Tag Archives: rosiglitazone mortality

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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Dr. Nissen: “Just Say No” to Learning About Avandia

As Steven Nissen, M.D., sees it, the only reason that the Food and Drug Administration followed through with its long-announced promise for an independent “re-adjudication” (re-judging) of the RECORD1 study was that “the leadership of the division of the FDA responsible for drug regulation, the Center for Drug Evaluation and Research (CDER), is seeking to avoid accountability for its role in the Avandia tragedy.”2

Dr. Nissen requested time to present his analyses about rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline) to the Food and Drug Administration, but when he told them what he had to say, they concluded that it would merely duplicate other presentations.3

Uh, oh.  Dr. Nissen is not happy.  According to him, “the meeting seems systematically designed to absolve the drug of harm and the CDER leadership of any responsibility for ignoring the public health hazard of Avandia.  The current effort is intended to ‘whitewash’ the Avandia scandal and re-write history.”  He alleges that this is because “The leadership of CDER was intensely embarrassed by these revelations and furious with us for publicly challenging the safety of Avandia (and indirectly the competence and integrity of CDER).”2

Really?  And we are to believe that the same Dr. Nissen whose meta-analyses, “history” shows, have not only failed scientific and statistical scrutiny,4 but, even worse, have not been supported by real studies5 (let alone his own “updated” meta-analysis6) was not the least bit fearful of further embarrassment7 from the RECORD data?  Are we also to believe that the man who worked for Takeda, maker of the rival pioglitazone (ACTOS, ACTOSPlusMet, DuetAct), but not for GlaxoSmithKline, manufacturer of  rosiglitazone (Avandia, Avandamet, Avandaryl), was not above attempting to “blackwash” his opponents?  Are we not to even consider that this Dr. Nissen, who has been so strident in his attacks on anyone who does not support him, might be blackmailing those who are reluctant to have him study their drugs with his intravascular (within blood vessels) ultrasound procedure?8

Remember, Dr. Nissen, that ““to censor public debate about a critical public health issue is unacceptable and represents a grave threat to academic freedom.”9  You said that.  Those are your own words.  You did not believe that they meant allowing the TIDE study to continue–and possibly embarrass you.10  Clearly, you did not believe that they meant that the Food and Drug Administration should keep its word and allow the RECORD study to be independently re-adjudicated–which did embarrass you.5  Did you protest when the Chief of the Department of Medicine gave the endocrinologists in your own Cleveland Clinic strict orders not to say a word about rosiglitazone, with either an explicit or implicit threat that exercise of their “academic freedom” would cost them their jobs11–or were you afraid of being embarrassed?

Dr. Nissen, we have heard you–over and over again.  Until you have nothing new to say, you should do something new and say nothing.

© 2014 Myron Shank, M.D., Ph.D.

1 Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes

2 Nissen Steven E.  Steven Nissen:  the hidden agenda behind the FDA’s new Avandia hearings. Forbes Pharma & Healthcare, May 23, 2013.  http://www.forbes.com/sites/matthewherper/2013/05/23/steven-nissen-the-hidden-agenda-behind-the-fdas-avandia-hearings/

3 Herper Matthew. The FDA responds to Steve Nissen’s criticism of upcoming Avandia meeting. Forbes Pharma & Healthcare, May 23, 2013.  http://www.forbes.com/sites/matthewherper/2013/05/23/the-fda-responds-to-steve-nissens-criticism-of-upcoming-avandia-meeting/

4 See my posts:  Steven Nissen and The Not-So-Great Avandia Controversy, December 18, 2013 https://drshank.wordpress.com/2013/12/18/steven-nissen-and-the-not-so-great-avandia-controversy/; Nissen, Wolski, and How Not to Do Meta-Analyses, December 19, 2013 https://drshank.wordpress.com/2013/12/19/nissen-wolsky-and-how-not-to-do-a-meta-analysis-2/; What is the Risk of Avandia?, December 23, 2013 https://drshank.wordpress.com/2013/12/23/what-is-the-risk-of-avandia/; “Where’s the Beef?” for Avandia’s Risk?, January 13, 2014 https://drshank.wordpress.com/2014/01/13/wheres-the-beef-for-avandias-risk/; Nissen and Wolski’s Avandia “Significance,” January 15, 2014 https://drshank.wordpress.com/2014/01/15/nissen-and-wolskis-avandia-significance/.  (For those who are wondering, yes, I have studied statistics at both the collegiate and graduate levels.)

5 See my posts:  ADOPT the DREAM of a RECORD for Avandia, December 26, 2013 https://drshank.wordpress.com/2013/12/26/adopt-the-dream-of-a-record-for-avandia/ and “But wait! There’s more!” The RECORD on Avandia, January 17, 2014 https://drshank.wordpress.com/2014/01/17/but-wait-theres-more/

6 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.

7 “Nevertheless, the results of RECORD do not substantiate the findings from the Nissen/Wolski meta-analysis on myocardial infarction and cardiovascular death.”  Furthermore, there was a “favorable trend for rosiglitazone on all-cause mortality.”  (Unger Ellis F.  FDA cardiologist’s perspective on RECORD:  joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Avandia® (rosiglitazone) – July 13-14, 2010. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm218485.pdf)

8 The story behind Dr. Nissen’s claims to have all payments from drug companies go to charities will have to wait for another post.  In the meantime, I disclose that 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).

9 Husten Larry.  EHJ editors rebuffed GSK efforts to suppress Nissen editorial on rosiglitazone.  Cardiobrief April 30, 2010.  http://cardiobrief.org/2010/04/30/ehj-editors-rebuffed-gsk-efforts-to-suppress-nissen-editorial-on-rosiglitazone/.

10 See my post:  Avandia’s TIDE Is Stopped, December 24, 2013.  https://drshank.wordpress.com/2013/12/24/avandias-tide-goes-out/

11 I know several endocrinologists from the Cleveland Clinic Foundation.  After Dr. Nissen’s original meta-analysis came out, every one of them refused to say so much as a word about rosiglitazone, explaining that their department chairman had emphatically prohibited them from doing so (One acknowledged that their chairman had ordered them to stop using the drug.).  It is obvious why their chairman would forbid criticism of a powerful member of the institution; it is equally obvious that there would be no reason to prevent the endocrinologists from speaking out (or from continuing to use rosiglitazone), if they had supported Dr. Nissen.  Not one endocrinologist I know (and I have represented one out of every nine in the United States) supported Dr. Nissen, and many (including myself) have been outspoken critics.