healthy4u: review articles

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

The Institute of Medicine Releases Reports on Practice Guidelines and Systematic Reviews Which Generate Few Echoes

Two days ago, the prestigious US Institute of Medicine <a href="http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=13058">released </a>two reports on important health care issues, clinical practice guidelines and systematic reviews.  <a href="http://iom.edu/Reports/2011/Finding-What-Works-in-Health-Care-Standards-for-Systematic-Reviews.aspx">Systematic reviews</a> of the relevant clinical research have been advocated by evidence-based medicine proponents as the appropriate basis for clinical and policy decisions.  <a href="http://iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx">Clinical practice guidelines</a> have been advocated by many health researchers, policy makers, and clinicians as the best way to encapsulate the evidence to inform clinical and policy decision making.  Both reports suggested series of standards for how systematic reviews and clinical practice guidelines should be developed.  These topics are of general importance to clinicians, health services researchers, and health policy makers.  The <a href="http://www.iom.edu/">Institute of Medicine</a>, part of the US National Academy of Sciences, is one of the most authoritative sources of opinion on medicine and health care.  Therefore, one would think that these reports would have gotten wide notice, and would hardly required Health Care Renewal to create some echoes. However, a Google News search today produced only six "hits" relevant to these reports, including the original press release.  All are in specialized medical/ health care news outlets.  None are in the national media, and none are from major medical/ professional journals or societies.  Let me suggest a theory about why these two major reports have generated so few echoes so far.  Let me quote from the <a href="http://iom.edu/~/media/Files/Report%20Files/2011/Clinical-Practice-Guidelines-We-Can-Trust/Clinical%20Practice%20Guidelines%202011%20Report%20Brief.pdf">summary</a> of the report on clinical practice guidelines: <blockquote>Most guidelines used today suffer from shortcomings in development. Dubious trust in guidelines is the result of many factors, including failure to represent a variety of disciplines in guideline development groups, lack of transparency in how recommendations are derived and rated, and omission of a thorough external review process. To be trustworthy, clinical practice guidelines should: • Be based on a systematic review of the existing evidence; • Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups; • Consider important patient subgroups and patient preferences, as appropriate; • Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest; • Provide a clear explanation of the logical relationships between alternative care options and health outcomes, and provide ratings of both the quality of evidence and the strength of recommendations; and • Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations. Additionally, as reflected in the committee’s standards for developing trustworthy clinical practice guidelines, guideline development groups optimally comprise members without conflict of interest. The committee recognizes that in some circumstances, a guideline development group may not be able to perform its work without members who have conflicts of interest—for example, relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the guideline. Therefore, the committee specifies that members of the guideline development group who have a conflict of interest should not represent more than a minority of the group.</blockquote> So it seems that the report on clinical practice guidelines emphasized two issues highly relevant to Health Care Renewal, the need for <a href="http://hcrenewal.blogspot.com/search/label/transparency">transparency</a> in guideline development, and the need to avoid <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interest</a> affecting the development process. The two first <a href="http://iom.edu/~/media/Files/Report%20Files/2011/Clinical-Practice-Guidelines-We-Can-Trust/Clinical%20Practice%20Guidelines%202011%20Insert.pdf">standards</a> for guidelines are about transparency and minimization of conflicts of interest.  Similarly, the report on systematic reviews also included fairly tough <a href="http://www.iom.edu/~/media/Files/Report%20Files/2011/Finding-What-Works-in-Health-Care-Standards-for-Systematic-Reviews/Standards%20for%20Systematic%20Review%202010%20Insert.pdf">standards</a> to minimize conflicts of interest. We on Health Care Renewal go on and on about the need to maximize transparency in health care, and particularly in health care leadership and governance, and about the need to disassemble the now pervasive web of conflicts of interest that has entangled health care.  However, as we know, these are not popular topics among the leadership of health care, which includes many individuals who have greatly benefited from lack of transparency and pervasive conflicts of interest.  We know these topics make these leaders, and many of those who report to, or work or associate with them very uncomfortable. So unfortunately, I am not surprised that the two new and likely authoritative reports from the Institute of Medicine, despite that organization's prestige, have started off relatively <a href="http://hcrenewal.blogspot.com/search/label/anechoic%20effect">anechoic</a>.  It also unfortunately likely that they will remain relatively anechoic.  In 2009, the IOM issued an authoritative <a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx">report on conflicts of interest</a> in medicine and health care which suggested fairly tough standards to decrease such conflicts and their influence (also see post <a href="http://hcrenewal.blogspot.com/2010/12/health-professionals-for-new-century.html">here</a>).  Since 2009, I just found 53 citations to that report in the medical literature using the ISI Web of Science, for a rate of 27/year.  In 1999, the IOM issued a report on medical errors, "To Err is Human."  Since then, it has received 1374 citations, a rate of 115/year.  As we noted above, the topic of conflicts of interest seems to make the powers that be in health care very uncomfortable.  In contrast, "To Err is Human" was widely interpreted to mean that physicians make a lot of dangerous errors, and the best way to decrease them is to impose more controls by bureaucrats, managers, and executives (even if that was not its intent).  Thus, that report could be twisted to fit the talking points of the powers that be, and hence has been anything but anechoic. So while Health Care Renewal is hardly a powerful tool for creating publicity, I thought we should try to get the word out about the new IOM reports on clinical practice guidelines and systematic reviews.  Every little bit helps. Meanwhile, the deathly quiet reception these reports have gotten so far emphasizes the need to combat the anechoic effect.  As long as the powers that be can command billions of dollars to influence the health care conversation through their marketing, public relations, and lobbying departments, expect the discussion not to question what they do, and how they benefit from the status quo to the financial and health detriment of patients and the population. We will not be able to truly reform health care until we can speak openly about what threatens health care values and what needs to be done about these threats.

The Institute of Medicine Releases Reports on Practice Guidelines and Systematic Reviews Which Generate Few Echoes

Two days ago, the prestigious US Institute of Medicine released two reports on important health care issues, clinical practice guidelines and systematic reviews. Systematic reviews of the relevant cl…

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25 Mar 2011

Why I Shouldn't Read Non-Systematic Review Articles: Special Pleadings and Undercover Authors

I usually resist looking at non-systematic review articles in medical journals, but because the title interested me, and things seem to be getting slow this holiday season, prompted by an update email from the American Journal of Medicine, I looked at Ram CVS. Beta-blockers in hypertension. Am J Cardiol 2010: 106: 1819-1825. (Link <a href="http://www.ajconline.org/article/S0002-9149%2810%2901631-0/abstract">here</a>.) The Ram Article in Praise of Vasodilating Beta-Blockers The article focused on the results of meta-analyses: <blockquote>Concerns have also been raised by meta-analyses in which β blockers were reported to have a suboptimal effect on reducing stroke risk and increasing the risk for new-onset diabetes compared with other antihypertensive agents.</blockquote> The article discussed several meta-analyses in which beta-blockers, [a specific class of blood pressure lowering drugs] but mostly atenolol (mostly sold generically), usually combined with a diuretic, were compared with other antihypertensive drugs, usually including angiotensin converting enzyme inhibitors (ACEIs) and calcium channel blockers. But after discussing these comparative results, the author jumped to descriptions of another group of drugs which were not included in any of these comparative studies. This was the category of vasodilating beta-blockers, consisting of labetolol (mostly sold generically), carvedilol (Coreg, GlaxoSmithKline [GSK]), and nebivolol (Bystolic, Forest Laboratories. Based on physiologic studies of these drugs and trials in which they were compared with placebo, but not on studies which directly compared clinical outcomes of patients given these drugs or other kinds of antihypertensives, Dr Ram reached conclusions that they were a better alternative: <blockquote>The review of the evidence provided herein confirms that there are valid reasons to question the utility of certain β blockers in treating hypertension. However, many of the perceptions about β blockers are derived from data obtained from studies of traditional agents or combinations of diuretics and β blockers. Evidence suggests, and the guidelines concur, that there are intrinsic differences among members of the β-blocker class. Indeed, the vasodilatory β-blockers, which have generally not been included in comparative meta-analyses, lower blood pressure to a similar degree as other antihypertensive drugs, may provide better central aortic pressure reductions than traditional β blockers, and are associated with neutral or favorable metabolic effects.</blockquote>Special Pleading Dr Ram's questioned the old-fashioned beta-blocker atenolol (perhaps only when added to a diuretic)  based on the results of meta-analyses which attempted to compare it to other drugs. Such meta-analyses could suggest that atentolol (again, perhaps only in combination with a diuretic) might be in some way less preferable than the other drugs to which it was compared. However, the meta-analyses did not address the vasodilating beta-blockers at all. Dr Ram concluded that they were preferable based on different kinds of and probably less definitive evidence. He did not seek to compare such studies done on the vasodilating beta-blockers to similar studies done on the conventional beta-blockers.  Thus it seems his conclusions were based on a double standard. In the vocabulary of logical fallacies, this was an example of a <a href="http://www.nizkor.org/features/fallacies/special-pleading.html">special pleading</a>: <blockquote>Special Pleading is a fallacy in which a person applies standards, principles, rules, etc. to others while taking herself (or those she has a special interest in) to be exempt, without providing adequate justification for the exemption. </blockquote> Here was more reason not to bother reading a narrative review articles to learn how to better practice clinical medicine.  They often are based on idiosyncratic, if not biased evidence used to support illogical arguments. But having read so far, I wondered why the authors of this article were so happy to use a double standard as the basis of their arguments. Undercover Author Those paying attention may also now be wondering why I referred to the authors in plural, when the citation lists only one author. The clue is at the end of the article: <blockquote>Acknowledgment I would like to thank Tamalette Loh, ProEd Communications, Inc. (Beachwood, Ohio), for her editorial assistance and literature validation in the preparation of this report.</blockquote> Sensitized as I have been to the many recent discussions of ghost-writing, I immediately wondered who Ms Loh is, and what sort of "editorial assistance and literature validation" she provided. So first I looked at what her company, ProEd Communications does, wondering if its business is to help syntactically challenged academics and professionals write better sentences and more organized papers. The ProEd Communications <a href="http://www.proedcom.com/">web-site </a>states: <blockquote>ProEd Communications balances diverse perspectives—clinical, regulatory, marketing, and customer—to create compelling messaging to maximize a product's potential. </blockquote> So it appears that ProEd Communications does not provide independent editorial services. Instead, it is a <a href="http://hcrenewal.blogspot.com/search/label/medical%20education%20and%20communication%20companies">medical education and communications company</a> (MECC) which works mainly to market its clients' products, and further, its <a href="http://www.proedcom.com/ExperienceAndClientList.aspx">clients</a> are essentially only pharmaceutical companies: <blockquote>Of the world's 50 largest pharmaceutical companies, ProEd has worked with 18 in the past 3 years and currently supports projects for 7 of the top 10 largest pharmaceutical companies, as ranked by MedAdNews (2008).</blockquote> Furthermore, a few minutes on Google reveals that Ms Loh seems to specialize in papers on anti-hypertensives, particularly Coreg (carvedilol), one of the three drugs in the vasodilating beta-blocker group favored by Dr Ram. In fact, two other papers whose authors she assisted sounded hauntingly familiar. Let me first display the quote above from the Ram paper: <blockquote>Concerns have also been raised by meta-analyses in which β blockers were reported to have a suboptimal effect on reducing stroke risk and increasing the risk for new-onset diabetes compared with other antihypertensive agents.</blockquote> Now see this quote from Frishman WH, Henderson LS, Lukas MA. Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfucntion. Vasc Health Risk Management 2008; 4: 1387-1400.  (Link <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663448/">here</a>): <blockquote>However, concerns have been raised recently from hypertension meta-analyses regarding suboptimal outcomes with use of beta-blockers, specifically atenolol, compared with outcomes for other antihypertensive drug classes.</blockquote> Also see this relatively similar quote from McGill JB. Optimal use of beta-blockers in high-risk hypertension: a guide to dosing equivalence. Vasc Health Risk Management 2010; 6: 363-372. (Link <a href="http://amec.glp.net/c/document_library/get_file?p_l_id=843157&folderId=754745&name=DLFE-19217.pdf">here</a>): <blockquote>Concerns about the use of β-blockers as first-line agents for hypertension have been raised because of a 2005 metaanalysis that found β-blockers do not significantly reduce cardiovascular events, especially stroke, compared with other antihypertensive drug classes</blockquote> Furthermore, read this discussion of Coreg by Ram: <blockquote>Carvedilol is a nonselective β blocker with α1 receptor–blocking activity and no intrinsic sympathomimetic activity. Clinical data suggest that carvedilol reduces systemic vascular resistance in patients with hypertension.</blockquote> Here is Frishman et al: <blockquote>Carvedilol is a third-generation, vasodilatory beta-blocker that nonselectively blocks both the beta 1- and beta 2-adrenergic receptors.... vasodilatory beta-blockers can lower blood pressure by reducing systemic vascular resistance (SVR) </blockquote> Both Frishman et al and McGill are very positive about Coreg.  Although the emphases of the three articles are different, they have organizational similarities.  Again, all three were written with the assistance of Ms Loh. At the end of the Frishman article we again find: <blockquote>The authors would like to thank Tamalette Loh, PhD, ProEd Communications, Inc.®, for her medical editorial assistance with this manuscript.</blockquote> At the end of the McGill article we find: <blockquote>Editorial assistance, specifically revisions to the final draft, was provided by Tamalette Loh, PhD, at ProEd Communications, Inc.®, whose services were also funded by GlaxoSmithKline. Dr Loh’s revisions were reviewed and approved by Dr McGill.</blockquote>Note that now it seems that Ms Loh has a doctoral degree, of unclear kind. Note also that now it seems that GSK, the manufacturer of Coreg, funded Dr Loh's work on the McGill article. Dr McGill further disclosed: <blockquote>Dr McGill is a consultant for GlaxoSmithKline and a speaker for AstraZeneca and Forest Pharmaceuticals. Financial support for medical editorial assistance was provided by GlaxoSmithKline, Philadelphia, Pennsylvania.</blockquote> Finally, in another article, about angiotensin converting enzyme blockers combined with diuretics to treat hypertension (Egras AM, Ram CVS. Reduced cardiovascular risk and healthcare expenditures with angiotensin receptor blocker/ hydrochlorthiazide. Am J Pharmacy Benefits 2010; 2: 127-135. Lin <a href="http://ajpblive.com/media/pdf/Ergas_2-2.pdf">here</a>. ), Dr Ram acknowledged: <blockquote>Dr Ram is in the speakers’ bureau pool of Cogenix, ProCom, and Genesis, which manage medical education programs for Bristol-Myers Squibb, GlaxoSmithKline, and Novartis.</blockquote> The series of articles above demonstrated a phenomenon I have not seen explored before. All articles were written with some sort of assistance from an employee of a MECC, perhaps partly funded by a company which marketed a drug which was the subject of all the articles. The assistance was openly acknowledged.  The three articles had some remarkable similarities not explained by an overlap among their listed authors.  This suggested that the ostensible editorial assistant they had in common was substantively involved in the content of the papers, that is, was truly an author. Her presence was not ghost-like. However, the substance of her contribution may have been downplayed.  So let's call her an "undercover author."  (If someone has a better term, please leave a comment to that effect.) Summary So the reasons I rarely read narrative review articles except to make teaching points about health care dysfunction are: - They often are based on idiosyncratic, if not biased selections of data - They may employ logical fallacies to make their points - They may be written by people with conflicts of interest, that is, with financial arrangements with companies seeking to market products, particularly drugs and devices. My conclusions for health care professionals are: be very skeptical of non-systematic review articles, look for evidence that they are parts of stealth marketing campaigns, and do not assume all conflicts of interest are disclosed and all authorship roles revealed. My conclusions for journal editors are: strictly demand more complete disclosure of conflicts of interest, or risk losing the trust of your readers. My conclusions in general: until we start to sweep away the pervasive web of conflicts of interest that is draped over medicine and health care, expect further discombobulation.

Why I Shouldn't Read Non-Systematic Review Articles: Special Pleadings and Undercover Authors

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16 Dec 2010

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