Adam S. Cifu

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

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.

Reversals of Established Medical Practices: Evidence to Abandon Ship

IDEALLY, GOOD MEDICAL PRACTICES ARE REPLACED BY BETter ones, based on robust comparative trials in which new interventions outperform older ones and establish new standards of care. Often, however, established standards must be abandoned not because a better replacement has been identified but simply because what was thought to be beneficial was not. In these cases, it becomes apparent that clinicians, encouraged by professional societies and guidelines, have been using medications, procedures, or preventive measures in vain. For example, percutaneous coronary intervention performed for stable coronary artery disease and hormone therapy prescribed for postmenopausal women cost billions of dollars and supported the existence of entire specialties for many years. Stable coronary artery disease accounted for 85% of all stenting in the United States at the time of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. Large, well-designed randomized trials that tested whether these practices improved major patient outcomes revealed that patients were not being helped. Defenders of these therapies and interventions wrote rebuttals and editorials and fought for their specialties, but the reality was that the best that could be done was to abandon ship. How many established standards of medical care are wrong? It is not known. Medical practice has evolved out of centuries of theorizing, personal experiences, bits of evidence, expert consensus, and diverse conflicts and biases. Rigorous questioning of long-established practices is difficult. There are thousands of clinical trials, but most deal with trivialities or efforts to buttress the sales of specific products. Given this conundrum, it is possible that some entire medical subspecialties are based on little evidence. Their disappearance probably would not harm patients and might help salvage derailed health budgets. However, it is unlikely that specialists would support trials testing practices that constitute their main source of income. Instead, the research community performs studies of modest incremental value without even knowing whether the basic standards of care are appropriate. Rarely, some investigators find the courage to test established “truths” with large, rigorous randomized trials. When this happens, empirical evidence suggests that “medical reversals” may be quite common. In an evaluation of 35 trials that were published in a major clinical journal in 2009 and that tested an established clinical practice, 16 (46%) reported results consistent with current beneficial practice, 16 (46%) reported evidence that contradicted current practice and constituted a reversal, and another 3 (9%) were inconclusive. Perhaps high-profile general medical journals are more prone to publish unusual results and less inclined to defend a clinical practice or specialized turf than specialty journals. However, it is unlikely that the selection filter in favor of reversal publications is stronger than the selection filter favoring the validation of standard of care. The mere testing of a standard of care generates interest because many standards of care are never tested. In another evaluation of trials published in 3 major general medical journals or high–impact factor specialty journals, of the 39 mostcited randomized trials published in 1990-2003 that found a significant benefit of a clinical intervention, 9 (23%) found effects stronger than those found in subsequent studies and 19 (49%) found results replicated in subsequent studies, but 11 (28%) remained largely unchallenged, with no large trial conducted on the same question. Many medical reversals involve conditions for which the standard of care has been promoted over the years based primarily on pathophysiological considerations. Often one or more trials exist, but they have not tested clinically relevant outcomes or have been biased. For example, vertebroplasty—the injection of polymethylmethacrylate cement into fractured bone—gained popularity in the early 2000s for the treatment of osteoporotic fractures. Initial studies addressed the pathophysiology of this therapy, delineated the technical skills required to optimally perform the procedure, and furthered the discussion about the benefits of vertebroplasty. Claims of benefit were strongly contradicted in 2 randomized trials that included a sham pro-

The Frequency of Medical Reversal

W e use the term reversal to signify the phenomenon of a new trial—superior to predecessors because of better design, increased power, or more appropriate controls—contradicting current clinical practice. In recent years, a number of such reversals have occurred. Use of hormone therapy, the class 1C antiarrhythmic agents, and the pulmonary artery catheter have decreased when trials demonstrated that they are either less effective than previously thought or harmful.

Between two worlds: a multi-institutional qualitative analysis of students' reflections on joining the medical profession.

BACKGROUNDRecent changes in healthcare system and training mandates have altered the clinical learning environment. We incorporated reflective writing into Internal Medicine clerkships (IMcs) in multiple institutions so students could consider the impact of clerkship experiences on their personal and professional development. We analyzed student reflections to inform curricula and support learning.METHODSWe qualitatively analyzed the reflections of students at 3 US medical schools during IMcs (N = 292) to identify themes, tone, and reflective quality using an iterative approach. Chi-square tests assessed differences between these factors and across institutions.FINDINGSStudents openly described powerful experiences. Major themes focused on 4 categories: personal issues (PI), professional development (PD), relational issues (RI), and medical care (MC). Each major theme was represented at each institution, although with significant variability between institutions in many of the subcategories including student role (PI), development-as-a-physician (PD), professionalism (PD) (p < 0.001). Students used positive tones to describe student role, development-as-a-physician and physician–patient relationship (PD) (p < 0.01–0.001), and negative tones for quality and safety (MC) (p < 0.05). Only 4% of writings coded as professionalism had a positive tone. Students employed a “reporting” voice in writing about clinical problem-solving, healthcare systems, and quality/safety (MC).DISCUSSIONReflection is considered important to professional development. Our analysis suggests that students at 3 institutions reflect on similar experiences. Theme variability across institutions implies curricula should be tailored to local culture. Reflective quality analysis suggests students are better equipped to reflect on certain experiences over others, which may impact learning. Student reflections can function as a mirror for our organizations, offer institutional feedback for support and improvement, and inform curricula for learners and faculty.

Chest pain in the emergency department: the case against our current practice of routine noninvasive testing.

Current clinical practice for patients presenting to the emergency department with a resolved episode of chest pain and no electrographic or biomarker abnormalities is to conduct routine noninvasive testing, in accordance with American College of Cardiology and American Heart Association guidelines. The rationale is to further reduce the risk of missing a myocardial infarction, a major source of suits filed against emergency department physicians. Patients with negative stress test results may be reassured, with low event rates in the subsequent 30 days. Patients with positive stress test results have higher 30-day event rates, and a small fraction undergo revascularization procedures. Despite this endorsement, open questions remain. Does our current practice lead to the stenting of asymptomatic patients in the inevitable cases where the inciting pain was noncardiac? And, most importantly, does our practice improve outcomes? Randomized trials evaluating routine stress testing in other contexts have yielded negative results, despite diagnosing significant coronary artery disease. Population data suggest that our current practice may be increasing the diagnosis of coronary artery disease and the rate of intervention while failing to decrease rates of myocardial infarction. We propose that randomized trials be conducted to evaluate whether any testing is better than no further intervention. Data from such an evidence-based approach has the potential to reverse our current practice.

On the supramolecular organization of gramicidin channels. The elementary conducting unit is a dimer.

The question, whether the conducting channels formed by the linear gramicidins are dimers (as is generally believed) or tetramers (as has been recently proposed [Stark G., M. Strässle, and Z. Takacz. 1986. J. Membr. Biol. 89:23-37; Strässle, M., G. Stark, M. Wilhelm, P. Daumas, F. Heitz, and R. Lazaro. 1989. Biochim. Biophys. Acta. 980:305-314]) has been addressed in single-channel experiments. The experimental approach was based on the ability of electrophysiological (single-channel) experiments to resolve the number of hybrid channel types that could form between gramicidin A or C and O-pyromellityl-gramicidin A or C (in which a pyromellitic acid residue has been esterified to the ethanolamine-OH group [Apell, H.-J., E. Bamberg, H. Alpes, and P. Läuger. 1977. J. Membr. Biol. 31:171-188]). The presence of the bulky, negatively charged pyromellityl group at the channel entrances endows the hybrid channels with characteristically different features and thus facilitates the resolution of the different hybrid channel types. Only two hybrid channel types were detected, indicating that the conducting channels are membrane-spanning dimers. There was likewise no evidence for lateral association between conducting channels and nonconducting monomers. These results can be reconciled with those of Stark et al. (op. cit.) if gramicidin channel formation involves a (slow) folding into beta 6.3-helical monomers followed by the dimerization step.

The Diagnosis and Treatment of Pulmonary Embolism: A Metaphor for Medicine in the Evidence-Based Medicine Era

BACKGROUND The history of pulmonary embolism (PE) provides a fascinating portrait of a well-established diagnosis and standard of care treatment moving into the age of evidence-based medicine. METHODS We examined the history of PE and the practice of treating PE with anticoagulation. RESULTS Pulmonary embolism is a diagnostic category whose definition and treatment have both changed in the past century. Initially, PE was recognizable only when massive, with the signs and symptoms of right heart failure. Anticoagulants were established as the cornerstone of PE management with a single randomized controlled trial of 35 patients in 1960 and based on commonsense pathophysiologic reasoning. Since then, the diagnostic category of PE has been broadened, and the advent of computed tomography pulmonary angiography has yielded nearly a doubling of the incidence of the disease, without a concordant decrease in mortality. Although anticoagulation remains the cornerstone of management, open questions remain: what end points are altered by anticoagulation? What is the number needed to treat? CONCLUSIONS Trials of newer anticoagulants and longer durations of anticoagulation have not yielded real improvements over heparin, inviting doubts regarding its efficacy. Thus, PE is the quintessential diagnosis of medicine not because it represents our greatest success, but because it captures all the complexity of medicine in the evidence-based era. It may serve as a metaphor for many other conditions in medicine, including coronary artery disease. New trials in the field continue to test trivialities, whereas fundamental questions are unanswered.

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0–75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7–3.5), P < 0.0001). No pharmacogenomically high‐risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision‐making is achievable through clinical integration of genomic medicine.

Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

of the Clinical Problem Hypertension is a leading risk factor for mortality and disability. Recent estimates are that 874 million adults worldwide have an SBP of 140 mm Hg or higher.1,2 With its association with CVD, stroke (cerebrovascular accident [CVA]), heart failure, and chronic kidney disease (CKD), hypertension is second only to cigarette smoking as a preventable cause of death in the United States.3 Given demographic trends and the increasing prevalence of hypertension with increasing age (79% of men and 85% of women >75 years old have hypertension), the consequences of hypertension are expected to increase.1,2 Characteristics of the Guideline Source This guideline was developed by the ACC and the AHA in partnership with other professional societies. The ACC/AHA Task Force on Clinical Practice Guidelines selected a writing committee that was notable for its inclusion of people with a breadth of backgrounds, wide scope of practice, and freedom from conflicts of interest. This writing committee reviewed the relevant evidence and commissioned an independent evidence review committee to conduct formal systematic reviews regarding 4 questions of critical importance. The guideline document was reviewed by individuals representing the partner specialty societies and other content reviewers. The writing committee was aware of any conflicts of interest among reviewers (Table). Viewpoint page 2073 and Editorial page 2083

Clinical Management of Opioid Use Disorder

of the Clinical Problem Death caused by drug overdose is a major problem in the United States. In 2014, nearly 29 000 people died of opiate overdose.1 Underlying this trend is a parallel increase in opioid use disorder, defined as a problematic pattern of opioid use leading to clinically significant impairment or distress. Opioid use disorder contributes to significant mortality, primarily from overdose, as well as morbidity. Guidelinesfortreatmentofpatientsaddictedtoopiatespotentially canimprovebothpatientandpublichealthoutcomes.Oftheestimated 2.5millionpeopleintheUnitedStateswithopioidaddiction,2 fewerthan half are able to access medication-assisted treatment (MAT), 53.4% of US counties do not have a single prescriber of medications to treat opioid use disorder, and, as of 2014, only 2.2% of US physicians had obtained the necessary waiver to prescribe buprenorphine.3 MAT is an evidence-based approach that combines medical therapy with an opioid agonist or antagonist with counseling and recovery support. MAT using agonist therapy with methadone or buprenorphine has been shown to be superior to withdrawal (“detox”) for important patientcenteredoutcomessuchasoverdosedeath,ratesofcommunicabledisease, retention in treatment, and relapse.4,5