nervous system caused by Pradaxa can be just as harmful as a stroke, which is what the drug is taken to prevent.
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. As a result, the FDA warns that taking Pradaxa may cause patients to bruise more easily, and it may take longer for any bleeding to stop while using the drug.
The risk of bleeding is highest in people:
- Age 75 and over
- With a stomach ulcer
- With recent or recurrent stomach or intestinal bleeding
- With kidney problems
- With a low body weight
While there is a risk of bleeding for anyone who takes Pradaxa, certain groups of people are more at risk than others.
People taking blood-thinners should let doctors and dentists know what medications they are on before undergoing surgeries or medical procedures in order to prevent bleeding complications. Patients should inform their doctor if they are taking blood-thinners, nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin or products that contain aspirin. These medications increase bleeding risk.
People should speak to a physician immediately or seek medical treatment if they experience bleeding, coughing up blood, pink or brown urine, unusual bruising, vomit that looks like coffee grounds, swelling or joint pain, or headaches, dizziness or weakness.
FDA Reviews Pradaxa Bleeding Cases
In 2011, the highest numbers of drug-related adverse events reported to the FDA were attributed to Pradaxa (ranked No. 1) and warfarin (ranked No. 2). A number of doctors, patients and their families began questioning why Pradaxa was approved without an antidote, especially when the drug’s manufacturer knew that uncontrollable bleeding was a serious side effect of blood-thinners.
In December 2011, the FDA responded to the high incidence of bleeding injuries and deaths by beginning a re-evaluation of Pradaxa’s bleeding risks in comparison to warfarin.
In November 2012, the agency completed its review and concluded 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, warfarin bleeds can be stopped by administering an antidote derived from vitamin K. The FDA failed to acknowledge the lack of an antidote for Pradaxa at that time.
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.”
In May 2014, the FDA alerted the public of an increased risk of major gastrointestinal bleeding with use of Pradaxa as compared to warfarin. The announcement came following a new Pradaxa study that included information from more than 134,000 Medicare patients older than 64 years of age. Even so, the FDA made no changes to the drug label or recommendations for use.
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 RE-LY trial sponsored by Pradaxa’s maker, Boehringer Ingelheim, and results of Pradaxa in real-world clinical practice.
The RE-LY trial showed that Pradaxa was safer and more effective. Critics say this is because the patients in the study were younger, had perfect kidney function and were at a healthy weight. According to the FDA, the risk of bleeding increases with age, and people with kidney problems and low body weight are at greater risk, too.
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 are candidates for Pradaxa 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 RE-LY study. 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.
Treatment for Pradaxa Bleeding
For the first five years Pradaxa was sold in the U.S., there was no way for doctors to stop internal hemorrhaging caused by the drug. The lack of an antidote generated great concern among members of the medical community who were trying to effectively treat Pradaxa bleeds. People who suffered from severe bleeding were seen by ER doctors who had to work quickly to reverse internal bleeding.
Because Pradaxa works by directly inhibiting the blood-clotting enzyme thrombin, doctors cannot inject just any clotting factors into the body to reverse the effects of the drug. Without an antidote, doctors were left with very few options to treat a patient suffering from a Pradaxa-induced bleed, and often doctors were forced to simply monitor the patient until the drug left 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.
Pradaxa is cleared from the body through the kidneys, so some doctors recommended 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 was usually administered in the form of fluids, blood and monitoring. For minor bleeds, delaying the next one or two doses of the drug was the only treatment available.
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 end 4,000 state and federal claims. Then in October 2015, the FDA granted accelerated approval to Praxbind (idarucizumab) — a Pradaxa antidote that allows doctors to reverse the drug’s blood-thinning effects in emergency situations when bleeding can’t be controlled. Still, medical experts remain skeptical of the drug’s safety.
“If you’re a patient on Pradaxa or Xarelto, I think you should talk to your physician and ask whether the drug should be switched to a safer and more effective oral [blood-thinner],” Dr. Curt Furberg, who serves as medical advisor of the Institute of Safe Medication Practices, told U.S. News and World Reports in October 2016.
Heart Attack & Other Pradaxa Side Effects
Though bleeding is the most frequently reported side effect of Pradaxa, other side effects, including acute kidney failure, stroke and suspected liver failure, have been reported with Pradaxa use.
A March 2012 study, published in the Journal of the American College of Cardiology, analyzed five trials of 30,470 patients using information from the U.S. National Institute of Health MEDLINE database. Researchers found that patients taking Pradaxa were more likely to have heart attacks than those taking warfarin.
That same month, a Cleveland Clinic study published in the Archives of Internal Medicine found similar results, revealing that Pradaxa causes a 33 percent increased risk of heart attack or severe symptoms of heart disease — which can include chest pain, dizziness, shortness of breath and loss of consciousness— compared with warfarin.
Patients taking 150 mg of Pradaxa had an increased incidence of gastrointestinal adverse reactions in clinical trials, and a small number of patients in clinical trials reported hypersensitivity reaction.
Reported side effects included:
- Abdominal pain and discomfort
- Gastroesophageal reflux disease (GERD)
- Erosive gastritis
- Gastric hemorrhage
- Hemorrhagic gastritis
- Hemorrhagic erosive gastritis
- Gastrointestinal ulcer
- Skin rash
- Itchy skin
- Severe, life-threatening allergic reaction
In addition, the FDA requires a black box warning — the agency’s strongest warning — to alert the public of the risk of spinal and epidural hematomas in patients treated with Pradaxa who are receiving neuraxial anesthesia or undergoing spinal puncture. The black box warning also cautions that suddenly stopping Pradaxa increases the risk of blood clot and stroke.