Commentary By: Sandeep Mangalmurti MD, JD PGY-1
The continuing legal battles over Vioxx remain at the center of a fascinating intersection of law and medicine. Most physicians are well acquainted with the basics of the case, but like most complicated health care issues, the deeper one probes, the more interesting it becomes.
The Vioxx saga begins in 2000, with the VIGOR trial. (1) This study was a randomized control trial comparing the gastrointestinal toxicity of Vioxx to naproxen, and was notable for demonstrating an increased risk of myocardial infarction for users of the former. Merck (the manufacturer of Vioxx) contended that the increased risk of MI was not due to Vioxx, but instead reflected a decreased risk of MI due to the cardioprotective effects of naproxen. Nevertheless, based on the VIGOR study, the Food and Drug Administration sent a warning letter to Merck in 2001 accusing them of minimizing the cardiovascular risks of Vioxx. (2) In 2002, Merck was forced to alter its packaging to include a new warning label explaining the potential cardiovascular risks of the medication. (3) These issues came to a boiling point in September, 2004, when Merck voluntarily removed Vioxx from the marketplace after the APPROVe study demonstrated an increased risk of thrombotic events for those who had used Vioxx for more than 18 months. (4)
Then began the lawsuits….. Keeping track of the multitude of Vioxx trials is beyond the scope of this article. For up to date information, please refer to learnaboutvioxx.com, a Merck sponsored website that provides updated information on pending lawsuits, as well as the company’s official response to its critics’ accusations. Thousands of claims against Merck were dismissed prior to trial, but approximately thirty have made it to a courtroom. Many of these were eventually dismissed as well; so far Merck has successful defended about 9 of these cases. Four verdicts have been returned in favor of the plaintiff; needless to say, Merck has vigorously appealed these decisions. (5)
The issues arising from the Vioxx cases will keep scholars in both law and medicine occupied for years. One case in particular, the landmark Ernst v Merck, Inc., is an excellent case study illustrating the difficulties in using courtrooms to prove medical causality. Ernst vs. Merck was the first Vioxx case decided in favor of the plaintiffs, and the judgment sent shock waves through the pharmaceutical industry. A jury decided by a vote of 10-2 that Merck was responsible for the death of Robert Ernst, a 59 year old who died in his sleep after a cardiac arrhythmia. The jury awarded his widow more than $250 million in compensatory and punitive damages, though that award may be significantly decreased due to Texas liability caps.
Closer analysis shows a case fraught with medical ambiguity. The first controversy was the cause of death. The plaintiff’s contention was that Vioxx increased the risk of thrombotic events, leading to coronary artery occlusion and death. However, Ernst’s autopsy showed no evidence of a coronary artery occlusion, only stenosis (in some cases, greater than 70%). In fact, the medical examiner’s report (written prior to the filing of the lawsuit) lists arrhythmia as the cause of death. This is a key issue, as there is absolutely no evidence to suggest that Vioxx is proarrhythmic; it is unlikely to have directly caused ventricular fibrillation. When confronted with this discrepancy, the medical examiner modified her conclusions; she contended that Ernst died of an arrhythmia caused by thrombosis, and that the clot was not found on autopsy because it may have been dislodged during resuscitative attempts. Needless to say, Merck’s medical experts strongly differed with this interpretation. (6)
In the end, proving or disproving that Vioxx caused a particular thrombotic event is an enormous challenge. A brief survey of the plaintiffs from other Vioxx cases show a patient population filled with cardiovascular co-morbidities, including angina, cardiomyopathy, multi-vessel coronary artery disease, obesity, hypertension, hyperlipidemia, diabetes. (7) Millions of dollars turn on answers to questions that, in the end, are unanswerable… small comfort to the losing party.
A second controversy in the Ernst case was the duration of treatment. Merck’s position, based upon its research findings, is that Vioxx begins to increase cardiovascular risk after 18 months of use; Robert Ernst took the drug for less than 9 months. On first glance, this appears to be an open and shut case for the defense…the plaintiff simply did not take the medication long enough to incur any additional risk. In fact, any plaintiff who did not take the medication for 18 months should have no plausible claim of harm.
All that changed in June, 2006, when the New England Journal of Medicine published a correction to APPROVe contending that the deleterious cardiac effects of Vioxx began immediately after beginning the medication, not after 18 months. (8) This startling assertion came on the heels of a December 2005 “Expression of Concern” when its editorial board accused researchers of deleting data in VIGOR which would have strengthened claims of increased cardiovascular risk. (9)
It is difficult to overstate the potential impact of the NEJM corrections. Patients/plaintiffs who suffered myocardial infarctions after only briefly taking Vioxx may now be able to plausibly argue a causal relationship. In fact, the NEJM corrections have already cost Merck a victory in the Humestone case. This decision, previously in Merck’s favor, was overturned in August, 2006; the New Jersey state judge specifically cited Merck’s exclusion of data from VIGOR as justification for a new trial. (10)
Merck continues to maintain that the deleterious effects of Vioxx do not begin immediately. On its website, while it acknowledges that there were errors in the statistical analysis of the APPROVe data, it contends that this recalculated analysis shows no change in cardiovascular risk. (11) It further contends that accusations of deleted data in VIGOR are unfounded. This data was excluded since it was obtained after a predetermined cutoff date for reporting cardiovascular events, and in any event, inclusion of this data would not have affected the author’s conclusions. (12)
So where does this leave Merck and injured plaintiffs? It is difficult to say at present, but there is every indication that these lawsuits are not going away. Plaintiffs have every incentive to continue to sue, since our system of contingency fees allows them to do so without substantial cost. Merck has every incentive to fight these suits, as settlement may only encourage a feeding frenzy of claims, even dubious ones. In the end, the only guaranteed winners are the attorneys on both sides. The battle continues…
1-Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-8. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:11087881&_char_set=utf8
2-See http://www.fda.gov/cder/warn/2001/9456.pdf for a copy of the letter.
3-See www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4090B1_04_E-FDA-TAB-C.htm – 34k for a copy of the label, and timeline for FDA action.
4-Bresalier et al., Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. N Engl J Med 2005 352(11):1092-1102. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:15713943&_char_set=utf8
5-See http://learnaboutvioxx.com/litigation_appell.asp
6-For an excellent running commentary on the first Vioxx trial, see http://www.firstvioxxtrial.blogspot.com/
7-See http://learnaboutvioxx.com/litigation_appell.asp
8-Lagakos S., Statistics and Medicine: Time-to-Event Analyses for Long-Term Treatments – The APPROVe Trial. N Eng J Med 2006; 355 (2):113-117 http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:16801354&_char_set=utf8
9-Curfman G, et al. Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:16339408 &_char_set=utf8
10-http://learnaboutvioxx.com/litigation_humeston.asp
11-http://learnaboutvioxx.com/inthenews-95.asp
12-Bombardier C, et al. Response to Expression of Concern Regarding VIGOR Study. N Engl J Med 2006; Vol 354:1196-1199. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:16544387&_char_set=utf8
One comment on “The Vioxx Wars”
This is an interesting summary of a complex issue. I suppose that one might want to add another list of findings just to complicate things. It is becoming increasingly apparent that chronic use of almost all NSAIDs (apparently excepting naproxen) is associated with a risk of atherosclerotic cardiovascular disease and its sequelae that approaches that of Vioxx. This has been seen in several observational studies and recent studies even ascribe cardiovascular risk to acetaminophen. Thus, I suppose that in the short term one might be able to make the case that residual risk associated with taking even over the counter drugs such as ibuprofen or acetaminophen could be responsible for ASCVD and the particular events under litigation.
Perhaps most notable in all of this is how the health policy issues became submerged in the feeding frenzy over Merck. As a result of the furor over Vioxx we have found, belatedly, that almost all NSAIDs and even acetaminophen carry higher risks of cardiovascular disease. Many of these drugs are sold without prescription and are consumed by many Americans. I have not heard anything about taking ibuprofen or acetaminophen off the market, making them available only by prescription or even putting warnings on their labels.
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