At 88-years-old, Gloria Glatz still embraced life.
The mother of three was an avid Scrabble player and made a phenomenal potato salad in between occasional visits to the casino.
Like as many as 5 million Americans, Glatz had atrial fibrillation, a known risk factor for stroke.
In December 2011, her doctor decided it was time to put her on an anticoagulant drug, but rather than choosing the decades-old standby, warfarin, the doctor prescribed Xarelto (rivaroxaban), 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 drugs known as novel (or newer) oral anticoagulants, NOACS (pronounced No-aks) for short. Widely promoted as more convenient than warfarin, the drugs came to market with much fanfare anticipating blockbuster status.
But unlike warfarin, which is a vitamin K antagonist that can be turned off in a bleeding emergency or prior to surgery by administering vitamin K, all of the NOACs were approved without an antidote, although packed red blood cells can slow their anticoagulation action.
When Glatz developed gastrointestinal bleeding, 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.
Convenience: Yes, Antidote: No
Since 2010, more than 58,000 people have reported a serious side effect, such as a major bleeding episode, after using one of the anticoagulants designed to replace warfarin, a 番茄社区/Milwaukee Journal Sentinel investigation found.
At least 8,000 deaths have been linked to three of the new anticoagulant drugs since 2010, compared with about 700 for warfarin. Mortality data for the fourth drug, approved in January, is not yet available.
These numbers are drawn from the FDA's adverse events reporting system, which is largely voluntary. Though the reports are not verified, the numbers suggest an imbalance: the three newer drugs accounted for less than 10% of all anticoagulant prescriptions, yet they were linked to more than 90% of deaths reported to the FDA since 2010.
Doctors are increasingly prescribing the newer, more expensive drugs to people with afib as a way to prevent strokes and also for short term use for both prevention and treatment of deep vein thrombosis (DVT).
A primary selling point to the drugs is that they don't require regular INR testing. With warfarin, also known as Coumadin, patients must have regular INR testing, which can be done at a doctor's office, an anticoagulation clinic, or can be monitored with home testing.
Patients must also follow dietary measures, such as not eating large or inconsistent amounts of foods that are rich in Vitamin K, which can lessen warfarin's effectiveness. That includes spinach, kale and brussels sprouts.
Alcohol also should be limited to small amounts.
Marketing campaigns highlight the convenience of the new drugs, featuring comedian Kevin Nealon, who has atrial fibrillation, and golfer Arnold Palmer and NASCAR driver Brian Vickers, who both 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.
More than 10 million prescriptions for the new drugs, costing about $3.5 billion, were dispensed in 2014, according to data from , a market research firm. Prescriptions for warfarin, which is a fraction of the price, went down slightly in 2014 compared with 2013 and 2012.
The NOAC Boom
The surge in use of the drugs has been bolstered by a new system for determining stroke risk that was devised by a British doctor who, the 番茄社区/Journal Sentinel investigation found, has extensive financial ties to companies that make or market the new drugs.
The new system was adopted as part of treatment guidelines by leading medical societies in the U.S. and Europe -- ones that themselves have received millions from drug manufacturers.
In addition, many of the doctors who wrote those guidelines or issued other recommendations had personal financial ties to those companies, such as working as speakers or consultants.
Some 5.2 million Americans have atrial fibrillation, according . That's higher than past estimates of about 3 million.
How many qualify for an anticoagulant under the new guidelines?
Applying new scale, the number of Americans deemed in need of an anticoagulant jumped overnight from an estimated 3.7 million to 4.7 million, according to .
That number includes nearly all women with atrial fibrillation and virtually everyone 65 or older with the condition are considered candidates for being on the drug.
Rita Redberg, MD, a cardiologist and editor of JAMA Internal Medicine, said she tells 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 . "My concern is that a lot of the people being put on the novel oral anticoagulants will have more harm than good."
The new drugs have proven to be an expensive alternative to warfarin, now a generic, which remains more frequently used.
In 2013, taxpayers paid more than $1 billion for prescriptions of just two of the drugs, Xarelto and Pradaxa (dabigatran), Warfarin was was dispensed about six times more often, but cost taxpayers significantly less -- $240 million.
The data for 2013 are the most recent available.
From Rat Poison to Rx
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, Wis. showed up the University of Wisconsin agriculture lab one day in 1933 with samples of moldy hay and a container of 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 would bleed to death.
It made the transition from rat poison to medicine after an Army inductee headed for Korea decided that death was preferable to war and took multiple doses of the rat poison, only to fully recover after being treated with vitamin K.
Continued work led to the development of the warfarin-based medical compound known as Coumadin, which the FDA approved in 1954, giving doctors a powerful new drug that would reign for decades.
Among the famous early patients was President Dwight Eisenhower, who was given the drug to help recover from a heart attack in 1955.
Though its patents expired in the 1970s, warfarin brought in $120 million in inflation-adjusted revenue to the university.
"It is still the most widely used blood thinner in the world," said Carl Gulbrandsen, managing director of the Wisconsin Alumni Research Foundation.
One key benefit of warfarin: Its blood-thinning 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 and may be on the market in the months to come.
Balancing Bleeds vs. Clots
People with Afib have a significant risk of stroke, a risk that increases if they have other common conditions such as high blood pressure, diabetes, or even simply advanced age.
But for some Afib patients, the potential for life-threatening bleeding posed by the new drugs can outweigh any benefit.
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 of 2012.
Doctors using an endoscope three times attempted ablation to stem the bleeding, to no avail, said daughter Dottie Glatz.
They also gave her transfusions, common in such cases to replace lost blood.
"As much as they were pumping it into her, she was losing it in her stomach," she 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 番茄社区/Journal Sentinel analysis.
Companies that make the new anticoagulants say the FDA data can be skewed so that more reports are filed for newer drugs because of their novelty and because of legal activity, whereas hemorrhage with warfarin, which has been on the market for 60 years, is less likely to generate a report.
"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 Newman, MD, director of clinical research for emergency medicine at Icahn School of Medicine at Mount Sinai Hospital in New York.
The MedPageToday/Journal Sentinel 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 bleeding that could not be stopped have been raised for years:
- In , doctors in Houston warned about trauma patients using Pradaxa who had poor outcomes because of excess bleeding. One of the patients who had been standing, fell and died a short time later.
- In , doctors in Salt Lake City warned of a similar case involving an elderly man who fell from ground-level and and suffered a brain hemorrhage.
- In , doctors in Detroit reported a case of a 39-year-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."
1-800-LAWSUIT
As NOACs market availability has increased so have lawsuits filed by injured patients.
In May of 2014, German drug maker Boehringer Ingelheim filed by people in the U.S. who allegedly were harmed after using its drug, Pradaxa (dabigatran).
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.
"We will continue to defend against the claims raised in the litigation," said Kristina Chang, a spokeswoman for the Janssen unit of Johnson & Johnson.
Like O'Connor with Pradaxa, Chang said the risk-benefit profile of Xarelto also remains favorable and consistent with its clinical trials.
But the balance between who should or should not be treated with an anticoagulant has been been upset by the emergence of the new drugs and the use of the new treatment guidelines.
The FDA Approval Train
The first NOAC to be approved by the FDA was Pradaxa (dabigatran) in 2010, which is the only direct thrombin inhibitor among the NOACs and is the only one that requires twice-daily dosing. Following Pradaxa to market were the Factor Xa inhibitors: Xarelto (rivaroxaban) in 2011, Eliquis (apixaban) in 2012, and last January, Savaysa (edoxaban).
Generally, the newer drugs offered have shown small percentage decreases in brain bleeding and small percentage benefits in stroke reduction.
For instance, in the ARISTOTLE-AF study of Eliquis, which involved 18,000 people, bleeding in the brain occurred in .3% of those who got Eliquis, compared .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 pivotal ROCKET-AF trial, which involved 14,000 people, .5% of those getting the Xarelto suffered intracranial hemorrhage (ICH), compared with .8% of the warfarin controls.
But major bleeding -- including GI bleeds -- occurred 5.6% of those who got Xarelto, compared with 5.4% who got warfarin.
Compared to warfarin, both Pradaxa and Xarelto showed small percentage benefits in ischemic stroke reduction, but there were caveats.
In RE-LY, the Pradaxa pivotal trial, 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 Xarelto and Pradaxa, 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, 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 U.S. was conducted around the world. In some countries, such as India, warfarin was not used 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 drug was approved.
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 were funded by the drug companies. And a 番茄社区/Journal Sentinel 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 , an expert in clinical trial design and assistant professor of medicine at Yale University Medical School.
He reviewed the two papers and the FDA material for this story.
"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," he said.
Who and When: The Anticoagulation Challenge
The risk of stroke is about five times greater in people with atrial fibrillation.
But 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, MD, 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.
But the new stroke scale -- the one developed by Gregory Lip, MD, a British doctor with financial ties to the drug companies -- identifies more people as candidates for anticoagulation.
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 woman age 66 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 is known as CHA2DS2-VASc.
Under that system, a 66-year-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 need a prescription anticoagulant.
At the same time -- regardless of gender -- a 66-year-old 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 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 more 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, MD, an associate professor of medicine at the University of California, San Francisco and medical director of its anticoagulation clinic.
Independent doctors say a person's risk of having a stroke as well as how well warfarin is working for them need to be taken into account before putting them on one of the newer drugs.
"Warfarin is a great drug," said Minang Turakhia, MD, 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."
John Fauber is a reporter with the Milwaukee Journal Sentinel. Coulter Jones is a reporter with 番茄社区. This story was reported as a joint project of the Milwaukee Journal Sentinel and 番茄社区.