healthy4u: American College of Cardiology

How Manipulated Clinical Evidence Could Distort Guidelines - the Case of Statins for Primary Prevention

The new American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on the primary prevention of cardiovascular disease, which we discussed <a href="http://hcrenewal.blogspot.com/2013/11/confused-thinking-about-new-cholesterol.html">here</a>, continue to generate controversy.  Articles in the media and online-first in medical journals underscored some of the issues we discussed before.  Jeanne Lenzer, in a news article in the British Medical Journal, found that the chair of the guideline panel had important past conflicts of interest that were not previously disclosed.(1)  The chair denied their significance (look <a href="http://healthland.time.com/2013/11/22/conflicts-of-interest-cholesterol-panel-head-defends-members-ties-to-industry/">here</a>).   Guideline panel members continued to justify their efforts, but in my humble opinion, raised no new evidence or logic to support it (look <a href="http://www.medscape.com/viewarticle/814711">here</a>  and <a href="http://www.medscape.com/viewarticle/814960">here</a>) Bigger Questions about the Validity of the Clinical Evidence However, several new articles suggested the need for a deeper look at one particular aspect of this case, the validity of the evidence from clinical research about the benefits and harms of statins for primary prevention. JAMA published a summary of the Cochrane review that provided a basis for the guideline developers' confidence in the worth of statin therapy in primary prevention.(2) <blockquote class="tr_bq"> results suggest that the benefits of statin therapy outweigh serious life-threatening hazards.</blockquote> However, almost as an aside, it noted, <blockquote class="tr_bq">Some trials included participants with CVD, but rather than exclude these trials, we included trials that contained 10% or fewer participants with documented CVD.</blockquote> Primary prevention in this case is defined as prevention for patients without existing cardiovascular disease.  There is evidence that statins may well have benefits that outweigh harms when given to patients with known cardiovascular disease, particularly documented coronary artery disease (CAD).  Mixing such patients in any numbers into "primary prevention trials" would likely exaggerate the benefits of statins.  Yet such not quite primary prevention studies were included in a systematic review of primary prevention.  In addition, a commentary by one of the guideline developers defending the group's work also underscored the fact that many of the supposedly primary prevention trials they used as evidence were not pure primary prevention trials.(3) <blockquote class="tr_bq">Notably, the 2013 cholesterol guideline cut points were derived from the placebo rates for myocardial infarction, stroke, and cardiovascular disease death observed in the 3 exclusively primary prevention statin trials, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, and the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).[4-6]</blockquote> The wording again suggests that all the other trials used as evidence about primary prevention were NOT "exclusively primary prevention studies," and hence, as I noted above, may have been biased so that they would likely exaggerate the apparent benefits of statins in primary prevention. This suggested to me that the systematic review that provided a basis for the guidelines' aggressive recommendations about statins for primary prevention, and the trials on which it was based needed further skeptical, critical reviews. The Cochrane Review: Was Evidence about Statin Benefits vs Harms Manipulated? We have frequently discussed the <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of clinical research</a>.  By that we have meant design, implementation, analysis or dissemination of research in ways likely to further vested interests.  In particular, when drug, biotechnology and device companies sponsor and control clinical research on their own products, they may set up the research in ways likely to make their products look better than they actually are.   We looked through the most recent Cochrane review of statins for primary prevention(7) with a skeptical eye out for suggestions that the trials reviewed could have been so manipulated.  We found quite a bit. First, we found that not all trials reported on the "hard" outcomes that one needs to consider when evaluating benefit vs harm of statins in primary prevention. <blockquote class="tr_bq">Data on all-cause mortality were provided in 11 trials.[of 19, and hence missing in 8].</blockquote> And, <blockquote class="tr_bq"> Twelve trials provided data on adverse events.[and hence 7 did not.]</blockquote>  Also, data on specific adverse events was often not reported: myalgia and rhabdomyolysis were reported in only 9/19 trials; new onset diabetes mellitus in only 2/18; hemmorhagic stroke in only 2/19; abnormal liver tests in only 10/19; kidney dysfunction in only 4/19; arthritis in only 2/19, and by implication, cognitive dysfunction in 0/19.     Failure to look for all the possible bad outcomes of treatment could obviously bias the study in the direction of minimizing the harms of the treatment. A substantial number of trials either failed to report on crucial aspects of their methods, or admitted to flaws that could have induced important biases.: 3/19 did not described randomization methods; 4/19 did not use double-blinding; 6/19 did not use intention to treat analysis; 7/19 did not report their drop-out rates. So it is very surprising to me that the authors concluded, <blockquote class="tr_bq">In general there was low risk of bias ... though all trials were either fully or partially funded by pharmaceutical companies.</blockquote>In my humble opinion, the Cochrane review showed many trials that had flaws could have biased their outcomes, and hence the outcomes of the overall review.  Some of the flaws clearly could have lead to biases that would have made statins look more efficacious, or less dangerous than they might actually be.  I do not understand the conclusion that the risk of bias was slow, and the lack of discussion about the direction the bias could have taken.  Review of the "3 Exclusively Primary Prevention Statin Trials" Given the Cochrane review's apparent lack of skepticism about methodologic problems in the industry funded statin prevention trials, I endeavored to take a closer look at the three trials that Dr Robinson held out as the real primary prevention trials.  Instances of manipulation, as we defined it above, for each trial are described below AFCAPS/ TexCAPS(4) Narrow Patient Population - This study excluded many patient for whom the statins were not contraindicated or warned against: uncontrolled hypertension; type 1 or type 2 diabetes mellitus on insulin or with a HgBA1C at least 10%; and body weight more than 50% "desirable limit for height."  (Based on the official contraindications and warnings for commonly used statins, e.g., see contraindications for Lipitor <a href="http://labeling.pfizer.com/ShowLabeling.aspx?id=587">here</a>, active liver disease, pregnancy for likely to become pregnant, nursing mothers, hypersensitivity to the medicine; and warnings: use of cyclosprine or strong CYP3A4 inhibitors, uncontrolled hypothyroidism, renal impairment.)  Thus the results may not generalize to many patients who would otherwise be considered statin candidates.  By excluding such patients, the results may bias the study towards minimizing the probabilities of harms that might occur were statins used on a wide population for primary prevention. Unknown Randomization and Allocation Concealment Procedures - According to the Cochrane Review, the study report did not explain how randomization or allocation concealment were accomplished.   Early Termination/ Multiple Comparisons - The study was terminated early based on an early look at the number of outcome events.  Two such early or interim analyses were planned.  Taking multiple looks at the data over time raises a multiple comparisons problem, and may lead to exaggerating the benefits of the treatment.(8). Furthermore, stopping early decreases the sample size and hence the power to find adverse effects of treatment. Implausible Dropout Rate, Missing Data - According to the Cochrane Review, the study reported no dropouts.  This seems somewhat improbable, suggesting skepticism about the accuracy and completeness of the data collection.  On the other hand, a study chronology suggests that of 6605 patients who started the study, 6540 had data on complete endpoint status, suggesting missing data.  Since dropouts and missing data may be due to different reasons in different arms of the study, they threaten the validity of data about benefits and harms.   Adverse Effects not Reported - The study provided no data about development of diabetes, hemmorhagic stroke, kidney dysfunction, arthritis, or cognitive dysfunction, suggesting incomplete data about harms, and hence bias towards minimizing harms.     MEGA (5) Narrow Patient Population -  [The patient population was not described in the main report, but only in an earlier methods article.](9)  The study excluded patients with congenital or rheumatic heart disease; chronic atrial fibrillation, current diagnosis of malignancy; poorly controlled hypertension or diabetes mellitus; current use of oral or parenteral corticosteroids; and other conditions at the discretion of the physician.  These exclusions seem unrelated to the contraindications or warnings on the stain label.  Again, such a narrow patient population reduces the generalizability of the study results, and may bias the study to minimizing the harms of statins. Only Single Blind - This was an open-label study, so patients and physicians knew who got statins and who got placebo.  Such knowledge could have biased patient management, including how diligently particular diagnoses and outcomes were pursued, and biased data collected from patients or physicians. Adverse Effects Not Reported - The study provided no data about diabetes, hemmorhagic stroke, kidney dysfunction, arthritis, or cognitive dysfunction, again suggesting bias towards minimizing harms.   JUPITER(6) Narrow, Unusual Patient Population - The study was limited to patients without hyperlipidemia but with an increased C-reactive protein.  Thus it is not clear that its results would generalize to a more typically defined primary prevention population.  The study excluded patients receiving post-menopausal hormone-replacement; with diabetes; uncontrolled hyertension; cancer other than non-melanoma skin cancer within 5 years; recent history of drug or alcohol abuse; "another medical condition that might compromise safety or the successful completion of the study;" also patients with "inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease...;" and also "patients taking immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids."  Again, this narrow patient population would reduce generalizability and bias towards minimizing harms. Early Termination/ Multiple Comparisons - This study was terminated early after an early look at the data.  Allowing for multiple looks at the data may exaggerate efficacy.   Implausible Dropout Rate - According to the Cochrane Review, the study had no dropouts.  This value seems implausible, again suggesting data collection problems.   Adverse Effects Not Reported - The study provided no data about <strike>hemmorhagic stroke</strike>, arthritis, or cognitive dysfunction, again suggesting bias towards minimizing harms.  [Revised December 9, 2013 - see comment below by Marilyn Mann.] Summary Aspects of the continuing controversy over the new ACC/ AHA guidelines for statins in the primary prevention of cardiovascular disease hinted that the clinical trials which provided the evidentiary basis for the guidelines, and for the use of statins in primary prevention in general, was more flawed than is widely appreciated.  The latest Cochrane Collaboration review of this data acknowledged multiple, important flaws affecting most of the studies.  Our more detailed review of the three studies held out as the purest found additional flaws.  Many of these flaws seemed likely to bias the studies towards exaggerating the efficacy and/or minimizing the harms of statins in primary prevention.  Since all these trials were funded, and presumably influenced by pharmaceutical companies that make statins, these flaws seem to be examples of <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of the clinical evidence</a>.  Rather than being the result of simple mistakes, or inevitable trade-offs, they seem to be study features intended the support the vested interests of the study sponsors. It is not clear why the Cochrane review did not temper its conclusions based on the flaws in the studies, and particularly by the possibility that these flaws represented study manipulation.   The multiple flaws, possibly due to study manipulation, in the clinical evidence about statins in primary prevention suggest that we should be extremely skeptical about whether the benefits of such treatment outweighs its harms, and hence about whether the recommendations in the latest guidelines to give statins to all patients predicted (but perhaps not accurately) to be at even slightly elevated risk are warranted. The flaws in multiple large studies of a very common clinical problem, and their effects on systematic reviews and clinical practice guidelines suggest that suppression and manipulation of research are rife in medicine and health care, presumably fueled by the pervasive web of <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interes</a>t that spans health care.  We need extreme skepticism about the integrity of clinical research, especially research sponsored by those whose products and services are being studied, and who thus have vested interests in the research turning out to make their products and services look good.   The good news is that we may not have to look too far to find ways to improve the trustworthiness of guidelines and the soundness of medical decision making.  Implementation of the Institute of Medicine's recommendations on reducing conflicts of interest (look <a href="http://www.iom.edu/Activities/Workforce/ConflictOfInterest.aspx">here</a>), and developing trustworthy guidelines (look <a href="http://www.iom.edu/Activities/Quality/ClinicPracGuide.aspx">here</a>) might lead to the development of sound guidelines in the future.   Furthermore, while endless discoveries of <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulated</a> and <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed research</a> may have lead some <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine </a>advocates to despair, our latest exercise suggests that the principles of evidence-based medicine, unflinchingly applied, could really do good.  Review of the three statin studies above based on standard principles of critical review readily spotted the multiple signs of manipulation.  The problem with the Cochrane review was not that it missed these signs.  Rather, the reviewers for some reason noted most of them, but then did not react.  If systematic reviews were done with sufficient skepticism about the possibility of manipulation of clinical research, and were willing to call out when the emperor seemed short on fabric, then a lot of mischief could be avoided.   References 1.  Lenzer J. Majority of panelists on controversial new cholesterol guideline have current or recent ties to drug manufacturers.  Brit Med J 2013.  Link<a href="http://www.bmj.com/content/347/bmj.f6989"> here</a>.  2.  Taylor FC, Huffman M, Shah E. Statin therapy for primary prevention of cardiovascular disease.  JAMA 2013.  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1785551">here</a>.   3.  Robinson JG.  Accumulating evidence for statins in primary prevention.  JAMA 2013;  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1785550">here</a>. 4.    Downs  JR, Clearfield  M, Weis  S,  et al; for the AFCAPS/TexCAPS Research Group.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279(20):1615-1622. Link <a href="http://dx.doi.org./10.1001/jama.279.20.1615">here</a>.  5.  Nakamura  H, Arakawa  K, Itakura  H,  et al; MEGA Study Group.  Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA study): a prospective randomised controlled trial. Lancet. 2006;368(9542):1155-1163. Link <a href="http://dx.doi.org./10.1016/S0140-6736(06)69472-5">here</a>. 6.  Ridker  PM, Danielson  E, Fonseca  FA,  et al; JUPITER Study Group.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. Link <a href="http://dx.doi.org./10.1056/NEJMoa0807646">here</a>.  7.  Taylor F,  Huffman MD, Macedo AF et al.  Statins for the prevention of cardiovascular disease. Cochrane Library 2013.  Link <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004816.pub5/abstract">here</a>. 8. Mueller PS, Montori VM, Bassler D et al.  Ethical issues in stopping randomized trials early because of apparent benefit.  Ann Intern Med 2007; 146: 878-881.  Link <a href="http://annals.org/article.aspx?articleid=735073">here</a>.   9.  Management of Elevated Cholesterol in the Primary Prevention Group of the Adult Japanese (MEGA) Study Group.  Design and baseline characteristics of a study of primary prevention of coronary events with pravastatin among Japanese with mildly elevated cholesterol levels.  Circ J  2004; 68: 860-867.  Link <a href="http://www.ncbi.nlm.nih.gov/pubmed/15329509">here</a>.

How Manipulated Clinical Evidence Could Distort Guidelines - the Case of Statins for Primary Prevention

The new American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on the primary prevention of cardiovascular disease, which we discussed here, continue to generate controversy…

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03 Dec 2013

Confused Thinking about New Cholesterol Guidelines - Were Conflicts of Interest to Blame?

For years, clinical practice guidelines promulgated by prominent health care organizations have been hailed with accolades as received wisdom.  However, there is increasing reason to be skeptical of such guidelines.  Many guidelines are not based on rigorous application of the principles of <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine,</a> and often seem to arise from the personal opinions of their authors.  This is particularly troublesome when those authors  have conflicts of interest, and when the organizations that sponsor guideline development have institutional conflicts of interest.  Back in 2011, an Institute of Medicine panel advocated standards for guideline development, including strict limits on conflicted panel members, to make their results more trustworthy.  However, as we noted <a href="http://hcrenewal.blogspot.com/2012/11/what-if-institute-of-medicine-wrote.html">here</a>, those standards have been largely ignored.    Therefore, it is good news that the just released, long awaited guidelines on the treatment of blood cholesterol from the American College of Cardiology (ACC) and American Heart Association (AHA)(1)  they provoked controversy rather than adulation.  However, connecting some dots reveals that the guideline development process and the defenses of the guidelines by its developers were even more confused than they first seemed.  That confusion may be explained by conflicts of interest affecting guideline development of the sort that the IOM report wanted eliminated.  . The New Cholesterol Guidelines - Background A striking feature of the guidelines was a new approach to drug treatment for primary prevention, that is, for patients who do not already have heart disease or other atherosclerosis.   Such drug based primary prevention has been controversial, although drug treatment for people with high cholesterol who also have documented coronary heart disease, secondary prevention, is well-established. The new cholesterol treatment guideline suggested drug treatment, essentially limited to statin medications, for patients believed to be at elevated risk of developing coronary artery disease or other forms of atherosclerotic disease, even in the absence of elevated cholesterol levels.   <blockquote class="tr_bq">Adults 40 to 75 years of age with LDL–C [so called "bad cholesterol"] ]70 to 189 mg/dL, without clinical ASCVD* [atherosclerotic cardiovascular disease] or diabetes and an estimated 10-year ASCVD risk ≥7.5% should be treated with moderate- to high-intensity statin therapy.</blockquote> Also, <blockquote class="tr_bq">It is reasonable to offer treatment with a moderate intensity statin to adults 40 to 75 years of age, with LDL–C 70 to 189 mg/dL, without clinical ASCVD* or diabetes and an estimated 10-year ASCVD risk of 5% to [less than] ... 7.5% </blockquote> Previously, guidelines and other recommendations for the treatment of cholesterol for primary prevention, that is, for patients without known atherosclerotic cardiovascular disease, suggested treatments according to the level of cholesterol or its components.   Less controversially, the guidelines recommended treatment for patients with existing ASCVD, very high LDL-C, and diabetes. The new guidelines raise some  questions: - Given the past controversy, how good is the evidence supporting cholesterol lowering drug treatment in primary prevention? - What is the evidence supporting deciding on drug treatment for primary prevention on predicted risk of atherosclerotic cardiovascular disease? - Can physicians make good enough risk predictions to use this approach? Evidence Supporting Drug Treatment of Cholesterol in Primary Prevention - Do Benefits Outweigh Harms? The reason that cholesterol lowering drug use for primary prevention has been controversial is the lack of clear evidence that such drug use leads to benefits to patients that outweigh its harms.  A central principle of evidence based medicine is that only treatments whose benefits clearly outweigh their harms should be prescribed.  . A recent commentary by Abramson et al in the British Medical Journal in October, 2013 outlines the issues.(2)  There is no good evidence that statins used in primary prevention increase overall survival, or decrease overall incidence of adverse events, defined as death, hospital admission, prolongation of admission, cancer or permanent disability. Individual trials and meta-analyses do show that statins lead to a small reduction in the rate of cardiovascular events.  For example, the authors' re-analysis of data from a patient level meta-analysis showed that of 140 low-risk primary prevention patients treated for five years, one patient would avoid a major coronary event or stroke. However, it is not clear that this small likelihood of benefit offsets the likelihood of adverse events due to treatment.  The data about the harms of statins in primary prevention is not very clear, partially because the relevant randomized controlled trials featured "reporting of adverse events ... [that was] generally poor, 'with failure to provide details of severity and type of adverse events or to report on health-related quality of life." In summary, Abramson et al wrote, <blockquote class="tr_bq">statin therapy prevents one serious cardiovascular event per 140 low risk people (five year risk ... [less than] 10%) treated for five years.  Statin therapy in low risk people does not reduce all cause mortality or serious illness and has about an 18% risk of causing side effects that range from minor and reversible to serious and irreversible.  Broadening the recommendations in cholesterol lowering guidelines to include statin therapy for low risk individuals will unnecessarily increase the incidence of adverse effects without providing overall health benefit.</blockquote> However, the new guideline focused on the ability of statins to prevent ASCVD,  <blockquote class="tr_bq">The RCTs identified in the systematic evidence review indicated a consistent reduction in ASCVD events from 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) therapy in secondary and primary prevention populations....</blockquote>However, the new guideline ignored the absence of evidence that statin treatment prolonged life, prevented serious illness overall, or improved health status, function or quality of life. Furthermore, the guideline seemed unreasonably optimistic about the harms of statins.  In particular, it ignored evidence about harms other than diabetes, myopathy (serious muscle disease), and stroke.  Yet there is evidence suggesting that statins at least might cause "liver dysfunction, acute renal failure, and cataracts; cognitive symptoms, neuropathy, and sexual dsyfunction; decreased energy and exertional fatigue; and psychiatric symptoms, including depression, memory loss, confusion, and aggressive reactions" as summarized by Abramson and colleagues. Thus the new guidelines did not make a new and improved case that statin treatment for primary prevention has benefits that outweigh its harms.  One could argue that this is their fatal flaw and thus all the rest of the guidelines' discussion about which patients should get primary prevention was pointless. Dr Abramson and his co-author, Dr Rita Redberg, did get to repeat their arguments about why statin use for primary prevention is not justified in a NY Times <a href="http://www.nytimes.com/2013/11/14/opinion/dont-give-more-patients-statins.html">op-ed,</a> but otherwise the fundamental problem with the guideline's argument for aggressive use of statins went unnoticed. Evidence Supporting Making Decisions about Statin Treatment as Primary Prevention According to Patients' Risks of Developing Atherosclerotic Cardiovascular Disease The guidelines suggested statin therapy for patients judged to have at least a 7.5% risk of ASCVD.  As noted above, there is no evidence that statin therapy in primary prevention in general increases survival, reduces serious events overall, improves health status, quality of life, or function, or has benefits that clearly outweigh its harms.  I could not find any reference in the guidelines to clear evidence about the effects of statin treatment in primary prevention for this sub-group of patients.  In the supplemental guideline on risk assessment,(3) there was this  <blockquote class="tr_bq">After deliberation, the Work Group endorsed the existing and widely employed paradigm of matching the intensity of preventive efforts with the individual’s absolute risk.. The Work Group acknowledges that none of the risk assessment tools or novel risk markers examined in the present document have been formally evaluated in randomized controlled trials of screening strategies with clinical events as outcomes.</blockquote> The wording is confusing, but might be stating that a strategy of using statins only for patients predicted to have a risk greater than 7.5% has not been assessed in a clinical trial.  (It might also, however, be stating that the specific method recommended by the guideline to assess this risk has never been tested in a clinical trial, see below.) The apparent lack of evidence in support of the specific strategy advocated by the guideline to use statins for primary prevention in patients whose risk of ASCVD exceeded the designated threshold did not otherwise attract any notice. Evidence Supporting the Ability of Physicians to Assess Risk of ASCVD Accurately Enough to Implement the Recommended Strategy The supplemental guideline stated that previously published methods of risk prediction would not be suitable for the new proposed approach, <blockquote class="tr_bq">As part of its deliberations, the Work Group considered previously published risk scores with validation in NHLBI cohort data as 1 possible approach. However, a number of persistent concerns with existing risk equations were identified including nonrepresentative or historically dated populations, limited ethnic diversity, narrowly defined endpoints, endpoints influenced by provider preferences (e.g., revascularizations), and endpoints with poor reliability (e.g., angina and heart failure [HF]). </blockquote> Since the recommended strategy requires an estimation of risk, the lack of availability of acceptable risk assessment methods would appear to be another fatal flaw.  However,  <blockquote class="tr_bq">Given the inherent limitations of existing scores, the Work Group judged that a new risk score was needed to address some of the deficiencies of existing scores, such as utilizing a population sample that approaches, to the degree possible, the ideal sample for algorithm development and closely represents the U.S. population.</blockquote> So the question now becomes: did the guideline provide sufficient evidence that the new risk prediction tool developed as part of guideline development predicts sufficiently well to be used to make decisions as recommended by the guidelines? Note that developing, validating, and publishing a new risk score normally would be considered to be tasks that are part of research, not guideline development.  Nonetheless, the guideline developers decided to take on these tasks as part of guideline development, which precluded independent publication of the the results of this research after peer review.  This makes it more difficult for others to critically evaluate the results of the research concerning the new risk score.  But let me attempt to do so. The work group went ahead to develop a new multivariate prediction model for ASCVD.  This means they used statistical methods to find variables, that is, patients' clinical or demographic characteristics, that independently could predict the outcome of interest, and then combined these variables in an equation (or algorithm) to make risk predictions for individual patients.  Such multivariate models to make diagnoses or, as in this case, prognostic predictions have been the subject of considerable research since at least the 1970s.  However, they have not been as useful as their initial advocates hoped. The issues turn out to be a bit complex.  I must digress into an area in which I previously did research. It is quite easy to develop multivariate diagnostic or prediction models.  The statistical analytic tools can almost always find multiple patient characteristics that independently correlate with the outcome of interest.  The problem is that such correlations can be based on random associations, or biases produced by idiosyncrasies in the particular data set used for model development.  That a new model can diagnose or predict accurately for patients who were not in the original data set thus is not assured, and should be considered to be merely a hypothesis. Models developed on one group of patients often do not work when tried prospectively on new patients, probably because the initial development group was somehow not completely representative of all the patients of interest.  For example, a model may have been developed using patients from a particular hospital which attracts different sorts of patients than found in other hospitals in which the model might be used.  .Therefore, before one has confidence in such a multivariate model, one must verify that the model predicted or diagnosed well not only in the group of patients from which it was derived, but prospectively on other patients like those on whom it would be used in clinical practice. The supplemental guidelines did assert that the new model was prospectively tested, <blockquote class="tr_bq"> The equations were also assessed in external validation studies using data from other available cohorts</blockquote> However, it did not specify what these cohorts were. There is some data buried in Appendix 4 of the supplemental guideline on the performance of the model.  They did not distinguish results from derived from prospective validation from those from model derivation. <blockquote class="tr_bq"> In summary, discrimination and calibration of the models were very good. C statistics ranged from a low of 0.713  (African-American men) to a high of 0.818 (African-American women). Calibration chi-square statistics ranged from a low of 4.86 (nonHispanic White men) to a high of 7.25 (African-American women).</blockquote> These two sentences do not provide strong evidence that the model would predict well when used prospectively. The C-statistic is an overall measure of the ability of the model to discriminate between patients who will go on to develop the diseases of interest and those who will not.  The statistic is formally equal to the probability that were two patients, one who developed disease, and another who did not, selected randomly, the model would predict disease more strongly for the patient who actually got it.  Thus, at best, for 20% of random pairs of African-American women, one who got disease, one who did not, the model would give a more pessimistic prediction for the women who would not get disease.  This is good, but not great discrimination ability.  (If this result referred to data from model derivation, not prospective validation, it is likely to be over-optimistic.) Furthermore, since the guideline would be used to make decisions based on the absolute risk, its calibration is also important.  Calibration is the measure of whether the model predictions of risk are close to reality.  To assess calibration, one ought to assess the whole range of predictions made by the model.  Given that the guidelines suggest a 7.5% risk threshold, it would be particularly important to determine whether patients given predictions above and below that value really have risks above and below that value. Unfortunately, the two sentences above are not helpful in this regard.  The chi-square statistic presented is a measure of overall calibration, but does not show calibration for groups of patients given predictions with particularly interesting values, like above or below 7.5% Note that the supplemental guideline on risk assessment includes a statement that details about the model validation done "internally and externally" are in a <a href="http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a/suppl/DC1">Full Panel Report Data Supplement</a>.  The download of that supplement so far does not seem to work Setting that aside for a moment, the published guidelines do not provide good evidence that the risk prediction tool the guidelines recommend should be used to assess ASCVD risk in order to make decisions on statin use for individual patients in primary prevention. The lack of a sufficiently accurate method to predict risk seems to a fatal flaw for a strategy that requires risk prediction. Controversy in the Media It turns out that I was not the first person to identify this problem. In fact, it appears that during the internal review process for the guidelines, major questions had already been raised about the risk prediction model's calibration. However, these questions did not seem to have been conveyed to the guideline authors, and hence were never addressed. As <a href="http://www.nytimes.com/2013/11/18/health/risk-calculator-for-cholesterol-appears-flawed.html">reported</a> by the New York Times on November 17, 2013, <blockquote class="tr_bq">The problems were identified by two Harvard Medical School professors whose findings will be published Tuesday in a commentary in The Lancet, a major medical journal. The professors, Dr. Paul M. Ridker and Dr. Nancy Cook, had pointed out the problems a year earlier when the National Institutes of Health’s National Heart, Lung, and Blood Institute, which originally was developing the guidelines, sent a draft to each professor independently to review. Both reported back that the calculator was not working among the populations it was tested on by the guideline makers. That was unfortunate because the committee thought the researchers had been given the professors’ responses, said Dr. Donald Lloyd-Jones, co-chairman of the guidelines task force and chairman of the department of preventive medicine  at Northwestern University.</blockquote> The article by Ridker and Cook was indeed published. on November 19, 2013(4).  It suggested major problems with the calibration of the risk assessment model, <blockquote class="tr_bq">Another concern for clinicians is whether the new prediction algorithm created by the ACC/AHA correctly assesses the level of vascular risk. To be useful, prediction models must not only discriminate between individuals with and without disease, but must also calibrate well so that predicted risk estimates match as closely as possible the observed risk in external populations. We calculated predicted 10-year risks of the same atherosclerotic events using the new ACC/AHA risk prediction algorithm and compared these estimates with observed event rates in three large-scale primary prevention cohorts, the Women's Health Study, the Physicians' Health Study, and the Women's Health Initiative Observational Study. As shown in figure 1, in all three of these primary prevention cohorts, the new ACC/AHA risk prediction algorithm systematically overestimated observed risks by 75–150%, roughly doubling the actual observed risk. As shown in figure 2, similar overestimation of risk was observed in two external validation cohorts used by the guideline developers themselves, an issue readily acknowledged in the report. Thus, on the basis of data from these five external validation cohorts, it is possible that as many as 40–50% of the 33 million middle-aged Americans targeted by the new ACC/AHA guidelines for statin therapy do not actually have risk thresholds that exceed the 7·5% threshold suggested for treatment. Miscalibration to this extent should be reconciled and addressed in additional external validation cohorts before these new prediction models are widely implemented. It is possible, for example, that the five external validation cohorts are more contemporary than the cohorts used in the risk prediction algorithm and thus reflect secular improvements in overall health and lifestyle patterns in the USA over the past 25 years. </blockquote> Note that Figure 1 of the Ridker and Cook article showed the calibration of the model in the patient cohorts newly tested by these authors, focusing in particular on whether patients predicted to have risks of cardiovascular disease just over the 7.5% threshold actually had rates of such disease greater than 7.5%.  They clearly did not   Note also that Figure 2 showed calibration of the model when the guideline authors attempted to test it on new patient cohorts, apparently the data found in the so far inaccessible Full Panel Report Data Supplement.  Again, the model overestimated risk for patients just over the crucial threshold. So the guideline developers knew that their model overestimated risk, buried this information in supplemental data, did not admit or perhaps appreciate how it threatened the credibility of their guidelines, and somehow were not given the internal review that suggested this was a fatal flaw of the proposed guidelines .  The Guideline Developers' Responses The media controversy over the accuracy of the prediction model incorporated into the new guidelines provoked responses from the guideline developers, but these responses were at best confused.  .   First, as reported by the NY times, <blockquote class="tr_bq">In a response on Sunday, Dr. [Sidney C] Smith of the guidelines committee said the concerns raised by Dr. Cook and Dr. Ridker 'merit attention.' <div itemprop="articleBody"> But, he continued, 'a lot of people put a lot of thought into how can we identify people who can benefit from therapy.' Further, said Dr. Smith, who is also a professor of medicine at the University of North Carolina and a past president of the American Heart Association, 'What we have come forward with represents the best efforts of people who have been working for five years.'</div></blockquote><div itemprop="articleBody"> </div><div itemprop="articleBody">Note that this response includes two logical fallacies.  First, it contained a <a href="http://www.nizkor.org/features/fallacies/straw-man.html">straw man argument</a>.  It appeared to respond to accusations no one made.  Nobody accused the guideline developers of being lazy, not putting in much effort, or not devoting much thought to the effort.  The response also included an implied <a href="http://www.nizkor.org/features/fallacies/appeal-to-authority.html">appeal to authority</a>: big experts came up with these guidelines so their opinions should be credited, even in the presence of data to the contrary.   </div><div itemprop="articleBody"> </div><div itemprop="articleBody">Also, as <a href="http://www.cnn.com/2013/11/18/health/cholesterol-calculator/">reported</a> by CNN,</div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph9">However, 'I can't speak to whether the calculator is valid or not,' Dr. Robert Eckel, co-chair of the American Heart Association committee that wrote the new guidelines and the association's past president, told CNN. 'That needs to be determined.'</div><div class="cnn_storypgraphtxt cnn_storypgraph9"> </div><div class="cnn_storypgraphtxt cnn_storypgraph10">'We trusted that the calculator worked,' he said. 'We trusted that the calculator is valid.'</div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph10"> </div><div class="cnn_storypgraphtxt cnn_storypgraph10">This was confusing.  Maybe Dr Eckel meant it to be another appeal to authority, the authority in question being that of the work group that developed the risk prediction model.  </div><div class="cnn_storypgraphtxt cnn_storypgraph10"> </div><div class="cnn_storypgraphtxt cnn_storypgraph10">Furthermore, again according to CNN,</div><div class="cnn_storypgraphtxt cnn_storypgraph10"> </div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph10">Researchers apparently did not receive the professors' responses, Dr. Donald Lloyd-Jones, chairman of the committee that developed the equation, told the Times.</div><div class="cnn_storypgraphtxt cnn_storypgraph10">  </div><div class="cnn_storypgraphtxt cnn_storypgraph18">But Lloyd-Jones told reporters Monday, 'There's nothing wrong with these equations.'</div><div class="cnn_storypgraphtxt cnn_storypgraph18"> </div><div class="cnn_storypgraphtxt cnn_storypgraph19">Committee members were aware there could be 'overestimation of risk in some populations,' he said.</div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph19"> </div><div class="cnn_storypgraphtxt cnn_storypgraph19">In addition,</div><div class="cnn_storypgraphtxt cnn_storypgraph19"> </div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph19"> 'Our risk assessment guideline doesn't tell you what to do. ... It just evaluates risk,' he said.</div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph19"> </div><div class="cnn_storypgraphtxt cnn_storypgraph19">I am not sure this even rises to the level of a logical fallacy.  It appears to be pure denial.  The whole point of the risk assessment tool was to determine whether a patient's risk is above or below the thresholds suggested by the treatment guideline, and thus to tell you what to do.  There clearly is something wrong with "these equations."  Using them appears to vastly overestimate risk, and thus implementation of the guideline would probably lead to vast over treatment of real people  . </div><div class="cnn_storypgraphtxt cnn_storypgraph19"> </div>Thus, after promulgating guidelines that seemed hardly based on evidence, when challenged, the guideline developers' response was confused and illogical.    What About the Issue of Benefits versus Harms? The other problems that I identified above, lack of evidence that primary prevention provides benefits that clearly outweigh harms, and lack of evidence that a strategy based on risk assessment would provide benefits that outweighs harms, did not get media coverage, and so did not provoke a response from the developers.  However, I  did find that one of the members of the guideline panel implied her approach to the benefits versus harms issue in a Medscape news <a href="http://www.medscape.com/viewarticle/814526">article</a>.   Dr Noel Bairey Merz gave a talk at the 2013 American Heart Association meeting about primary prevention for women, first saying <blockquote class="tr_bq">Although the randomized clinical trial evidence supporting primary prevention with statin therapy in women is not perfect, 'the absence of data means negative data.' That is the argument formulated by Dr Noel Bairey Merz (Cedars Sinai Medical Center, Los Angeles, CA), who spoke today here at the American Heart Association 2013 Scientific Sessions.   'How confident are we that statins do not save lives in the week before a heart attack, but they do save lives the week after a heart attack, for women and men?'</blockquote> Also, <blockquote class="tr_bq">in the overall JUPITER study of 18 000 patients, there was no treatment benefit when women were studied as a subgroup. Merz argues that JUPITER is powered for the total sample size only, not for women alone. In addition, the statistical test for heterogeneity revealed the interaction by sex was not statistically significant. 'Pretty much all the subgroups fall beyond the statistically significant range,' said Merz. 'So should we withhold treatment for women, who now are the majority of victims of cardiovascular disease, because of low precision and a trial that was not designed to address or answer this question?'</blockquote> So Dr Merz seemed to assume that statins work for particular patients in the absence of evidence that they do not work, maybe implying a general assumption that all treatments are beneficial until proven otherwise.  This stands a central precept of evidence-based medicine, and perhaps the ancient dictum to physicians to do no harm, on their heads. <div class="cnn_storypgraphtxt cnn_storypgraph19">Unwarranted Enthusiasm for (Over) Treatment and Conflicts of Interest The new cholesterol guidelines, and those who developed them, seem enthused about the treatment of cholesterol with statin drugs for primary prevention in the absence of evidence that such treatment produces benefits that outweigh its harms.  They also seem enthused about basing treatment decisions on a statistical prognostic model that has not been shown to be accurate, and in fact which appears to be biased towards promoting excess treatment in the context in which it would be used.   The excess enthusiasm occurred in spite of evidence, and at times in spite of logic.  One possible reason that the guideline developers got so enthused that they seemed unable to think straight appears to be their own conflicts of interest, as first publicly noted in a <a href="http://www.pharmalive.com/cholesterol-guidelines-panelists-and-their-conflicts-of-interest">post</a> on Pharmalot. Reviewing the disclosure forms provided with the guidelines revealed more detail. Of the 13 people on the main treatment guideline panel who were not NHLBI staffers serving ex-officio, 7 had financial relationships with pharmaceutical companies that manufacture statins: - Jennifer Robinson, co-chair, research funded by AstraZeneca and Merck; - C Noel Bairey Merz, consulting for Abbott, Bristol-Myers Squib Novartis, and Pfizer; - Robert H Eckel, consulting for Merck, Pfizer and Abbott; - Anne Carol Goldberg, consulting for Abbott and Merck, research funded by Abbott, Merck, and Novartis; - J Sanford Schwartz, consulting for Abbott, Merck and Pfizer, research funded by Pfizer; - Karol Watson, consulting for Abbott, AstraZeneca, Merck and Pfizer, research funded by Merck; - Peter W F Wilson, consulting for and research funded by Merck. Of the 10 expert reviewers for this panel, 3 had financial relationships with pharmaceutical companies that manufacture statins -  William Virgin Brown, consultant for Abbott, Bristol-Myers Squibb, and Pfizer; -  Matthew Ito, consultant for Kowa; - Robert S Rosenson, consultant for Novartis and Pfizer. Of the 11 people on the risk prediction panel who were not NHLBI staffers serving ex-officio, 5 had financial relationships with pharmaceutical companies that manufacture statins -David C Goff Jr, co-chair, research funded by Merck; - Raymond Gibbons, consultant for AstraZeneca; - Jennifer Robinson, research funded by AstraZeneca, and Merck; - J Sanford Schwartz, consulting for Abbott, Merck and Pfizer, research funded by Pfizer [although these relationships were not listed as relevant to this panel, but found in the listing for the panel above]; - Peter W.F Wilson, consultant for and research funded by Merck. Also, in the Abramson and Redberg NY Times op-ed, the authors noted <blockquote class="tr_bq">both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies </blockquote> As noted on Pharmalot, the prevalence of conflicted panel members did not appear to conform to the <a href="http://www.iom.edu/Activities/Quality/ClinicPracGuide.aspx">standards for the development of trustworthy guidelines</a> recently published by the Institute of Medicine: <blockquote class="tr_bq">whenever possible, guideline development group members should not have conflicts of interest… and the chair or co-chairs should not be a person(s) with conflicts of interest.</blockquote> Also, <a href="http://www.latimes.com/science/sciencenow/la-sci-sn-statins-risk-calculator-wrong-20131118,0,3734255.story">noted</a> by the Los Angeles Times was this comment from Dr John Abramson, lead author of the commentary on statins in primary prevention(4), <blockquote class="tr_bq">'There is overtreatment that’s been built into the risk calculator, and this is a warning sign about the overtreatment that’s built into the guidelines themselves and the conflicts of interest in the organizations that are overseeing the production of these guidelines,' said Dr. John Abramson, a Harvard University cardiologist who has argued that statins offer little value for people with a 10-year risk level of heart attack or stroke of less than 20%. 'There aren’t brakes being put on the enthusiasm and overreaching of the experts.' 'There are statin believers, and when you hear these experts talk, they’re talking emotionally, not scientifically,' Abramson added. 'The experts are using emotion, not science.'</blockquote> As Joe Collier  observed, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult."(5) This difficulty giving clear advice, when amplified by a guideline for a common problem supported by prestigious non-profit organizations, and promoted by vigorous public relations, could lead to "more than 45 million middle-aged Americans who do not have cardiovascular disease being recommended for consideration of statin therapy" (per Ridker and Cook[4]) unnecessarily, likely resulting in millions suffering unneeded side effects, and billions in costs.   Summary Guidelines for management of a very common problem promulgated by a major medical society and a major disease oriented non-profit organization suggested a strategy that would vastly increase drug treatment of currently healthy patients.  The strategy appears not to have been based on good evidence.  When some of the problems with this evidence were pointed out, the guideline developers responded with illogic.  Apparently many of the guideline developers have financial relationships with the drug companies that would most profit from increases in drug treatment as recommended by the guidelines  Implementation of the new guidelines might results in millions of people in the US receiving unneeded drugs, with resultant side effects and costs. . Do we need more examples of how conflicts of interest are causing the poor outcomes and excess costs that are wrecking our health care system?  Do we need more excuses not to eliminate conflicts of interest from guideline development?  Do we need more delay implementing the standards provided by the Institute of Medicine report on trustworthy guidelines?  Do we need more excuses not to drastically reduce conflicts of interest affecting academic medicine, medical societies, and disease specific non-profits, specifically starting with the earlier (and so far generally disregarded) Institute of Medicine <a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx">report on conflicts of interest in medicine</a>? While we in the US argue incessantly in the details of minor reforms of our supposed free health care market, we ignore the rot at its foundations.  True health care reform would attack the conflicts of interest that have put money, not patients at the center of health care. </div> References 1.  Stone NJ, Robinson J, Lichtenstein AH,  et al.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation 2013.  Link <a href="http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a">here</a>. 2.  Abramson JD, Rosenberg HG, Jewell N et al.  Should statins be prescribed to people at low risk of cardiovascular disease. Brit Med J 2013; 347: 15-17.  Link <a href="http://www.bmj.com/content/347/bmj.f6123">here</a>. 3.  Goff Jr DC, Lloyd-Jones DM, Bennett G, et al.  2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.  Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.11.005.  Link <a href="http://content.onlinejacc.org/data/Journals/JAC/0/11005.pdf">here</a>. 4.  Rikder PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.  Lancet 2013;   Link <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962388-0/fulltext">here</a>. 5.   Collier J. The price of independence. Br Med J 2006; 332: 1447-9.  Link <a href="http://bmj.bmjjournals.com/cgi/content/full/332/7555/1447">here</a>

Confused Thinking about New Cholesterol Guidelines - Were Conflicts of Interest to Blame?

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22 Nov 2013

BLOGSCAN - An Ex-Pharmaceutical Company CEO to Run the American College of Cardiology?

Marilyn Mann's blog <a href="http://marilynmann.wordpress.com/2013/04/28/should-a-former-drug-company-executive-be-ceo-of-the-american-college-of-cardiology/">discussed</a> the appointment of a former pharmaceutical company executive, most recently at Actelion, and previously at Hoffman La Roche, Abbott Canada, Nordic Labs and Marion Merrill Dow (now known as Aventis), as president of the American College of Cardiology.  Although Mr Jacobovitz, who boasts a bachelor's degree in biology but no obvious experience in direct health care or biomedical science, was <a href="http://www.cardiosource.org/News-Media/Publications/Cardiology-Magazine/2013/04/CEO-Announcement.aspx">touted </a>by the ACC as having "developed a strong patient- and customer-centered corporate strategy," Ms Mann provided documentation that his trajectory at Actelion seemed more money- than patient-centered.   During his watch, Actelion was cited for not reporting 3500 deaths of patients taking two of its drugs to the US Food an Drug Administration (FDA).  Actelion blocked availability of samples of one of its drugs to generic drug companies, an action that the US Federal Trade Commission (FTC) alleged violated anti-trust laws.  Actelion purchased a company that was working on a drug that could have become a competitor to Actelion's most remunerative product, and then shut down development, possibly preventing a drug that might help patients from reaching them.  Finally, Acetelion's marketing practices seem to be currently under investigation by a US Attorney.    One wonders why cardiologists would want such an individual representing them as leader of their premier organization?  (Dr Wes<a href="http://drwes.blogspot.com/2013/04/the-american-college-of-cardiology-gets.html"> wondered</a> as well.)

BLOGSCAN - An Ex-Pharmaceutical Company CEO to Run the American College of Cardiology?

Marilyn Mann's blog discussed the appointment of a former pharmaceutical company executive, most recently at Actelion, and previously at Hoffman La Roche, Abbott Canada, Nordic Labs and Marion Merrill…

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07 May 2013

Again, Logical Fallacies in Defense of Conflicts of Interest: a Rebuttal to Rothman et al Appears in JACC

Earlier this year, a remarkable commentary in JAMA suggested major reconsideration of the relationships among professional medical associations (PMAs) and health care corporations.(1) Because of the influence of PMAs on clinical care, education, research, and policy, Rothman et al suggested that these organizations sever most of their financial ties to corporations such as pharmaceutical, device, and biotechnology companies. The authors suggested that the only acceptable payments to PMAs from these companies are those for advertising in publications that is clearly labeled as such, and advertising exhibits in meetings, again that is clearly labeled. Furthermore, the authors suggested that people with current or recent (within the last two years) relationships with such corporations ought not to serve as officers or trustees of PMAs, and ought not to serve on program or practice guideline committees. Rothman et al thus suggested that professional medical associations return to their roots, to be advocates for their physician members, and those members’ core values, not marketers of drugs and devices, and promoters of the interests of health care corporations. The Journal of the American College of Cardiology (JACC) just published the first rebuttal of Rothman et al to appear in a peer-reviewed journal, written by Dr Alfred A Bove, President of the American College of Cardiology (ACC), one of the more influential PMAs.(2) Dr Bove contended that there is nothing wrong with the current relationships among corporations and PMAs, and PMAs should be free to relate to health care corporations any way they want. Dr Bove also asserted that “the assumptions that lead to ... [Rothman and colleagues’] conclusions can be challenged on many fronts.” However, in my humble opinion, Dr Bove supported these contentions with logical fallacies, rather than evidence and logic. Appeals to Authority, Fear, and Pity Early on, Dr Bove used a striking set of <a href="http://www.nizkor.org/features/fallacies/appeal-to-authority.html">appeals to authority</a>. (Note that his relevant quotes below appear in italics.) “There is no comment about trust or virtue as a characteristic of the medical profession.” “We are not to be bribed by a cheap pen or a free lunch.” “The authors' assumptions imply that physicians as a group are not responsible people, yet physicians are among the most responsible professionals.” These appear to be appeals to the traditional authority of the medical profession. Dr Bove simply asserts that physicians are inherently virtuous and deserving of trust, and thus no one could question the virtue of the profession. He then compounded these appeals to authority with a veiled appeal to fear. “The authors' assumption that the worst behavior is the average behavior of all physicians insults the profession.” As noted below, Rothman et al did not make this assumption, so the appeal in turn rests on a straw man argument. This appears to be <a href="http://www.nizkor.org/features/fallacies/appeal-to-fear.html">an appeal to fear </a>in that an “insulted” profession might be expected to take action, legal or otherwise, to avenge the insult. It also could be a form of <a href="http://www.nizkor.org/features/fallacies/appeal-to-pity.html">an appeal to pity</a>, in that the reader might be inclined to pity the poor “insulted” physicians. Straw Man Arguments The bulk of the editorial consisted of a string of straw man arguments. A <a href="http://www.nizkor.org/features/fallacies/straw-man.html">straw man </a>argument propounds a distorted, exaggerated, or misrepresented version of his opponent’s argument, and then attacks it, rather than his opponent’s actual argument. “The sole source for support of PMAs could only come from government or foundation grants....” Actually, Rothman et al included membership dues, and by implication, meeting registration fees, journal subscription fees etc as acceptable sources of support. “The article implies that all physicians who receive support from industry will forever be biased to support the products of the related pharmaceutical or device company.” Actually, Rothman et al seemed to assume that conflicts of interest might affect someone for up to two years, but not forever. Thus, they suggested that board members should be “conflict free for a 2-year period before assuming the position.” [The Rothman article] “also implies that industry does not work for the best interests of patients or the better [sic] public good, but only for profit.” Actually, Rothman et al stated “the pharmaceutical and medical device industries make important contributions to medical progress. Their role in the development and testing of new compounds and instruments is essential for the diagnosis and treatment of disease and disability.” “First, to assume that physicians would not be responsible for providing the best care for their patients after being associated with an industry study or consultation is inappropriate. The authors cited isolated examples of errant physicians who received large sums of money from industry and then promoted their products. They presume that all physicians are represented by these few—that we all have a price.” Actually, Rothman et al did not discuss any particular cases of “errant physicians.” What Rothman suggested was that gifts, even of “modest value,” can bias decision making, and that the receipt itself of the gift may itself be influential. However, if even modest gifts have some influence, it is logical that large financial transactions might have major influence. “Society understands that reward drives innovation, so expecting a financial gain from a commercial medical enterprise is not wrong. In fact, it is the only way that new ideas will move from the laboratory to the public good. Using public funds for manufacture and distribution would add an enormous burden to government costs and, based on past experience, would be unproductive.” Rothman et al were not remotely suggesting nationalizing the drug and device industries. “If one of us has an idea for a new device and needs industry to help refine its design, fund its development and manufacture, and establish its value by animal and clinical studies, this process should be honored, not condemned. Will the government fund the development of the next new drug? Would the government have funded the development and manufacture of an implantable pacemaker?” At the most, Rothman et al recommended not allowing physicians who are paid by companies in conjunction with their development work to serve as top leaders, and on certain committees of PMAs. They never broadly “condemned” physicians who work with industry to develop devices. “Governments have not shown an interest in funding the development of new drugs and devices. Industry raises the funds, takes the risks, and should reap the rewards for its role in creating a better life for our patients.” Actually, governments have helped development considerably by funding much of the underlying basic science research. Again, Rothman et were not remotely suggesting nationalization of drug development. Summarizing the Arguments So Dr Bove ended up by warning that the suggestions Rothman et al made about reducing institutional conflicts of interest affecting professional medical societies, and individual conflicts of interest affecting their leaders would “destroy the best of what we have in our science and industry,” that is, destroy biomedical and clinical science, and lead to nationalization of important forms of medical production. None of that was suggested or implied by Rothman et al. After positing this dire future, Dr Bove then asserted that professional societies ought to be entitled to money from industry limited only by their “professionalism.” Thus, “industry should be able to support unbiased programs aimed at educating physicians and other health care providers about the therapies available for the care of their patients. Professional societies should be able to receive unconditional educational grants to provide up-to-date information to their members on medical therapies.” Furthermore, “the proper relationships should allow us to work with industry and allow our professional societies to receive undesignated funds from industry to foster better patient care.” So, Dr Bove wound up where he started, asserting that doctors and professional societies are inherently virtuous, and thus should be trusted to do whatever they think is right, without any external scrutiny or accountability. Yet he never demonstrated the virtue of the ACC under his leadership, or of PMAs in general, or showed why they should be trusted. Why did the president of one of the nation’s most important medical associations publicly make such poor arguments to support his organization's current financial relationships with health care corporations? I can only speculate, but there may be some clues found by looking at what is publicly known about the current relationships of the ACC and its leaders to health care corporations. Publicly Disclosed Relationships Among the ACC and Its Leaders and Health Care Corporations My sources for these clues were a <a href="http://www.acc.org/about/overview/industry%20support%20revenue%20sources%20detail%202%2011%2008%20(revised%207%2031%2008%2016h00).pdf">report</a> on the ACC web-site on its relationships with health care corporations (through 2007), and the form 990s that the ACC is and the highly related ACC Foundation are required to file with the US Internal Revenue Service. (The form 990s are publicly available from GuideStar with a free membership. The ACC form is <a href="http://www.guidestar.org/FinDocuments//2007/311/781/2007-311781555-04a0f423-9O.pdf">here</a>, the ACCF, <a href="http://www.guidestar.org/FinDocuments//2007/135/641/2007-135641985-0494dd32-9.pdf">here</a>.) Perhaps unsurprisingly, it turns out that the ACC gets a large proportion of its income from industry. In 2007, it acknowledged receiving $35,882,095.15 from industry. The largest categories of industry support were "promotional/quality program support," $12,664,650; "charitable contributions," $7,603,639; and "exhibits" at meetings, $7,318,807; and "educational grants," $5,084,600. The total revenues of the ACC (which include the ACC Foundation), were $94,560,000, so that industry support accounted for 38% of total revenue. These figures should be compared to the revenue the society received from membership dues (found on its 990 form), $11,995,056, and the income it claimed from its annual scientific session, $8,400,632. So to put it another way, the ACC got about three times as much money from industry as it got from its members' dues, and almost twice as much money from industry as it got from dues and its annual meeting combined. So were the suggestions made by Rothman et al to be implemented by the ACC, it would stand to lose at least $28 million a year (given that in 2007, about $1 million of its industry revenue was from advertising , and about $ 7.3 million was from exhibits at meetings.) The organization's lavish revenues have allowed it to pay its full-time managers very well. In 2007, its CEO received $534,452 in total compensation; its general counsel, about $394,000; and its CFO, about $336,000. It seems obvious that were the organization to foreswear industry revenue, the organization's top full-time managers would be unable to continue to live in the style to which they are now accustomed to. In addition, the organization's form 990 reveals that it pays its supposedly voluntary officers and some of its trustees substantial amounts as well. In 2007, it paid its president $147,750; its president-elect, $80,000; its two immediate past presidents, $79,500 and $70,000; its vice president (at that time, Dr Bove), $63,751; its treasurer, $32,500; its secretary for the board of governors, $52,500; its board of governors chair-elect, $25,000; its immediate past board of governors chair, $25,000; and some trustees amounts from $1000 to $20,520. To my knowledge, it is unusual for a professional society to pay salaries to its voluntary officers (as opposed to full-time, hired managers.) However, given that the ACC does, it seems that were the organization to foreswear industry revenue, its officers' personal income might be threatened to some extent. Finally, Dr Bove has his own personal financial relationships with industry. Some were <a href="http://www.cardiosource.com/ACCELaudio/policies.asp">disclosed</a> because of his role on ACCs Cardiosource editorial board, including "Consultant Fees/Honoraria: Insight Telehealth Inc,""Research/Research Grants: Astella Pharma, INC," and "Royalty Income: Elsevier." In addition, in a 2008 article(3), he disclosed receiving speakers fees from Medical Seminars, Inc, and serving as a consultant to Vasocom Inc. For a 2009 conference, he also <a href="http://www.acc.org/education/programs/brochures/tct_09disclosure.pdf">disclosed</a> "modest" equity interests in Cardiovascular Therapeutics, and Merck. So, in summary, it seems that the ACC gets a very substantial portion of its revenue from health care corporations, and that were it to carry out the suggestions of Rothman et al, it would lose much of that revenue. Thus, it is not surprising that ACC leadership would take exception to Rothman and colleagues' point of view. This is not the first time that an ACC president has defeneded the organization's dependence on industry funding (see post<a href="http://hcrenewal.blogspot.com/2008/10/another-industry-supported-physician.html"> here</a>). However, as I said in that post, <blockquote> My questions are how could a society which requires such a substantial proportion, 38% of funding from commercial sponsors ignore the preferences of the sponsors for particular topics and content areas? How could such a society dare to allow criticism of the sponsors, their products, or their activities? Knowing that the society is dependent on this level of support, could society leaders really hold industry representatives at arms' length? Knowing that industry supplies more than one-third of their salaries, would society staff really keep industry outside of some bureaucratic, but not concrete 'firewall?' </blockquote> In addition, it now seems the ostensibly voluntary officers of the ACC may have a personal stake in the ACCs receipt of health care corporate funding, since it is the apparent policy of the organization to pay these officers five- and six-figure salaries. Dr Bove did not disclose this apparent conflict of interest, nor did he disclose his other personal financial relationships with industry. As we have noted before, people with conflicts of interest tend to have trouble making coherent, logical and evidence-based arguments for positions related to their conflicts. As Joe Collier wrote in the BMJ, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult. "(4) In any case, a previous ACC president wrote about the importance of "disclosure" and "transparency" in dealing with conflicts of interest. Whether disclosure of conflicts is sufficient to manage them, at least Dr Bove could have done the courtesy of disclosing that he is actually a salaried employee of the ACC, and disclosing his personal financial relationships with industry so that readers could try to evaluate how these financial entanglements might have affected what he wrote. Summary In conclusion, the first published rebuttal of Rothman and colleagues' suggestions for ensuring the independence of professional medical associations from outside vested interests was not based on evidence, but on logical fallacies rather than clear reasoning, and failed to disclose its authors' relevant financial relationships. We will see if anyone can make a better attempt. ADDENDUM (17 July, 2009) - see <a href="http://brodyhooked.blogspot.com/2009/07/cardiologists-on-coi-tripping-over-your.html">additional comments </a>by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog. ADDENDUM (22 July, 2009) - see <a href="http://cardiobrief.org/2009/07/22/cardiology-strikes-back-bove-lewin-weber-black-defend-ties-to-industry/">this post </a>on the Cardiobrief blog, which alludes to the post above, but also discusses an interesting response by the CEO of the ACC to the Rothman paper, and adds original commentary on larger issues. References 1. Rothman DJ, McDonald WJ, Berkowitz CD et al. Professional medical associations and their relationships with industry. JAMA 2009; 301: 1367-1372. (Link <a href="http://jama.ama-assn.org/cgi/content/full/301/13/1367">here</a>.) 2. Bove AA. President's page: relations with industry: thoughts on claims of a broken system. J Am Coll Cardiol 2009; 54: 177-179. (Link <a href="http://content.onlinejacc.org/cgi/content/full/54/2/177">here</a>.) 3. Somers VK, White DP, Amin R et al. Sleep apnea and cardiovascular disease: an American Heart Association/ American College of Cardiology Foundation scientific statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. Circulation 2008; 118: 1080-1111. (Link <a href="http://circ.ahajournals.org/cgi/content/full/118/10/1080">here</a>.) 4. Collier J. The price of independence. Br Med J 2006; 332: 1447-9. (Link <a href="http://bmj.bmjjournals.com/cgi/content/full/332/7555/1447">here</a>.)

Again, Logical Fallacies in Defense of Conflicts of Interest: a Rebuttal to Rothman et al Appears in JACC

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16 Jul 2009

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