Updated: Pivotal oral anticoagulant trial under scrutiny

Thursday, 4 Feb 2016


An investigation by The BMJ  has questioned the validity of a pivotal trial used to support the use of the world’s best selling new oral anticoagulant.

There are now calls from the medical community for an independent investigation and access to the original trial data to clarify the drug’s benefits and harms.

The investigation by The BMJ questions the results of the ROCKET-AF trial that was published in the New England Journal of Medicine in 2011. The study compared rivaroxaban (Xarelto) with the older anti-clotting drug warfarin for preventing strokes in patients with atrial fibrillation.

Concerns first came to light after the journal discovered that the INRatio device used in the trial had been recalled in December 2014 after giving falsely low-test results.

“In terms of the trial results, it could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best selling new oral anticoagulant,” said The BMJ’s Associate Editor, Dr Deborah Cohen in a special report.

Spokespeople for manufacturers Johnson and Johnson and Bayer issued the following statement in December last year: “We have conducted a number of sensitivity analyses. These sensitivity analyses confirm the results of the ROCKET-AF study and the positive benefit-risk profile of Xarelto (rivaroxaban) in patients with non valvular atrial fibrillation.”

In a letter to the NEJM published today researchers from the Duke University’s Clinical Research Institute, who carried out the trial on behalf of the manufacturer, said a series of post hoc analyses of the ROCKET AF data were “consistent with the overall trial findings.”

“Possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” they wrote.

However Professor of Medicine at Yale University Harlan Krumholz said the NEJM should place an “immediate Expression of Concern” on the paper to notify the medical community, and that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

Towards the end of last week the European Medicines Agency said that the INR device used in the ROCKET study did not distort its main findings and does not “change its conclusions on the overall safety or benefit-risk balance of Xarelto”.

 

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