Prevention with a dose of danger
Newer, more costly anticoagulant drugs are increasingly being prescribed to reduce the risk of stroke despite deadly side effects
At 88, Gloria Glatz still embraced life. She was an avid Scrabble player and made a phenomenal potato salad between occasional visits to the casino.
Like 3 million to 5 million Americans, Glatz had a type of irregular heartbeat known as atrial fibrillation. The condition is not normally life-threatening, but can cause clots to form and increase the risk of a stroke. So in December 2011, her doctor put her on a blood thinner.
Instead of choosing the decades-old standby, warfarin, the doctor prescribed Xarelto, which had been approved by the U.S. Food and Drug Administration just a few months earlier. Xarelto is one of four anticoagulants approved since 2010 that make up a class of lucrative new drugs marketed as more convenient than warfarin.
While warfarin has a blood thinning action that can be halted in a bleeding emergency, none of the newer drugs has an approved antidote.
When Glatz developed gastrointestinal bleeding, a few months after she started taking Xarelto, doctors could not make it stop. She died March 23, 2012, at a Kenosha hospital.
“They said there was nothing they could do,” said her daughter, Dottie Glatz.
Since 2010, at least 8,000 deaths have been linked to three of the new anticoagulant drugs, compared to 700 for warfarin, a Milwaukee Journal Sentinel/MedPage Today investigation found. By contrast, last year warfarin accounted for roughly three times as many prescriptions.
While the three drugs accounted for less
than 10% of all anticoagulant prescriptions, they are linked to more than 90% of deaths reported to the FDA since 2010, the analysis found. The numbers are drawn from the agency’s adverse events reporting system, which is largely voluntary.
Additionally, more than 58,000 people have reported a serious side effect — such as a major bleeding episode — from the three drugs, Pradaxa, Xarelto and Eliquis. That compares with more than 8,000 for warfarin.
The fourth new anticoagulant, Savaysa, was approved in January, so such data is not yet available.
Doctors are increasingly prescribing the newer, more expensive drugs to people with atrial fibrillation as a way to prevent strokes, and for short-term use by people who develop blood clots.
A primary selling point of the new drugs is that they don’t require regular blood testing. With warfarin, also known as Coumadin, patients must give a blood sample regularly, often every four to six weeks, at a doctor’s office.
The blood is then tested to see how long it takes to clot. Too little of the drug and it is ineffective against clots and strokes. Too much and there is a substantial risk of severe bleeding.
Patients must also follow stricter dietary measures on warfarin, such as not eating large or inconsistent amounts of foods rich in vitamin K, which can lessen the drug’s effectiveness. That includes spinach, kale and brussels sprouts.
Marketing campaigns highlight the convenience of the new drugs, including a recent TV ad for Xarelto featuring comedian Kevin Nealon, who has atrial fibrillation, and golfer Arnold Palmer and NASCAR driver Brian Vickers, who both have had blood clots in their legs.
The three sit at a table at a golf course.
“Let’s see, golf clinic or blood clinic?” Nealon says. “Ooh, that’s a tough one.”
The surge in use of the patented drugs has been bolstered by a new system for determining stroke risk devised by a British doctor who has extensive financial ties to companies that make or market the new drugs, the Journal Sentinel/MedPage Today investigation found.
Under the new scale, the number of Americans deemed in need of an anticoagulant jumped overnight from about 3.7 million to 4.7 million, an increase of 27%, according to the paper published in May by the journal JAMA Internal Medicine.
For example, nearly all women with atrial fibrillation and virtually everyone 65 or older with the condition are now considered candidates for treatment.
The scale has been adopted as part of treatment guidelines by leading medical societies in the United States and Europe. And those groups have received at least $40 million from companies that manufacture or market the anticoagulants in the last three years.
In addition, many of the doctors who wrote the guidelines or issued other recommendations boosting sales of the drugs had personal financial ties to the drug companies, working as speakers or consultants.
Rita Redberg, a cardiologist and editor of JAMA Internal Medicine, said she has advised patients to wait a few years until the true risks and benefits of the new drugs are known.
“I don’t prescribe any of the newer oral anticoagulants,” said Redberg, a professor of medicine at the University of California, San Francisco. “My concern is that a lot of the people being put on the novel oral anticoagulants will have more harm than good.”
Expensive alternative
The new drugs have proved to be an expensive alternative to warfarin.
More than 10 million prescriptions for the new drugs, costing about $3.5 billion, were dispensed in 2014, according to data from IMS Health, a market research firm. Prescriptions for warfarin, which as a generic is a fraction of the price, went down slightly during that period.
At Walgreens, the cash price for a one-month prescription for the new drugs ranges from $333 to $391. The price for a typical one-month warfarin prescription is $21. Warfarin also requires regular blood testing, about once a month, which Medicare pays for at about $10 a test.
In 2013, taxpayers paid more than $1 billion for prescriptions of just two of the drugs, Xarelto and Pradaxa, according to a Journal Sentinel/ MedPage Today review of Medicare data. Warfarin was dispensed about six times more often, but cost taxpayers significantly less — $244 million. The 2013 data is the most recent year available.
The discovery of warfarin unfolded in the 1930s when cattle in Wisconsin and elsewhere bled to death after grazing on moldy sweet clover hay.
A farmer from Deer Park showed up at the University of Wisconsin agriculture lab one day in 1933 with samples of moldy hay and a container of uncoagulated cow blood.
From the rancid hay, UW biochemist Karl Paul Link was able to isolate a chemical anticoagulant known as dicumarol.
UW patented the research under the name warfarin in 1948 and marketed it not as medicine but as a commercial rat poison. If rodents ate it, they bled to death.
Continued work led to the development of the warfarinbased medical compound known as Coumadin, which the FDA approved in 1954, giving doctors a powerful new drug that has reigned ever since.
Among the famous early patients was President Dwight Eisenhower, who was given the drug to help recover from a heart attack in 1955.
Though the patents on warfarin expired in the early 1980s, the drug earned $120 million in revenue, adjusted for inflation, for the university from the time it appeared on the market.
“It is still the most widely used blood thinner in the world,” said Carl Gulbrandsen, managing director of the Wisconsin Alumni Research Foundation, or WARF, the drug’s namesake.
Increased stroke risk
People with atrial fibrillation are especially at risk for a stroke. And that risk increases if they have other common conditions, such as high blood pressure, diabetes or even simply advanced age.
In patients with atrial fibrillation, the atria — the two smaller, upper chambers of the heart — can beat irregularly or quiver and get out of sync with the heart’s two lower, main chambers, the ventricles.
That can cause blood to pool in the atria and the formation of clots that can travel to the brain and cause death or disability.
One key benefit of warfarin is its anti-clotting action can be reversed in a bleeding emergency by giving intravenous vitamin K. None of the new drugs has an antidote, though reversal agents are being developed.
For some with atrial fibrillation, the potential for lifethreatening bleeding posed by the new drugs and warfarin outweighs any benefit, independent doctors say.
Consider Gloria Glatz, the woman who died at the Kenosha hospital.
Because she was on Xarelto, there was no antidote when she began bleeding internally in March 2012.
Three times, doctors tried to stop the bleeding with an endoscope — a flexible tube that can be used to see and treat internal bleeding — to no avail, daughter Dottie Glatz said.
Doctors also gave Gloria Glatz transfusions to replace lost blood.
“As much as they were pumping it into her, she was losing it in her stomach,” Dottie Glatz said. “It was awful.”
In March, Glatz’s family filed a federal lawsuit against the Janssen unit of Johnson & Johnson and Bayer HealthCare, the two companies that jointly market Xarelto.
Some form of gastrointestinal or brain hemorrhaging accounted for nearly two-thirds of the death reports sent to the FDA for the three new anticoagulants in the Journal Sentinel/MedPage Today analysis.
Companies that make the new anticoagulants say the FDA data can be skewed because the drugs are new, and because of attention surrounding the lawsuits. Warfarin, on the market for 60 years, is less likely to generate a report, they say.
“It is certainly worrisome to see this kind of profound disparity in the harm numbers between new and older drugs, particularly because the current process for FDA drug approval often means it takes years after a drug is approved before we learn of its dangers,” said David New-
man, director of clinical research for emergency medicine at Icahn School of Medicine at Mount Sinai Hospital in New York.
The Journal Sentinel/MedPage Today analysis is a signal that independent research is needed to determine if the drugs are as safe to use in the general population as they are in carefully selected clinical trial, Newman said.
Concerns about the new drugs causing bleeding that could not be stopped have been raised for years:
In a 2011 letter to the New England Journal of Medicine, doctors in Houston warned about trauma patients using Pradaxa who had poor outcomes because of excessive bleeding. They described one patient who fell and died a short time later.
In a 2012 letter in the Journal of Neurosurgery, doctors in Salt Lake City warned of a similar case involving an elderly man who fell and suffered a brain hemorrhage.
In a 2014 paper in a hematology journal, doctors in Detroit reported a case of a 39year-old woman who developed severe vaginal bleeding while on Xarelto. The bleeding eventually was stopped, but the doctors warned: “With the ever increasing number of patients using these new oral anticoagulants, the frequency of acute bleeds similar to our case encountered by physicians will continue to rise.”
Developing a medication and protocol to immediately reverse the effects of the drugs, they added: “is of paramount importance.”
$650 million settlement
In May 2014, German drugmaker Boehringer Ingelheim agreed to pay $650 million to settle about 4,000 lawsuits filed by people in the United States who allegedly were harmed after using its drug, Pradaxa.
In an email, Boehringer Ingelheim spokeswoman Kate O’Connor said the company “stands resolutely behind Pradaxa and believed from the outset that the plaintiffs’ claims lacked merit.”
She said a big reason the company agreed to the settlement was that the litigation diverted time from research and patient care.
Ned McWilliams, a Florida attorney who was involved in the Pradaxa litigation, said at least 550 Xarelto cases have been filed nationwide. He expects that number to eventually top the Pradaxa cases.
Among other things, the Glatz family lawsuit alleges that the companies that market Xarelto overstated the drug’s effectiveness in preventing strokes and failed to adequately disclose that there was no drug or agent to reverse its anticoagulation effects, which could lead to death.
“We will continue to defend against the claims raised in the litigation,” said Kristina Chang, a spokeswoman for the Janssen unit of Johnson & Johnson, which co-markets Xarelto. She was speaking generally about the lawsuits, and would not comment specifically on the Glatz claim.
Both companies said the risk-benefit profile of their drug remains favorable and consistent with its clinical trials.
Drug trial comparisons
Generally, when compared to warfarin in trials, the newer drugs have shown small percentage decreases in brain bleeding, an undesired side effect of anticoagulants, and small percentage benefits in stroke reduction, but with important reservations.
Savaysa, the newest of the four drugs, was about as effective as warfarin in preventing strokes and clots, but not in people whose kidneys worked really well.
In those patients, Savaysa actually was tied to a higher rate of strokes and clots.
The difference was so concerning that a black box warning — the most stringent FDA caution — was placed on the drug, saying it should not be used in people whose kidneys are functioning beyond a certain level.
In the trial of Eliquis, which involved 18,000 people, bleeding in the brain occurred in 0.3% of those who got Eliquis, compared with 0.8% of those who got warfarin.
Among Eliquis users, 1.3% had a stroke or a blood vessel clot, compared with 1.6% who got warfarin.
In the clinical trial of Xarelto, which involved 14,000 people, 0.5% of those getting the drug suffered a type of stroke caused by bleeding in the brain, compared with 0.8% of those who got warfarin.
But major bleeding, in all parts of the body, occurred in 5.6% of those who got Xarelto, compared with 5.4% who got warfarin.
Both Pradaxa and Xarelto showed small percentage benefits in stroke reduction, but there were caveats.
Unexpectedly, those getting Pradaxa also were more likely to have a heart attack, though the difference was small: 1.5%, compared with 1.1% of those getting warfarin.
In trials of both drugs, there were questions raised by FDA reviewers about whether warfarin got a fair shake.
In the Pradaxa trial, the entire benefit disappeared when the results were compared only with those warfarin users whose levels were well-controlled, according to an FDA review. That is, when coagulation levels were kept within the appropriate range.
“Thus, the superiority is really conditional, and depends on how well warfarin is used,” the review said.
Similar concerns were raised by FDA reviewers about Xarelto.
The clinical trial that led to the approval of Xarelto in the United States was conducted around the world. In some countries, such as India, warfarin was not managed well.
That may have biased the results in favor of Xarelto, said an FDA reviewer, who recommended against approving Xarelto for atrial fibrillation. “Patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully,” the reviewer wrote.
Despite the reviewer’s concern, the FDA’s Center for Drug Evaluation and Research approved the drug, in a letter signed by Norman Stockbridge, director of the division of cardiovascular and renal products. The FDA commissioner at the time was Margaret Hamburg, an appointee of President Barack Obama.
Asked about the FDA concerns, spokesmen for the companies that market Pradaxa and Xarelto each cited papers suggesting the performance of their drugs was consistent regardless of the level of warfarin control at the various clinical trial centers.
The two papers cited were funded by the drug companies. And a Journal Sentinel/ MedPage Today review showed most of the co-authors were consultants, speakers or employees of the companies.
Any study comparing a new anticoagulant to warfarin that is not skillfully used will tend to bias the results against warfarin, said F. Perry Wilson, an expert in clinical trial design and assistant professor of medicine at Yale University Medical School.
“I have no doubt that (warfarin) patients who are kept in a nice, therapeutic range will have better outcomes in terms of both stroke prevention and bleeding,” said Wilson, who reviewed the two papers and FDA material for this story.
Hard to predict strokes
The risk of stroke is about five times greater in people with atrial fibrillation.
However, predicting who will have a stroke and when is an imprecise science. It is complicated by other conditions such as diabetes and high blood pressure.
“We don’t have a good idea of who is going to have a stroke,” said James Stein, a professor of cardiovascular medicine at the University of Wisconsin School of Medicine and Public Health. “We act like we do.”
Ultimately, it’s a matter of weighing the risk vs. the benefit.
One scale, known as the CHADS2 score, has been in use for nearly 15 years. At the lower end of that scale are people with atrial fibrillation and no other contributing conditions.
For instance, a 66-year-old woman with atrial fibrillation and no other conditions would get a score of zero. Based on the scale, her estimated annual stroke risk is 1.9%. A daily aspirin is the only medication recommended.
The newer, more aggressive stroke scale — developed by Gregory Lip, the British doctor with financial ties to the drug companies — is known as CHA2DS2-VASc.
Under that system, a 66year-old woman would get one point for her age and one point for her gender. Her annual stroke risk would be 2.2%, tipping the scale enough for her to be prescribed an anticoagulant.
At the same time, a 66-yearold woman who is put on an anticoagulant faces a 1% to 2% annual chance of suffering a major bleeding episode.
In an email, Lip said his research shows there is a net benefit in using anticoagulants in people with atrial fibrillation, even those who might be considered at intermediate risk for a stroke under the older system.
“Patients are desperate to avoid a stroke, even at the cost of up to 4 major bleeds,” he wrote. “AFib patients see a stroke as a fate worse than death, given the major disability and dependency. In contrast, physicians seem more concerned about bleeds, even at the risk of AF patients getting strokes.”
But independent doctors say treating people at low risk for a stroke may be more harmful than beneficial.
“If you are giving a medication that causes bleeding to people who might not get much benefit, then you may actually create net harm,” said Margaret Fang, an associate professor of medicine at the University of California, San Francisco and medical director of its anticoagulation clinic.
Doctors say many things must be considered before putting a patient on one of the new anticoagulants, not just their much higher cost and the lack of an antidote to reverse dangerous bleeding episodes. These include a person’s risk of having a stroke and how well warfarin is working for them.
“Warfarin is a great drug,” said Minang Turakhia, an assistant professor of cardiovascular medicine at Stanford School of Medicine. “It’s cheap. It works. In my practice, if someone is well-controlled (on warfarin), I don’t switch them.”