Whitehouse Station, NJ - Media outlets across the US carried mistaken headlines yesterday assuring doctors and patients that stopping rofecoxib (Vioxx, Merck) confers no added cardiovascular risk. But results of the study summary that journalists were reporting on say the opposite [1]. "Merck, in presenting these data, misrepresented the results," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "Media reports are now saying there is no increased risk after Vioxx is stopped, when the results show that there is actually a 74% excess risk of cardiovascular thrombotic events compared with placebo."

Dr Steven Nissen

Nissen continued, "This is a very surprising result, because many believed that when patients stopped taking Vioxx, the prothrombotic effect would be eliminated." He says physicians and patients need to be aware that there is an ongoing cardiovascular risk for those previously exposed, and vigilant follow-up is in order.

But during a conference call with reporters yesterday, Merck executives said the findings should make it difficult to link rofecoxib to cardiovascular events after patients have stopped taking the drug. The new data are from the off-drug period from the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial—the study that brought rofecoxib down in 2004. The latest findings released by Merck provide data on confirmed thrombotic cardiovascular events and mortality from the off-drug extension of the trial.

This is a very surprising result, because many believed that when patients stopped taking Vioxx, the prothrombotic effect would be eliminated.

APPROVE was a 2587-patient, multicenter, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy of three years of treatment with Vioxx 25 mg in preventing the recurrence of polyps in patients with a history of colorectal adenomas. As previously reported in the 156-week base study, there was an increased relative risk for confirmed thrombotic cardiovascular events beginning after 18 months of treatment in patients taking rofecoxib compared with those on placebo [2].

Merck faces thousands of lawsuits and has already lost half of the six cases that have come to trial so far. "Our strategy has been to defend the product litigation on a case-by-case basis," Kenneth Frazier, Merck's general counsel, said during the conference call with the press. "The follow-up data from APPROVE do not change that strategy."

Responding to questions from reporters, Dr Peter Kim, president of Merck Research Laboratories, said, "If you look at the confirmed cardiovascular thrombotic events in these patients after they stopped taking Vioxx, there's not a statistically significant difference between patients who took Vioxx vs patients who took placebo. If, however," he continued, "you look at the full four-year data in this intention-to-treat type of analysis, which includes the time when the patients were on drug as well as when they were off drug, there's a statistically significant difference."

My gut feeling is that I would be very surprised if there were an ongoing effect.

This is what Nissen says is worrying. Merck's study summary shows that the relative risk of patients having confirmed thrombotic cardiovascular events in the 156-week on-drug base study was 1.92 (95% CI 1.19-3.11; p=0.008). And this difference remained significant after data from the off-drug follow-up period were included. In the intention-to-treat analysis through week 210, the relative risk was 1.74 (95% CI 1.19-2.55; p=0.004). Mortality was found to be similar between groups.

But the lead investigator of the APPROVE trial, Dr Robert Bresalier (University of Texas MD Anderson Cancer Center in Houston), says it's still too early to tell whether there is an appreciable ongoing risk when rofecoxib is withdrawn. His group will be further analyzing the findings over the next couple of weeks.

"My gut feeling is that I would be very surprised if there were an ongoing effect," Bresalier told heartwire. "This is definitely not the end of the story."