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Context of '1998: Merck Study Suggests Increased Risk of Heart Problems among People Taking Vioxx'

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Merck official Briggs Morrison sends an e-mail warning that if the company conducts a proposed trial of the drug Vioxx (see also November 21, 1996), and the subjects do not take aspirin, there will be “more thrombotic events [i.e., more blood clots] and kill [the] drug.” In response, Merck scientist Alise Reicin laments that the company is in a “no-win situation.” She suggests that people with a high risk of cardiovascular problems be excluded from the study so the association between Vioxx and thrombotic events “would not be evident.” (Mathews and Martinez 11/1/2004)

A Merck clinical trial of Vioxx conducted on 978 patients suggests the drug substantially increases the risk of serious cardiovascular events, including heart attack and stroke. Patients who take Vioxx are six times as likely to suffer heart problems than patients taking an alternative painkiller or a placebo. The study, named Study 090, is never published. Merck later says this is because the sample size was not large enough to provide statistically significant data. (US Food and Drug Administration 2/1/2001, pp. 31-34 pdf file; Topol 2004; Bradley 4/28/2005)

Merck says it does not want to begin developing a plan to analyze the data on the large number of deaths from heart problems that has occurred during a clinical trial for its drug Vioxx (see December 22, 1999 and November 18, 1999). Michael Weinblatt, who is heading the study, sent a request to Merck the month before asking the company to develop such a plan (see December 22, 1999). Merck suggests that they wait and combine the cardiovascular results of this study with the results from other clinical studies for the drug. But Weinblatt is adamant that the company needs to begin analyzing the data immediately, and continues discussing the matter with Merck, which finally agrees to a plan the following month (see Early February 2000). (Prakash and Valentine 6/8/2006; National Public Radio 6/8/2006)

Merck files a patent application with the US Patent Office for a drug that would contain a combination of Vioxx and an anti-clotting agent, or thromboxane inhibitor. The new drug would hopefully reduce the risk of cardiovascular problems while preserving Vioxx’s gastrointestinal benefits. Merck never develops the drug. Critics later note that Merck’s interest in this new drug contradicted its assertions that Vioxx was safe for the heart. (Associated Press 6/22/2005)

Merck issues a press release titled “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx” asserting that there is no evidence that patients taking the prescribed dosage levels of Vioxx have an increased risk of having heart problems. It says that the higher number of heart troubles experienced by patients taking Vioxx compared to naproxen during the VIGOR study (see March 2000) was likely because naproxen has similar properties to aspirin, which is known to prevent heart attacks. (Merck 5/22/2001) The FDA later issues a warning to Merck calling this press release “simply incomprehensible, given the rate of MI and serious cardiovascular events compared to naproxen” (see September 17, 2001). (US Food and Drug Administration 9/17/2001, pp. 1-2 pdf file)

After six months of negotiations, Merck and the FDA finally agree on the text for a warning about Vioxx’s cardiovascular side effects that will be added to the drug’s label. The FDA had wanted to include a clear message that Vioxx increases the risk of heart problems since the current version of the label includes no information about such risks. An excerpt from the FDA’s originally proposed text reads: “VIOXX should be used with caution in patients at risk of developing cardiovascular thrombotic events… . The risk of developing myocardial infarction in the VIGOR study was five-fold higher in patients treated with VIOXX 50 mg (0.5 percent) as compared to patients treated with naproxen (0.1 percent).…” The FDA also wanted to include a graph showing that the risk of heart problems increases with continued exposure to the drug. Merck objected to the FDA’s proposals. It insisted that a description of the cardiovascular risks be included in the “Precaution” section of the label, instead of the more severe “Warning” section, as proposed by the FDA. The company also wanted to include results from several disparate clinical studies that had been conducted prior to the drug’s release. These are the same tests that are cited in the “Cardiovascular Card” that Merck sales people show to doctors (see April 28, 2000). But the FDA objected, telling the company that the studies were “trials of different design, size, and duration, using different doses of VIOXX and different comparators” and therefore did not provide useful data for determining the drug’s cardiovascular risk. The FDA eventually concedes to several of Merck’s requests. The final text of the warning is included in the “Precaution” section of the label, as Merck wanted, and does not include the graph that had been requested by the FDA. The text of the cautionary statement is also watered down. The section summarizing the results of the VIGOR study (see March 2000) and two other studies states: “The significance of the cardiovascular findings from these 3 studies (VIGOR and 2 placebo-controlled studies) is unknown.” (Merck 2001; US Food and Drug Administration 1/30/2002 pdf file; US Food and Drug Administration 2005; Office of Representative Henry A. Waxman 5/5/2005, pp. 16-19 pdf file)

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