Merck considers conducting a trial to prove Vioxx is gentler on the stomach than traditional painkillers. To highlight the difference Vioxx patients could not take any aspirin. A Merck official’s memo cautions that in such a trial, “there is a substantial chance that significantly higher rates” of cardiovascular problems would be seen in the Vioxx group.
February 25, 1997
Merck official Briggs Morrison argues in an e-mail that unless patients in the Vioxx group also get aspirin, “you will get more thrombotic [blood clot] events and kill [the] drug.” In response,Alise Reicin, now a Merck vice president for clinical research, e-mails that the company is in a “no-win situation…Giving study subjects both Vioxx and aspirin could increase the ‘relative risk’… the possibility of increased CV [cardiovascular] events is of great concern.” She adds that she cannot wait to propose to senior management that people with high risk of cardiovascular problems be kept out of the study so the difference in the rate of cardiovascular problems between the Vioxx patients and others “would not be evident.”
Merck’s clinical trial, known as “Study 090” finds that serious cardiovascular events occur about six times more often in patients taking Vioxx than those taking other arthritis drugs or a placebo. The study is never published.
Merck begins the VIGOR (Vioxx Gastrointestinal Outcomes Research) study involving 8100 rheumatoid arthritis patients treated with either Vioxx or naproxen.
May 21, 1999
FDA approves Vioxx. Vioxx is launched in the US and is marketed in more than 80 countries.
Merck submits results of the VIGOR study for peer review and national publication. Test data show that the risk of gastrointestinal toxicity with Vioxx is less than with naproxen – an older arthritis medication. But more than four times as many arthritis patients using Vioxx have heart attacks than those who take naproxen. Later analyses show the rate to be five times as high. Merck argues that Vioxx does not cause the heart attacks, but rather naproxen’s protective effect prevents them.
March 9, 2000
In an e-mail, Merck’s Dr. Scolnick admits that VIGOR results show the cardiovascular events “are clearly there” and “it is a shame but it is a low incidence and it is mechanism based as we worried it was.” A Merck news release the same month mentions nothing about Vioxx’s mechanism-based problem.
March 27, 2000
A Merck press release highlights that Vioxx causes fewer digestive tract problems than naproxen, but admits that “significantly fewer thromboembolic events [heart attacks and strokes] were observed in patients taking naproxen.” April 2000 Merck issues another news release entitled: “Merck confirms favorable cardiovascular safety profile of Vioxx” which states that VIGOR trial results are “consistent with” clot-preventing effects of naproxen.
Merck executives reject pursuing a study focused on Vioxx’s cardiovascular risks, noting that “the implied message is not favorable.”
MERCK Drug and Food US to results VIGOR submits Administration.
Merck official threatens a Stanford researcher will “flame out” if he continues “anti-Vioxx” lectures.
The New England Journal of Medicine publishes the VIGOR study.
FDA’s Arthritis Advisory Committee meets to discuss concerns about the potential cardiovascular risks associated with rofecoxib. Merck tries to convince an FDA advisory committee that Vioxx be allowed to drop the digestive tract warning from its labeling, but the committee cannot ignore the cardiovascular findings. Merck resists, complaining that the agency is putting more weight on the negative findings than on the positive gastrointestinal features. The two sides ultimately compromise. The new Vioxx label – which is not cut in until
Notes the favorable data about fewer upset stomachs first, followed by two tables with the unfavorable increased incidence of heart attacks and strokes.
August 22, 2001
A team of researchers from the Cleveland Clinic, including Eric J. Topol, chairman of the department of cardiovascular medicine at the Cleveland Clinic, review the data from the FDA Advisory Committee meeting and publish an analysis of all available data in The Journal of the American Medical Association. The team reports that Vioxx has a five times greater heart attack risk compared to naproxen, a commonly used over-the-counter anti-inflammatory drug with similar benefits. The team also reports that Celebrex appears to increase the risk of heart attack and stroke, but that the danger from Vioxx appears greater. Dr. Topol immediately calls for trials to specifically determine whether Vioxx and Celebrex >increase cardiovascular risk.
September 17, 2001
The FDA sends a warning letter to Merck stating: “You have engaged in a promotional campaign for Vioxx that minimizes the potentially serious cardiovascular findings that were observed in the VIGOR study, and thus, misrepresents the safety profile for Vioxx. Specifically, your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).”
Merck rejects a study of Vioxx in patients with severe chest pain proposed by Dr. Deepak L. Bhatt, a Cleveland Clinic cardiologist.
FDA follows its advisory panel’s recommendation and requires that Merck add information about cardiovascular risk to Vioxx’s label to reflect VIGOR results. At the same time Merck is spending more than $100 million per year in direct-toconsumer Vioxx advertising.
Dr. Wayne Ray, an epidemiologist at Vanderbilt University, reports results of a study of Medicaid patients in Tennessee who are taking high doses of Vioxx, dosages greater than the recommended long-term dosage of 25 ms. Daily. These patients have significantly more heart attacks and strokes than similar patients not taking high doses.
Elucida Research, a small laboratory in Massachusetts, analyzes the mechanism by which Vioxx and other antiinflammatory drugs interact with lipids or fatty compounds in the blood. R. Preston Mason, lead investigator, reports the study finds that Vioxx damages the lipids in a way that makes them more susceptible to clotting.
Worldwide sales total $2.5 billion.
Merck-funded study finds patients taking Vioxx are at a 39% increased risk of heart attack within the first 90 days, compared with Celebrex.
April 19, 2004
In Circulation, Daniel. H. Solomon, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, publishes the results of a study to determine the relative risk of heart attack among users of Vioxx, Celebrex and non-steroidal antiinflammatory drugs (NSAID). Dr. Solomon concludes that Vioxx is associated with a 24-percent increased risk of heart attack compared with Celebrex or NSAIDs. The risk is elevated in the first 90 days of use but not thereafter. The matched case-control study involves 54,475 patients 65 years or older who receive their medications through two statesponsored pharmaceutical benefits programs in the US.
David J. Graham, MD, MPH, an epidemiologist with the FDA, presents data at an international conference in Bordeaux, France, showing that Vioxx increases the incidence of heart attack and cardiac death. Researchers analyze the medical records of nearly 27,000 Kaiser patients using Vioxx and compare their experience to more than 40,000 on Celebrex, another COX-2 inhibitor. Those taking more than 25 mg of Vioxx daily have a 3.7-fold increase in the risk of serious coronary heart disease and a 1.5-fold increase at the standard dose. The study finds 8199 heart attacks and cases of sudden cardiac death among the Kaiser members between 1999 and
Extrapolating these data to the 92,791,000 Vioxx prescriptions dispensed in the US over the years 1999 to 2003, the estimated number of excess cases of acute myocardial infarction and sudden cardiac death attributable to Vioxx use is 14, 845 at the standard dose and 12,940 at the high dose greater than 25 mg. per day). The study also shows that naproxen is not protective against serious coronary heart disease, but may actually confer an increase in risk – refuting Merck’s rationalization of VIGOR results
August 26, 2004
Merck fires off a press release refuting Dr. Graham’s study, stating it “stands behind the efficacy, overall safety and cardiovascular safety of Vioxx.”
The APPROVe (Adenomatous Polyp Prevention on Vioxx) study shows that patients have twice the risk of cardiovascular events (including heart attack and stroke), when taking the drug for longer than 18 months. Designed to determine the effect of Vioxx on the recurrence of neoplastic polyps of the large bowel in patients with a history of colorectal adenoma, this prospective, randomized, placebo-controlled double-blind international multi-center clinical trial started in 2000 and enrolled 2600 patients. Among patients taking Vioxx for more than 18 months, there are 15 heart attacks or strokes for every 1,000 patients compared with 7.5 per 1,000 who are on placebo. Researchers believe these numbers greatly underestimate the risk since Merck’s trial does not include anyone with known heart disease – patients who might be expected to have the highest risk.
September 30, 2004
Merck announces the withdrawal of Vioxx, the antiinflammatory drug 84 million people have used since 1999. Merck estimates a $2.5 billion blow to revenue this year, or more than 10% of total expected sales. On hearing the news investors dump shares reducing value $12.07, nearly 30%, to $33, their lowest closing price in more than eight years. Merck shares had been trading in the $45 range, with a high of $49 per share in February 2004. With its cash hoard of $6.2 billion, Merck intends to withstand the fallout.
October 2, 2004
In The New York Times, Dr. Eric Topol, of the Cleveland Clinic, reports that none of the manufacturers of COX-2 inhibitor agents have studied the risk of cardiovascular injury in patients who already have heart disease. He states: “The number of patients who may have sustained heart attack or stroke as a result of using these drugs could be tens of thousands.”
November 1, 2004
The Wall Street Journal reports that internal e-mails and marketing materials show the company knew as far back as 2000 that Vioxx was linked to an increased risk of heart attack but tried to discredit such evidence. The news leads Merck to post the largest percentage decline on that date among stocks in the S&P 500 index. Shares are down $3.03, or 9.7 percent, to close at $28.28 on the New York Stock Exchange.
November 2, 2004
FDA posts on its website an early version of a recently completed observational study into the safety of Vioxx. FDA investigators now estimate that over 27,000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the US between 1999 and 2003.
November 5, 2004
In the editorial of The Lancet, Richard Horton states: “Today we publish results from a cumulative meta-analysis which show that the unacceptable cardiovascular risks of Vioxx (rofecoxib) were evident as early as 2000 – a full 4 years before the drug was finally withdrawn from the market by its manufacturer, Merck.” Swiss researchers pooled the results of 29 different studies, many completed before 2001, to show Vioxx patients experienced twice the risk of heart attack.
November 9, 2004
Moody’s Investors Service cuts the ratingon Merck’s $4.9 billion in long-term debt by two levels, from Aaa to Aa2.
Not counting its Vioxx costs, Merck expects to have $20 billion in sales and $6 billion in profits.