Merck repeatedly contended that it was actively investigating possible reasons for the adverse findings in the short VIGOR study. One of them was that the difference between Vioxx and naproxen could be best explained as a cardio-protective benefit of naproxen as opposed to an untoward side effect of Vioxx. Most researchers disagree. To date, no large-scale study has demonstrated more than a possibly small protective effect of naproxen, and certainly not of the magnitude that would explain the VIGOR difference. In fact, a recent study of naproxen and prevention of Alzheimer's disease was halted because of an apparent increase in C.V. events.

Listen to Peter S. Kim, president of Merck Research Laboratories, explain why Vioxx had a higher C.V. complication rate than naproxen. "Because the VIGOR study compared two drugs -- Vioxx and naproxen -- and did not contain a placebo arm, it was not possible to conclude, based on this study alone, whether naproxen was having a beneficial CV effect or whether Vioxx was having a detrimental CV effect."

When I asked Merck why it didn't include a placebo group in the study, which would have underscored the C.V. effects of Vioxx, it referred me again to its court statement: "For ethical reasons, Merck could not conduct a placebo-controlled study in a population that required pain medicine (because patients in the placebo arm would receive no pain relief)."

Yet placebo control studies are commonly used to study anti-pain medications. Indeed, many peer-reviewed osteoarthritis and rheumatoid arthritis studies of NSAIDs and coxibs, including Vioxx, have included a placebo group for comparison. (Unfortunately, these studies were of too short a duration -- 6-12 weeks -- to assess any long-term C.V. effect. Merck, nevertheless, cites the data to show no evidence of C.V. effect of Vioxx.)

In an August 2001 article in the Journal of the American Medical Association, Drs. Mukherjee, Topol and Nissen from the Cleveland Clinic compared rates of heart attacks in trials performed with selective COX-2 inhibitors, including Vioxx, to heart attack rates compiled from a large number of studies on aspirin for heart disease prevention. Their review included 48,000 patients; the Merck VIGOR trial had 8,000.

The authors concluded: "The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors." Even more compelling, they stated: "We believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."

Merck did make a motion in that direction. According to an article in the New York Times earlier this year, the company planned to initiate a major C.V. risk study called VALOR in 2002. But just days before company researchers were to submit the study's protocol to the FDA, the project was abruptly halted. Merck did not explain why. It issued a general statement, saying that as it was designing the study, "we continued to ask ourselves and our consultants whether this was the right way to definitely answer" the question of whether Vioxx posed C.V. risks. "We ultimately decided not to conduct that particular study."

In 2002, with Vioxx selling extremely well, Merck was no doubt convinced that the odds of keeping the painkiller on the market remained in its favor. After all, when the VIGOR study revealed that patients who took Vioxx showed a twofold increase in heart attacks, Merck must have figured that it could face potential lawsuits. Just as all Big Pharma companies do, Merck must have calculated that profits from sales would outweigh losses from lawsuits.

In fact, as a study in the Archives of Internal Medicine would later show, Merck, through heavy promotion, sought to create as wide a market as possible for Vioxx. (The study revealed that 73 percent of people who took Vioxx did not need a coxib, that a standard NSAID like aspirin would have been sufficient.) Apparently, selling Vioxx as a niche drug for people who really did suffer G.I. problems from NSAIDs, and who were at low risk for heart disease, did not meet Merck's profit-and-loss forecast.

Merck initiated several more studies of Vioxx, all primarily intended to uncover further potential markets for the drug. In each case, it avoided delving specifically into possible C.V. complications. Most notable was the APPROVe study, which looked toward the prevention of colon polyps, as well as other studies for possible treatments for colorectal and prostate cancer.

In September 2004, when the APPROVe trial revealed the same twofold increase in C.V. complications as the VIGOR study, Merck recalled Vioxx. Even then, Dr. Alise Reicin, vice president of clinical research at Merck, reiterated that this was a puzzling finding. She said that Merck has so far been unable to identify a mechanism behind the increased risk. The fact is that Merck avoided initiating studies to find one.

To further distance Merck from any responsibility for those who had recently begun taking Vioxx, Kim added, "While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed CV events beginning after 18 months of continuous therapy."

No, the risk didn't begin after 18 months. This would be analogous to saying that daily sunbathing for 18 months poses no risk for melanoma if no melanomas are detected during that time, and that the risk doesn't begin until the melanomas are first discovered. The risk is present from the beginning but only evident at 18 months.

Finally, Merck is asking us to believe that it didn't suspect from the outset that Vioxx might increase the risk of heart attacks and strokes. It's telling us that its studies were adequately designed to detect both the incidence and possible underlying mechanisms of cardiovascular risks. It wants us to accept that a nine-month study, abruptly concluded, was insufficient evidence for the withdrawal of Vioxx because it was reasonable to presume that naproxen had a cardio-protective effect.

For me, the sad but inescapable conclusion is that Merck made an informed decision to avoid knowing the full extent of Vioxx's potential risks for heart attacks and strokes.

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