In my post, “Where’s the Beef?” for Avandia’s Risk?, I had several occasions to point out the weaknesses of both of Nissen and Wolski’s meta-analyses,1,2 the fact that the review accompanying their first meta-analysis1 had to admit “the fragility of their findings,”3 the fact that their own “updated meta-analysis”2 could not confirm their original meta-analysis,1 and the fact that the Food and Drug Administration’s review,4 after not only raising questions about both the quality of their first meta-analysis1 and its integrity, concluded, “When considering all data available at this time , however, the overall evidence of increased myocardial ischemic event risk with rosiglitazone is weak.” In Nissen and Wolski’s Avandia “Significance”, January 15, 2014, I pointed out that Hiatt, Kaul, and Smith obtained very different results, in their meta-analysis5 of exactly the same set of data as Nissen and Wolski’s original1 meta-analysis.
As the saying goes, “But wait! There’s more!”
The Interim Analysis of RECORD
Unlike the meta-analyses that preceded it, RECORD was a randomized study of rosiglitazone for type 2 (non insulin-dependent) diabetes mellitus (specifically Avandia; GlaxoSmithKline), as compared to metformin (Glucophage; Bristol Myers Squibb) and the various sulfonylureas (members of a group of drugs that increase insulin secretion).
According to the Food and Drug Administration’s own criteria, the interim analysis of RECORD’s results showed that rosiglitazone was not associated with an unacceptable increase in the risk of major adverse cardiovascular events.6 Not only was the prespecified hypothesis (that the relative risk of of cardiovascular hospitalization or death for rosiglitazone was greater than or equal to 1.2, as compared to metformin, sulfonylureas, or their combination) not confirmed, but it actually appeared that rosiglitazone might have less risk than the other drugs. In other words, while not statistically significant, most of the trends favored rosiglitazone, not Nissen and Wolski.
There were challenges to the original evaluation of RECORD. Although they were often overstated, some of the challenges had merit. On the other hand, there were also strengths in the study. I have listed a few of them, below:
- Randomization was preserved in RECORD.
- Unlike Nissen and Wolski’s meta-analyses,1,2 statistical heterogeneity (attempting to draw conclusions by combining studies that are extremely unlike each other) was not a problem in RECORD.
- Unlike the observational studies included in Nissen and Wolski’s meta-analyses,1,2 unmeasured confounders (factors) were not a problem in RECORD.
- There were more major adverse cardiovascular events (myocardial infarctions or “heart attacks,” anginal chest pain, strokes, and cardiovascular deaths) available for evaluation in RECORD than in all of the studies in the Food and Drug Administration’s 2007 meta-analysis, combined, but there was no evidence of an increased risk from rosiglitazone for any of them, except for congestive heart failure (which is also increased with pioglitazone, just as with troglitazone, before it was taken off of the market).
- Analyses by subgroups generally gave results similar to those obtained with the main analyses and for analyses for myocardial infarctions (“heart attacks”).
- Analysis based upon the time period during which patients were actually on the specified treatments were generally consistent with those based upon the treatments that were originally planned for them, showing that there was no difference between the effects of actual treatments and those to which patients had been randomly (by chance) assigned.
- Even the upper limits (highest value) of the estimates for major adverse cardiovascular events met the Food and Drug Administration’s own standards for showing that rosiglitazone was not associated with an unacceptable increased in the risk.
- The overall death rates favored treatment with rosiglitazone over treatment without rosiglitazone, the opposite direction of what Nissen and Wolski1,2 claim.
The Re-Analysis of RECORD
The Food and Drug Administration commissioned the Duke University’s Clinical Research Institute to independently re-adjudicate (re-judge) the data from RECORD. From everything that I can tell, they did a masterful job of it. “This well-conceived and comprehensive re-adjudication of the RECORD trial mortality experience demonstrated no evidence of a difference in all-cause mortality, cardiovascular plus unknown-cause mortality or non-cardiovascular mortality between the RSG [rosiglitazone] and MET/SU [metformin/sulfonylurea] treatment arms of RECORD.”7 In fact, for every one of the numerous sensitivity analyses’ multiple comparisons (each of which increased the likelihood of a false finding against rosiglitazone;8 see “Nissen, Wolski, and How Not to Do Meta-Analyses“), a lower death rate was found with rosiglitazone than for metformin/sulfonylurea.9 For fatal and non-fatal myocardial infarctions (“heart attacks”) and strokes, alone or in combinations, there was no evidence for any difference between rosiglitazone and metformin/sulfonylureas.9 In the end, there was no evidence of an increased risk from rosiglitazone for all-cause mortality, major adverse cardiovascular events, strokes, or myocardial infarctions.10
At best, the evidence against rosiglitazone was always doubtful, no matter how much the Nissen-Wolski duet acted otherwise. As will become increasingly evident, at worst, Steven Nissen, himself, was doubtful.
© 2014 Myron Shank, M.D., Ph.D.
4 Parks Mary H. (Untitled). In: FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf
6 Mahoney Karen Murry. Advisory committee clinical briefing document: preliminary Endocrine Medical Officer review of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, and update on cardiovascular safety information from large clinical trials of rosiglitazone New Drug Application 21071 Avandia® (rosiglitazone maleate). In: FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf
7 Dunnmon Preston M. DCRP consult to review and to comment on both all-cause and CV deaths from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of glycaemia and Diabetes trial (RECORD, BRL-049653/231), according to the Phase-I re-adjudication of the trial’s mortality outcomes by the Duke Clinical Research Institute (DCRI). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf
8 Remember that performing these “subgroup analyses” within a category that has already been found not to show a statistically significant difference risks making it appear that there are differences when there are none. See “Nissen, Wolski, and How Not to Do Meta-Analyses. The fact that this did not happen, despite so many comparisons, is testimony that the overall results were not even close. Although I do not have access to their raw statistical analysis, the Clinical Research Institute described this as a “sensitivity analysis,” strongly suggesting not only that they recognized the problem, but that they also interpreted negative results despite multiple comparisons as demonstrating the robustness of their overall negative conclusions.
9 Dunnmon Preston M. Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products consultation for NDA 021071 SDN 1652. In: FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf
10 Andraca-Carrera Eugenio, Soukup Mat, Chakravarty Aloka. Background information for advisory committee on rosiglitazone: statistical briefing material for the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, June 5-6, 2013. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf