The research behind a blockbuster stroke drug may have included false data, while its serious and potentially fatal side effects were kept secret, official US documents have revealed.
In 2009, the distinguished British medical journal The Lancet published a major study on the blood thinner rivaroxaban, which seemed to show it to be safe and effective. But now the journal has warned about “inaccuracies” in the trial data and said it would investigate the research further.
Rivaroxaban, often sold under the brand name Xarelto, is approved by NICE health watchdogs for the prevention of stroke and embolism – blocked blood vessels, usually caused by blood clots. It received the green light from international health watchdogs in 2011, and is now taken by thousands of Britons and millions around the world every year.
If the claims against the initial trial of rivaroxaban, called Record4, are true, patients may have been misled about the likelihood that they will experience side effects, including the risk of serious and even life-threatening bleeding. That study tested the drug’s role in preventing blood clots after surgery, but it has since been cited thousands of times by other researchers as proof of its safety.
Rivaroxaban, often sold under the brand name Xarelto, is approved by NICE health watchdogs for the prevention of stroke and embolism (file image)
“If serious side effects are more common than officially reported, the risk is higher than patients have been led to believe,” says Dr. Peter Wilmshurst, a cardiologist at Royal Stoke University Hospital who also does campaign against research fraud. “Without reliable data, patients and doctors don’t know exactly how safe this drug is.”
He added that following warnings about rivaroxaban in other medical reports over the past 10 years, The Lancet has had “plenty of time” to issue corrections or retract the article.
The same year that The Lancet published the results of the Record4 trial, the US drug approval body, the Food and Drug Administration (FDA), rejected the study. It concluded: “The data used…were unreliable.” Two years later, after three subsequent studies by a different research group, rivaroxaban was approved in the US and UK for the prevention of stroke.
In 2015, an American medical journal reviewed 57 FDA reports of research misconduct, including the controversial rivaroxaban trial. It alleged ‘falsification, missing records and improper storage of drugs’. The Lancet issued its warning after pressure from rival publication The British Medical Journal which, in December, submitted evidence of FDA reports alleging there were “serious and numerous data deficiencies” in the results from eight of the 16 hospitals involved. in the rivaroxaban trial.
According to The British Medical Journal, it also said that two of the 16 hospitals reported no serious side effects and that four of the patients taking rivaroxaban in the trial died, which the researchers did not explain.
Dr Wilmshurst says: “It is shocking that a death can be allowed to go unexplained when a patient dies during a three-week trial.”
Responding to the allegations, the trial’s lead author, Alexander Turpie, emeritus professor of medicine at McMaster University in Ontario, told The British Medical Journal that the FDA “is not the arbiter of what data is reliable or not.” He added: ‘Many controlled studies are submitted to journals and rejected as unreliable, then resubmitted elsewhere where they can eventually be accepted and published. We believe the Record4 data falls into that category: they are unreliable by the FDA but robust in their main conclusions of efficacy and safety.”
Record4 was funded in part by the German firm Bayer, one of the pharmaceutical companies that developed the drug. In 2019, it was reported that companies raked in nearly £5.4bn in sales of the drug in just one year.
The new allegations are the latest in a series of scandals that have rocked the field of drug investigation. In October 2021, this journal revealed that up to one in five of the estimated two million medical studies published each year could contain fabricated or plagiarized results. And last summer it was revealed that a pivotal study on Alzheimer’s disease may have been falsified. It meant that the development of effective treatments was potentially hampered and seriously ill patients were given false hope.
The experts argued that the editors of major medical journals were doing too little to stop the wave of “tainted data”, which ultimately put lives at risk, and that they should face heavy fines if they are found to have published studies without permission. due diligence.
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Rivaroxaban is one of a family of drugs called new oral anticoagulants, or NOACs. It is commonly prescribed to patients with heart disease who are at high risk of stroke, as well as those who are at risk of a clot after joint replacement.
Many patients find the drug easier to take than warfarin, which has been the most widely prescribed anticoagulant drug for more than 50 years. But warfarin can’t be taken along with other common medications, and patients must be checked every six weeks to monitor dangerous side effects, such as uncontrollable heavy bleeding.
With NOACs such as rivaroxaban, these risks were thought to be minor, which meant that continuous hospital monitoring was not necessary.
Dr. Wilmshurst says, “Cardiologists have been sold on the idea that these drugs are a safer option than warfarin, but that may not necessarily be the case.”
In the US, a series of lawsuits have been brought against the pharmaceutical companies responsible for rivaroxaban by relatives of patients who allegedly died of fatal rivaroxaban-related bleeding. In 2019 they moved to settle by agreeing to a payment of £650m, though they did not accept liability and maintained their safety.
Dr Wilmshurst says: ‘These drugs have advantages, I prescribe them often, but there is not enough evidence to show that they are necessarily superior to the alternatives. And it’s hard to draw firm conclusions when we can’t trust the trials that were supposed to tell us if they were safe and effective.
In a statement, The Lancet Group said: “We take issues of scientific misconduct very seriously and follow the best practice guidelines set out by the Publication Ethics Committee. The Lancet published a correction to the original article in December 2022. When we brought to our attention more details from the FDA report, we contacted the authors’ institution to request an investigation.
Last night Bayer said: ‘The Lancet is investigating the reliability of the study, not the drug itself. The study in question concerns a very specific use of rivaroxaban in a particular group of patients: to prevent blood clots after an operation. He used a different dosage for the use of the drug for the prevention of strokes.
