RECORD4 Trial of Rivaroxaban, Published in 2009, Still Turning Heads

Concerns around the integrity of data from the RECORD4 trial of rivaroxaban (Xarelto; Bayer/Janssen), which were identified by the US Food and Drug Administration more than a decade ago, have been revived, resulting in a new investigation that was first reported by the BMJ.

The phase III trial, published in the Lancet in May 2009, compared oral rivaroxaban with subcutaneous enoxaparin for thromboprophylaxis after total knee arthroplasty, showing that rivaroxaban was superior when it came to the primary efficacy outcome of any deep vein thrombosis, nonfatal pulmonary embolism, or all-cause death up to 17 days after surgery.

The results, along with those from the first three RECORD trials, were reviewed by the FDA as it considered approval of rivaroxaban for prophylaxis of deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Agency documents from 2011, however, highlight problems with data integrity in RECORD4, which rendered the information “unreliable.”

The FDA ultimately approved rivaroxaban in July 2011, but based only on data from the first three RECORD trials, which were deemed reliable. Several other indications have been added for the direct oral anticoagulant since then.

But the story doesn’t end there. A JAMA viewpoint from 2020 discussing what FDA inspection reports can illustrate about irregularities and misconduct in clinical trials highlighted the problems uncovered in the RECORD4 trial, which included postoperative randomization (a violation of protocols) in a substantial proportion of patients, hundreds of unreported adverse events, and incomplete record-keeping at several trial sites.

That viewpoint was cited in a November 2022 BMJ investigation into “grossly inadequate” FDA oversight of clinical trials. “The violations were so numerous and severe that the FDA excluded [RECORD4] from its pile of evidence during the drug’s approval. But when the study was published in the Lancet in 2009 there was no mention of the data integrity problems and the paper has been cited more than 1,100 times by others,” the story reads. “When the BMJ sought comment from the authors of the RECORD4 study, some said they were not fully aware of the data integrity problems prior to our inquiries. The lead author, Alexander Turpie, said he was seeking more information from the drug company. The Lancet told the BMJ it was looking into the matter.”

The matter is under investigation. Alexander Turpie

A further response from the Lancet and Turpie, an emeritus professor at McMaster University in Hamilton, Canada, came on December 10, 2022, when the journal posted a formal correction along with correspondence from Turpie. The correction clarifies that randomization occurred before or after the procedure and also states that the safety data in Table 4 of the original paper “are inaccurate and should be disregarded.”

In his correspondence, Turpie says: “We are disappointed to learn this information, particularly at this late date, and it is most important that the medical community be informed of the inaccuracies. . . . On behalf of the RECORD4 steering committee and my co-authors, I regret and apologize for the errors in the 2009 article.”

According to another story published December 30, 2022, the BMJ then asked Turpie and the Lancet whether they would consider retracting the paper, with both indicating that the correction and correspondence were enough. “However,” the BMJ reports, “the Lancet has since reconsidered its position after the BMJ presented it with details of the FDA review, which has been available on the FDA website since at least 2011.”

A Lancet spokesperson told TCTMD that McMaster University would be performing the new investigation. “The Lancet journals take issues relating to scientific misconduct extremely seriously and follow best practice guidelines as set by the Committee on Publication Ethics (COPE),” she said. And after publication of the correction and correspondence, “when further details of the FDA report were brought to our attention, we contacted the authors’ institution requesting an investigation as per COPE's guidance. We await the results of this investigation.”

Contacted by TCTMD, a spokesperson for McMaster University said, “We can confirm that the Lancet has been in touch regarding the RECORD4 trial, and we are in the process of responding to the journal for additional information.”

Turpie responded briefly to a request for comment, saying, “The matter is under investigation.”

These issues are not likely to have a clinical impact on use of rivaroxaban. A spokesperson for Janssen, responsible for marketing rivaroxaban in the United States, noted that the RECORD4 trial has not been used to support any approved indications for the drug.

The company acknowledged the issues raised by the FDA, but said, “With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups, and the safety and efficacy conclusions of the study remained unchanged. Thus, the RECORD 4 findings reported in the Lancet remain consistent with the overall results from the total RECORD program.”