This post was written for my legal blog — patients injured by Pradaxa should read my Pradaxa bleeding problems page.
In our medical malpractice and nursing home abuse work, we see one case with disturbing frequency: warfarin overdoses. A recent CDC study confirmed that warfarin, anti-platelet medications, and diabetes control medications together accounted for a whopping two-thirds of all drug-related emergency hospitalizations of senior citizens. Errors in dosing and monitoring warfarin by health care professionals, too, account for a significant (over 1%) of medical malpractice claims. It’s a great drug, but a dangerous one.
Warfarin has a fascinating history. In nature, the molecule on which warfarin is based is produced when the plant compound coumarin — which produces the sweet smell of freshly cut grass or hay — is metabolized by fungi and then reacts with formaldehyde. (The name “warfarin” is a combination of “Wisconsin Alumni Research Foundation” and coumarin.) The chemical was first discovered by veterinarians trying to figure out what killed their cattle (they were eating spoiled sweet grass), and warfarin was literally used as a rat poison before it was used in humans.
Warfarin works in treating or preventing the deadly conditions venous thrombosis, blood clots, and pulmonary embolism by almost creating a different deadly condition: excessive bleeding. It doesn’t take much to push a patient into dangerously high prothrombin ratio (INR) levels, and so healthy patients need to have blood tests weekly or at least monthly, and hospitalized patients need to be monitored every few hours. Warfarin is thus both a wonder drug — which has saved the lives of my own family members diagnosed with pulmonary embolism — and a double-edged sword, because it causes major bleeding episodes in 3-5% of people taking it. Scientists have been trying to find safer replacements for the whole fifty years that it’s been used.
Pradaxa (dabigatran etexilate), manufactured by Boehringer Ingelheim Pharmaceuticals, was supposed to be one of those replacements. In September 2009, the initial results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study sponsored by the company were released, with the study’s authors — the bulk of whom reporting in the study “receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim” — concluding:
In conclusion, we compared two doses of dabigatran with warfarin in patients who had atrial fibrillation and who were at risk for stroke. As compared with warfarin, the 110-mg dose of dabigatran was associated withsimilar rates of stroke and systemic embolism and lower rates of major hemorrhage; the 150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage.
Note the use of the word “similar” in the study’s conclusion. It’s not a scientific term, it’s a term of art. In fact, when the RE-LY study came out, there was already concern among the FDA advisory panel members that the drug didn’t really offer an improvement over warfarin in preventing stroke in patients with atrial fibrillation, but rather offered just a different balance of the risk of bleeding versus the risk of stroke:
“The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke,” said [advisory panel member Dr. Sanjay] Kaul. “In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative.”
Asked about the approved doses, FDA spokesperson Sandy Walsh said that FDA reviewers felt the data strongly support the 150-mg dose, noting that it was superior to warfarin on the primary end point and similar in terms of bleeding rates. In reviewing the data, FDA officials noted, like Kaul, there were numerically more ischemic strokes in the dabigatran 110-mg arm when compared with warfarin, and this dose was only statistically noninferior to warfarin in terms of efficacy.
In other words, a 110-mg dose was substantially less effective than warfarin in reducing strokes, while the 150-mg reduced strokes but had the same bleeding rates as warfarin.
On the surface, that makes it sound like Pradaxa is an improvement over warfarin, but it’s not the whole story.
If a patient has overdosed on warfarin and starts to bleed, the effects can be quickly reversed with a dose of Vitamin K. If a patient overdoses on Pradaxa and starts bleeding, there’s nothing anyone can do but wait for their kidneys to process the Pradaxa and excrete it in the urine — a process that takes hours at best, potentially long if Pradaxa has slowed kidney function, as many people expect it can.
Based on the RE-LY conclusions, in October 2010 the FDA approved Pradaxa “for the prevention of stroke and blood clots in patients with abnormal heart rhythm (atrial fibrillation).” The FDA-approved warning label, however, mentioned only “Pradaxa can cause serious and, sometimes, fatal bleeding,” without mentioning the key part: that a Pradaxa overdose, unlike warfarin, can’t be reversed. In the tiny print buried deep in the “full prescribing information,” it mentions that dialysis can be attempted, but admits “data supporting this approach are limited.” If a patient slips into excessive Pradaxa levels — which is a real risk, given that Pradaxa affects kidney function and given that Pradaxa’s primary marketing “hook” to doctors and patients was the claim that INR levels don’t need to be checked as frequently — then there’s no treatment.
It’s even worse given how Pradaxa’s label also admits, again in tiny print buried in the prescribing information, that “risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs),” which a large number of the target patients are taking. I’ve mentioned before the danger of acetaminophen poisoning; doctors aware of that put their patients on NSAIDs, which combined with Pradaxa can make the inherent bleeding problems with Pradaxa more likely to occur.
In February 2011, the American College of Cardiology Foundation and American Heart Associationadded it to the guidelines of non-valvular atrial fibrillation. Sales skyrocketed — and so did adverse drug events. The Institute for Safe Medication Practices reported that, in the first quarter of 2011 alone, “Dabigatran (PRADAXA), a new drug approved to reduce the risk of stroke by inhibiting blood coagulation, generated a strong signal illustrating the substantial bleeding risks of this treatment, with more than 500 reports of fatal, disabling and other severe hemorrhages.”
Reports of internal bleeding, kidney failure, heart attack, and other blood thinning complications including death continued to mount, so that in December 2011 the FDA announced it was evaluating the post-marketing data on Pradaxa, with a warning to doctors to closely monitor renal function — because the problem may be that Pradaxa is clearly quickly enough in patients with below normal renal function — and a warning to patients about reporting any signs of bleeding (e.g., the gums, the nose, coughing, etc) to their doctor.
A month later, in January 2012, Boehringer Ingelheim updated part of the fine print on its label, but not by much. The new label admits that “protamine sulfate and vitamin K” are useless in treating a Pradaxa overdose, then speculates about various ways an overdose can be treated, including the use of various recombinant protein factors, although the label admits “their use has not been evaluated in clinical trials.”
Two days ago, though, the other shoe dropped, when the Journal of Neurosurgery published a case report explaining how neurosurgeons were completely unable to treat “an elderly patient, being treated with dabigatran [Pradaxa] for atrial fibrillation, who presented with a rapidly expanding intracranial hemorrhage after a ground-level fall.” In the course of six hours, the patient’s brain bleed expanded extensively, despite attempting treatments like recombinant factor VII. The authors concluded, “in the event of catastrophic hemorrhage no effective reversal agent exists.” Put simply, if a patient on Pradaxa suffers a serious trauma, doctors are helpless to treat it.
All of which puts into context the lawsuit the lawsuit filed Monday in Tennessee, believed to be the first Pradaxa lawsuit yet filed. A number of Pradaxa lawyers have been investigating the cases, but none have made it to suit yet, due to the considerable investigation that needs to be done beforehand thanks to recent Supreme Court cases like Iqbal and Twombly that require plaintiffs almost win their case the day it’s filed, and the recent efforts by many federal courts to throw out pharmaceutical negligence cases before they can even reach a jury.
Although the complaint alleges multiple theories — strict liability, negligent, negligent design, consumer fraud, et cetera — the bulk of drug liability claims these days allege some form of failure to warn. Which raises the right question: why can’t Pradaxa warn patients that the drug is more dangerous than warfarin if a patient falls or has an accidental overdose? Some pharmaceutical questions really are comparable in difficulty with rocket science, but some aren’t. There’s no question among neurosurgeons and pharmaceutical researchers that, at the moment, Pradaxa has no antidote — and Boehringer Ingelheim has a legal duty to inform patients of that fact, just as Takeda had a legal duty to inform consumers that Actos causes an increased chance of bladder cancer and Forest Laboratories had a duty to warn Lexapro causes birth defects.
These aren’t complicated questions beyond the realm of science and medicine; all the companies need to do is take the basic steps to ensuring that consumers are informed about the real risks of the drugs, and they will in many cases be absolved of liability (the wisdom of that is suspect, but it’s effectively the law in many states). It’s telling that they don’t.