Tag Archives: Avandia cardiovascular

Strange Omissions in Nissen’s Avandia Analysis

In my post of January 27, 2014, Concerns at FDA:  Nissen’s Avandia Analysis, I discussed concerns expressed by Deputy Director Robert Temple, in a  memo to Janet Woodcock, Director of the Food and Drug Administration’s Center for Drug Evaluation and Research:  Nissen and Wolski’s2 peculiar and unblinded1 selective choices from those studies that qualified for their meta-analysis,3 their potential bias in doing the analysis,1 and their (improper) inclusion of DREAM (Diabetes REduction Assessment With ramipril And rosiglitazone Medication) after using it to develop their hypothesis.4  Dr. Temple concluded that “there was potential bias in its development (or at least the analysis was done with knowledge of what would emerge).”  Then, in my January 29, 2014 post, More Concerns With Nissen’s Avandia Analysis, I discussed some of Nissen and Wolski’s2 improper use of statistics related to their multiple comparisons between those who were treated with and those who were treated without rosiglitazone (Avandia; GlaxoSmithKline).

Nissen and Wolski did not consider the combined endpoint of acute myocardial infarctions plus cardiovascular deaths, attributing this to uncertainty about the possibility of counting the same event twice.2  However, for any reasonable assumption about the occurrence of both acute myocardial infarction and cardiovascular death in the same patient, the effect would be much less than the problem of multiple comparisons, which they ignored.

Speaking of multiple comparisons, Steven Nissen’s “Flaws, Bias, Misinterpretation and Fraud in Randomized Clinical Trials” showed that he was aware of the problem, but, although he used his own meta-analysis2 as an example to impugn another paper, Dr. Nissen hypocritically omited mention that he and Kathy Wolski2 were guilty of the very same multiple comparisons that he decried in others.5

“Stroke is not mentioned at all” by Nissen and Wolski, “a strange omission as almost all CV [cardiovascular] event trials include it.”1  Nissen and Wolski might have lacked the data, but, if so, they “apparently, did not seek it.”1  Ironically, Nissen and Wolski2 claim to have used Peto’s method in their meta-analysis,2 but “Peto, for example, has emphasized the need to find critical missing data (strokes, for example, or time of events) . . . .”1  Then again, as the Food and Drug Administration’s own analyses have shown, “rosiglitazone treatment was in fact associated with fewer strokes.”1

Since Nissen and Wolski did not believe that they had the data to combine acute myocardial infarctions and did not evaluate strokes, it is no surprise that they did not address major adverse cardiac events1 (acute myocardial infarctions plus strokes plus cardiovascular deaths), either.

Of course, acute myocardial infarctions can cause cardiovascular deaths, although not all cardiovascular deaths are caused by acute myocardial infarctions (Some, for example, are caused by strokes, which were curiously not even considered by Nissen and Wolski.).  Unless just one of these outcomes was counted per person, the number of independent observations (in statistical jargon, “n”) will also be exaggerated, giving us too much confidence in the apparent differences between groups.  Nissen and Wolski mentioned this problem, with respect to the measure, acute-myocardial-infarctions-plus-cardiovascular-deaths,2 but the same problem would also have affected the techniques of multiple stage statistical testing (See More Concerns With Nissen’s Avandia Analysis, January 29, 2014.), had actually used such techniques for their multiple comparisons.  Once again, however, for any reasonable assumptions, the potential magnitude of the error would have been far less than the errors introduced by not correcting for multiple comparisons.

The Food and Drug Administration’s own meta-analysis of fifty-two studies6 included all of the measures that Nissen and Wolski ought to have included.  In the meta-analysis of fifty-two studies, acute myocardial infarctions were “nominally statistically significant,”7 strokes trended “favorably for rosiglitazone,” neither cardiovascular nor all-cause mortality was even close to being “nominally statistically significant,”7 and the major adverse cardiovascular events category was not statistically significant.  Unlike Nissen and Wolski,2 The Food and Drug Administration at least acknowledged the impact of multiple comparisons:  “Any sort of correction for multiplicity leaves the finding well short of nominal statistical significance.”1,7

Nissen and Wolski’s2 “strange omissions” would have been bad enough, but there was plenty more.

© 2014 Myron Shank, M.D., Ph.D.8

1 Temple Robert.  Memorandum to Janet Woodcock:  Data on Rosiglitazone, August 8, 2010.  http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm226066.pdf

2 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

3 Schachtman Nathan A.  Learning to embrace flawed evidence–the Avandia MDL’s Daubert opinion.  Schachtman Law January 10th, 2011. http://schachtmanlaw.com/learning-to-embrace-flawed-evidence-the-avandia-mdls-daubert-opinion/.

4 To review, I observed that “It is never appropriate to test a hypothesis with the same data that was used to generate it.”    For the statistically literate, I pointed out that excluding the statistical “degrees of freedom” that were improperly included from DREAM would, by itself, eliminate even the appearance of statistical significance.  I also noted that this was inexcusable from Dr. Nissen’s co-author, Kathy Wolski, since she is a statistician.

5 Steven Nissen.  Flaws, bias, misinterpretation and fraud in randomized clinical trials.  http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=3132

6 In other words, twenty-four percent more than the Nissen and Wolski meta-analysis.2

7 The phrases, “nominally statistically significant” and “nominal statistical significance” may refer to a “p” value of less than 0.05 or to the fact that an apparently statistically significant “p” value does not take into consideration complicating factors, such as multiple comparisons.  In the source memo, it is not always clear from the context whether the former, the later, or both meanings were intended.

I served:  in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000).  In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline.  Before it became impractical to continue prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).

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Are Avandia Advantages in VADT “Statistical Nonsense” (Nissen)?

Steven Nissen, M.D., “scoffed at the analysis” of the Veterans Administration Diabetes Trial which showed statistically “significantly reduced rates of cardiovascular events with rosiglitazone,”1 before he even knew how it was done (See my post, Steven Nissen Calls the Kettle “Black”–VADT’s Avandia Analysis, January 22, 2014.).

So how were the Veterans Administration Diabetes Trial analyses of the safety of rosiglitazone  (Avandia; GlaxoSmithKline) conducted, and what did they show?

There were three types of analyses2 (which I will explain as simply as I can):

  • Case-control analysis
  • Time-dependent covariate survival analysis
  • Propensity matching analysis

Case-Control Analysis

In a case-control analysis, patients who have a particular event (cases) are matched to those who do not have that event (controls).

In this analysis of the Veterans Administration Diabetes Trial, the event categories were myocardial infarctions (heart attacks), strokes, death due to either of these causes, or major adverse cardiovascular events (any of the other events).  Cases and controls were matched on prior history of myocardial infarctions and strokes, use of insulin at the beginning of the study, time to the event (up to the end of the study, for the controls), age, total cholesterol, and at least one other characteristic:  duration of diabetes, obesity as measured by body mass index, systolic blood pressure, diastolic blood pressure, HDL (“good”) cholesterol, or HbA1c (an estimate of average blood glucose).  The cases and controls were then compared on the number of visits for which rosiglitazone was prescribed and the average dose of rosiglitazone at each of those visits.2

For each of the four categories, the patients who had the “events” were prescribed rosiglitazone at fewer visits and at lower doses than those who did not have the “events.”2  While these results were not statistically significant (they could easily have occurred by chance), and while both the “events”2 and the lower doses and duration of rosiglitzone therapy might have been related due to episodes of hypoglycemia (low blood sugar), it is still telling that the results were opposite in direction to those predicted from Nissen and Wolski’s meta-analyses.3,4

Time-Dependent Covariate Analysis

In this analysis, the effect of rosiglitzone was examined with respect to the time until the first “event,” where the event categories were the same as for the case-control analysis, above.2  Time-dependent covariate analysis allows evaluation of the effects of variables whose values change with time,2 unlike the case-control analysis, above.

For both the 4 and the 8 mg doses of rosiglitazone, the risk ratio5 for first events was lower, regardless of whether or not the data was adjusted for patient characteristics at entry into the study (age, use of insulin, systolic blood pressure, and HDL), or characteristics both at entry into the study and throughout the study (age, use of insulin at entry, HDL, and HbA1c).2

For myocardial infarctions with the 4 mg dose, only the unadjusted risk ratio was statistically significant (in other words, unlikely to have occurred by chance alone), but with the 8 mg dose, the only the risk ratio that was not statistically significant was the one adjusted for characteristics both at entry and throughout the study.  For strokes, cardiovascular deaths, and major adverse cardiovascular events, the risk ratios were statistically significantly lower with both doses of rosiglitazone, regardless of adjustment or non-adjustment.2  The higher the dose (0, 4, or 8 mg), the better rosiglitazone looked–not what one would expect from an unacceptably risky drug.

Interestingly, in each case, the “adjusted” and “unadjusted” results were almost identical.2

Just as importantly as their statistical significances, the sizes of each of these apparent differences were clinically highly significant.2

Note that statistical significance of the overall comparison (major adverse cardiovascular events) was justified comparison within its subclasses, “protecting” them from being falsely identified as “significant” as an artifact (artificial result) of multiple comparisons.6

Propensity Analysis

“Propensity analysis” is just a hard way of saying that those who were always prescribed rosiglitazone were compared with those who were never prescribed rosiglitazone.

Overall, there were generally small, but important, differences in for these groups’ characteristics, upon entering the study.  Except for a nearly two-fold difference in smoking, these differences made the “events” less likely in those who were always treated with rosiglitazone than in those who never were.2

However, after matching them with a mathematical model (known as a “step-wise logistic regression”), the characteristics at entry into the study were almost identical between the two groups.2

Again, whether adjusted or not, the risk ratios for all four “events” were much lower in the group that had always been treated with rosiglitazone than in the group that never had been (The overall analysis, major adverse cardiovascular events, was statistically significant, justifying statistical testing of the subgroups, which were not significantly different6).  Once again, the “adjusted” and “unadjusted” results were almost identical.2

Conclusions

“Based on the results from the VADT study, there is no evidence to suggest that use of rosiglitazone increases the risk for cardiovascular mortality or morbidity in patients with type-2 diabetes.”7

Actually, for cardiovascular results (heart attacks, strokes, related deaths, and the combination of the other results) that were uniformly clinically, and often statistically, significant in rosiglitazone’s favor,7 that was a major understatement–especially when, unlike Nissen and Wolski’s meta-analyses,3,4 the results were fairly robust, being demonstrated with very different approaches to the data.7  More to the point, “If anything, rosiglitazone had a protective effect.”1

Of perhaps the greatest importance, severe hypoglycemia (blood sugar low enough to require assistance from someone else) powerfully predicted cardiovascular events.1  Treating with higher doses, or with additional drugs, to lower the blood sugar will almost always increase the risk of hypoglycemia–which may be the “real” cause of any apparent increase in cardiovascular events from a diabetes drug.  This may help to explain the general lack of benefit from “tight” blood glucose control seen in the Veterans Administration Diabetes Trial7 and multiple other studies.  It might even be relevant to Nissen and Wolski’s own meta-analyses!3,4

No one claims that these unplanned analyses of the Veterans Administration Diabetes Trial are ideal.  They were not even published with the other results.7  However, despite the limitations of these analyses, it is clear that the chief statistician for the Veterans Administration Diabetes Trial, Thomas E. Moritz, M.S., actually knows statistics,7 unlike heart doctor, Steven E. Nissen, M.D.8

“Statistical nonsense,” Dr. Nissen?  It is time for you to stop calling kettles black.

© 2014 Myron Shank, M.D., Ph.D.9

1 Gever John.  ADA:  VA Diabetes Trial appears to vindicate rosiglitazone (Avandia) safety.   MedPage Today June 8, 2008.   http://www.medpagetoday.com/MeetingCoverage/ADA/9749

2 Moritz Thomas E.  Impact of the use of rosiglitazone in VADT.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM224743.pdf

3 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

4 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited:  an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

5 See my post: What is the Risk of Avandia?, December 23, 2013.

6 See my post: Nissen, Wolski, and How Not to Do Meta-Analyses, December 19, 2013.

7 Duckworth William, Abraira Carlos, Moritz Thomas, Reda Domenic, Emanuele Nicholas, Reaven Peter D., Zieve Franklin J., Marks Jennifer, Davis Stephen N., Hayward Rodney, Warren Stuart R., Goldman Steven, McCarren Madeline, Vitek Mary Ellen, Henderson William G., Huang Grant D., for the VADT Investigators.  Glucose control and vascular complications in veterans with type 2 diabetes.  New England Journal of Medicine 2009; 360:129-139.

8 While Kathy Wolski, Dr. Nissen’s co-author for both his original5 and his updated6 rosiglitazone meta-analyses, is a statistician, not only is her opinion of the statistical analysis for the Veterans Administration Diabetes Trial not available, but the quality of her own work has been found seriously wanting7  (See also my posts:  “Where’s the Beef?” for Avandia’s Risk?, January 13, 2014; Nissen and Wolski’s Avandia “Significance”, January 15, 2014; and “But wait! There’s more!” The RECORD on Avandia, January 17, 2014.).  In particular, even though her own “updated” meta-analysis with Dr. Nissen6 was statistically non-significant,7 she was not deterred from claiming otherwise.  While Dr. Nissen could (but will not) claim ignorance, she is a statistician and should be held to a higher standard.  (For those who are wondering, yes, I have studied statistics, at both the collegiate and graduate levels.)

9 I served:  in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000).  In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline.  Before prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline) became impractical (and then restricted), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).

Steven Nissen Calls the Kettle “Black” (VADT’s Avandia Analyses)

Nissen’s Prescience of the Veterans Administration Diabetes Trial

Without ever having read the (at that time) unpublished results of the Veterans Administration Diabetes Trial (VADT),  “Dr. Nissen scoffed at the analyses” of safety of rosiglitazone (Avandia, GlaxoSmithKline) before it had even been presented.1

“The VADT trial provides no useful insights into the cardiovascular safety of rosiglitazone,” Dr. Nissen said in an email.

“Approximately 80% of patients in both the intensive and standard treatment groups received rosiglitazone [Avandia; GlaxoSmithKline].2  Therefore, a statistical analysis of the safety of this drug is not possible from VADT,” he said.  “Any assertion that VADT demonstrates the safety of rosiglitazone is statistical nonsense.”1

Oops, Dr. Nissen!

Actually, it is quite possible, inspite of Dr. Nissen’s statistical pontifications.

The Veterans Administration Diabetes Trial was designed to evaluate the effects of intensive and conventional glucose control for diabetes,3 not to compare drug regimens.4  However, after Nissen and Wolski’s original meta-analysis,5 the investigators “agreed to conduct” the “specific analysis of events with rosiglitazone” with their data.1

Dr. Nissen “scoffed at the analyses Moritz reported,” which showed statistically “significantly reduced rates of cardiovascular events with rosiglitazone.”  Simply comparing the intensive with the conventional glucose control arms would have revealed nothing about rosiglitazone, since most of the patients in each arm received that drug at some point, but that is not what Mr. Moritz did.4

In my next post, I will explain how the Veterans Administration Diabetes Trial analyses of rosiglitazone’s safety were conducted and what they showed.

© 2014 Myron Shank, M.D., Ph.D.6

1 Gever John.  ADA:  VA Diabetes Trial appears to vindicate rosiglitazone (Avandia) safety.   MedPage Today June 8, 2008.   http://www.medpagetoday.com/MeetingCoverage/ADA/9749

2 I do not know how Dr. Nissen came up with these numbers.  “Almost every VADT patient received rosiglitazone sometime during the study.”3 The percentages steadily trended downward from approximately 90% in both groups, at the beginning of the study, to about 25 and 30% in the conventionally- and intensively-treated groups, respectively, by the study’s end.3  Apparently, there no time when the percentage approximated 80% in both groups, and, during most of the study, it was less than that in both groups.3

3 Moritz Thomas E.  Impact of the use of rosiglitazone in VADT.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM224743.pdf

4 Duckworth William, Abraira Carlos, Moritz Thomas, Reda Domenic, Emanuele Nicholas, Reaven Peter D., Zieve Franklin J., Marks Jennifer, Davis Stephen N., Hayward Rodney, Warren Stuart R., Goldman Steven, McCarren Madeline, Vitek Mary Ellen, Henderson William G., Huang Grant D., for the VADT Investigators.  Glucose control and vascular complications in veterans with type 2 diabetes.  New England Journal of Medicine 2009; 360:129-139.

5 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

6 I served:  in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000).  In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline.  Before prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline) became impractical (and then restricted), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).

“But wait! There’s more!” The RECORD on Avandia

A Recap

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 [2010], 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

Commentary

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.

1 Nissen Steven E., Wolski Kathy.   Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited:  an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

3 Psaty Bruce M., Furberg Curt D.  Rosiglitazone and cardiovascular risk.  New England Journal of Medicine 2007; 356:2522-2524.

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

5 Hiatt William R., Kaul Sanjay, Smith Robert J. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. New England Journal of Medicine 2013; 369:1285-1287.

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

Steven Nissen and The Not-So-Great Avandia Controversy

Controversy about Avandia (rosiglitazone) began with the rushed publication of an article in the New England Journal of Medicine.  The article, which itself has always controversial, suggested that Avandia was associated with an increased risk of myocardial infarctions1–doctor-speak for “heart attacks.”

The authors, Steven Nissen, M.D., and Kathy Wolski, used data that had been published by GlaxoSmithKline, Avandia’s manufacturer, on its website,1 without the data having been first critically examined (“adjudicated”).  In fact, Nissen and Wolski’s “verification” of the data consisted of checking the data from the website against articles published in the medical literature, but, whenever there was a discrepancy, simply ignoring the discrepancy and using the data from the website anyway.1  Nissen and Wolski made no attempt to find all of the studies that might have yielded evidence.2  Avandia is not to be used in patients with congestive heart failure, but Nissen and Wolski included a study of in patients with congestive heart failure.2  Three of the studies that they included were of non-diabetics with either Alzheimer’s disease or psoriasis, and they included other studies of patients who were merely at risk for diabetes.2  The designs and assessment of outcomes of the studies were a hodgepodge; Nissen and Wolski combined them, since a statistical test for variability did not confirm that variability;1 however, the statistical test they used was not suitable for sparse data,2 such as theirs.  Again, rather than using statistical techniques that would have allowed the use of data from studies without any myocardial infarctions and deaths, Nissen and Wolski ignored the studies.1  Furthermore, the statistical technique that they used requires balance between the numbers in the Avandia groups and the comparison groups, but there were two- and three-fold differences.2  Only by discarding part of the data and using improper statistical techniques were Nissen and Wolski able to conclude that the “data suggest a cardiovascular risk associated with the use of rosiglitazone.”1

Notwithstanding the problems with the studies selected by Nissen and Wolski, using appropriate statistical techniques and all of the data from those same studies yields very different conclusions:  “The risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain.  Neither increased nor decreased risk is established.”2

Nissen and Wolski were sloppy, at best, but is that all?  Dr. Nissen acknowledged receiving research support from Takeda.1  What he did not mention is that Takeda manufacturers the rival drug, ACTOS (pioglitazone), which he pointedly compared to Avandia.  Was his campaign against Avandia punitive, because GlaxoSmithKline did not support his research?  In addition, he was widely promoted for the top position at the Food and Drug Administration3,4 for his muckraking.  Whether or not he actively sought the position, he apparently never demurred, either.  Dr. Nissen’s campaign against Avandia seems incompatible with a love of the truth, but it has all the hallmarks of an ego-inspired crusade.

As will become apparent in future posts, whatever his motives, Dr. Nissen has since demonstrated conspicuous lack of objectivity and unprofessional intolerance for other points of view about Avandia.

© 2013 Myron Shank, M.D., Ph.D.    

1 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 Diamond George A., Bax Leon, Kaul Sanjay.  Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.  Annals of Internal Medicine 2007; 147:578-581.

3 Reuters.  FDA chief to leave post when Obama takes office.  December 16, 2008.

4 Mundy Alicia.  Horse race begins for new leaders at FDA and HHS.  Health Blog November 5, 2008.