Benjamin Wu, MD
Faculty Peer Reviewed
The year started with a bang at NYU and brought with it new faces, opportunities, and challenges. At the height of summer, we find the changes that are affecting the politics in the United States are similar to those affecting healthcare. We have a looming debt crisis that may have lasting implications for our nation. While the government is changing the mentality of ‘business as usual’ with regard to the debt ceiling, healthcare providers find themselves seeing that the evidence behind the standard of care may not be as strong as previously believed. As new research on familiar subjects starts to trickle into the medical literature, the subtle phenomenon of reversal is being recognized as newly published trials are challenging and even contradicting familiar medical truths.
In a research letter published by The Archives of Internal Medicine, Prasad, Gall, and Cifu discussed these recent reversals in current literature. The authors defined reversals as new trials with increased power, improved design, and stricter controls that contradict current medical practice.  The authors analyzed publications during 2009 that appeared in the New England Journal of Medicine. They found 212 original articles, and of those 16 (13%) were considered reversals. Notable reversals that the research letter pointed to were the Quality of Life after Late Invasive Therapy for Occluded Arteries, Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma, and Intensive Versus Conventional Glucose Control in Critically Ill Patients.  The authors cited “Confidence that the pathophysiologic concepts underlying practices were rational” as one of the main reasons the prior research was found to be contraindicated by newer studies. They further conclude that reversals in medical literature are no longer so uncommon and at least 10% of new trials contraindicate, reverse, or at least challenge the commonly held standard of care. Furthermore, results from the ACCORD trial raise more questions than provide answers in our treatment of patients with diabetes.  Unfortunately, the authors do not give a very thorough reason why there seems to be an increase in reversals in medical literature, but they assume that newer research based upon better-controlled and better-powered studies will give “stronger” truth claims.  The implications of the letter are serious. Will reversals continue to challenge our standard of care? Have we as healthcare providers placed patients at increased risk for morbidity and mortality based upon trials, only to have our current thinking contraindicated by another study? Further clarification of the true impact of reversals will be needed, as more research may show us that our current standard of care and pathophysiological principles are misguided.
In challenging old beliefs, the British Medical Journal published a meta-analysis of randomized controlled trials that demonstrated a mortality risk associated with tiotropium mist inhalers.  Prior research based upon the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial did not report a mortality risk in patients who used powdered tiotropium versus placebo.  However, physicians need to recognize that powdered tiotropium and mist-inhaled tiotropium are distinctly different medications. Mist-inhaled tiotropium reached 35% higher blood concentration in the 5 ug dose and threefold higher in the 10 ug dose compared to the powered version.  The anticholingeric properties are used to explain both the physiological effects for symptomatic benefit in patients with chronic obstructive pulmonary disease (COPD) and the potential cause of major cardiovascular events in patients using the long-acting drug. The primary end point the authors examined was mortality. The meta-analysis found that the relative risk for mortality was 1.52 (95%, CI 1.06 to 2.16; P = 0.02).  Cardiovascular risks also differed between doses of inhaled tiotropium. The 5 ug dose of tiotropium was associated with a 46% increase in mortality (1.46, CI 1.01 to 2.10; P = 0.04), and the 10 ug dose doubled the relative risk (2.15, CI 1.03 to 4.51; P = 0.04).  The authors also examined the number needed to cause one mortality and estimated that one mortality was caused by124 patients treated with the 5 ug dose.  The authors conclude that further examination of these results is needed to quantify the safety differences between mist inhalers and the powdered form of tiotropium. The conclusions reached by the study were limited because at the time of the publication there is currently an on-going trial comparing mist inhalers and powered inhalers that will hopefully answer the mortality question definitively.
In patients with reactive airway disease, a recent New England Journal of Medicine article addressed the role of albuterol, sham acupuncture, placebo or no intervention . The researchers sought to explore the powerful placebo effect in patients who suffered from mild-moderate asthma in a double-blind, crossover pilot study.  Not surprisingly, the patients who received albuterol had the only significant quantitative response. Patients who received albuterol had a 20.1% improvement in their FEV1 compared to placebo (7.5%), sham procedure (7.5%), and no-intervention (7.5%, P<0.001).  What was unexpected was that in all three groups, excluding the patients who had no intervention, patients reported significant subjective improvement. The patients who received albuterol reported 50% subjective improvement with placebo (45%) and sham acupuncture (46%) reporting very similar improvements (P<0.001). The no-intervention group reported a 21% improvement.  Given that there were no pre-existing subjective measurements for acute asthma response, the authors created their own subjective assessment for the improvement in dyspnea.  The study was limited by small sample size, only 39 patients finished the study and seven (15%) dropped out by the time the study ended.  The impact of the dropouts may have a significant effect on the response to placebo in the study. Did the patients who dropped out of the study do so because they found the sham procedure, placebo, or albuterol itself unhelpful? Or did these patients actually have asthma with increased severity? Furthermore, only patients in acute asthmatic exacerbations were studied while chronic asthmatics and other patients with reactive airway disease were not, yet may provide further insight into the placebo effect. Regardless, this study provides some insight into the subtle, yet powerful impact of the placebo in patients suffering from asthma.
Straight from the Netherlands comes a new study for the use of steroids in patients who present with community acquired pneumonia (CAP). In The Lancet, an article titled “Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial” showed that a small dose of dexamethasone decreased length of hospital stay in patients with CAP.  Researchers took 304 patients and randomized them into two arms. 151 patients received dexamethasone 5mg once a day for four days and the other 153 patients received a placebo. All patients were given antibiotics at the start of the study.  The primary endpoint was length of hospital stay until discharge or death. Other secondary endpoints included admission to intensive care units, mortality, development of empyema, super-infection, readmission, level of C-reactive protein, interleukin-6, and interleukin-10, pulmonary function at day 30, and general quality of life by Rand-36 generic health survey.  The authors found that the length of hospital admission in those patients who received dexamethasone was 6.5 days (5.0-9.0) compared to patients who did not receive dexamethasone 7.5 days (5.3-11.5). The hazard ratio for discharge was 1.46 (95%, CI 1.13-1.89) favoring earlier discharge in patients who received dexamethasone therapy. They conclude that the administration of steroids modulates the immune response and point to the rapid normalization of C-reactive protein and IL-6 as evidence for these changes in the systemic inflammatory response. The study was limited by a lack of patients with COPD (as patients with COPD exacerbations required steroids) and overrepresentation of Q fever as there was an outbreak in the spring of 2009.  Furthermore, the study is difficult to apply to US guidelines, as the antibiotic treatment is different given regional differences in flora.  The authors disclosed one particular adverse event with a patient developing a gastric perforation on dexamethasone.
Finally, the Journal of the American Medical Association presents another reason why primary prevention can save lives in patients with prostate cancer. In an article titled “Smoking and Prostate Cancer Survival and Recurrence” authors conducted a prospective observational study of 5366 men diagnosed with prostate cancer between 1986 and 2006 with hazard ratios related to prostate cancer mortality, cardiovascular disease (CVD) mortality, and biochemical recurrence of cancer.  While the connection between smoking and increased mortality may be apparent from prior research, the current article explores the differences between never smokers, patients who stopped smoking 10 years prior to their diagnosis, patients who quit smoking less than 10 years prior to diagnosis, and those who currently were smoking at the time of their diagnosis and the impact on prostate and CVD mortality.  The patients who continued to smoke when compared to those who never smoked had a hazard ratio of 1.61 (95% CI 1.11-2.32) for prostate cancer mortality, 1.80 (95% CI 1.04-3.12) for prostate cancer with clinical stage T1 to T3, and 1.80 (95% CI 1.16-2.22) for biochemical recurrence. When examining patients for overall mortality the patients who were smoking at the time of their diagnosis had a hazard ratio of 2.28 (95% CI 1.87-2.80) for overall mortality and 2.13 (95% CI 1.39-3.26) for CVD mortality when compared to their never smoker cohorts.  Furthermore, the authors found that those smokers who quit for 10 or more years or quit less than 10 years, but smoked less than 20 pack-years had prostate cancer mortality risks similar to those who never smoked.  The authors suggest that smokers are at higher risk from carcinogen production in cigarette smoke (nitrosamines and cadmium) with gene variants in detoxification possibly promoting more aggressive cancers. Aggressive prostate cancer in smokers may also be increased by testosterone or other androgens, and nicotine-induced angiogenesis.  Unfortunately, patients who quit less than 10 years prior to diagnosis (n = 297) and current smokers (n = 277) were underrepresented compared to never smokers (n = 2449) and 10-year quitters (n = 2063). Researchers also found that smokers tend to have less PSA testing, and may explain why the smoking population was found with more advanced prostate cancer.  However, after adjusting for PSA screening the authors claim that associations between smoking and fatal prostate cancer were stronger, as opposed to there being an attenuation of the association. This article further emphasizes the importance of smoking cessation and how it may be the best care that we can provide to our patients.
July in the hospital is filled with great potential and new encounters. Recent evidence shows us that our understanding of the present medical literature can be challenged and possibly contradicted by new trials appearing on the horizon. As our understanding of pathophysiology improves, better-controlled and better-powered research may flip our present understanding of medicine on its head. As physicians we must be able to digest contradictory evidence and respond to an educated and informed patient population. If newer trials and studies represent true reversals of the standard of care, we can keep abreast of the changes and respond in kind. Like all science, medicine continues to be a vibrant and dynamic field, where truths are always ready to be found.
Benjamin Wu is a 2nd year resident at NYU Langone Medical Center
Peer reviewed by Robert Gianotti, MD, Associate Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
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2. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. “Long-term effects of intensive glucose lowering on cardiovascular outcomes.” N Engl J Med. 2011 Mar 3;364(9):818-28. http://www.nejm.org/doi/full/10.1056/NEJMoa1006524
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6. Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH. “Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.” Lancet. 2011 Jun 11;377(9782):2023-30. Epub 2011 Jun 1. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60607-7/fulltext
7. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. “Smoking and prostate cancer survival and recurrence.” JAMA. 2011 Jun 22;305(24):2548-55. http://jama.ama-assn.org/content/305/24/2548.long