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A Decade of Reversal: An Analysis of 146 Contradicted Medical Practices

      Abstract

      Objective

      To identify medical practices that offer no net benefits.

      Methods

      We reviewed all original articles published in 10 years (2001-2010) in one high-impact journal. Articles were classified on the basis of whether they addressed a medical practice, whether they tested a new or existing therapy, and whether results were positive or negative. Articles were then classified as 1 of 4 types: replacement, when a new practice surpasses standard of care; back to the drawing board, when a new practice is no better than current practice; reaffirmation, when an existing practice is found to be better than a lesser standard; and reversal, when an existing practice is found to be no better than a lesser therapy. This study was conducted from August 1, 2011, through October 31, 2012.

      Results

      We reviewed 2044 original articles, 1344 of which concerned a medical practice. Of these, 981 articles (73.0%) examined a new medical practice, whereas 363 (27.0%) tested an established practice. A total of 947 studies (70.5%) had positive findings, whereas 397 (29.5%) reached a negative conclusion. A total of 756 articles addressing a medical practice constituted replacement, 165 were back to the drawing board, 146 were medical reversals, 138 were reaffirmations, and 139 were inconclusive. Of the 363 articles testing standard of care, 146 (40.2%) reversed that practice, whereas 138 (38.0%) reaffirmed it.

      Conclusion

      The reversal of established medical practice is common and occurs across all classes of medical practice. This investigation sheds light on low-value practices and patterns of medical research.
      We expect that new medical practices gain popularity over older standards of care on the basis of robust evidence indicating clinical superiority or noninferiority with alternative benefits (eg, easier administration and fewer adverse effects). The history of medicine, however, reveals numerous exceptions to this rule. Stenting for stable coronary artery disease was a multibillion dollar a year industry when it was found to be no better than medical management for most patients with stable coronary artery disease.
      • Boden W.E.
      • O'Rourke R.A.
      • Teo K.K.
      • et al.
      Optimal medical therapy with or without PCI for stable coronary disease.
      Hormone therapy for postmenopausal women intended to improve cardiovascular outcomes was found to be worse than no intervention,
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • et al.
      Writing Group for the Women's Health Initiative Investigators
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
      and the routine use of the pulmonary artery catheter in patients in shock was found to be inferior to less invasive management strategies.
      • Sandham J.D.
      • Hull R.D.
      • Brant R.F.
      • et al.
      Canadian Critical Care Clinical Trials Group
      A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients.
      Previously, we have called this phenomenon (when a medical practice is found to be inferior to some lesser or prior standard of care) a medical reversal.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      • Prasad V.
      • Cifu A.
      • Ioannidis J.P.A.
      Reversals of established medical practices: evidence to abandon ship.
      • Prasad V.
      • Cifu A.
      Medical reversal: why we must raise the bar before adopting new technologies.
      Medical reversals occur when new studies—better powered, controlled, or designed than their predecessors—contradict current practice.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      In a prior investigation of 1 year of publications in a high-impact journal, we found that of 35 studies testing standard of care, 16 (46%) constituted medical reversals.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      Another review of 45 highly cited studies that claimed some therapeutic benefit found that 7 (16%) were contradicted by subsequent research.
      • Ioannidis J.A.
      Contradicted and initially stronger effects in highly cited clinical research.
      Identifying medical practices that do not work is necessary. The continued use of such practices wastes resources, jeopardizes patient health, and undermines trust in medicine. Interest in this topic has grown in recent years. The American Board of Internal Medicine launched the Choosing Wisely campaign,
      • Cassel C.K.
      • Guest J.A.
      Choosing wisely: helping physicians and patients make smart decisions about their care.
      a call on professional societies to identify the top 5 diagnostic or therapeutic practices in their field that should not be offered.
      • Brody H.
      Medicine's ethical responsibility for health care reform—the top five list.
      In England, the National Institute for Health and Clinical Excellence has tried to “disinvest” from low-value practices, identifying more than 800 such practices in the past decade.
      • Garner S.
      • Littlejohns P.
      Disinvestment from low value clinical interventions: NICEly done?.
      Other researchers have found that scanning a range of existing health care databases can easily generate more than 150 low-value practices.
      • Elshaug A.G.
      • Watt A.M.
      • Mundy L.
      • Willis C.D.
      Over 150 potentially low-value health care practices: an Australian study.
      Medical journals have specifically focused on instances in which more health care is not necessarily better. The Archives of Internal Medicine created a new feature series in 2010 entitled “Less is More.”
      • Grady D.
      • Redberg R.F.
      Less is more: how less health care can result in better health.
      Given ongoing and vigorous efforts to identify medical practices that offer little benefit and minimal empirical studies documenting the rate at which current practices are contradicted, we performed a review of 10 years of original publications in one high-impact journal.

      Methods

      We used methods similar to our prior survey of 1 year of publications in a high-impact journal.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      We reviewed all articles under the heading “Original Articles” in the New England Journal of Medicine from 2001 to 2010. These years were the last complete 10 years when we began our investigation. Our choice of journal was made on the basis of the 5-year Hirsch index for medical journals.

      Top Publications Health & Medical Sciences. http://scholar.google.com/citations?view_op=top_venues&hl=en&vq=med. Accessed June 30, 2011.

      Two reviewers (C.T., A.V., M.C., J.R., S.Q., S.J.C., D.B., V.G., or S.S.) and V.P. independently extracted information for each calendar year. This study was conducted from August 1, 2011, through October 31, 2012.
      On the basis of published abstracts, articles were classified as to whether they addressed a clinical practice. Articles addressing a medical practice were defined as any investigation that assesses a screening, stratifying, or diagnostic test, a medication, a procedure or surgery, or any change in health care provision systems. Many research articles concern the novel molecular basis of disease or novel insights in pathophysiology. These articles were excluded. When practice information could not be ascertained by abstract alone, full articles were read.
      Two reviewers (C.T., A.V., M.C., J.R., S.Q., S.J.C., D.B., V.G., or S.S.) and V.P. read articles addressing a medical practice in full. On the basis of the abstract, introduction, and discussion, articles were classified as to whether the practice in question was new or existing. Methods were classified as one of the following: randomized controlled trial, prospective controlled (but nonrandomized) intervention study, observational study (prospective or retrospective), case-control study, or other methods. End points for articles were classified into those that reached positive conclusions and those that found negative or no difference in end points. Lastly, articles were given 1 of 4 designations. Replacement was defined as a new practice surpassing an older standard of care. Back to the drawing board was defined as a new practice failing to surpass an older standard. Reversal was designated when a current medical practice was found to be inferior to a lesser or prior standard. Reaffirmation was defined as an existing medical practice being found to be superior to a lesser or prior standard. Finally, articles in which no firm conclusion could be reached were termed inconclusive. The designation of an article was also performed in duplicate. When there were differences in opinion between the 2 reviewers, adjudication first involved discussion between the 2 readers to see whether agreement could be reached. If disagreement persisted, a third reviewer (A.C.) adjudicated the discrepancy. Less than 3% of articles required discussion, and less than 1% required adjudication. A table detailing each medical reversal was constructed (Supplemental Appendix; available online at http://www.mayoclinicproceedings.org), and the third reviewer (A.C.) reviewed all reversals.
      Data are summarized using counts and percentages. A linear regression was performed to determine the relationship between percentage of reversals and time, and the Pearson χ2 test was used when appropriate. Analyses were conducted using Stata statistical software, version 12 (StataCorp LP).

      Results

      From 2001 through 2010, 2044 original articles appeared in one high-impact journal. Most articles (1344 [65.8%]) addressed a medical practice. A total of 981 studies (73.0%) examined a new medical practice, whereas 363 (27.0%) addressed an existing practice. During these 10 years, there were 911 (67.7%) randomized controlled trials, 220 (16.4%) prospective controlled but nonrandomized studies, 117 (8.7%) observational studies, 43 (3.2%) case-control studies, and 53 (3.9%) studies using other methods.
      Concerning the study results, 947 (70.5%) reached positive conclusions, whereas 397 (29.5%) reached negative conclusions or found no difference between comparators. As such, 756 articles (56.3%) found a new practice surpassing current standard of care (replacement), 165 (12.3%) found a new practice failing to improve on the current practice (back to the drawing board), 146 (10.9%) were reversals, and 138 (10.3%) upheld standard of care over a lesser or prior standard (reaffirmation). A total of 139 (10.3%) were deemed inconclusive. Figure 1 shows a breakdown of articles. The single most common study type was a randomized trial examining a new practice and finding benefit for that practice; 530 (39.4%) of all 1345 articles were classified as such.
      Figure thumbnail gr1
      Figure 1A breakdown of articles concerning a medical practice.
      Of the 363 articles that tested an existing medical practice, 146 (40.2%) found it ineffective compared with a previous standard or its omission (reversals), whereas 138 (38.0%) upheld the practice, and 79 (27.3%) were inconclusive. Table 1 and Figure 2 provide, for articles testing existing standard of care, a breakdown of reversal, reaffirmation, and inconclusive articles by year. Of the 146 reversal articles, most were randomized controlled trials (111 [76.0%]); 13 (8.9%) were prospective, nonrandomized studies; 20 (13.7%) were retrospective studies; 1 was a case-control study; and 1 used an alternative study design.
      Table 1Number (Percentage) of Reversal, Reaffirmation, and Inconclusive Articles by Year
      YearReversalReaffirmationInconclusive
      2001 (n=48)14 (29.2)2014
      2002 (n=26)12 (46.2)95
      2003 (n=31)12 (38.7)127
      2004 (n=33)12 (36.4)156
      2005 (n=41)19 (46.3)148
      2006 (n=20)12 (60.0)53
      2007 (n=54)18 (33.3)1719
      2008 (n=32)15 (46.9)134
      2009 (n=35)16 (45.7)163
      2010 (n=43)16 (37.2)1710
      Total (N=363)146 (40.2)138 (38.0)79 (21.7)
      Figure thumbnail gr2
      Figure 2Percentage of reversal, reaffirmation, and all articles testing standard of care.
      Articles that tested new practices were more likely to find them beneficial than articles that tested existing ones (77.1% vs 38.0%; P<.001). Conversely, articles that tested existing standards were more likely to find those practices ineffective than articles testing new practices (40.2% vs 17.0%; P<.001).
      Several of the reversal articles concerned the same topic. Four articles called into question the drug aprotinin,
      • Mangano D.T.
      • Tudor I.C.
      • Dietzel C.
      The risk associated with aprotinin in cardiac surgery.
      • Schneeweiss S.
      • Seeger J.D.
      • Landon J.
      • Walker A.M.
      Aprotinin during coronary-artery bypass grafting and risk of death.
      • Shaw A.D.
      • Stafford-Smith M.
      • White W.D.
      • et al.
      The effect of aprotinin on outcome after coronary-artery bypass grafting.
      • Fergusson D.A.
      • Hébert P.C.
      • Mazer C.D.
      • et al.
      A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.
      which was widely used in cardiac surgery but found to increase mortality. Three articles addressed use of a primary rhythm control strategy for patients with atrial fibrillation.
      • Roy D.
      • Talajic M.
      • Nattel S.
      • et al.
      Atrial Fibrillation and Congestive Heart Failure Investigators
      Rhythm control versus rate control for atrial fibrillation and heart failure.
      • Van Gelder I.C.
      • Hagens V.E.
      • Bosker H.A.
      • et al.
      Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group
      A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation.
      Three articles in a single issue found increased risks of cardiovascular events from using the cyclooxygenase 2 inhibitors, including rofecoxib.
      • Solomon S.D.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • et al.
      Adenoma Prevention with Celecoxib (APC) Study Investigators
      Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.
      • Nussmeier N.A.
      • Whelton A.A.
      • Brown M.T.
      • et al.
      Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.
      • Bresalier R.S.
      • Sandler R.S.
      • Quan H.
      • et al.
      Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators
      Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
      Three articles provided extended follow-up for a trial of children randomly assigned to early myringotomy with the insertion of tympanostomy tubes or a delayed procedure. Although the procedure was the most common operation performed on children beyond the newborn period
      • Paradise J.L.
      • Feldman H.M.
      • Campbell T.F.
      • et al.
      Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years.
      and bolstered by expert guidelines,
      no difference was found in an early vs delayed strategy on outcomes at 3,
      • Paradise J.L.
      • Feldman H.M.
      • Campbell T.F.
      • et al.
      Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years.
      6,
      • Paradise J.L.
      • Campbell T.F.
      • Dollaghan C.A.
      • et al.
      Developmental outcomes after early or delayed insertion of tympanostomy tubes.
      or 9 to 11 years of age.
      • Paradise J.L.
      • Feldman H.M.
      • Campbell T.F.
      • et al.
      Tympanostomy tubes and developmental outcomes at 9 to 11 years of age.
      Three articles further contradicted routine hormone therapy in postmenopausal women.
      • Hays J.
      • Ockene J.K.
      • Brunner R.L.
      • et al.
      Women's Health Initiative Investigators
      Effects of estrogen plus progestin on health-related quality of life.
      • Hodis H.N.
      • Mack W.J.
      • Azen S.P.
      • et al.
      Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group
      Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.
      • Manson J.E.
      • Hsia J.
      • Johnson K.C.
      • et al.
      Women's Health Initiative Investigators
      Estrogen plus progestin and the risk of coronary heart disease.
      Two articles contradicted routine use of the pulmonary artery catheter,
      • Sandham J.D.
      • Hull R.D.
      • Brant R.F.
      • et al.
      Canadian Critical Care Clinical Trials Group
      A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients.
      • National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wheeler A.P.
      • Bernard G.R.
      • Thompson B.T.
      • et al.
      Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury.
      and 2 articles found worse outcomes with recommended glycemic targets (as opposed to more permissive standards) for patients with diabetes.
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • et al.
      ADVANCE Collaborative Group
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      The benefit of stenting in patients with stable coronary artery disease was undermined by the Occluded Artery Trial,
      • Hochman J.S.
      • Lamas G.A.
      • Buller C.E.
      • et al.
      Occluded Artery Trial Investigators
      Coronary intervention for persistent occlusion after myocardial infarction.
      Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
      • Boden W.E.
      • O'Rourke R.A.
      • Teo K.K.
      • et al.
      COURAGE Trial Research Group
      Optimal medical therapy with or without PCI for stable coronary disease.
      trial, and a follow-up quality-of-life study from the Occluded Artery Trial.
      • Mark D.B.
      • Pan W.
      • Clapp-Channing N.E.
      • et al.
      Occluded Artery Trial Investigators
      Quality of life after late invasive therapy for occluded arteries.
      Two studies suggested that although ezetimibe improves low-density lipoprotein values, it does not improve carotid artery intima media thickness.
      • Kastelein J.J.
      • Akdim F.
      • Stroes E.S.
      • et al.
      ENHANCE Investigators
      Simvastatin with or without ezetimibe in familial hypercholesterolemia.
      • Taylor A.J.
      • Villines T.C.
      • Stanek E.J.
      • et al.
      Extended-release niacin or ezetimibe and carotid intima-media thickness.
      Arthroscopic surgery of the knee for osteoarthritis was called into question by 2 studies 5 years apart,
      • Moseley J.B.
      • O'Malley K.
      • Petersen N.J.
      • et al.
      A controlled trial of arthroscopic surgery for osteoarthritis of the knee.
      • Kirkley A.
      • Birmingham T.B.
      • Litchfield R.B.
      • et al.
      A randomized trial of arthroscopic surgery for osteoarthritis of the knee.
      whereas vertebroplasty for osteoporotic fracture was contradicted by 2 paired articles.
      • Kallmes D.F.
      • Comstock B.A.
      • Heagerty P.J.
      • et al.
      A randomized trial of vertebroplasty for osteoporotic spinal fractures.
      • Buchbinder R.
      • Osborne R.H.
      • Ebeling P.R.
      • et al.
      A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures.
      Adjusting for the fact that several reversals concerned the same practice, 128 medical practices were contradicted during these 10 years.
      Eight of the reversals we identified overlapped with an Australian study of 156 low-value practices
      • Elshaug A.G.
      • Watt A.M.
      • Mundy L.
      • Willis C.D.
      Over 150 potentially low-value health care practices: an Australian study.
      (Supplemental Figure; available online at http://www.mayoclinicproceedings.org). These reversals include arthroscopic surgery for knee osteoarthritis,
      • Kirkley A.
      • Birmingham T.B.
      • Litchfield R.B.
      • et al.
      A randomized trial of arthroscopic surgery for osteoarthritis of the knee.
      vertebroplasty for osteoporotic fractures,
      • Fergusson D.A.
      • Hébert P.C.
      • Mazer C.D.
      • et al.
      A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.
      endovascular repair of infrarenal abdominal aortic aneurysms,
      • De Bruin J.L.
      • Baas A.F.
      • Buth J.
      • et al.
      DREAM Study Group
      Long-term outcome of open or endovascular repair of abdominal aortic aneurysm.
      stenting in patients with stable coronary artery disease,
      • Boden W.E.
      • O'Rourke R.A.
      • Teo K.K.
      • et al.
      Optimal medical therapy with or without PCI for stable coronary disease.
      amnioinfusion for women with meconium staining,
      • Fraser W.D.
      • Hofmeyr J.
      • Lede R.
      • et al.
      Amnioinfusion Trial Group
      Amnioinfusion for the prevention of the meconium aspiration syndrome.
      C-reactive protein testing,
      • Danesh J.
      • Wheeler J.G.
      • Hirschfield G.M.
      • et al.
      C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
      screening men with the prostate specific antigen test,
      • Andriole G.L.
      • Crawford E.D.
      • Grubb R.L.
      • et al.
      PLCO Project Team
      Mortality results from a randomized prostate-cancer screening trial.
      and routine revascularization or stress testing before surgery.
      • McFalls E.O.
      • Ward H.B.
      • Moritz T.E.
      • et al.
      Coronary-artery revascularization before elective major vascular surgery.
      Thus, we provide at least 138 unique low-value practices.
      Table 2
      • Harding G.K.
      • Zhanel G.G.
      • Nicolle L.E.
      • Cheang M.
      Manitoba Diabetes Urinary Tract Infection Study Group
      Antimicrobial treatment in diabetic women with asymptomatic bacteriuria.
      • Patterson J.E.
      • Andriole V.T.
      Bacterial urinary tract infections in diabetes.
      • US Preventive Services Task Force
      Screening for asymptomatic bacteriuria, hematuria and proteinuria.
      • Tallman M.S.
      • Gray R.
      • Robert N.J.
      • et al.
      Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer.
      • Somlo G.
      • Doroshow J.H.
      • Forman S.J.
      • et al.
      High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.
      • Tomas J.F.
      • Perez-Carrion R.
      • Escudero A.
      • Lopez-Lorenzo J.L.
      • Lopez-Pascual J.
      • Fernandez-Ranada J.M.
      Results of a pilot study of 40 patients using high-dose therapy with hematopoietic rescue after standard-dose adjuvant therapy for high-risk breast cancer.
      • Woodcock A.
      • Forster L.
      • Matthews E.
      • et al.
      Medical Research Council General Practice Research Framework
      Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma.
      • Terreehorst I.
      • Hak E.
      • Oosting A.J.
      • et al.
      Evaluation of impermeable covers for bedding in patients with allergic rhinitis.
      Ad Hoc Working Group on Environmental Allergens and Asthma
      Position statement. Environmental allergen avoidance in allergic asthma.
      • Bousquet J.
      • Van Cauwenberge P.
      • Khaltaev N.
      Aria Workshop Group; World Health Organization
      Allergic rhinitis and its impact on asthma.
      • Strupp M.
      • Zingler V.C.
      • Arbusow V.
      • et al.
      Methylprednisolone, valacyclovir, or the combination for vestibular neuritis.
      • Baloh R.W.
      Clinical practice: vestibular neuritis.
      • Todd M.M.
      • Hindman B.J.
      • Clarke W.R.
      • Torner J.C.
      Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators
      Mild intraoperative hypothermia during surgery for intracranial aneurysm.
      • Pemberton P.L.
      • Dinsmore J.
      The use of hypothermia as a method of neuroprotection during neurosurgical procedures and after traumatic brain injury: a survey of clinical practice in Great Britain and Ireland.
      • Gibbons R.J.
      • Abrams J.
      • Chatterjee K.
      • et al.
      American College of Cardiology; American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina)
      ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina).
      • Smith Jr., S.C.
      • Feldman T.E.
      • Hirshfeld Jr., J.W.
      • et al.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines; American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention
      ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention).
      • Mastenbroek S.
      • Twisk M.
      • van Echten-Arends J.
      • et al.
      In vitro fertilization with preimplantation genetic screening.
      • Wilton L.
      Preimplantation genetic diagnosis for aneuploidy screening in early human embryos: a review.
      • Sermon K.D.
      • Michiels A.
      • Harton G.
      • et al.
      ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004.
      • Verlinsky Y.
      • Cohen J.
      • Munne S.
      • et al.
      Over a decade of experience with preimplantation genetic diagnosis: a multicenter report.
      • Gerstein H.C.
      • Miller M.E.
      • Byinton R.P.
      • et al.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      • American Diabetes Association
      Standards of medical care in diabetes–2007.
      • Wheatley K.
      • Ives N.
      • Gray R.
      • et al.
      ASTRAL Investigators
      Revascularization versus medical therapy for renal-artery stenosis.
      • Kalra P.A.
      • Guo H.
      • Kausz A.T.
      • et al.
      Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis.
      • Bennett-Guerrero E.
      • Pappas T.N.
      • Koltun W.A.
      • et al.
      SWIPE 2 Trial Group
      Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery.
      • Rutten H.J.
      • Nijhuis P.H.
      Prevention of wound infection in elective colorectal surgery by local application of a gentamicin-containing collagen sponge.
      lists the 10 selected reversals in the decade and how each article contradicted current standard of care. The Supplemental Appendix details all 146 reversals. Figure 2 shows the percentage of articles that tested standard of care and, of those, the percentage of reversals and reaffirmations. The percentage of reversals among articles that tested standard of care were constant during the decade (P=.51).
      Table 2Key Reversals, 2001-2010
      Reference, yearDescription
      Antimicrobial treatment in diabetic women with asymptomatic bacteriuria (Harding et al,
      • Harding G.K.
      • Zhanel G.G.
      • Nicolle L.E.
      • Cheang M.
      Manitoba Diabetes Urinary Tract Infection Study Group
      Antimicrobial treatment in diabetic women with asymptomatic bacteriuria.
      2002)
      In contrast to European societies, several groups
      • Patterson J.E.
      • Andriole V.T.
      Bacterial urinary tract infections in diabetes.
      • US Preventive Services Task Force
      Screening for asymptomatic bacteriuria, hematuria and proteinuria.
      in the United States recommended screening and treating for asymptomatic bacteriuria in women with diabetes. This randomized trial found that although this practice leads to more antibiotic use, it did not reduce complications or improve the time to symptomatic infection
      Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer (Tallman et al,
      • Tallman M.S.
      • Gray R.
      • Robert N.J.
      • et al.
      Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer.
      2003)
      Multiple studies have claimed that high-dose chemotherapy with stem cell transplantation improves disease-free survival at 3 years to 65%-70%, an improvement of 20%-30% beyond standard adjuvant chemotherapy.
      • Somlo G.
      • Doroshow J.H.
      • Forman S.J.
      • et al.
      High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.
      • Tomas J.F.
      • Perez-Carrion R.
      • Escudero A.
      • Lopez-Lorenzo J.L.
      • Lopez-Pascual J.
      • Fernandez-Ranada J.M.
      Results of a pilot study of 40 patients using high-dose therapy with hematopoietic rescue after standard-dose adjuvant therapy for high-risk breast cancer.
      High-dose chemotherapy and autologous stem cell transplantation became a common, costly, and controversial practice for more than a decade. This trial randomized patients with primary breast cancer with involvement of at least 10 ipsilateral axillary lymph nodes to standard adjuvant chemotherapy vs adjuvant chemotherapy followed by high-dose chemotherapy and stem cell transplant. The study arm was found to reduce risk of relapse, but no improvement in survival was found
      Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma (Woodcock et al,
      • Woodcock A.
      • Forster L.
      • Matthews E.
      • et al.
      Medical Research Council General Practice Research Framework
      Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma.
      2003)
      The cost of impermeable bed covers is in the millions of dollars annually, whereas the cost of all preventive interventions for asthma and allergic rhinitis is in the billions.
      • Terreehorst I.
      • Hak E.
      • Oosting A.J.
      • et al.
      Evaluation of impermeable covers for bedding in patients with allergic rhinitis.
      US
      Ad Hoc Working Group on Environmental Allergens and Asthma
      Position statement. Environmental allergen avoidance in allergic asthma.
      and European
      • Bousquet J.
      • Van Cauwenberge P.
      • Khaltaev N.
      Aria Workshop Group; World Health Organization
      Allergic rhinitis and its impact on asthma.
      guidelines recommend these covers be used among many patients with asthma. This double-blind, randomized, placebo-controlled trial of >1100 patients found no benefit on any clinical or physiologic outcome for this practice
      Methylprednisolone, valacyclovir, or the combination for vestibular neuritis (Strupp et al,
      • Strupp M.
      • Zingler V.C.
      • Arbusow V.
      • et al.
      Methylprednisolone, valacyclovir, or the combination for vestibular neuritis.
      2004)
      The cause of vestibular neuritis is presumed to be a viral infection,
      • Baloh R.W.
      Clinical practice: vestibular neuritis.
      and yet it is unknown whether corticosteroids, an antiviral medication, or a combination of both have any benefit in treating this disease. At the time of this publication, physicians prescribed either or both. A prospective, randomized, double-blind, 2-by-2 factorial trial was performed assessing whether placebo, methylprednisolone, valacyclovir, or a combination of the 2 would improve symptoms. Only the corticosteroids, and not the antiviral, improved the recovery of patients with vestibular neuritis
      Mild intraoperative hypothermia during surgery for intracranial aneurysm (Todd et al,
      • Todd M.M.
      • Hindman B.J.
      • Clarke W.R.
      • Torner J.C.
      Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators
      Mild intraoperative hypothermia during surgery for intracranial aneurysm.
      2005)
      Hypothermia was found to be helpful as a neurosurgical adjunct in 1955, especially for ischemic and traumatic insults. At the time of this publication, the practice was used in nearly 50% of aneurysm surgeries.
      • Pemberton P.L.
      • Dinsmore J.
      The use of hypothermia as a method of neuroprotection during neurosurgical procedures and after traumatic brain injury: a survey of clinical practice in Great Britain and Ireland.
      This large randomized study, the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST), found no improvement in neurologic outcomes with hypothermia, while noting an increase in bacterial infections with the intervention
      Optimal medical therapy with or without PCI for stable coronary disease (Boden et al,
      • Boden W.E.
      • O'Rourke R.A.
      • Teo K.K.
      • et al.
      COURAGE Trial Research Group
      Optimal medical therapy with or without PCI for stable coronary disease.
      2007)
      Although treatment guidelines recommended an initial approach of intensive medical therapy, reduction of risk factors, and lifestyle modification (optimal medical therapy) for patients with stable coronary artery disease, percutaneous coronary intervention (PCI) was still a common initial treatment strategy for patients with stable coronary artery disease at the time this study was performed.
      • Gibbons R.J.
      • Abrams J.
      • Chatterjee K.
      • et al.
      American College of Cardiology; American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina)
      ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina).
      • Smith Jr., S.C.
      • Feldman T.E.
      • Hirshfeld Jr., J.W.
      • et al.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines; American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention
      ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention).
      The authors found that PCI added to optimal medical therapy did not reduce the risk of death, myocardial infarction, or other major cardiovascular events
      In vitro fertilization with preimplantation genetic screening (Mastenbroek et al,
      • Mastenbroek S.
      • Twisk M.
      • van Echten-Arends J.
      • et al.
      In vitro fertilization with preimplantation genetic screening.
      2007)
      Because low pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) may result from chromosomal abnormalities, the use of preimplanation genetic screening had become increasingly more common at the time of this study.
      • Wilton L.
      Preimplantation genetic diagnosis for aneuploidy screening in early human embryos: a review.
      • Sermon K.D.
      • Michiels A.
      • Harton G.
      • et al.
      ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004.
      • Verlinsky Y.
      • Cohen J.
      • Munne S.
      • et al.
      Over a decade of experience with preimplantation genetic diagnosis: a multicenter report.
      However, this multicenter, double-blind randomized controlled trial comparing IVF with and without preimplantation genetic screening found that screening significantly reduced rates of ongoing pregnancies and live births after IVF in women of advanced maternal age
      Effects of intensive glucose lowering in type 2 diabetes (Action to Control Cardiovascular Risk in Diabetes Study Group et al,
      • Gerstein H.C.
      • Miller M.E.
      • Byinton R.P.
      • et al.
      Action to Control Cardiovascular Risk in Diabetes Study Group
      Effects of intensive glucose lowering in type 2 diabetes.
      2008)
      A target hemoglobin A1c of 7.0% or less as recommended for most patients with diabetes.
      • American Diabetes Association
      Standards of medical care in diabetes–2007.
      The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial found that target of <7.0% sustained for 3.5 years increased mortality and did not significantly reduce major cardiovascular events compared with a more permissive goal
      Revascularization versus medical therapy for renal-artery stenosis (ASTRAL Investigators et al,
      • Wheatley K.
      • Ives N.
      • Gray R.
      • et al.
      ASTRAL Investigators
      Revascularization versus medical therapy for renal-artery stenosis.
      2009)
      Renal artery stenosis is associated with hypertension and kidney disease, but it is unclear if the relationship is causal. Despite this uncertainty, data from studies in the United States indicate that revascularization is performed in 16% of patients with newly diagnosed atherosclerotic renovascular disease and hypertension.
      • Kalra P.A.
      • Guo H.
      • Kausz A.T.
      • et al.
      Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis.
      This large randomized trial of revascularization with medical management vs medical management alone found substantial risks but no evidence of benefit from revascularization in this population
      Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery (Bennett-Guerrero et al,
      • Bennett-Guerrero E.
      • Pappas T.N.
      • Koltun W.A.
      • et al.
      SWIPE 2 Trial Group
      Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery.
      2010)
      The gentamicin-collagen sponge has been approved for use in numerous countries and used in millions of patients worldwide since 1985. A single-center, randomized trial found a 70% decrease in surgical site infection with implantation of the sponge.
      • Rutten H.J.
      • Nijhuis P.H.
      Prevention of wound infection in elective colorectal surgery by local application of a gentamicin-containing collagen sponge.
      However, this large, multicenter, phase 3 trial found that the gentamicin-collagen sponge paradoxically resulted in significantly more surgical site infections, was associated with more visits to the emergency department or surgical office, and more frequently precipitated subsequent hospitalization for the infection

      Discussion

      Our review of 10 years of publications in a high-impact journal involved examining 2044 articles in duplicate to identify 146 medical reversals. Reversals included medications, procedures, diagnostic tests, screening tests, and even monitoring and treatment guiding devices. We were unable to identify any class of medical practice that did not have some reversal of standard of care (Supplemental Appendix).
      The bispectral index monitor (BIS) illustrates many of the principles of medical reversal. Although rare, anesthesia awareness (or intraoperative awareness) is debilitating and is associated with posttraumatic stress disorder and anxiety.
      • Lennmarken C.
      • Bildfors K.
      • Enlund G.
      • Samuelsson P.
      • Sandin R.
      Victims of awareness.
      The BIS monitor was developed to ensure that patients were receiving adequate anesthesia by using a single electroencephalographic lead to calculate a dimensionless measure of consciousness. In theory, anesthesia could be titrated to the BIS reading. In 1997, the US Food and Drug Administration approved the device. Only 2 trials existed before the reversal study. One, an industry-sponsored trial, did not use a standardized protocol for the comparator arm and found the device reduced awareness.
      • Myles P.S.
      • Leslie K.
      • McNeil J.
      • Forbes A.
      • Chan M.T.V.
      Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial.
      The other was underpowered to make any conclusions.
      • Puri G.D.
      • Murthy S.S.
      Bispectral index monitoring in patients undergoing cardiac surgery under cardiopulmonary bypass.
      Nevertheless, the monitor's use increased. By July 2007, half of all operating rooms in the United States had a BIS monitor.

      Lang J. Awakening. The Atlantic. January/February 2013.

      Then in 2008, a large, randomized trial comparing the BIS monitor with a standardized sedation monitoring strategy found no benefit for the device on anesthesia awareness.
      • Avidan M.S.
      • Zhang L.
      • Burnside B.A.
      • et al.
      Anesthesia awareness and the bispectral index.
      Many reversals have similar narratives.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      Although there is a weak evidence base for some practice, it gains acceptance largely through vocal support from prominent advocates and faith that the mechanism of action is sound. Later, future trials undermine the therapy, but removing the contradicted practice often proves challenging.
      • Hall J.B.
      Use of the pulmonary artery catheter in critically ill patients: was invention the mother of necessity?.
      • Tatsioni A.
      • Bonitsis N.G.
      • Ioannidis J.P.
      Persistence of contradicted claims in the literature.
      Although the BIS monitor was designed to prevent a rare event (anesthesia awareness), many reversals concern common end points, such as mortality.
      Recently, a project of BMJ, entitled Clinical Evidence,

      What conclusions has Clinical Evidence drawn about what works, what doesn't based on randomised controlled trial evidence? http://clinicalevidence.bmj.com/x/set/static/cms/efficacy-categorisations.html. Accessed June 30, 2011.

      completed a review of 3000 medical practices. The project found that slightly more than a third of medical practices are effective or likely to be effective; 15% are harmful, unlikely to be beneficial, or a trade-off between benefits and harms; and 50% are of unknown effectiveness. Our investigation complements these data and suggests that a high percentage of all practices may ultimately be found to have no net benefits.
      To our knowledge, this is the largest and most comprehensive study of medical reversal. Previously, we have considered the causes and consequences of reversal.
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      • Prasad V.
      • Cifu A.
      • Ioannidis J.P.A.
      Reversals of established medical practices: evidence to abandon ship.
      • Prasad V.
      • Cifu A.
      Medical reversal: why we must raise the bar before adopting new technologies.
      • Prasad V.
      • Cifu A.
      A medical burden of proof: towards a new ethic.
      When medical practices are instituted in error, most often on the basis of premature, inadequate, biased, and conflicted evidence,
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      the costs to society and the medical system are immense.
      • Prasad V.
      • Cifu A.
      • Ioannidis J.P.A.
      Reversals of established medical practices: evidence to abandon ship.
      As such, we favor policies that minimize reversal. Nearly all such measures involve raising the bar for the approval of new therapies
      • Prasad V.
      • Cifu A.
      Medical reversal: why we must raise the bar before adopting new technologies.
      • Prasad V.
      • Rho J.
      • Cifu A.
      The diagnosis and treatment of pulmonary embolism: a metaphor for medicine in the evidence-based medicine era.
      • Prasad V.
      • Rho J.
      • Cifu A.
      The inferior vena cava filter: how could a medical device be so well accepted without any evidence of efficacy?.
      and asking for evidence before the widespread adoption of novel techniques. In all but the rarest cases,
      • Prasad V.
      • Cifu A.
      A medical burden of proof: towards a new ethic.
      large, robust, pragmatic randomized trials measuring hard end points (with sham controls for studies of subjective end points) should be required before approval or acceptance. Our position is in contrast to efforts to lower standards for device and drug approval,
      • Kozauer N.
      • Katz R.
      Regulatory innovation and drug development for early-stage Alzheimer's disease.
      which further erodes the value of the regulatory process.
      One surprising type of reversal we observed was potentially beneficial therapies being withheld because of unfounded concerns about their potential to cause harm. Long-standing concerns that vaccinations precipitate flare of multiple sclerosis led many physicians to omit this intervention, but the concerns were largely undermined by the results of 2 studies in 2001.
      • Confavreux C.
      • Suissa S.
      • Saddier P.
      • Bourdès V.
      • Vukusic S.
      Vaccines in Multiple Sclerosis Study Group
      Vaccinations and the risk of relapse in multiple sclerosis.
      • Ascherio A.
      • Zhang S.M.
      • Hernán M.A.
      • et al.
      Hepatitis B vaccination and the risk of multiple sclerosis.
      Concerns that oral contraceptives increase lupus flares created reluctance to prescribe this class of medications to women. This practice may contribute to a higher rate of elective abortions among patients with lupus.
      • Fine L.G.
      • Barnett E.V.
      • Danovitch G.M.
      • et al.
      Systemic lupus erythematosus in pregnancy.
      In 2005, 2 trials reported that oral contraceptives do not increase lupus flares.
      • Sánchez-Guerrero J.
      • Uribe A.G.
      • Jiménez-Santana L.
      • et al.
      A trial of contraceptive methods in women with systemic lupus erythematosus.
      • Petri M.
      • Kim M.Y.
      • Kalunian K.C.
      • et al.
      OC-SELENA Trial
      Combined oral contraceptives in women with systemic lupus erythematosus.
      Although the American College of Obstetrics recommended that epidural anesthesia be delayed until cervical dilation has reached 4 cm
      • Goetzl L.M.
      ACOG Committee on Practice Bulletins-Obstetrics
      ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists Number 36, July 2002. Obstetric analgesia and anesthesia.
      —out of concern that earlier administration increases rates of cesarean section—randomized trials reported that this fear was unfounded.
      • Wong C.A.
      • Scavone B.M.
      • Peaceman A.M.
      • et al.
      The risk of cesarean delivery with neuraxial analgesia given early versus late in labor.
      Warnings that turned out to be wrong represent a unique form of reversal and raise questions about other dubious restrictions taken at face value, for instance, that patients with Clostridium difficile infection should not be treated with antimotility agents for fear of increasing rates of toxic megacolon.
      • Koo H.L.
      • Koo D.C.
      • Musher D.M.
      • DuPont H.L.
      Antimotility agents for the treatment of Clostridium difficile diarrhea and colitis.
      Discerning readers may yet identify other novel patterns of contradiction.
      The current study has several limitations. Our choice of journal was made on the basis of impact factor rankings; thus, we are unsure whether our results apply to all journals. As in any study of published research findings, one may wonder whether there exists a publication bias favoring certain studies, in this case, those that contradict standard of care. However, the testing of standard of care is rarely done
      • Prasad V.
      • Cifu A.
      • Ioannidis J.P.A.
      Reversals of established medical practices: evidence to abandon ship.
      and accordingly is in itself noteworthy. It seems unlikely that there exists a selection filter against reaffirmation articles.
      Our classification scheme was based on prior work,
      • Prasad V.
      • Gall V.
      • Cifu A.
      The frequency of medical reversal.
      but others may have alternative preferences for grouping medical articles. Whether a medical practice was considered new or existing was decided on the basis of the article's abstract, introduction, and discussion. We did not perform an independent search to verify that existing practices were indeed in use and new practices were not. As such, we may have made errors both of inclusion and exclusion. Some authors may have chosen to downplay a therapy's real-world use, whereas others may have chosen to overemphasize it. An independent evaluation of practice patterns would have strengthened our investigation but would have been overly time-consuming because it would have required investigation of hundreds of topics, many of which are common medications that lack unique coding for their varying indications.
      The reversals we have identified by no means represent the final word for any of these practices. Simply because newer, larger, better controlled or designed studies contradict standard of care does not necessarily mean that older practices are wrong and new ones are right. On average, however, better designed, controlled, and powered studies reach more valid conclusions.
      • Ioannidis J.P.A.
      Why most published research findings are false.
      Nevertheless, the reversals we have identified at the very least call these practices into question. Some practices ought to be abandoned, whereas others warrant retesting in more powerful investigations. One of the greatest virtues of medical research is our continual quest to reassess it.
      It is likely that others may feel differently about some of the reversals we have identified (Supplemental Appendix). Although we performed our analysis in duplicate, with little disagreement, others may nevertheless draw different conclusions. We interpreted articles in good faith, as the authors presented the results. In addition, the purpose of our investigation was to outline broad trends in medical practice and identify a large number of potential low-value practices. We do not seek to issue a final determination regarding any particular practice. Changing a dozen classifications would make little difference in the interpretation of our results.

      Conclusion

      We present 146 medical practices that were reversed in 10 years of publications in a high-profile journal. Our results may be of interest to practitioners and policymakers who seek to identify low-value practices and methodologists and scientists who are interested in the patterns of medical research.

      Acknowledgments

      The views and opinions of Dr Prasad do not necessarily reflect those of the National Cancer Institute or National Institutes of Health.

      Supplemental Online Material

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