Bayer says Xarelto (rivaroxaban) is the most studied oral anticoagulant in the world. But one large study that was used to support the drug’s approval became the focus of controversy and ethical questions about hiding data.
The U.S. National Library of Medicine has 320 studies involving Xarelto in its archives. Covered topics range from AIDS to wounds. The highest number of studies — 179 — relate to vascular diseases.
In 2016, questions surfaced regarding the validity of the clinical trial, titled ROCKET-AF. The study was a large part of the reason the U.S. Food and Drug Administration approved Xarelto in 2011. The trial compared patients taking Xarelto to people using warfarin.
The controversy began when a device called the Alere INRatio was recalled. Researchers used the device to monitor warfarin therapy in the control group of the study. The device was recalled due to its propensity to provide falsely low results.
CBS News reported that the manufacturer of the faulty device confirmed that “the problem dated back to 2002.” Critics accused manufacturers Janssen and Bayer of misleading a peer reviewer at the New England Journal of Medicine.
Some feared the device’s flaw could have skewed the results of the study. The study showed no significant difference between warfarin and Xarelto in the risk of major bleeding. But some feared that the device’s flaw could have skewed those results. This could have made Xarelto seem like the safer choice compared to warfarin when that might not be the reality.
But the FDA later performed an assessment of the impact of the device on the study results. The agency determined that the effects were minimal. The FDA concluded that “Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation.”
Sometimes, clinical studies don’t last as long as planned. Researchers may stop either for positive or negative reasons.
In February 2017, for example, Janssen and Bayer announced that they were stopping a large-scale clinical study earlier than planned because data had shown Xarelto combined with aspirin to be superior to aspirin alone for prevention of major cardiac events in patients with coronary artery disease or peripheral artery disease. That study — known as COMPASS — involved more than 27,000 patients in 30 countries.
Some patients received 2.5 milligrams of Xarelto twice a day with 100 milligrams of aspirin a day, while others received 5 milligrams of Xarelto twice daily alone or aspirin once a day alone.
Study results published six months later in the New England Journal of Medicine confirmed the manufacturers’ claims.
Researchers wrote that the risk of several adverse outcomes was lower by 24 percent with Xarelto plus aspirin than with aspirin alone.
However, the researchers also wrote that treatment with Xarelto put patients at 70 percent higher risk for major bleeding events.
Researchers concluded that among patients with stable atherosclerotic vascular disease, those who were given Xarelto plus aspirin had “better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone.” Xarelto alone “did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.”
“Bleeding is an inevitable consequence of more effective antithrombotic treatment, but you have to look at the overall benefit — the net clinical benefit and the reduction in mortality, and we have shown significant benefits in both these end points”
But in October 2017, Bayer and Janssen announced they were halting another clinical study into the effectiveness and safety of Xarelto for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source.
The phase III clinical study ended early because it showed no better results “and had little chance of showing overall benefit” compared to treatment with low-dose aspirin.
Although Xarelto was first approved for the U.S. market in 2011, studies continue.
In May 2018, for example, researchers at the University of Warwick reported in the Journal of Clinical Oncology that Xarelto taken once a day lowered recurrence of venous thromboembolism in cancer patients.
And in February 2018, Canadian researchers found aspirin was as good as Xarelto in preventing clots after total hip- or knee-replacement surgery.
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