FDA Rallies Around Pradaxa with New Study, Still No Antidote

A review by the FDA finds no additional risk of myocardial infarcation (MI) or a heart attack when Pradaxa (dabigatran) is compared to Coumadin (warfarin). An MI occurs when blood suddenly stops flowing to parts of the heart injuring the heart muscle.

This latest study is trying to push Pradaxa as the drug of choice to replace warfarin, the standby that has been used by patients with non valvular atrial fibrillation (AF) for more than 50 years. This study, which was conducted by the Food and Drug Administration, involved data from more than 134,000 Medicare patients. The FDA researchers were looking for any elevations in the risk of gastrointestinal (GI) bleeding, bleeding in the brain, stroke, MI and death. When compared to warfarin, Pradaxa patients had a lower risk of those events, however, there was an increase in the risk of GI bleeding among Pradaxa users. Based on these results, the FDA is not recommending the product label be altered for Pradaxa.

The FDA frequently sounds like a cheerleader for a drugmaker and in this case it really seems to be behind an improved picture for Pradaxa.

Heart_attack-NIH“We still consider Pradaxa to have a favorable benefit-to-risk profile and have made no changes to the current label or recommendation for use,” according to an FDA press release.

Pradaxa, like warfarin, is an anticoagulant drug prescribed to patients who need their blood thinned following a stroke, heart attack or surgery. Back in 2012 the FDA noted a large number of post-marketing reports of bleeding problems among Pradaxa users, including GI bleeding and intracranial hemorrhage.

Drugmaker Boehringer Ingelheim produced a large clinical trial called RE-LY which concluded that the rates of serious bleeding were roughly comparable between the two drugs. Ingelheim and the FDA interestingly conclude that warfarin’s adverse events are “likely underreported compared to events occurring with the more recently available Pradaxa,” though why that would be is not clear.

It’s interesting that neither study mentions that there is still no antidote to Pradaxa to stop uncontrolled bleeding when compared to warfarin. With warfarin, vitamin K can be taken to stop the blood thinning effect. While it may be easier to take Pradaxa because it does not need to be closely monitored in the blood, there is no way to rapidly reverse the action of thinning the blood. That can leave people in a life-threatening situation. More than 500 have died using Pradaxa according to the Institute for Safe Medical Practices.

The company announced last November it was working a specific antidote for the reversal of Pradaxa, but to date, it has not been announced or released.

FDA Eyes Pradaxa Again

Despite all the company assurances that the anticoagulant Pradaxa is a superior alternative to warfarin, the Food and Drug Administration (FDA) plans to once again compare the two. Pradaxa was approved in 2010 but has since then brought a high complication rate to its users  – including dangerous and uncontrolled bleeding for which there is no antidote.

Pradaxa (dabigatran) is prescribed to patients with nonvalvular atrial fibrillation. Made by the German company Boehringer Ingelheim, the FDA will look at the bleeding risks for the drug through its Mini-Sentinel Program, which uses healthcare data, such as insurance claims, to assess the risks of FDA-approved drugs. Potentially upward of 100 million patients could end up participating through their anonymous data.


Because warfarin is ranked No. 2 by the FDA for adverse events, newly developed anticoagulants have found willing and receptive users. Competitors, including Xarelto and Eliquis, would like to get in on the action. Unfortunately, all three of the newer anticoagulants do not have an antidote to stop uncontrolled bleeding. The companies say they are working on one. The other two companies are not under a re-review by the FDA.

Boehringer is expected to generate $1 billion in sales in 2014 and anticoagulants are the fastest growing area for drug sales.

The FDA has posted a request for public comment, reports Forbes. Specifically the agency is looking to “assess systematically the rates of bleeding and the thromboembolic outcomes associated with the use of dabigatran and warfarin for patients with atrial fibrillation using data from the FDA Mini-Sentinel Distributed Database (MSDD).”

The goal is to identify which users are at a higher risk for major bleeding and which are not. Boehringer reminds the public that just because the FDA is requesting data does not mean there is any problem with the safety of the drug.

Two previous Mini-Sentinel reports, one issued in November 2012 and the other in April 2013 comparing warfarin to Pradaxa, found the bleeding rates to be roughly comparable.

Despite that, the Institute for Safe Medication Practices found that in 2012 Pradaxa topped the list of adverse event reports to the FDA and represented that the risk of fatal bleeding may be five times higher among Pradaxa users. At the same time more than 580 patients suffered fatal outcomes linked to Pradaxa.

The adverse event reports keep coming in, so much so that multidistrict litigation has consolidated about 2,100 cases in the Southern District of Illinois (MDL No. 2385) among patients who experienced life-threatening and uncontrolled bleeding and internal hemorrhage.

NEJM Claims Pradaxa Adverse Events Due to Hyper-vigilant Reporting

This report is confusing to the many people who know from experience that taking the anticoagulant Pradaxa (dabigatran) is more dangerous than warfarin (Coumadin), the treatment that’s been the standard of care for decades.

According to a published perspective in the online March 14, New England Journal of Medicine (NEJM), the concern over Pradaxa may be due to heightened vigilance and “stimulated reporting” and not because there are more patients injured by the drug when compared to other anticoagulants.

The perspective article is authored by researchers within the FDA’s Center for Drug Evaluation and Research (CDER).

It flies in the face of adverse event reports (FAERS) coming into the FDA that claim Pradaxa users experienced excessive and uncontrolled cerebral, rectal and gastrointestinal bleeding have resulted in over 500 deaths.

It also conflicts with the findings of the Institute for Safe Medication Practices (ISMP), a nonprofit that monitors drug safety. According to the group, Pradaxa is at the top of the list of over 800 medication complaints the group monitors.  And ISMP reported earlier this year that Pradaxa users were five times more likely than warfarin users to have a fatal outcome.

This is the same division within the FDA that approved Pradaxa (dabigatran) in late 2010 as a more convenient alternative to the 1954-approved warfarin to treat the risk of stroke in patients with nonvalvular atrial fibrillation, that is AF not caused by heart valve problems.

They used the RE-LY trial (Randomized Evaluation of Long-term Anticoagulation Therapy) as a basis for the FDA approval. The RE-LY trial found no difference in the cases of excessive and uncontrolled bleeding when comparing Pradaxa to warfarin. The FDA also looked at insurance records and its own internal data to come to that conclusion.

What any report on adverse drug events should consider is the degree to which the drug maker takes advantage of a waiver to submit to the agency any report about an adverse event that the drug maker considers “not serious.” How might these waivers affect the unreliability of the data gathered?

The heightened vigilance concerning Pradaxa does not extend to the drug’s warning. Many patients and their doctors still do not understand there is no reversal agent to this anticoagulant as there is with warfarin. The only treatment is dialysis which is not a practical solution if you are bleeding to death. And, that is the real danger for people who urgently require reversal and bleed out because no agent is available to accomplish reversal of the anticoagulant effects of Pradaxa.

Yet the FDA continues to defend releasing Pradaxa with no antidote.

Meanwhile the manufacturer, Boehringer Ingelheim, plans to continue looking for a reversal agent and the FDA plans to continue postmarket surveillance of Pradaxa.

Boehringer Ingelheim Must Pay $95 Million to U.S. Government in Qui Tam Lawsuit

Boehringer Ingelheim, a German drug company and maker of the blood thinner Pradaxa, must pay the federal government $95 million in compensation for defrauding Medicare.

The government charged that Boehringer Ingelheim promoted their drug “off label” meaning for uses they had not received regulatory approval by the U.S. Food and Drug Administration (FDA). Doctors may prescribe “off label” but drugmakers may not advertise that use.

Corporate Whistleblower

The actions were brought to light by a former Florida employee of Boehringer. Robert Heiden was Florida-based in the 14 years he worked for the company. He alerted authorities when he felt patients may be endangered by the reckless marketing of four off-label drugs.

He filed his so-called Qui Tam lawsuit against the company in federal court in Baltimore about seven years ago.

Aggrenox had been approved by the FDA to prevent secondary strokes, however Heiden saw it was being promoted by the drug company to reduce the risk for heart attack and heart conditions, even though there was no evidence supporting that use. Attrovent and Combivent were being pushed as a cold, cough and asthma remedy in children, but the drug had never even been tested for use in children.

A Qui Tam lawsuit is filed by a private individual with insider information who assists in putting together part of the case. In exchange, they can receive 15 to 25 percent of any recovered damages. Heiden wore a wire to help the Federal Bureau of Investigation confirm the allegations and he combed over millions of pages. For his work, Heiden and his attorneys will receive about $20 million.

Boehringer Ingelheim’s current blockbuster drug, Pradaxa, is used to treat atrial fibrillation.

Ever since December of last year, reports have been coming into the FDA about serious bleeding incidents among those patients taking Pradaxa. The agency has listed Pradaxa among the top drugs for adverse event calls coming into the FDA.

New Injury Linked to Pradaxa – Alveolar Hemorrhage

Physicians from American University in Lebanon published a case report regarding Pradaxa (dabigatran etexilate) that was published in the July 28, 2012, edition of the Journal of Thrombosis and Thrombolysis.  In this article, the authors wrote about an 85 year old patient who developed shortness of breath, anemia, and white sputum a few months after starting Pradaxa 110 mg twice daily.  The patient was admitted to the hospital in respiratory distress with severe hypoxia.  A workup for bleeding tendencies was negative.  The patient had pre-existing pulmonary fibrosis, but that condition had been stable prior to admission; however, a CT scan upon admission showed significant “ground-glass opacities.”  A bronchoscopy also showed evidence of significant, chronic bleeding in the patient’s bronchial tubes.  The old blood was suctioned from the patient and Pradaxa was discontinued.  The patient’s respiratory failure quickly improved with this treatment, and no blood products or transfusions were required.  Evaluations for connective tissue disease or vasculitis as an explanation for the source of the patient’s significant bronchial bleeding were negative.  Repeat CT scans prior to discharge also showed significant improvement in the patient’s pulmonary fibrosis following discontinuation of Pradaxa.

The authors of this case report noted that other physicians had warned that Pradaxa must be prescribed with caution in light of published reports Pradaxa-induced injuries to patients, especially those who are elderly, have impaired renal function, or have low body weight.  This particular patient was significant in that the patient had normal kidney function, was active, not underweight, and his only risk factors for a Pradaxa-induced injury were his age and pre-existing pulmonary fibrosis.  Most of the reports of Pradaxa-induced injuries have focused on GI bleeding and intracranial hemorrhage.  This group of physicians urged others to use caution in prescribing Pradaxa to patients with pulmonary fibrosis and noted that an enhancement to the warning label for the drug might be appropriate to alert patients and their doctors to the risks of bronchoalveolar hemorrhage caused by the drug (a condition that may be difficult to diagnose if the public is not aware of the drug’s potential to cause this harm).

As an aside, it is important to note that this is not the patient in Lebanon is not the first documented case of alveolar hemorrhaging associated with Pradaxa use.  About a year ago, the Japanese MHLW, the government agency in Japan that is similar to the Food & Drug Administration, issued a safety alert after receiving reports of 5 patient deaths and 81 patients who suffered Pradaxa-related injuries in the first few months of 2011 after the drug was approved in Japan.  Those adverse event reports relating to patient deaths included digestive tract hemorrhage, pulmonary alveolar bleeding, respiratory failure, and hemorrhagic shock.  The patient deaths and injuries occurred within 8 to 104 days of initiation of Pradaxa therapy.  This Japanese safety alert urged physicians to look for signs of anemia and bleeding in the body (not just gastric or GI bleeding) and to perform renal function testing on patients in hopes of avoiding administration to vulnerable patients with underlying (and perhaps undiagnosed) renal insufficiency.


Pradaxa Tops FDA’s List for Serious Adverse Events

According to an analysis by the Institute for Safe Medication Practices, Pradaxa drug (Dabigatran) topped the list of direct reports to the FDA for serious adverse drug events in 2011.  Pradaxa took the lead with 817 direct reports, followed by Coumadin (Warfarin) with 490 direct reports, Levaquin (Levofloxacin) with 393, Carboplatin with 376, and Zestril (Lisinopril) with 351.

The QuarterWatch medical surveillance program is designed to keep track of any serious and/or fatal adverse drug events. QuarterWatch is published by the Institute for Safe Medication Practices, a Pennsylvania-based nonprofit organization that monitors adverse drug events reported to the FDA.  The reports are funded by the institute and are based on the analysis of excerpts that the FDA releases from its Adverse Event Reporting System for research use.  According to QuarterWatch, the FDA received 179,855 reports of serious, disabling, and fatal adverse drug events in the U.S. in 2011.  This number is up 9.4% from 2010.  Eighty-eight percent (88%) of the adverse event reports were submitted by drug manufacturers, and the remaining 12% were submitted by health professionals and patients.  It has long been believed that the FDA adverse event database may only capture less than 1% of the serious injuries and deaths that have been caused by medical devices and drugs in the United States.

Cerebral Hemorrhage

According to adverse event data analysts, Pradaxa resulted in 542 cases of patient deaths, 2,367 cases of hemorrhage, 291 cases of acute renal failure, 644 cases of stroke, and 15 cases of suspected liver failure.  Pradaxa had a total of 3,781 adverse event reports in 2011.  In 2011, Coumadin had 1,106 cases overall, 72 of those resulting in death.  In the QuarterWatch report, the authors wrote: “Two drugs that inhibit the formation of blood clots ranked first and second among all direct reports to the FDA in 2011, emphasizing that the combination of a vulnerable patient population and a powerful pharmacological action rank among the highest risks in prescription drug therapy.”  This data is also very telling in that part of Boehringer Ingelheim’s aggressive sales pitch to encourage Pradaxa prescriptions to doctors and consumers was to create fear about the safety of Coumadin. Apparently, patients and doctors should be far more fearful of Pradaxa.

By filing numerous reports with the FDA, consumers and health professionals singled out the dangers of Pradaxa. This further bolstered the underlying concerns of many that the blood thinner is simply not safe and has been improperly promoted for use in a number of patients with atrial fibrillation for which Coumadin was a better (and safer) choice.  No patient or his doctor can make accurate decisions about the risks of a drug versus the benefit, especially when the raw data regarding patient injuries and deaths is not readily available.  This recent data from QuarterWatch is a big first step in giving prescribing physicians the critical risk information that they need to assist patients in making informed choices about whether the perceived convenience of taking Pradaxa is really worth even a fraction of the now-known (and perhaps escalating) risks of the drug.