With less than 3 months to go before the statute of limitations runs out on Vioxx (rofecoxib) lawsuits in some states, plaintiffs' attorneys have been handed a prize, thanks to a correction that will appear in the July 13 New England Journal of Medicine.The unsigned correction to the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial report acknowledges that the statistical analysis in the published study, which concluded that the cardiovascular relative risk associated with Vioxx (vs placebo) begins to climb only after 18 months of use, erred because "the test for proportionality of hazards used linear time rather than the logarithm of time that was specified in the Methods section."1,2

When the correct test was applied to the data, no increase in risk after 18 months was found. "Therefore, statements regarding an increase in risk after 18 months should be removed from the Abstract ... and from the Discussion section...." the correction states.

"The results of the APPROVe trial have been misinterpreted by some to mean that treatment with rofecoxib for less than 18 months poses no excess cardiovascular risk." — Stephen W. Lagakos, PhD
This problem is explored in a a detailed analysis of the APPROVe data conducted by statistician Stephen W. Lagakos, PhD, who is professor of biostatistics at the Harvard School of Public Health, Boston.3 

"The APPROVe investigators planned to use an interaction test with the logarithm of time as the primary basis for testing the proportional-hazards assumption [that the relative risk remains constant over time]. This test resulted in a P value of .07, which did not quite meet the criterion of .05 specified for rejection of the assumption. However, the original report of the APPROVe trial mistakenly gave the P value as .01, which was actually the result of an interaction test involving untransformed time," Dr. Lagakos writes.

"The results of the APPROVe trial have been misinterpreted by some to mean that treatment with rofecoxib for less than 18 months poses no excess cardiovascular risk," Dr. Lagakos writes." ....since the [confidence] band would necessarily include the estimated excess risk associated with the 36-month course...one could not conclude from the data that a shorter course of rofecoxib is safe."

The July 13 issue of the New England Journal of Medicine also carries letters from Steven E. Nissan, MD (Cleveland Clinic Foundation, Cleveland, Ohio) and Curt D. Furberg, MD, PhD, (Wake Forest University School of Medicine, Winston-Salem, NC) criticizing several aspects of the APPROVe study and data analysis.4,5

Dr. Nissan writes, "The original article included a post hoc hypothesis that curves for confirmed thrombotic events would not begin to diverge until after 18 months of exposure to rofecoxib. However, all intention-to-treat analysis in the newly released report shows that the event curves begin to diverge much earlier, generally within 4 to 6 months. The most useful Kaplan-Meier curves, involving intention-to-treat analysis of the APTC [Antiplatelet Trialists' Collaboration] endpoint, show divergence after only 3 months of exposure to rofecoxib."

Dr. Furberg points out that cardiovascular events in the patients who discontinued rofecoxib were not counted if  they occurred more than 14 days after early discontinuation of the medication. He notes that updated data include 12 thrombotic events that occurred more than 14 days after the study drug was stopped but less than 36 months after randomization and that 8 of these events occurred in the rofecoxib group, which "had a clear effect on the published survival curve for rofecoxib."

"At the time the APPROVe trial was submitted and published, was the complete data set available to the authors for an intention-to-treat analysis? Did they perform a proportionality test of the 3-year event data before publication?" Dr. Furberg asks.

In response, APPROVe authors Robert S. Bresalier, MD, (University of Texas M. D. Anderson Cancer Center, Houston) and John A. Baron, MD. (Dartmouth Medical School, Hanover, NH) say that the new data Drs. Nissen and Furberg mention, "a preliminary analysis of new data that was released by Merck to the Food and Drug Administration on May 11, 2006," were not available to them when they wrote the original APPROVe report.

"The decision to perform a systematic event follow-up that covered the period more than 14 days after the discontinuation of therapy was motivated by the cardiovascular findings reported in September 2004. This additional follow-up, which required submission of a formal protocol revision to the human-subjects committee at each participating center, was initiated in the winter of 2004-2005," Drs. Bresalier and Baron say. They also note that an in-depth analysis of extended data from the APPROVe trial is underway and will include "An independent statistical analysis of the cardiovascular data."

The Wall St. Journal  recently estimated that 11,500 Vioxx lawsuits have been filed by people who blame the drug for causing their heart attacks or strokes and that this might surge to 30,000 over the coming weeks. Merck's defense strategy has been based in part on the argument that Vioxx couldn't have caused injuries in people who took it for less than 18 months. So far the company has won three cases and and lost three.

References

 

1. Correction. N Engl J Med 2006; July 13, 2006. Available at: www.nejm.org. Accessed July 11, 2006.
2. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102.
3. Lagakos SW. Time-to-even analyses for long-term treatments – The APPROVe trial. N Engl J Med. 2006; July 13, 2006. Available at: www.nejm.org. Accessed July 11, 2006.
4. Nissen SE. Adverse Cardiovascular Effects of Rofecoxib (letter). N Engl J Med. 2006, July 13, 2006. Available: at www.nejm.org. Accessed July 11, 2006.
5. Furberg CD. Adverse cardiovascular effects of rofecoxib (letter). N Engl J Med. 2006, July 13, 2006. Available at: www.nejm.org. Accessed July 11, 2006.
6. Bresalier RS, Baron JA. Adverse cardiovascular effects of rofecoxib (letter). N Engl J Med. 2006, July 13, 2006. Available at: www.nejm.org. Accessed July 11, 2006.