Preview Newsletter
Xarelto Media Report 8/9/16
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F.D.A. Asks If Faulty Blood Monitor Tainted Xarelto Approval
Feb 22, 2016 | New York Times
By Katie Thomas
The Food and Drug Administration is investigating whether a faulty blood-testing device may have compromised the results of a clinical trial that led to the approval of Xarelto, a blockbuster anticlotting drug that has been prescribed to millions of Americans since it arrived on the market in 2011. -
Accuracy Concerns on Testing Device for Blood-Thinning Drug
Mar 17, 2016 | New York Times
By Katie Thomas
Dr. Gary Goldstein, a Florida internist, knew something was wrong with a blood-testing device in his office when, all of a sudden, it began giving out odd results. The device, an INRatio monitor by Alere, is crucial to helping doctors manage patients on warfarin, a blood-thinning drug. When he checked the INRatio’s results against those from an outside laboratory and found they did not match, he got worried and called Alere. Then, he said, after sensing a lack of interest from the company, he filed a report about the event with the Food and Drug Administration. -
Bayer, J&J Face Calls to Consolidate Xarelto Blood-Thinner Suits
Dec 4, 2015 | Bloomberg
By Jef Feeley
Bayer AG (BAYN) and Johnson & Johnson (JNJ) are fighting calls to consolidate lawsuits over a blood-thinning drug blamed for causing some patients to bleed to death after a settlement this year by the maker of a competing product. -
Xarelto Marketed as ‘One Size Fits All'; No Disclosure on Lack of Reversal Agent
Apr 23, 2016 | Bloomberg BNA
By Lisa Helm
Two wrongful death suits alleging Johnson & Johnson Pharmaceutical failed to warn that the blood thinner Xarelto could cause potentially fatal bleeding have been filed in federal courts in New Jersey and New York (Padrick v. Janssen Research & Development, LLC, D.N.J., 3:15-cv-02774-MAS-DEA, complaint filed, 4/20/15)(Romano v. Janssen Research & Development, LLC, S.D.N.Y., No. 1:15-cv-03111, 4/21/15). -
CardioBrief: Warfarin Monitoring System Cited in Controversy Withdrawn
Jul 13, 2016 | Med Page Today
By Larry Husten
The Alere INRatio and INRatio2 PT/INR Monitoring System are being pulled from the market. Alere, the manufacturer of the devices, which are used by people taking warfarin (Coumadin) to monitor their INR, said that the action follows a "collaborative process" with the FDA. The company said it "is working with the FDA to determine the most appropriate timing for product discontinuation and will provide guidance on transitioning patients to an alternate solution to allow them to continue anti-coagulation monitoring in the least disruptive manner possible." -
J&J, Bayer Sued For Downplaying Risks Of Xarelto
Sep 11, 2015 | Law360
By Joe Van Acker
More than two dozen people claimed in Louisiana federal court on Thursday that Johnson & Johnson and Bayer Corp. downplayed the risk of internal bleeding caused by the blood-thinner Xarelto, accusing the companies of deliberately concealing the potentially fatal side effect. -
Bayer and J&J push back against consolidation of Xarelto suits
Dec 4, 2015 | FiercePharma
By Emily Wasserman
Bayer and Johnson & Johnson ($JNJ) are fighting a consolidation of lawsuits over their top-selling anticoagulant Xarelto, which patients say had more severe bleeding risks than the companies let on. Patients who took Xarelto and their lawyers today will ask a panel of federal judges in Charleston, SC, to send 21 cases filed so far in 10 federal courts to U.S. District Judge David Herndon in East St. Louis, IL, for pretrial information exchanges, Bloomberg reports. Consolidating the cases for pretrial exchanges of evidence is a potential time and money saver, as one judge can oversee the collection of documents and testimony regarding the drug's performance. -
Drug Problems: Duke Reassessing Data From Trial Led By FDA Nominee
Nov 20, 2015 | Pogo.org
By David Hilzenrath and Chalres R. Babcock
Four years after the FDA approved the blood thinner Xarelto for cardiac patients based on a global clinical trial, the institute that coordinated the study is trying to determine whether the use of potentially malfunctioning medical devices affected the trial results. -
Anticoagulation Rx Expanded After NOAC Launch
Nov 12, 2015 | MedPage Today
By Ed Susman
More patients with atrial fibrillation are receiving anticoagulation therapy since the direct oral agents have reached the market -- but not just because warfarin is being replaced by easier-to-use newer drugs, researchers suggested here. -
Xarelto patient alleges fraud, negligence
Apr 20, 2016 | Madison-St. Claire Record
A California man is suing a number of pharmaceutical manufacturers in St. Clair County over the drug Xarelto. Kenneth Niemeier filed a lawsuit March 31 in St. Clair County Circuit Court against Janssen Research & Development, formerly known as Johnson and Johnson Pharmaceutical Research and Development; Janssen Ortho; Janssen Pharmaceuticals Inc., formerly known as Janssen Pharmaceutica Inc.; Bayer Healthcare Pharmaceuticals Inc.; Bayer Pharma AG of Germany; Bayer Corporation; Bayer Healthcare; and Bayer Healthcare AG and Bayer AG of Germany, alleging product liability. -
Patient sues pharmaceutical manufacturers for alleged fraudulent misrepresentations surrounding Xarelto
Nov 17, 2015 | Madison County Record
By Angelino Menconi
A disgruntled Xarelto patient filed a lawsuit against major pharmaceutical manufacturers, developers and researchers alleging they fraudulently misrepresented the dug's benefits, risks and dangers -
New anticoagulant drugs provide stroke prevention with dose of danger
Aug 2, 2015 | Milwaukee Journal Sentinel
By John Fauber and Coulter Jones
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. -
Philadelphia court establishes Xarelto mass tort docket
Jan 22, 2016 | The Pennsylvania Record
By Jim Boyle
Philadelphia Court of Common Pleas Administrative Judge Kevin Dougherty has created a mass tort docket for Xarelto blood thinner injury cases filed against Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, according to an order issued Wednesday.
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F.D.A. Asks If Faulty Blood Monitor Tainted Xarelto Approval
Feb 22, 2016 | New York Times
By Katie Thomas
The Food and Drug Administration is investigating whether a faulty blood-testing device may have compromised the results of a clinical trial that led to the approval of Xarelto, a blockbuster anticlotting drug that has been prescribed to millions of Americans since it arrived on the market in 2011.
The agency has asked the drug’s manufacturer, Johnson & Johnson, detailed questions about whether there was evidence that the device was malfunctioning while the trial was underway, according to a legal brief filed in federal court on Monday by lawyers for patients and their families who say they were injured by the drug. The lawyers also cited internal company documents that they said showed doctors were complaining to the trial leadership during the course of the study.
The clinical trial, known as Rocket AF, was led by Dr. Robert M. Califf, currently President Obama’s nominee for head of the Food and Drug Administration. It involved more than 14,000 patients worldwide and took place from 2006 to 2010.
Xarelto, which is also known by its scientific name, rivaroxaban, is one of a new class of drugs that are seen as a replacement for warfarin, a cumbersome 60-year-old drug used to prevent strokes in people with a heart-rhythm disorder known as atrial fibrillation. Warfarin requires careful monitoring of a patient’s diet and drug regimen, and frequent blood tests to ensure that is working. If patients receive too little of the drug, they could experience a stroke. But if they receive too much, their lives could be threatened by catastrophic bleeding.
Questions about the trial have been stirring since last fall, when Johnson & Johnson and Bayer, which sells Xarelto overseas, notified regulators that the device that was used in the trial had been recalled in 2014 because it was understating patients’ risk of bleeding. The device, the INRatio sold by Alere, was used in the trial to help doctors gauge whether patients were getting the right dose of warfarin. The trial compared the number of strokes and bleeding events experienced by patients taking Xarelto to those of patients who were given warfarin.
Regulators are looking at whether the malfunctioning device might have led doctors to give patients the wrong dose of warfarin, which could have led to additional bleeding episodes and given an unfair advantage to Xarelto.
This month, researchers with the Duke Clinical Research Institute, which oversaw the trial, published their own analysis in the New England Journal of Medicine and concluded that the faulty device did not affect the trial’s outcome. A few days later, an analysis by the European Medicines Agency, the F.D.A.’s European counterpart, came to the same conclusion.
But rather than settling the matter, the analyses have raised additional questions and have come under harsh criticism from some medical experts. The Duke researchers, for example, never mentioned the existence of central laboratory tests — taken at two points during the trial — that could have been used to assess whether the device’s readings were accurate. And the analysis released by the European drug agency, while it did include those readings, was done by the companies themselves and not by independent statisticians.
“There are so many questions that are yet unaddressed,” said Dr. Harlan M. Krumholz, a cardiologist and director of the Yale University Open Data Access Project, which has an agreement with Johnson & Johnson to make the company’s data from clinical trials available to outside researchers. He has asked the company for access to the trial data, he said, and the company has agreed — but Bayer has refused.
Dr. Krumholz called on Alere to release more information about its device. “We do not know why the device did not work well,” he said.
In a statement, a spokeswoman for the F.D.A. said that while the agency was looking into the issue, it had not changed its recommendations for the drug, which “provides an important health benefit when used as directed.”
A spokeswoman for Alere declined to comment, and a representative for Duke referred to an earlier statement detailing the results of its reanalysis.
Johnson & Johnson said the INRatio device was selected because it was F.D.A.-approved and easy to use. It said it was not informed of the device recall until last September, when it and Bayer “acted with urgency, diligence and in the best interests of patients and prescribers.” The company said that it has provided answers to the questions the F.D.A. asked and that the analysis published in the New England Journal of Medicine confirmed the safety and efficacy of the drug.
A spokesman for Bayer said the company was confident in the results of the trial and dismissed the issue as being driven by plaintiffs’ lawyers, saying, “They have cherry-picked testimony and documents divorced from any context.”
Dr. Califf is the former director of the Duke Clinical Research Institute, which conducted the trial, and served as the study’s co-chairman. He has since left Duke and is now a deputy commissioner of the F.D.A. Dr. Califf, who did not respond to an email, has no role in the inquiry into the Rocket AF trial, the F.D.A. has said. The Senate was expected to vote Tuesday on whether to confirm his nomination as head of the agency.
Just as the trial was getting underway in 2006, the INRatio was facing scrutiny by the F.D.A. In 2005 and 2006, the agency sent warning letters to HemoSense, then the manufacturer of INRatio, claiming that the devices were generating “clinically significant” erroneous values and that the company, which was later acquired by Alere, was not properly investigating the complaints.
In 2014, Alere recalled the INRatio monitors, saying that they might provide inaccurate results.
However, the connection to the Rocket trial was not made public until this past fall, when a journalist for the British Medical Journal began asking the companies about it. A spokesman for Johnson & Johnson told the journal that the company had been unaware of the recall. The revelation led to the reanalysis by the Duke researchers as well as inquiries by the European Medicines Agency and the F.D.A.
But while the European agency concluded that the trial outcome was not affected by problems with the device, the F.D.A. appears to be taking a closer look, asking pointed questions about whether the company had evidence that the device was malfunctioning during the trial and what actions it took, according to the legal document, which was filed with Judge Eldon E. Fallon in the Eastern District of Louisiana.
The legal motion filed on Monday also cited internal emails that, the lawyers said, showed that some doctors were questioning the accuracy of the device while the trial was underway. The lawyers said so many concerns were raised about the device that a special program was set up to investigate the malfunctions, but none of these details were provided to the F.D.A. when Johnson & Johnson responded to the agency this month.
The Rocket trial has previously come under criticism. In 2011, the F.D.A.’s medical reviewers recommended against approval of Xarelto, citing concerns that the patients receiving warfarin during the trial were being poorly managed, which could give an unfair advantage to Xarelto.
An outside advisory committee later voted to approve the drug — although several members cited reservations — and the agency allowed it to go on the market. It has since become the best-selling drug in its class, bringing in $1.9 billion in the United States in 2015, according to Johnson & Johnson.
Some said the fact that Xarelto has been on the market since 2011 gave them faith in the safety of the product. “The real world has already made the case for this drug,” said Dr. Jürgen vom Dahl, a German cardiologist who served as an investigator in the trial, who said he did not recall encountering any problems with the device.
Dr. vom Dahl also said that he and his German colleagues have wondered whether Dr. Califf’s F.D.A. nomination was playing a role in the renewed questions about the trial. “We don’t know what is real science, and what is more politics,” he said.
But others say that plenty of questions remain, and that they are disheartened by a seeming reluctance by Duke, Johnson & Johnson and Bayer to be forthright about the problem.
“It depends on where you put the flashlight,” said Robert Powell, a clinical pharmacologist who has worked in the drug industry, as well as for six years at the F.D.A. “I think they were directing people away from the problem.”
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Accuracy Concerns on Testing Device for Blood-Thinning Drug
Mar 17, 2016 | New York Times
By Katie Thomas
Dr. Gary Goldstein, a Florida internist, knew something was wrong with a blood-testing device in his office when, all of a sudden, it began giving out odd results.
The device, an INRatio monitor by Alere, is crucial to helping doctors manage patients on warfarin, a blood-thinning drug. When he checked the INRatio’s results against those from an outside laboratory and found they did not match, he got worried and called Alere. Then, he said, after sensing a lack of interest from the company, he filed a report about the event with the Food and Drug Administration.
“I don’t do them regularly,” Dr. Goldstein said. “But this was a potential harm to patients.”
Dr. Goldstein was not alone. Since the INRatio and a later model, the INRatio2, were cleared for use in 2002, the F.D.A. has received more than 9,000 reports of malfunctions with the products, and more than 1,400 reports of injuries, according to an analysis in December by the Public Citizen Health Research Group, a consumer organization. Reports of injuries associated with the INRatio devices are far higher than similar products on the market, a review of F.D.A. records shows.
The device’s problems also led last fall to a new analysis of a large drug trial that relied on the INRatio to monitor patients.
These reports, in addition to a series of F.D.A. warning letters and recalls, have raised questions among doctors and public health experts about why the device remains on the market. Neither the F.D.A. nor Alere have yet said publicly that the device appears to malfunction.
“It very well may be an unsafe device,” said Dr. Robert G. Hauser, a retired cardiologist and an advocate for improved safety of medical devices. “I think the F.D.A. has to look at this device very seriously, and ask whether it’s a safe device and should be used by patients for this purpose.”
The device is almost certainly going to be a topic of debate on Friday, when the F.D.A. is holding a workshop about the accuracy of it and similar devices. Although the agency has not singled out the INRatio device by name, the Alere product is the only device that has come under recent scrutiny for its accuracy, and the workshop was announced after concerns were raised.
Jackie Lustig, a spokeswoman for Alere, declined to answer any questions about the INRatio.
A spokesman for the F.D.A. said Alere had informed the agency that it was working on an improvement to the device. “We cannot share more details,” the spokesman, Eric Pahon, said.
The INRatio and other similar devices measure the blood’s clotting ability and have been welcomed by many doctors and their patients who take the drug warfarin, a blood-thinning drug that requires careful monitoring. Instead of sending blood samples to an outside laboratory, doctors can learn with the prick of a finger if warfarin is working properly.
The stakes are high: Too little warfarin and patients could suffer a stroke, but too much and they could bleed to death.
“It’s not like checking cholesterol,” said Doug Patterson, the chief executive of CoaguSense, which makes the Coag-Sense, a competing device. “Too much or too little, and you can end up with trouble.”
Public records show that problems began to arise with the INRatio only a few years after it went on the market. In 2005 and 2006, the F.D.A. issued two warning letters to HemoSense, the device’s maker at the time. The letters argued that the company had failed to act on complaints that the devices were giving erroneous results.
INRatio, a warfarin monitor made by Alere. CreditAndrew Sullivan for The New York Times
In 2007, doctors at a clinic in London tested five of the point-of-care testing devices then on the market and concluded that the INRatio performed the worst, departing the most significantly from central laboratory results compared with its competitors on a number of measures.
The F.D.A. was receiving thousands of reports of malfunctions and injuries. The INRatio was associated with 1,451 injury reports, according to an analysis of adverse-event reports to the F.D.A. By contrast, CoaguChek, the market leader that is made by Roche, logged 95 injury reports over the same period.
Such reports are voluntarily submitted to the F.D.A. and can contain errors because they are not independently verified. Still, the difference between the products was significant, said Dr. Sidney M. Wolfe, founder and senior adviser to the Public Citizen Health Research Group. The group wrote the F.D.A. in December to raise concerns about the device.
Once a product is on the market, the F.D.A. is supposed to keep track of reports of problems with devices and it inspects companies to ensure that they are manufacturing high-quality products. It can issue warning letters, as it did in the case of the INRatio, and it can also pressure companies to recall their products or issue restrictions for how the device can be used.
But some, including Dr. Wolfe, have criticized the agency for not properly monitoring devices once they arrive on the market and say they are too slow to take action.
“What would it take for this device to be taken off the market?” Dr. Wolfe said in an interview.
Mr. Pahon, the F.D.A. spokesman, said the intent of Friday’s workshop was to gather just such information. “We will certainly take that input into serious consideration as we move forward with any regulatory approach,” he said.
Dr. Wolfe’s December letter laid out several alarming examples of patients who experienced serious bleeding — including from the nose, gums and rectum — after they said they received an erroneous result from the INRatio device.
In 2014, a year after Dr. Goldstein complained to Alere, the company announced it was recalling the strips for its INRatio2 device because they were providing erroneous readings. The company switched patients and doctors to its earlier system, the INRatio.
Later that year, Alere issued a new warning about that product, saying that customers of both the INRatio and INRatio2 should stop using the products if they had certain medical conditions, including the flu or other infections and chronic diseases like rheumatoid arthritis.
Then, last fall, new questions arose about the device after it was discovered that the INRatio was used in a large clinical trial that led to the approval of the drug Xarelto, an alternative to warfarin.
A comparison of the blood samples of more than 5,000 patients in that trialfound that, 35 percent of the time, the INRatio readings differed from a central laboratory test result in a way that was clinically significant. Johnson & Johnson, which sells Xarelto, said it had turned over the data from the trial to Alere.
The Xarelto trial, known as Rocket AF, was led by Dr. Robert M. Califf, who is now the head of the F.D.A.
Eric Rosenberg, a retired lawyer, has been using an INRatio device for years. Every three months, he said, he checks his blood with an outside laboratory to ensure the device is working properly.
The reading is slightly higher than the lab result, but he said it’s reliable enough. “I’ve been pleased with it,” said Mr. Rosenberg, 67, who lives in Mamaroneck, N.Y.
But given recent news about the device, he said he was considering switching to a competitor.
“I am concerned now that I’ve read more about the possibility that there is less accuracy,” he said.
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Bayer, J&J Face Calls to Consolidate Xarelto Blood-Thinner Suits
Dec 4, 2015 | Bloomberg
By Jef Feeley
Bayer AG (BAYN) and Johnson & Johnson (JNJ) are fighting calls to consolidate lawsuits over a blood-thinning drug blamed for causing some patients to bleed to death, a move that would make it easier for plaintiffs to prepare their cases.
Patients who took Xarelto accuse the drugmakers of downplaying the medicine’s bleeding risks and asked that the cases be gathered before U.S District Judge David Herndon in East St. Louis, Illinois, for pretrial information exchanges, according to court filings. Consumers contend 65 deaths have been linked to bleeding caused by the drug, which has no antidote, according to court filings.
Collecting the suits before a single judge could benefit both sides by saving them time and money. The judge would oversee the collection of documents and testimony about the drug’s development and performance to help attorneys prepare for trial.
Some lawyers for former Xarelto users and their families today asked a panel of federal judges in Charleston, South Carolina, to send Herndon 50 cases filed so far in 15 federal courts.$650 Million Settlement
The push to consolidate the Xarelto cases follows a $650 million settlement of similar claims over Boehringer Ingelheim Gmbh’s blood thinner Pradaxa. Researchers linked Pradaxa to more than 500 users’ deaths, and the company wound up resolving more than 4,000 suits over the medicine. Herndon presided over the consolidation of the Pradaxa suits and the accord.
“If you have a judge already familiar with these blood-thinner suits, the cause of efficiency would be better served by sending the cases to him,” said Carl Tobias, who teaches product-liability law at theUniversity of Richmond in Virginia.
“We stand behind our product and will defend ourselves in the litigation,” Chris Loder, a U.S.-based spokesman for Bayer, said in an e-mailed statement.
Kristina Chang, a J&J spokeswoman, said that after three years on the U.S. market, “the benefit-risk profile of Xarelto remains favorable and consistent with the clinical trials.”
“All anticoagulants carry the risk of bleeding, and the prescribing information for Xarelto has always warned of these risks,” Chang said in an e-mail.New Jersey
In court filings, the companies urged the panel to rebuff the request to consolidate the Xarelto cases. If a consolidation is granted, however, J&J and Bayer want the case sent to a New Jersey federal court near their U.S. corporate offices.
“Several judges in New Jersey have the experience and docket capacity to handle these cases,” Bayer said in a Nov. 24 filing. The company said U.S. District Judge Freda Wolfson in Trenton already is presiding over two Xarelto cases.
Susan Sharko, a lawyer for J&J’s Janssen unit, touted New Jersey “as the only rationally based forum” for the Xarelto cases.
“Both companies are there, the executives are there and the other witnesses are there,” she added.
Roger Denton, a St. Louis-based lawyer who handled Pradaxa cases before Herndon, said the panel should focus on Herndon’s expertise with blood-thinner cases rather than the location of witnesses and documents.‘Knows More’
“Judge Herndon knows more about this than anyone,” Denton told the panel today.
If Herndon isn’t available, other lawyers for Xarelto patients suggested the cases be sent to U.S. District Judge Eldon Fallon in New Orleans. Fallon oversaw the consolidation of suits against Merck & Co. over its withdrawn Vioxx painkiller that resulted in a $4.85 billion settlement in 2007.
U.S. regulators originally approved Xarelto in 2011 to prevent blood clots in patients undergoing knee and hip surgeries. The drug’s use has been extended to patients with irregular heartbeats and potentially deadly leg and lung blood clots.
Xarelto and Pradaxa belong to a class of drugs known as new oral anticoagulants, intended to replace for Bristol-Myers Squibb Co. (BMY)’s Coumadin, used to thin stroke patients’ blood since the 1960s.
Xarelto was marketed as more effective at preventing strokes than Coumadin and easier to use, because Xarelto patients didn’t need frequent tests to monitor their blood-plasma levels.$2 Billion
By 2013, Xarelto had racked up more $2 billion in sales. Bayer produces the drug, and J&J owns the U.S. rights to the blood thinner. That same year, U.S. regulators rejected the company’s request to expand the use of the drug to heart-surgery patients.
Xarelto’s U.S. sales generated $414 million for J&J in the third quarter of this year while Bayer’s sales in other markets generated $522.5 million over the same period, according to data compiled by Bloomberg.
Lawyers for Xarelto patients argue the companies didn’t properly test the blood thinner before putting it on the market, hid the fact the medicine had no antidote and overstated the drug’s effectiveness, according to court filings.
They said more than 1,000 reports of side effects were filed with the U.S. Food and Drug Administration by June 2012, including reports of at least 65 deaths, according to the filings.‘Sheer Volume’
While the companies contend “this litigation is lawyer-driven, the sheer volume of reported serious adverse events shows their claim is simply not true,” lawyers for Kimberly West, a former Xarelto user who hemorrhaged while on the drug, said in a Nov. 4 filing.
Given the number of Xarelto side-effect reports, plaintiffs’ attorneys contend Bayer & J&J may face thousands of suits over the drug. The companies also face suits in state courts, including several in Pennsylvania.
The five federal judges on the Multidistrict Litigation Panel heard about a half hour of arguments today on whether and where the Xarelto cases should be consolidated.
Under the multidistrict-litigation system, suits filed in federal courts around the U.S. can be consolidated before a single judge for pretrial hearings.
Once pretrial information exchanges are done, the cases are sent back to the courts where they were filed for trials. Consolidation cuts expenses for both sides.
The case is Xarelto Products Liability Litigation, MDL No. 2592, U.S. Judicial Panel on Multidistrict Litigation.
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Xarelto Marketed as ‘One Size Fits All'; No Disclosure on Lack of Reversal Agent
Apr 23, 2016 | Bloomberg BNA
By Lisa Helm
Two wrongful death suits alleging Johnson & Johnson Pharmaceutical failed to warn that the blood thinner Xarelto could cause potentially fatal bleeding have been filed in federal courts in New Jersey and New York (Padrick v. Janssen Research & Development, LLC, D.N.J., 3:15-cv-02774-MAS-DEA, complaint filed, 4/20/15)(Romano v. Janssen Research & Development, LLC, S.D.N.Y., No. 1:15-cv-03111, 4/21/15).
The plaintiffs allege that drug manufacturers and suppliers failed to disclose that no agent exists to reverse the anticoagulation effects of Xarelto and that serious bleeding may be life-threatening.
The suits also allege that the defendants negligently represented that “one dose size fit all patients,” when they should have known that proper dosage depended on individualized factors in users.
“We expect these two cases to join others already filed around the country in a multidistrict litigation which has been established in New Orleans, the Eastern District of Louisiana,” said Paul D. Rheingold, a partner with the law firm, in a statement.
The U.S. Judicial Panel on Multidistrict Litigation sent other suits over Xarelto bleeding to the Eastern District of Louisiana in December and assigned the MDL to Judge Eldon E. Fallon.
Johnson & Johnson Pharmaceutical Research and Development LLC, its Janssen division and Bayer Healthcare Pharmaceuticals Inc. are named as defendants in the suits, which were filed by the widows of two men who allegedly rapidly developed bleeding in their brains after being prescribed Xarelto.
“After more than three years on the U.S. market, and more than 2 million patients prescribed in the U.S. to date, the benefit-risk profile of Xarelto remains favorable and consistent with the clinical trials. All anticoagulants, or blood thinners, carry the risk of bleeding, and the prescribing information for Xarelto has always warned of these risks,” Janssen said in a statement Wednesday.
“Blood thinners are important and potentially life-saving medicines that should be taken by patients as prescribed by a doctor and should not be discontinued without a discussion with a doctor. We will continue to defend against the claims raised in the litigation,” the statement also said.
Xarelto is categorized as a direct action oral anticoagulant.
Bleeding, Then Death
In January 2013, Graham Padrick, then 76, was switched to Xarelto from Coumadin for treatment of atrial fibrillation. He died February 14, 2013, after developing a subdural hematoma, or bleeding outside the brain.
Padrick's widow, Dorothy Padrick, filed the wrongful death suit on behalf of his estate.
In the second case, Bonzena Romano, the widow of Ladson Romano, then 67, alleged Ladson was placed on Xarelto in November 2014 because of the potential for development of a deep vein thrombosis.
Ladson died December 20, 2014, after developing hemorrhaging in his brain stem.
In both cases, hospital doctors tried to reverse the bleeding, but there wasn't a remedy for a Xarelto-induced bleed, the plaintiffs' firm said in a press release issued April 21.
The suits assert defective design, manufacturing defect, inadequate warning and other claims. They also challenge the promotion of Xarelto as a blood thinner that, unlike its treatment alternative, warfarin, doesn't need periodic monitoring with blood tests.
Rheingold, Valet, Rheingold, McCartney & Giuffra LLP represents the plaintiffs.
Information about counsel for the defendants was not immediately available.
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CardioBrief: Warfarin Monitoring System Cited in Controversy Withdrawn
Jul 13, 2016 | Med Page Today
By Larry Husten
The Alere INRatio and INRatio2 PT/INR Monitoring System are being pulled from the market.
Alere, the manufacturer of the devices, which are used by people taking warfarin (Coumadin) to monitor their INR, said that the action follows a "collaborative process" with the FDA. The company said it "is working with the FDA to determine the most appropriate timing for product discontinuation and will provide guidance on transitioning patients to an alternate solution to allow them to continue anti-coagulation monitoring in the least disruptive manner possible."
The portable monitoring systems were relatively obscure until last year, when the findings of the pivotal ROCKET AF trial were called into question after it was revealed that the Alere device used to monitor and calibrate warfarin usage in the trial had been defective and the subject of a serious FDA recall.
Since then the FDA, the European Medicines Agency, and the trial investigators have sought to confirm the findings of ROCKET AF, which compared rivaroxaban (Xarelto) with warfarin in patients with atrial fibrillation. Recently the trial investigators published a letter in the New England Journal of Medicine comparing readings from the Alere device with stored blood samples taken during the trial. The trial investigators found that there were potentially important differences between the two methods, but that the main findings of the trial did not appear to have been compromised.
In December 2014, Alere issued the first alert informing users that the devices should not be used by patients with certain medical conditions. Alere said that, at the end of 2015, it submitted software enhancements to the FDA that corrected the earlier problems, but "the FDA notified the company that it believes the company's studies do not adequately demonstrate the effectiveness of the software modification and advised Alere to submit a proposed plan to voluntarily remove the INRatio device from the market."
In February, Abbott agreed to purchase Alere for $5.85 billion. It has since tried to back away from the deal because of a U.S. investigation into Alere's foreign operation, according to a report in Bloomberg.
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J&J, Bayer Sued For Downplaying Risks Of Xarelto
Sep 11, 2015 | Law360
By Joe Van Acker
Law360, New York (September 11, 2015, 2:45 PM ET) -- More than two dozen people claimed in Louisiana federal court on Thursday that Johnson & Johnson and Bayer Corp. downplayed the risk of internal bleeding caused by the blood-thinner Xarelto, accusing the companies of deliberately concealing the potentially fatal side effect.
The plaintiffs, two of whom represent estates of patients who died of severe bleeding, accused the pharmaceutical companies of cherry-picking positive points of studies on Xarelto for marketing, while failing to stress steps to avoid gastrointestinal bleeding.
“The use of Xarelto without appropriate blood monitoring, dose adjustment and twice a day dosing can cause major, life-threatening bleeding events,” the plaintiffs said. “Importantly, Xarelto’s significant risk of severe, and sometimes fatal, internal bleeding has no antidote to reverse its effects.”
The studies that the defendants relied on in their ads were also unreliable and poorly managed, the plaintiffs said, reporting instances of falsification, discarded medical records and improper dosing.
Primarily prescribed to patients suffering from nonvalvular atrial fibrillation, deep vein thrombosis or pulmonary embolism, Xarelto is also used to treat recipients of hip and knee replacements, the plaintiffs said.
Xarelto was at one point the most heavily advertised drug in medical journals, but J&J and Bayer focused their ads on the drug’s ability to prevent stroke and systemic embolism, according to the plaintiffs, who said the marketing campaign induced their physicians to prescribe Xarelto instead of safer alternatives. They claimed that their physicians weren’t aware of the drug’s risks because the defendants intentionally provided inadequate warnings.
“Defendants’ fraudulent representations and concealment evidence flagrant, willful, and depraved indifference to health, safety, and welfare,” the plaintiffs said, accusing the companies of acting with “callous indifference.”
Even after receiving word of thousands of “adverse events” involving the drug in the U.S. and Germany, as well as dozens of deaths in both countries, the companies didn’t perform any additional investigation of Xarelto or provide adequate warnings, according to the complaint.
The complaint included charges of fraud, negligence, breach of warranty, wrongful death and other claims, and the plaintiffs requested damages to cover their pain and suffering and medical expenses, as well as punitive damages.
The plaintiffs also said that their spouses, heirs and domestic partners have suffered a loss of consortium that may require psychological treatment.
The defendants have been hit with numerous similar complaints, many of which were consolidated in Louisiana federal court late last year by the U.S. Judicial Panel on Multidistrict Litigation, which rejected the companies' argument that the cases involved too many variables, such as medical histories and dosages.
Representatives for the defendants didn’t respond to requests for comment on Friday.
The plaintiffs are represented by Randi Kassan of Sanders Phillips Grossman LLC.
Counsel information for the defendants wasn’t available.
The case is Adams et al v. Janssen Research & Development LLC f/k/a Johnson and Johnson Pharmaceutical Research and Development LLC et al, case no. 2:15-cv-04273 in the U.S. District Court for Louisiana’s Eastern District.
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Bayer and J&J push back against consolidation of Xarelto suits
Dec 4, 2015 | FiercePharma
By Emily Wasserman
Bayer and Johnson & Johnson ($JNJ) are fighting a consolidation of lawsuits over their top-selling anticoagulant Xarelto, which patients say had more severe bleeding risks than the companies let on.
Patients who took Xarelto and their lawyers today will ask a panel of federal judges in Charleston, SC, to send 21 cases filed so far in 10 federal courts to U.S. District Judge David Herndon in East St. Louis, IL, for pretrial information exchanges, Bloomberg reports. Consolidating the cases for pretrial exchanges of evidence is a potential time and money saver, as one judge can oversee the collection of documents and testimony regarding the drug's performance.
J&J and Bayer are pushing the panel to reject plaintiffs' request for consolidation, but if one is granted, the companies want the case sent to a New Jersey federal court near their federal offices, according to court filings seen by Bloomberg.
Patients' lawyers argue that 65 deaths have been linked to bleeding caused by the drug, and that J&J and Bayer hid the fact that Xarelto has no antidote. But J&J and Bayer are standing by their product, maintaining that "the benefit-risk profile of Xarelto remains favorable and consistent with the clinical trials," J&J spokeswoman Kristina Chang told Bloomberg in an emailed statement. "All anticoagulants carry the risk of bleeding, and the prescribing information for Xarelto has always warned of these risks," she said.
The push for consolidation comes on the heels of more legal drama surrounding new anticoagulants, as Boehringer Ingelheim in May agreed to shell out $650 million to wrap up 4,000 lawsuits claiming that its clot-fighting drug Pradaxa caused serious, sometimes fatal, bleeding in some patients. The German drugmaker said at the time that while it stood by its drug's safety, a settlement would allow it to avoid the cost and effort-drain of long-term litigation.
Meanwhile, J&J and Bayer are working hard to build a lead on the competition, as big names like Bristol-Myers Squibb ($BMY) and Pfizer ($PFE) push their own next-generation anticoagulant therapies. A slew of recent indications in the U.S. and the EU have helped Xarelto bring in an eye-popping $1.09 billion through the first 9 months of the year. But J&J/Bayer faced a setback in February when theFDA gave the med a thumbs-down for treating acute coronary syndrome (ACS), a potentially lucrative designation as the malady accounts for some 1.1 million hospital admissions annually in the U.S.
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Drug Problems: Duke Reassessing Data From Trial Led By FDA Nominee
Nov 20, 2015 | Pogo.org
By David Hilzenrath and Chalres R. Babcock
Four years after the FDA approved the blood thinner Xarelto for cardiac patients based on a global clinical trial, the institute that coordinated the study is trying to determine whether the use of potentially malfunctioning medical devices affected the trial results.
Robert Califf, a former Duke University researcher who is now President Obama’s nominee to head the FDA, co-chaired the executive committee that designed and oversaw the trial.
Records show that the Xarelto trial used “INRatio” blood-testing devices and that the reliability of INRatio devices was the subject of two FDA warning letters before the trial began in late 2006. In 2014, four years after the trial ended, a recall notice warned that certain INRatio devices could deliver false test results and that use of those devices may “cause severe or life-threatening injuries, including death.”
Based on those records, over the past two weeks POGO asked Califf, the Duke Clinical Research Institute (DCRI), the FDA, European regulator EMA, the makers of Xarelto, and others involved how if at all the trial might have been affected by defects in blood-testing devices.
“The DCRI is conducting an independent analysis of the trial data to understand what effect, if any, the potential device malfunction might have had in subpopulations and specific patient groups,” DCRI said Thursday in a statement to POGO provided by spokeswoman Susan Landis.
“The results of the Institute’s independent analysis will be shared with the public, as are all study results from trials and studies conducted by the DCRI,” the statement added.
A member of an FDA advisory committee that reviewed Xarelto in 2011 said he was unaware of the 2005 and 2006 warning letters when the advisory committee recommended that the FDA approve the drug for patients with a heart condition called atrial fibrillation.
“This information should have been available to us,” Vasilios Papademetriou, a cardiologist at the VA Medical Center in Washington, said in an email.
Depending on how widespread any inaccurate readings were, the results of the trial could have been skewed, he added. “It all depends on how often it happened and in how many patients,” he told POGO.
The FDA advisory committee endorsed approval of Xarelto by a 9-to-2 vote with one abstention. Papademetriou voted that the drug should be approved.
The FDA in 2011 approved the use of Xarelto to prevent patients with atrial fibrillation from developing blood clots and strokes. The agency issued that approval over the objections of the primary FDA reviewers responsible for assessing the drug’s safety and effectiveness. FDA officials and advisory committee members criticized various aspects of the clinical trial, as POGO recently reported. Those criticisms did not focus on the blood testing devices used in the study.
Xarelto, promoted in television ads featuring comedian Kevin Nealon and golfer Arnold Palmer, among other celebrities, generated U.S. sales of $1.5 billion last year, according to a financial report by drug-maker Johnson & Johnson. The drug has been prescribed for more than 3 million patients in the United States, Kristina Chang, a spokeswoman for Johnson & Johnson subsidiary Janssen, has said.
Califf founded DCRI, which conducts clinical trials for drug companies, and since early this year has been a deputy commissioner of the FDA. He sailed through a November 17 confirmation hearing at which Senators from both parties said they supported his appointment as FDA commissioner.
Califf did not respond directly to questions POGO sent on November 10. Spokespeople for the FDA, its parent the Department of Health and Human Services, the EMA, and the makers of Xarelto—Bayer and Johnson & Johnson subsidiary Janssen—provided no comment on the blood testing.
HHS Assistant Secretary for Public Affairs Kevin Griffis referred POGO to a researcher at Duke, Manesh Patel, who was the first author listed on a New England Journal of Medicine article reporting the results of the Xarelto trial. Patel, who said by email that he was traveling, looped in the DCRI spokeswoman.
Later, in an email apparently sent to POGO in error, Patel advised the spokeswoman not to answer follow-up questions about the statement.
“I would suggest that we stop responding to him,” Patel wrote. “[T]hanks for the help today but I would suggest one statement emails and then no further engagement until we are ready,” Patel added.
The DCRI spokeswoman said the institute’s statement also served as a response for the trial’s executive committee.
According to an article Califf co-authored in a European medical journal, the executive committee he co-chaired “designed the trial and was responsible for oversight of study conduct, retained independent ability to analyse and present the data, and take[s] responsibility for the accuracy and completeness of data analyses.”
The Xarelto clinical trial, known as ROCKET AF, compared Xarelto to warfarin, which has been on the market since the 1950s.
The INRatio testing devices were used to monitor the blood clotting rates, known as INRs (international normalized ratios) of trial subjects on warfarin. The tests were meant to help doctors running the Xarelto trial determine whether and how much those patients’ warfarin doses should be adjusted to keep their clotting in the desired range. If their blood got too thick, they would be at increased risk of developing blood clots and suffering strokes caused by clots traveling to their brains. If their blood got too thin, they would be at increased risk of hemorrhages, including strokes caused by bleeding in the brain.
Among the advertised advantages of Xarelto are that, unlike warfarin, it does not require regular blood monitoring or frequent dose adjustments. In the clinical trial, subjects on Xarelto were also tested with INRatio devices, but for them the devices were programed to deliver sham readings; the purpose of their INRatio tests was to prevent doctors and patients involved in the trial from knowing which subjects were taking the experimental drug,
The December 2014 recall notice said certain INRatio devices could deliver falsely low INR test results.
A falsely low reading could indicate that more blood thinner should be administered than was needed. That could lead to increased bleeding in clinical trial subjects on warfarin. In comparison to warfarin, it could make Xarelto appear better than it was at reducing the risk of bleeding.
“Relative to warfarin, which would have more bleeding than it should, [Xarelto] would look better in terms of intracranial hemorrhage,” Sidney Wolfe of the consumer advocacy group Public Citizen said.
The FDA has said that Xarelto and other anticoagulants approved in recent years are substantially less likely than warfarin to cause a hemorrhagic stroke, which involves bleeding in the brain.
Among the questions Califf, the HHS spokesman, and the DCRI spokeswoman left unanswered:
●What if anything did Califf, the FDA, and DCRI do before, during, and after the clinical trial to determine the accuracy of the INR readings the devices produced?
●Did they examine whether there were any discrepancies between measurements taken from the devices and measurements based on lab samples at two points in the trial when, according to the clinical trial protocol, parallel tests were run?
●What reason, if any, is there to believe that the INRatio devices used in the Xarelto trial were free of the defects cited in the FDA warning letters and recall notice?
The first warning letter, dated October 4, 2005, said an FDA inspection found that HemoSense Corp., the manufacturer of INRatio devices, had information indicating the devices “were generating clinically significant erroneous values.” Test results that are too high or too low “have the potential to cause or contribute to a death or serious injury, because: they may result in erroneous dosing and thus improper control of coagulation,” the letter said. The firm’s initial response was inadequate, the letter said, giving the company 15 days to take corrective action.
The second warning letter to HemoSense, dated November 29, 2006, said a subsequent inspection that found INRatio devices were “adulterated,” that the company had not investigated complaints about the possible failure of the devices, and that it was slow reporting a complaint about a malfunction that resulted in a death.
The ROCKET-AF trial, which involved more than 14,000 test subjects in 45 countries, began in December 2006 and ran until the fall of 2010.
Jackie Lustig, a spokeswoman for Alere, said by email that the FDA told HemoSense in 2005 and again in 2007 that the company had adequately addressed the concerns raised in the warning letters.
In December 2014 a recall was issued for INRatio devices made after April 1, 2008. The recall notice said Alere, a corporate successor HemoSense, received 18,924 reports of malfunctions, including 14 serious injuries. “According to the firm, all affected devices may fail,” the notice said.
However, the 2014 recall didn’t require that Alere retrieve the devices from patients, Lustig noted.
Instead, the recall notice said patients with specific medical conditions should stop using the recalled devices, and other patients should have their INR readings verified by lab tests.
The FDA has permitted the INRatio systems to remain on the market, Lustig said, and the company “is working diligently to develop a software upgrade” for the devices to “address the potential for inaccuracies.”
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Anticoagulation Rx Expanded After NOAC Launch
Nov 12, 2015 | MedPage Today
By Ed Susman
More patients with atrial fibrillation are receiving anticoagulation therapy since the direct oral agents have reached the market -- but not just because warfarin is being replaced by easier-to-use newer drugs, researchers suggested here.
At the beginning of the study in 2008, 51.1% of patients eligible for anticoagulation therapy were treated, which rose to 61.2% in 2014, reported Lucas Marzec, MD, a cardiac electrophysiology fellow at the University of Colorado, Aurora.
Starting in 2010, blips of use of the first new oral anticoagulant (NOAC) -- dabigatran (Pradaxa) -- began showing up and by 2014, about one-quarter of eligible patients were receiving a NOAC, Marzec said in his oral presentation at the annual scientific sessions of the American Heart Association.
"You can see that from the time dabigatran was introduced there was a decrease in warfarin use and an increase in the NOACs, but the increase in the NOACs more than made up for the decrease in warfarin use," he said. Warfarin was used by virtually all of the patients eligible for anticoagulant therapy -- about 51% of the total -- prior to dabigatran, and that percentage decreased to about 37% at the end of the study in 2014, he said.
Over the study's 2008-2014 time period, NOACs went from zero to 40% of anticoagulant use.
After each new oral anticoagulant was approved by the FDA, Marzec said, "there was an uptake of the new medication into clinical practice. With the introduction of rivaroxaban (Xarelto) there was a decrease in dabigatran." In 2012, apixaban (Eliquis) was approved. By the end of the study, Marzec said rivaroxaban was the most commonly prescribed NOAC.
"Anticoagulation reduces the rate of stroke and thromboembolism in selected patients with atrial fibrillation," Marzec said. "However, despite the benefits or oral anticoagulation, it is underutilized. The majority of the evidence that shows that anticoagulation is underused comes from the era in which warfarin was really the only option for anticoagulation. This is despite the fact that warfarin has a well-known safety and efficacy profile and has been in use in the United States for more than 60 years. Warfarin does have disadvantages, namely a narrow therapeutic window, it requires frequent INRs and has several food and drug interactions that can complicate its use.
"The approval of novel anticoagulants now present alternatives to warfarin. NOACs don't require monitoring but they lack long-term safety data of warfarin, they are more expensive, and there is no available reversal agent except for dabigatran," he said.
Marzec and colleagues analyzed data from the National Cardiovascular Data Registry. They included all patients aged 18 or older with nonvalvular atrial fibrillation and a CHADS-VASc score greater than 1 in the clinical registry, or nearly 447,770 patients with almost 1,428,600 visits between 2008 and the end of September 2014. Patients with valvular atrial fibrillation or those who had surgery for heart valves were excluded.
The records of these patients who would have been eligible for anticoagulant therapy were scrutinized to determine if they had been prescribed an oral anticoagulant and which agent had been prescribed -- warfarin, dabigatran, rivaroxaban, or apixaban.
The patients in the study were 75.6 years of age, and 51.8% were men. About 88% had a history of hypertension; about 25% were diabetic; about 35% had been diagnosed with heart failure; about 52% had coronary artery disease; 16% had a previous heart attack; the average CHADS-VASc score was 3.6. "That score suggests that our cohort was a group of patients with atrial fibrillation who were at high risk for stroke and therefore were likely to benefit from anticoagulation," Marzec said.
He said that further analysis suggested that risk factors for being prescribed anticoagulants were the patient's age, weight, presence of high cholesterol, hypertension, diabetes, a history of stroke or transient ischemic attacks, and a higher CHADS-VASc score.
Session co-moderator William Borden, MD, associate professor of medicine at George Washington University, Washington, told MedPage Today that one of the promises of the new anticoagulants is that the ease of use would increase the overall rate of anticoagulation among eligible patients.
"I think that is likely one factor," he said. "There is also the element of just greater attention and a spotlight on anticoagulation which has providers thinking about this therapy. It also speaks to the fact that there is a large gap yet in the anticoagulation therapy for patients for whom it would be appropriate."
Borden noted that there are still almost 40% of people who probably should be on anticoagulation who are not treated with anything. "This represents a real opportunity, and it is encouraging that there is an increase in the overall number of people that are being anticoagulated," he said.
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Xarelto patient alleges fraud, negligence
Apr 20, 2016 | Madison-St. Claire Record
A California man is suing a number of pharmaceutical manufacturers in St. Clair County over the drug Xarelto.
Kenneth Niemeier filed a lawsuit March 31 in St. Clair County Circuit Court against Janssen Research & Development, formerly known as Johnson and Johnson Pharmaceutical Research and Development; Janssen Ortho; Janssen Pharmaceuticals Inc., formerly known as Janssen Pharmaceutica Inc.; Bayer Healthcare Pharmaceuticals Inc.; Bayer Pharma AG of Germany; Bayer Corporation; Bayer Healthcare; and Bayer Healthcare AG and Bayer AG of Germany, alleging product liability.
According to the complaint, the defendants manufactured, marketed and distributed Xarelto as a product intended to reduce the risk of stroke and embolism in certain patients but study results have raised questions about dosage and pointed out that in the case of adverse side effects, there is no antidote to reverse the drug’s effects. Niemeier maintains the defendants overstated the efficacy of the drug, misleading consumers.
Niemeier alleges the defendants failed to: fully research Xarelto’s safety or provide adequate instructions, disclosures, and warnings, and knowingly concealed its defects from the public. He says he suffered health consequences including physical pain, mental anguish, diminished enjoyment of life, loss of earnings and medical expenses.
The plaintiff claims product liability, intentional and negligent infliction of emotional distress, common law fraud, negligent and fraudulent misrepresentation and breach of warranty.
Niemeier seeks damages in excess of $50,000, plus attorney fees and costs. He is represented by attorneys John Driscoll and Christopher Quinn of The Driscoll Firm in St. Louis.
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Nov 17, 2015 | Madison County Record
By Angelino Menconi
A disgruntled Xarelto patient filed a lawsuit against major pharmaceutical manufacturers, developers and researchers alleging they fraudulently misrepresented the dug's benefits, risks and dangers.
Plaintiff Chezarea Jones filed a 32-count complaint in the St. Clair County Circuit Court on Oct. 13 against pharmaceutical manufacturers Johnson and Johnson, Inc., Bayer Ag, and others, alleging the drug companies fraudulently and knowingly misrepresented the benefits, risks and dangers of Xarelto.
According to the complaint, Chezarea alleges the defendants did not properly warn doctors and health care providers of the dangers and risks associated with Xarelto and also knowingly exaggerated its benefits and uses compared to other drugs.
The plaintiff seeks in excess of $50,000, plus attorney fees and costs of litigation.
St. Clair County Circuit Court case number 15-L-581
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New anticoagulant drugs provide stroke prevention with dose of danger
Aug 2, 2015 | Milwaukee Journal Sentinel
By John Fauber and Coulter Jones
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 the 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 warfarin-based 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.
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 life-threatening 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 Newman, 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 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."
$650 million settlement
In May 2014, German drug-maker 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 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 be prescribed an anticoagulant.
At the same time, a 66-year-old 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."
ABOUT THIS REPORT
John Fauber is a reporter with the Journal Sentinel. Coulter Jones is a reporter with MedPage Today. This story was reported as a joint project of the Journal Sentinel and MedPage Today, which provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.
Reporters from the Milwaukee Journal Sentinel and MedPage Today examined four new anticoagulants approved by the U.S. Food and Drug Administration since 2010 — the first new medicines in decades aimed at preventing strokes that can be caused by atrial fibrillation. The drugs are marketed as more convenient and safer alternatives to warfarin, which for decades has been the standard treatment.
To assess safety and effectiveness of the new drugs, reporters reviewed hundreds of pages of FDA approval documents, including clinical trial information, and analyzed data from the agency’s Adverse Events Reporting System. That data does not capture every adverse event or indicate correlation. Still, it provides the best view of potential problems associated with drugs. Only cases reported by drug companies or medical professionals where the anticoagulant drug was the “primary suspect” were used in the analysis.
Additionally, reporters reviewed prescription patterns nationwide for Medicare patients, as well as nationwide prescription sales data from IMS Health, a market research firm.
To identify drug company payments to doctors, reporters reviewed the federal Open Payments database, which covers the final five months of 2013 through 2014.
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Philadelphia court establishes Xarelto mass tort docket
Jan 22, 2016 | The Pennsylvania Record
By Jim Boyle
Philadelphia Court of Common Pleas Administrative Judge Kevin Dougherty has created a mass tort docket for Xarelto blood thinner injury cases filed against Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, according to an order issued Wednesday.
The order says that approximately 75 cases alleging uncontrollable and sometimes fatal bleeding will be transferred to the court’s Complex Litigation Center, following a petition filed by the plaintiffs attorneys.
“The creation of a mass tort program benefits the Court system and the parties by eliminating duplicative discovery, inconsistent rulings and promoting the efficient prosecution and resolutions of similar cases,” attorney Michael Weinkowitz said in an emailed statement.
“The defendants (Bayer and Janssen) have strong ties to Pennsylvania making this an appropriate and convenient forum.”
Xarelto – an oral anticoagulant indicated for prevention of pulmonary embolism, deep vein thrombosis and strokes in patients with atrial fibrillation – was initially approved by the FDA in July 2011.
According to the petition submitted to Dougherty last week, Xarelto has been marketed as the next generation of blood-thinning drugs designed to replace Warfarin, which has been on the United States market for more than 50 years.
Xarelto has been widely prescribed to prevent pulmonary embolism and deep vein thrombosis, as well as strokes in patients suffering from atrial fibrillation. However, the petition says, Xarelto carries a significant risk of severe, and sometimes even fatal, internal bleeding – and there is no reversal agent available if serious bleeding occurs.
In addition, Xarelto has been marketed as a single daily dose pill that does not require the need to measure the blood plasma levels, and thus touted as the more convenient option to warfarin (which does require testing and monitoring), the petition claims.
The approved use of Xarelto was expanded months later to include treatment to reduce the risk of strokes or embolisms in patients with non-valvular atrial fibrillation. According to the petition, the makers of Xarelto highlighted the positive results of their clinical studies while failing to equally inform patients of reports showing increased gastrointestinal bleeding requiring transfusions.
According to court papers, the defendants’ aggressive marketing efforts resulted in Xarelto becoming a blockbuster drug, going from $582 million in global sales for 2011 to more than $2 billion in 2013. In the U.S., the petition says, more than one million prescriptions for Xarelto were ordered by the end of 2013.
The petition claims that the drug’s success was made possible by concealing Xarelto’s deadly effects from prescribing doctors. The makers are also accused of failing to warn emergency rooms that Xarelto had no reversing agents.
“Therefore, Xarelto treatment leaves trauma professionals without effective means to treat and stabilize patients who experience uncontrolled or excessive bleeding while taking Xarelto,” the petition says.
The court documents say that more than 1,000 Xarelto-related adverse events were filed with the FDA in the year leading up to June 30, 2012, including at least 65 deaths. The attorneys anticipate that there will be thousands of Xarelto claims filed throughout the country, with large numbers in Pennsylvania.
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