Pradaxa Patients Can't Stop the Bleeding

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Less than 24 hours after Loraine Franklin fell on the kitchen floor of her Georgetown home, she was dead.

It was December 29, 2011, and Franklin's daughters say today that, had Franklin, 80, not been prescribed a blood thinner called Pradaxa, she'd have lived to see the new year and subsequently celebrate her 60th wedding anniversary.

Instead, they say, the fall caused a blow to her head, which caused an intracranial hemorrhage, which doctors at the hospital could not stop. All the doctors could do, the daughters say, is make Franklin as comfortable as possible as her speech became slurred and the blood pooled in her skull.

Like hundreds of thousands of others with a heart condition called atrial fibrillation, which raises the risk of stroke, Franklin had been told of the benefits of the recently FDA-approved Pradaxa over its comparatively ancient counterpart, Coumadin. What she hadn't been told about, according to her daughters, was Pradaxa's most significant drawback: There is no effective reversal agent for a traumatic bleeding event.

Had Franklin been taking Coumadin — as she had years before — she would have left the hospital with a headache and a slight concussion, her daughters say. With Coumadin, doctors have a variety of ways to keep a patient from bleeding to death. Instead, according to Franklin's daughters, Pradaxa turned a simple fall into a death sentence.

Which is why Franklin's daughters are suing Pradaxa's German manufacturer, Boehringer Ingelheim, in federal court. They say the company did not adequately warn doctors and patients of the lack of an antidote. They're just two of dozens of clients represented by the Texas law firm Watts Guerra Craft, whose mass-tort team opened the floodgates by filing the first Pradaxa-related cases in November 2011.

The timing coincided with Boehringer's announcement that it had recorded 260 Pradaxa-related fatal bleeding events worldwide between March 2009 and October 2011. The FDA followed suit by announcing a post-market safety review. Regulators in Japan had already asked Boehringer to issue "Dear Doctor" letters to health-care professionals warning of the bleeding risk, and Australian regulators issued a safety advisory as well.

However, the FDA, per its announcement, "continues to believe that Pradaxa provides an important health benefit when used as directed," and Boehringer representatives told the Houston Press that 260 recorded deaths are not outside the parameters of a major clinical trial that the FDA and its global counterparts relied on in approving the drug in the first place. Company representatives also say the risks were not hidden or minimized.

Pradaxa has been a boon to Boehringer's bottom line. But if Loraine Franklin's daughters get their way, the drug will be off the market — just not soon enough for their mother.

If ever there was a drug that could use a makeover, it's warfarin.

Warfarin (brand name Coumadin) was introduced to the marketplace in 1948 not as a medicine but as a rat poison. Six years later, probably to the surprise of rats as much as anyone else, the FDA approved warfarin as an anticoagulant, and it remained the choice of treatment for patients with a type of irregular heartbeat — atrial fibrillation — for more than 50 years.

The most common type of arrhythmia, atrial fibrillation occurs when one or both of the heart's upper chambers do not beat in sync with the lower chambers. With blood flow disrupted, clots can form, which can lead to heart attack and stroke. The U.S. Centers for Disease Control and Prevention estimates that about 2.6 million Americans currently suffer from atrial fibrillation; the CDC predicts the number will grow to 12 million by 2050. (The median age is 66.8 years for men and 74.6 years for women.)

Medically speaking, warfarin is what some physicians refer to as "a pain in the ass." It interacts negatively with a legion of other drugs, and because it works in part by interfering with vitamin K, patients have to avoid any foods high in that vitamin like leafy greens, liver, green tea and cauliflower. Patients' blood must also be regularly monitored — once every three or four days at first, then once or twice a month; the test, known as the International Normalized Ratio, measures how "thick" or "thin" a patient's blood is. Too thick, and the patient is at an elevated risk of clotting; too thin, and the higher the risk of bleeding.

Even the nonprofit watchdog group the Institute for Safe Medication Practices — which never has a shortage of what it considers frightening new Pradaxa statistics — is blunt when describing warfarin's risks.

According to the institute's April 2012 report, "Inhibiting the blood clotting process in elderly patients ranked as one of the highest risk outpatient drug treatments in all of medicine, with the leading agent, warfarin, accounting for 33 percent of all emergency hospitalizations for drug adverse effects in the elderly patient population."

Yet because of its low cost and respectable success rate (given the complications), this highly annoying, inconvenient treatment has been the standard-bearer for the treatment of atrial fibrillation. In the mid-2000s, however, no fewer than eight pharmaceutical companies took a fresh look at this market, estimated to be worth $10 billion-$20 billion.

In 2010, Boehringer, a 120-year-old family-owned company, beat everyone to the U.S. market with Pradaxa. According to the FDA, approximately 1.1 million prescriptions were dispensed between October 2010 and August 2011; an estimated 371,000 patients filled their prescriptions from outpatient retail pharmacies during that period.

Available in a single, 150-milligram pill (in the U.S.), Pradaxa doesn't have warfarin's myriad drug interactions or dietary restrictions, nor does it require monitoring.

However, there's one difference that works in warfarin's favor: Pradaxa has no reversal agent.

Doctors can reverse a major bleeding event on warfarin by administering vitamin K, fresh frozen plasma or PCCs (prothrombin complex concentrates). If some bleeding is caught early enough in a patient on Pradaxa, doctors can take the person off the pill and administer dialysis to expel the rest of the drug, which has a considerably shorter half-life than warfarin.

The lack of a reversal agent was apparently not a significant factor in Boehringer Ingelheim's massive clinical trial comparing warfarin to Pradaxa, called RELY, involving 18,133 patients at 951 testing sites in 44 countries. (The study's nifty name appears to be a contortion of one of those after-the-fact acronyms, since it somehow stands for "Randomized Evaluation of Long-term anticoagulant therapY.") The trial reported 3.36 percent "major" bleeding events for the warfarin patients, compared to 3.11 percent for those on Pradaxa. The numbers were also in Pradaxa's favor for patients who experienced "life-­threatening" bleeding events (1.8 percent versus 1.45 percent).

But these numbers haven't done much to ease Houston trauma surgeon Bryan Cotton's mind.

With two of his colleagues, Cotton, an associate professor of surgery at the University of Texas Medical School at Houston and a physician-scientist in coagulation research at the Center for Translational Injury Research, penned a letter to the editor of The New England Journal of Medicine in November 2011, outlining his experience with patients on Pradaxa. (Cotton and his colleagues referred to Pradaxa by its generic name, dabigatran.)

"Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert)," they wrote. "The ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level 1 trauma centers."

Cotton is even more blunt when describing his frustration over his and his fellow surgeons' inability to stop the bleeding in some of the patients admitted to the trauma center after Pradaxa was approved. Of 11 patients he treated for severe bleeds while on Pradaxa, all but three or four died, he says.

"It's irreversible — that's a great idea; a drug that makes you bleed to death and there's no reversal agent..." he says. "So that's when we started getting both emotionally involved with it as well as academically involved."

The final straw — the decision to write to the NEJM — came, Cotton says, when two University employees were prescribed Pradaxa by doctors who didn't mention the lack of a reversal agent.

Of course, Cotton points out that as trauma surgeons, he and his colleagues see only the complications.

"We don't see all the successes with it that a cardiologist or a family-practice doc might, but it was just kind of distressing that [Pradaxa's benefits were] detailed out on this new, wonderful agent to replace the old, dirty Coumadin — and it's got all these issues that really weren't brought to the forefront," Cotton says. "And I'm not saying that they were hidden by any means from the FDA, but it got through and really no one really looked into the ability to reverse it or need to reverse it. Again, if you're talking [about] any drug that thins out your blood, why you wouldn't do something like that..."

Cotton says Boehringer Ingelheim representatives contacted him and his co-authors after the NEJM letter ran.

"They made it out that they were surprised and that they didn't have these bleeding issues with their big trials," he says. "I'm shocked that they didn't find more bleeding issues."

In response to Cotton's letter, two Canadian researchers who disclosed financial ties to Boehringer Ingelheim took up pen in defense of Pradaxa, writing that while "specific antidotes...are desirable," there was "no evidence that the lack of an antidote contributed to the deaths" of Cotton's patients.

In a brief rebuttal, Cotton raised two important, commonsense points: that despite the doctors' contention that the deaths could not be attributed to the lack of an antidote, the patients came in bleeding, and that "the multidisciplinary team caring for them could not control their hemorrhages."

And as for an antidote being "desirable," Cotton wrote: "When prescribing a drug with side effects that include life-threatening hemorrhage, reversal is not 'desirable,' it is essential."

It's just a little story, but one of the most telling things about Loraine Franklin was the way, after her death, one of her former fifth-grade students remembered her.

Franklin's daughters, Becky Hormann and Jane Ann Salazar, say the former student sent their father, Darold, a letter describing how gently Loraine Franklin had handled the student's hearing disability. Shy about his situation, the student never wanted to bring attention to himself. Without broadcasting it to the rest of the class, Franklin sat the boy near the front of the room so he could read her lips. Thirty-odd years later, the boy wrote Darold Franklin to say how much of a difference that made in his life.

Franklin taught for 30 years and stayed active in retirement, her daughters say. There were the stamp club, Bible reading, church committees, the Red Hat Society; she even went for strolls with friends in a dog-walking group, even though she didn't have a dog.

A decidedly upbeat, positive person, Franklin never complained, which is why Salazar says it was a surprise when she saw how her mother answered the door a few weeks before she passed away. Salazar says she had come to tend to her father, who had recently fallen. Salazar says Franklin was stooped over, so weak she couldn't stand straight.

"I wasn't even coming for him anymore — it was for her," she says.

Franklin's daughters say that, while Franklin never wanted to burden her family — or apparently even her doctor — with her health concerns, she did confide in a close friend.

Salazar says that after her mother passed, the friend disclosed that Franklin had told her that "she didn't know if she could take this pain anymore."

The daughters say they didn't even know Franklin was on Pradaxa, which they say she had started taking in June, six months before she died. It wasn't until the night of her fall, they say, when doctors explained about the irreversible bleeding, that they were told. Afterward, when the daughters were sorting through Franklin's belongings, they say, they found tampons and maxi-pads. Quite a surprise for an 80-year-old woman. They believe she'd been bleeding all along.

Her daughters believe the bleeding had made their mother weak, leading to the fall that because of Pradaxa was fatal. They feel the drug robbed them of maybe ten more years with their mom.

"I would not give Pradaxa to my dog," Hormann says.

Lead attorney Mikal Watts is even more cynical, accusing Boehringer of rushing what it knew was a defective drug to market.

"The RELY study is completely cooked," Watts says. "Boehringer released the study to enable it to sell two to three years of Pradaxa before the real data would mandate its recall from the market."

A veteran of pharmaceutical lawsuits — he has won big verdicts in cases against the manufacturers of Vioxx, Ortho Evra, Rezulin and others — and a man who knows his way around a soundbite, Watts says, "I have seen bad drugs on the front end and seen the inevitable recall that will follow. Pradaxa is the worst drug I have seen, and there is no doubt in my mind that they will be forced to recall it in order to stop the serial killing of Americans that are on this bad drug."

Watts hasn't filed anything in court supporting his contention that RELY was cooked, but the study has taken some heat in the two years since its release. Even Boehringer's own chest-thumping over the study begs a closer look at its claims, such as when Boehringer spokesperson Emily Baier pointed out RELY's findings that, compared to warfarin, dabigatran reduced the risk of stroke by 35 percent.

Sounds amazing. And it's mathematically accurate. But in context, it loses some of its luster: The RELY study's rate of stroke among dabigatran patients was 1.11 percent (134 people), and the rate was 1.69 percent (199 people) for those on warfarin.

But John Smith, Boehringer's senior vice president of clinical development and medical affairs, believes the reduced stroke rate has real-world significance. And while the RELY study showed a higher risk of gastrointestinal bleeding among those on dabigatran, it showed a lower rate (59 percent) of intracranial hemorrhage.

"That's really...kind of the trade-off in terms of one type of bleeding versus another," Smith says. "And clearly, intracranial hemorrhage is a very devastating event for a patient and their family. It leads to death about a third of the time and significant disability a large proportion of the time as well, if you survive."

When asked about Cotton's complaint that there is no way to monitor a dabigatran patient's blood, Smith says there actually is a readily available test — a curious stance, given that one of Pradaxa's chief selling points is that unlike with warfarin, a patient doesn't have to undergo regular monitoring.

Smith says the test — called "activated partial thromboplastin time" — would be useful for a physician who's concerned with a patient who's already bleeding. Even more confusingly, Smith also says it provides a way to "follow the reversal of Pradaxa." In this context, "reversal" means discontinuation of the drug, or possibly dialysis, in the absence of the type of life-threatening bleed that trauma surgeons like Cotton are concerned about.

This is why, when told about Smith's contentions, Cotton wrote in an e-mail: "He obviously doesn't practice medicine on the planet Earth."

Franklin's daughters might also be surprised by Smith's perspective, especially surprised to hear the line about the lower risk of intracranial hemorrhaging, since they believe the blow to the head she sustained in the fall is what killed her.

"It's just scary to think that she could be sitting here right now, you know? It just bothers me," Salazar says.

As the lawsuits against Boehringer continue to pour in, so do new claims from doctors and watchdog groups questioning the reliability of the RELY findings in the real world.

In a March 2012 case report for the Journal of Neurosurgery, a Salt Lake City physician wrote of an 83-year-old man who was rushed to the emergency room after falling at home. He had started taking dabigatran a month earlier. The case echoes the claims made by Franklin's daughters: After two hours, the man's speech slurred; after six hours, CT scans showed extensive intracranial hemorrhaging. Not long after, he died.

"Patients treated with dabigatran are often elderly individuals with multiple comorbidities," the case study states. "Imbalance and falls are common in this population, and intracranial hemorrhage resulting from minor trauma may occur with increasing frequency as use of this drug becomes more widespread."

In April 2012, The Institute for Safe Medication Practices claimed that for the first quarter of 2011, dabigatran accounted for a higher total of serious adverse events than any other drug the group monitored, with the exception of a drug used to treat a rare lung disorder.

The institute's report states that when representatives for Boehringer were contacted, they "also observed the large volume of serious adverse event reports for its new drug, but noted that bleeding was a known risk of anticoagulant drugs, and substantial warnings were in place. The company attributed the report volume in part to the rapid acceptance of the drug into the market and an active sales force with extensive contact with physicians, resulting in more frequent reports."

It's that "active sales force" that convinced so many doctors of Pradaxa's benefits by neglecting to mention the irreversibility, attorney Watts says. He says doctors are not to blame and that the responsibility lies with a manufacturer that chose "sales over responsible disclosures."

And Watts's conspiracy theory — that Boehringer knowingly marketing a faulty product — has the proceeds from those sales vastly outweighing any damages from litigation.

"The lawsuits are a small pimple on the ass of huge profits that come from selling a drug like this," he says.

Franklin's daughters say being part of the lawsuit is something their mother would have wanted.

"I don't want other people to go through what we just went through," Hormann says. "And I know that my mom would feel the same."

Recalling how her mother was devoted to her students and how she tried not to complain to her family about whatever pain she may have been suffering, Salazar echoes her sister. Fighting to pull Pradaxa off the market is the "one thing she would want us to be doing," Salazar says. "Because she was such a caregiver for everyone."


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