nejm - year in review 2013

2013YEAR IN REVIEW

Original Perspectives on the Year’s Most Important Clinical Topics in General Medicine, from the Editors of NEJM Journal Watch

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EDITOR-IN-CHIEFAllan S. Brett, MD, Professor of Medicine and Director, Division of General Internal Medicine, University of South Carolina School of Medicine

EXECUTIVE EDITORCharleen M. Hamilton, PhD Massachusetts Medical Society

DEPUTY EDITORThomas L. Schwenk, MD, Dean, University of Nevada School of Medicine; Vice President of Health Sciences, University of Nevada

FOUNDING EDITORAnthony L. Komaroff, MD, Senior Physician, Division of General Medicine, Brigham and Women’s Hospital, Boston; Professor of Medicine, Harvard Medical School

ASSOCIATE EDITORSDavid J. Amrol, MD, Associate Professor of Internal Medicine, Director of the Division of Allergy and Immunology, University of South Carolina School of Medicine Jonathan S. Cobyln, MD, Associate Professor, Harvard Medical School; Vice Chair of Medicine and Director of Clinical Rheumatology; Brigham and Women’s Hospital, Boston, MAKirsten E. Fleischmann, MD, MPH, Attending Physician, Medical Center at the University of California, San Francisco; Professor of Clinical Medicine, University of California, San FranciscoPatricia Anne Kritek, MD, EdM, Associate Professor, Division of Pulmonary and Critical Care Medicine, University of Washington, SeattleJamaluddin Moloo, MD, MPH, Associate Professor of Medicine, Department of Medicine and Radiology, University of Colorado Health Sciences CenterPaul S. Mueller, MD, MPH, FACP, Chair, Division of General Internal Medicine, Professor of Medicine, Mayo Clinic College of Medicine, Rochester, MNBruce Soloway, MD, Associate Professor and Vice Chair, Department of Family and Social Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, NYAbigail Zuger, MD, Associate Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Senior Attending Physician, St. Luke’s-Roosevelt Hospital Center, NY

CONTRIBUTING EDITORRobert W. Rebar, MD, Executive Director, American Society for Reproductive Medicine, Birmingham, AL

Dear Reader,

Each year, the editors of NEJM Journal Watch General Medicine choose the year’s most important thematic areas in clinical research. We try to strike a balance among relevance to primary care, recognition of landmark studies, and acknowledgment of media publicity and public awareness. Some of our stories emerge from one important study, and others come from several studies on a single topic. We remain devoted to providing clinicians with the information they need to give their patients the best care, and, as part of NEJM Group, we now are poised to do so better than ever.

— Allan S. Brett, MD

Editor-in-Chief NEJM Journal Watch General Medicine

http://nejmgroup.org

TABLE OF CONTENTS

NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society.©2014 Massachusetts Medical Society. All rights reserved.

New Cholesterol Guidelines Spur Debate

New Data on Early Treatment of Stroke and Transient Ischemic Attack

Restrictive Transfusion Strategy Lowers Mortality in Patients with Upper Gastrointestinal Bleeding

Questions About Risks and Benefits of Testosterone Therapy

Lung Cancer Screening with Computed Tomography — Now Recommended

Renal Artery Stenting Receives the Death Knell

Proning? Yes. Gastric-Residual Monitoring? No.

Ongoing Battles with ICU Infections

Five-Day Prednisone Therapy Should Be the Norm for Treating COPD Exacerbations

Dual Blockade of the Renin-Angiotensin-Aldosterone System Doesn’t Benefit Anyone

Mediterranean Diet Tested in a Randomized Trial

Electronic Cigarettes: Increasingly Used, Still Unregulated, Poorly Understood

Increasing Evidence That the Human Microbiome Plays a Major Role in Health

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16The order of these stories is not intended to reflect their relative importance. All citations refer to 2013, unless otherwise noted.

YEAR IN REVIEW | 2013

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Back to Table of Contents

New Cholesterol Guidelines Spur DebateThe guidelines, if followed precisely, likely would lead to more statin use by asymptomatic older adults.

Two new guidelines from the American Heart Association and American College of Cardiology — one on cardiovascular risk assessment, the other on cholesterol management — spurred considerable controversy towards the end of 2013.

The risk-assessment guideline pre sents new sex-specific equations, developed from multiple large cohorts, to predict 10-year risk for first atherosclerotic cardiovascular disease events (ASCVD; nonfatal myocardial infarction, coronary heart disease–related death, or fatal or nonfatal stroke). An online risk calculator, which requires input of age, sex, total and HDL cholesterol levels, and several other risk factors, enables clinicians to generate 10-year risk estimates for specific patients.* If treatment decisions are still uncertain after risk assessment, use of risk markers such as family history, high-sensitivity C-reactive protein level, coronary-artery calcium score, or ankle-brachial index (but not carotid intima-media thickness) should be considered (NEJM JW Gen Med Dec 15, p. 193, and J Am Coll Cardiol Nov 12; [e-pub ahead of print]).

The cholesterol-treatment guideline establishes new protocols for lowering blood cholesterol to diminish cardio vascular risk in adults (NEJM JW Gen Med Dec 15, p. 194, and J Am Coll Cardiol Nov 12; [e-pub ahead of print]). Treating to LDL cholesterol targets is no longer recommended; rather, clinicians should focus on assessing patients’ risk of ASCVD and whether they fall into one of four high-risk patient groups, for which moderate- or high-intensity statin therapy is recommended:

• Patients with clinical ASCVD

• Patients with LDL cholesterol levels ≥190 mg/dL

• Older diabetic patients (age range, 40–75) with LDL cholesterol levels of 70–189 mg/dL and without clinical ASCVD

• Patients without clinical ASCVD or diabetes but with LDL cholesterol levels of 70–189 mg/dL and estimated 10-year ASCVD risk ≥7.5%

With few exceptions, use of lipid-modifying drugs other than statins is discouraged, and lifestyle modifica-tion is recommended. Guideline authors acknowledge that some patients will not tolerate high-dose statins and that patient preferences should be discussed for individualized decision making, particularly in primary prevention.

Taken together, these two guidelines represent a paradigm shift and have generated considerable controversy in professional and lay presses (New York Times Nov 12). In particular, the idea of not treating to LDL targets — which is based on the fact that randomized statin trials did not specifically do so — overturns 2 decades of standard practice. The new calculator has been criticized for potentially overestimating risk (Lancet Nov 30; 382:1762), and the 7.5% threshold for instituting statin therapy in primary prevention is much lower than previous thresholds. The prospect of an estimated 33 million Americans without ASCVD exceeding the 7.5% risk threshold and receiving stain therapy is a tough pill to swallow for some ( JAMA Dec 2; [e-pub ahead of print]). Expect to see many more analyses of the performance and implications of the new guidelines in 2014.

— Kirsten E. Fleischmann, MD, MPH

*The risk calculator is available at http://my.americanheart.org/cvriskcalculator free of charge.

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New Data on Early Treatment of Stroke and Transient Ischemic AttackLarge randomized trials addressed blood pressure lowering, endovascular therapies, and dual antiplatelet therapy.

Several important large randomized trials that addressed early stroke treatment were published in 2013.

Standard treatment of patients with ischemic stroke or transient ischemic attack (TIA) includes aspirin given within 24 to 48 hours. To determine whether dual antiplatelet therapy might be better than aspirin alone, Chinese re searchers conducted a randomized trial that involved 5170 patients with high-risk TIA or minor ischemic stroke (NEJM JW Gen Med Aug 1, p. 117, and N Engl J Med Jul 4; 369:11). Starting within 24 hours of symptom onset, one group received daily aspirin alone; the other group received aspirin plus clopidogrel for the first 21 days, followed by clopidogrel alone. At 90 days, new strokes had occurred in 8.2% of aspirin-clopidogrel patients and 11.7% of aspirin-alone patients — a highly significant difference. Dual-therapy recipients had no excess of serious bleeding events or hemorrhagic strokes. This study makes a compelling case for dual antiplatelet therapy; a similar trial (POINT), currently underway in the U.S., will determine whether the findings can be extrapolated to other populations.*

Endovascular stroke therapies, such as intra-arterial tissue plasminogen activator (t-PA) or mechanical clot disrup-tion or retrieval, are employed increasingly, despite limited proof of efficacy. In three randomized trials published in March 2013 that involved >1100 patients, endovascular interventions were not superior to stand ard treatments in pa-tients with mainly anterior circulation strokes. In an editorial entitled “Endovascular treatment for acute ischemic stroke — Still unproven” (N Engl J Med Mar 7; 368:952), the author discourages use of endovascular therapies outside of clinical trials (NEJM JW Gen Med Apr 15, p. 61, and N Engl J Med Mar 7; 368:904).

A longstanding controversy is whether hypertension — a common finding when stroke patients first present to the hospital — should be treated during the first day or two. For ischemic stroke patients who are not receiv-ing thrombolytic therapy, recent guidelines (Stroke Mar; 44:870) recommend treatment only when blood pres-sure exceeds 220/120 mm Hg; the concern is that early BP-lowering will worsen outcomes through hypoperfu-sion of the ischemic penumbra. In 2013, the first large randomized trial of early BP-lowering was published: 4700 Chinese patients with acute ischemic stroke and BP lower than 220/120 mm Hg received either early anti-hypertensive therapy (target, 140/90 mm Hg) or no treatment. The findings were straightforward — no benefit and no harm: The endpoint of death or major disability occurred with identical frequency in the two groups (NEJM JW Gen Med Jan 1 2014, p. 1, and JAMA Nov 17; [e-pub ahead of print]).

For hemorrhagic stroke, guidelines do recommend lowering BP acutely to less than 160/90 mm Hg (Stroke 2010 Sep; 41:2108); the assumption is that excessively high BP will increase hematoma size. In a large random-ized trial, 2800 patients with hemorrhagic stroke and systolic BP between 150 and 220 mm Hg were treated to a target of either 180 or 140 mm Hg. The outcome was a close call: For a dichotomous outcome — the proportion of patients with death or major disability — the difference between the intensive- and standard-treatment groups just failed to reach significance (52.0% and 55.6%; P=0.06). However, a more fine-grained analysis that con-sidered five degrees of disability favored intensive treatment (P=0.04; NEJM JW Gen Med Jul 1, p. 101, and N Engl J Med Jun 20; 368:2355).

In sum, during the first 24 hours: (1) consider dual antiplatelet therapy for patients with minor ischemic stroke or TIA; (2) in patients with substantially elevated BP, moderate BP-lowering is neither ben eficial nor harmful for ischemic stroke and might be beneficial for hemorrhagic stroke; (3) the efficacy of endovascular interventions for anterior circulation strokes remains unproven.


*Information about the POINT trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00991029 free of charge.




http://dx.doi.org/10.1056/NEJMe1215730


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Restrictive Transfusion Strategy Lowers Mortality in Patients with Upper Gastrointestinal BleedingThe restrictive approach was particularly effective in lowering risk for rebleeding in patients with portal hypertension.

Randomized trials in critically ill adults and children have demonstrated better outcomes with a restrictive approach to red-cell transfusion (NEJM JW Gen Med Mar 1 1999, p. 37; N Engl J Med 1999 Feb 11; 340:409; NEJM JW Gen Med May 15 2007, p. 77; and N Engl J Med 2007 Apr 19; 356:1609). However, patients with acute gastrointestinal (GI) bleeding were not included in these studies. Transfusion for massive exsanguination obviously can be lifesaving, but the value of transfusion when lesser amounts of bleeding occur has been unclear — until now.

Spanish investigators randomized 921 patients with nonmassive acute GI bleeding (most with ulcers or esophageal varices) and low risk for rebleeding to either a restrictive or a liberal transfusion strategy (transfusion at hemoglobin level <7 or <9 g/dL, respectively). Mean hemoglobin level on admission was 9.5 g/dL. About half of the restrictive-strategy group eventually received transfusions, compared with 86% of the liberal-strategy group. At 45 days, mortality was 5% in the restrictive group and 9% in the liberal group. The difference was particularly significant in patients with Child-Pugh Class A or B cirrhotic disease. Rebleeding occurred in 10% of the restrictive group and 16% of the liberal group, with par ticular benefit in patients with mild-to-moderate cirrhotic disease (NEJM JW Gen Med Mar 15, p. 45, and N Engl J Med Jan 3; 368:11).

This study is a good example of how our intuition to restore normal physiology can sometimes cause harm. Although this study obviously could not be blinded, it was a robust approach and should influence our decision-making. Both the lower transfusion rate and the clinical benefits are substantial. Patients with mild-to-moderate cirrhotic disease ex perience particular benefits, presumably because they are protected against increases in portal pressure.

— Thomas L. Schwenk, MD




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Questions About Risks and Benefits of Testosterone TherapyWe know very little about risks associated with testosterone therapy, but that fact isn’t inhibiting its vigorous promotion by pharma.

Use of testosterone therapy, marketed to consumers for a condition vaguely labeled as “low T,” is increasingly common. How ever, in a short-term randomized trial published in 2010, the incidence of adverse cardiovascular events was higher in older men with comorbidities who received testosterone therapy (NEJM JW Gen Med Aug 1 2010, p. 120, and N Engl J Med 2010 Jul 8; 363:123). Many clinicians are concerned that patient requests for testosterone are getting ahead of a full understanding of its risks and benefits. In the past year, two studies shed light on those concerns.

In a retrospective study, researchers identified 8700 male veterans with, or at high risk for, coronary artery disease (CAD) whose blood testosterone levels had been measured and were <300 ng/dL; 1200 of these men re-ceived testosterone therapy, and 7500 did not. During a mean 27-month follow-up, myocardial infarction, stroke, or death occurred in 26% of testosterone patients and in 20% of those not receiving therapy. Higher risk for ad-verse events with testosterone therapy occurred regardless of the presence or absence of CAD. Analyses were ad-justed for potentially confounding variables (NEJM JW Gen Med Dec 15, p. 189, and JAMA Nov 6; 310:1805).

In another study, 140 men (age, 40–70) with erectile dysfunction and low testosterone levels received opti-mized sildenafil therapy and then were ran domized to add daily transdermal tes tosterone (5–15 g) or placebo for 14 weeks. Erectile function improved with sildenafil, but add-on testosterone led to no further improvement (NEJM JW Gen Med Jan 15, p. 13, and Ann Intern Med 2012 Nov 20; 157:681).

We clearly need a large, long-term, controlled study of testosterone therapy, similar in design to the Women’s Health Initiative, but no such study has been registered — and we likely will never see one. We know very little about risks associated with testosterone therapy, but that fact doesn’t seem to be inhibiting its vigorous promo-tion by pharmaceutical companies and some physicians who serve as spokespeople for those companies (New York Times Nov 24). For now, clinicians are confronted regularly with the need to balance demands of men who seek to improve their strength, energy, and appearance with theoretical (and now, empirical) concerns about long-term risks of testosterone therapy.

— Thomas L. Schwenk, MD








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Lung Cancer Screening with Computed Tomography — Now RecommendedThe U.S. Preventive Services Task Force and American College of Chest Physicians give screening a green light.

In July 2013, the U.S. Preventive Services Task Force (USPSTF) issued a preliminary draft statement, recom mend-ing lung cancer screening with computed tomography (CT). As of now, the guideline is still in its review phase following public comment and has not yet been finalized (NEJM JW Gen Med Sep 1, p. 139); however, a final recommendation in favor of screening is a near certainty. Notably, in May 2013, the American College of Chest Physicians also published a guideline recommending CT screening (NEJM JW Gen Med Jun 15, p. 100, and Chest May; 143[5 Suppl]:e78S).

The USPSTF guideline recommends annual screening with low-dose CT in older people (age range, 55–79) with smoking histories ≥30 pack-years; former smokers are eligible if they quit during the past 15 years. The impetus for this recommendation came from the randomized National Lung Screening Trial (NLST), in which three annual screening CTs reduced lung cancer mortality from roughly 1.6% to 1.3% during 6 years of follow-up. Although the absolute benefit was small, the result was statistically significant in a study involving 53,000 people (NEJM JW Gen Med Aug 1 2011, p. 117, and N Engl J Med 2011 Aug 4; 365:395). The biggest concern about screening is the high false-positive rate: In the first round of screening alone, 27% of NLST patients had at least one abnormality, but only 4% of those patients were eventually diagnosed with lung cancer (NEJM JW Gen Med Jun 15, p. 99, and N Engl J Med May 23; 368:1980). A related concern is overdiagnosis — the detection of indolent cancers that would not have become symptomatic in the absence of screening; by one estimate, overdiagnosis was substantial in the NLST ( JAMA Intern Med Dec 9; [e-pub ahead of print]).

Two important studies with relevance to the false-positive problem were published in 2013. In one study, researchers used eight demographic and clinical variables to predict a smoker’s 5-year risk for lung cancer– related death. According to this prediction model, screening people in the lowest-risk quintile would save virtually no lives but would still cause harms associated with false-positive results. These refined criteria for screening could allow us to narrow the eligibility criteria for screening, while retaining the overall mortality benefit (NEJM JW Gen Med Aug 15, p. 125, and N Engl J Med Jul 18; 369:245).

The other key study was development of a model to indicate the probability that a pulmonary nodule found in a smoker who undergoes CT screening will be diagnosed as malignant during 3 years of follow-up. Knowing the probability that a nodule is malignant could help clinicians and patients decide on the relative merits of follow-up imaging, immediate biopsy, or no further intervention. The risk cal culator — which requires input of nine demo graphic, clinical, and radiologic variables — is available online (NEJM JW Gen Med Oct 15, p. 157, and N Engl J Med Sep 5; 369:910).*

In the end, benefits of screening will outweigh harms only if patients are selected carefully for screening and if screen-positive patients are managed in centers where expert multidisciplinary follow-up is available.


*The risk calculator is available at http://www.brocku.ca/lung-cancer-risk-calculator free of charge.












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Renal Artery Stenting Receives the Death KnellA third large trial shows that stenting does not benefit patients with moderate or severe renal stenoses.

Renal artery stenting for patients with atherosclerotic stenoses and hypertension seemed like an obvious and elegant solution to restore blood flow and lower blood pressure. Yet, as we reported in 2009, two randomized trials, ASTRAL and STAR, failed to show a significant benefit of stenting among patients with hypertension and stenoses of ≈50% or higher (NEJM JW Gen Med Aug 15 2009, p. 125; Ann Intern Med 2009 Jun 16; 150:840; NEJM JW Gen Med Dec 1 2009, p. 181, and N Engl J Med 2009 Nov 12; 361:1953). The primary criticism of these earlier studies was that they included patients who did not have clinically significant renal artery stenosis. In 2013, CORAL addressed this primary criticism.

In CORAL, 947 patients with resistant hypertension or stage ≥3 chronic kidney disease and atherosclerotic renal artery stenosis (mean stenosis, 73%) were randomized to optimal medical therapy alone or to optimal medical therapy with stenting. At a median follow-up of 43 months, no significant difference was found in the primary endpoint (composite of death from cardiovascular or renal causes, acute myocardial infarction, stroke, hospitalization for heart failure, renal insufficiency, and need for permanent renal replacement therapy); rates were about 35% in both groups. Similarly, no individual component of the primary endpoint differed significantly (NEJM JW Gen Med Dec 15, p. 189, and N Engl J Med Nov 18; [e-pub ahead of print]).

Results of ASTRAL, STAR, and CORAL do not leave room for debate — patients who have moderately severe atherosclerotic renal artery stenoses and hypertension or stage 3 chronic kidney disease should receive medical therapy without stenting. Some people might continue to argue that stenting could benefit patients with higher degrees of stenoses; however, secondary analyses in CORAL failed to show a benefit of stenting even among patients with >80% stenoses.

— Jamaluddin Moloo, MD, MPH






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Proning? Yes. Gastric-Residual Monitoring? No.Two changes worth making for mechanically ventilated patients in intensive care

These two studies, published in 2013, should change the way we manage mechanically ventilated patients in intensive care units.

• Patients with acute respiratory distress syndrome (ARDS) often develop consolidation of the dependent lung regions. For many years, physicians have transitioned severely hypoxemic patients from supine to prone posi-tions to improve aeration of these areas and to promote gas exchange. To determine whether this practice prevents ARDS-associated mortality, French researchers randomized 466 mechanically ventilated patients with moderate-to-severe ARDS to daily prone positioning or to supine positioning only. Intervention patients underwent an average of four sessions of proning (mean duration per daily session, 17.3 hours). Mortality at 28 days was 16% in the prone group and 33% in the supine group (NEJM JW Gen Med Jul 15, p. 109, and N Engl J Med Jun 6; 368:2159). These results give new life to the practice of proning. Although proning is not suitable for all ARDS patients, it should be considered early for most patients with severe disease. Delivering care safely to patients in this position will require additional training of nurses and other providers.

• In most hospitals, gastric residuals are monitored for all patients who receive enteral feeding. The theory is that patients with larger residuals are at greater risk for vomiting, subsequent aspiration, and ventilator- associated pneumonia (VAP). French investigators randomized 449 mechanically ventilated patients either to routine gastric-residual monitoring every 6 hours or to no monitoring. Residual volumes >250 mL in the monitored group were considered to be a sign of intolerance and triggered treatment with a prokinetic drug and a decrease in tube-feeding rates. Despite more vomiting in the unmonitored group than in the monitored group, no difference was reported in the incidence of VAP (16.7% and 15.8%), mechanical ventilation, length of stay, or mortality (NEJM JW Gen Med Feb 15, p. 29, and JAMA Jan 16; 309:249). Monitoring adds to the work of bedside nurses and probably results in excessively cautious feeding, so the time has come to reconsider this practice.

— Patricia Anne Kritek, MD






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Ongoing Battles with ICU InfectionsInvestigators explore more powerful alternatives to current isolation protocols.

Eliminating hospital-acquired, antibiotic-resistant infections has long bedeviled epidemiologists, especially in the close quarters of intensive care units (ICUs). Several studies in 2013 emphasized the elusiveness of this goal.

The standard of care in most hospitals calls for screening patients at ICU admission for carriage of methicillin- resistant Staphylococcus aureus (MRSA) or other resistant organisms and then placing colonized patients in con-tact isolation. However, the supporting evidence is not particularly strong (NEJM JW Gen Med Apr 1 2008, p. 55; JAMA 2008 Mar 12; 299:1149; NEJM JW Gen Med Apr 15 2008, p. 61; and Ann Intern Med 2008 Mar 18; 148:409).

In one 2013 study, investigators evalu ated expanding use of contact precautions to all patients rather than just those who were colonized or infected (NEJM JW Infect Dis Oct 17 2013). Staff in 10 ICUs used gloves and gowns for all patient interactions during 9 months. Rates of colonization with resistant organisms proved to be similar to rates in control ICUs (in which contact precautions were used only for infected patients). Only a small decline in the rate of MRSA acquisition in the intervention group reached even marginal significance, and no improve-ment in clinical endpoints was found.

In other studies, researchers evalu ated the strategy of bolstering standard screening and isolation precau-tions with topical use of the antiseptic chlorhexidine. In one study, investigators found that rates of colonization with antibiotic-resistant organisms were 23% lower when ICU or bone-marrow transplant patients were bathed daily with chlorhexidine; rates of hospital-acquired bacteremias were 28% lower with chlorhexidine (NEJM JW Infect Dis Feb 6 2013).

In a larger study, U.S. investigators evaluated both universal and targeted decontamination. They randomized ICUs in 43 hospitals to (1) treat all patients with daily chlorhexidine baths plus 5 days of intranasal mupirocin oint-ment, (2) use these interventions only in patients who were MRSA carriers, or (3) continue standard screening and isolation precautions.

ICUs in which all patients were decontaminated reported a significant fall in rates of MRSA in clinical cul-tures and lower bacteremia rates compared with their own baselines. ICUs in which only colonized patients were decontaminated reported a nonsignificant fall in culture-proven MRSA and significantly fewer bacteremias. No changes were seen in the control group (NEJM JW Gen Med Aug 1, p. 117, and N Engl J Med Jun 13; 368:2255).

These results have elicited a range of responses, with many experts expressing disillusion with standard screening and contact-isolation protocols. One set of editorialists even calls for hospitals to stop using them completely, in favor of broader universal strategies, such as decontamination (N Engl J Med Jun 13; 368:2314); indeed, some ICUs have already implemented universal decontamination. Other commentators endorse build-ing on existing targeted strategies. One reason — They are mandated by law in many states. Meanwhile, the big worry with decontamination is that routine, large-scale deployment of mupirocin, chlorhexidine, and other topi-cal agents might result in large-scale resistance to these agents among nosocomial pathogens that already are resistant to numerous antibiotics (NEJM JW Infect Dis Oct 17 2013).

— Abigail Zuger, MD






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Five-Day Prednisone Therapy Should Be the Norm for Treating COPD ExacerbationsA Swiss study provides the final piece of evidence that short-course steroids are equivalent to longer courses.

Treatment for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) includes inhaled broncho dilators, antibiotics, and systemic glucocorticoids. In a 1999 randomized trial, 2-week courses of glucocorticoids (methyl prednisolone for 72 hours, followed by tapered oral prednisone) were as effective as 8-week courses and more effective than placebo (NEJM JW Gen Med Jul 15 1999, p. 112, and N Engl J Med 1999 Jun 24; 340:1941). Subsequently, shorter-course and lower-dose glucocorticoid therapies were shown to be effective as well, but the optimal dosage and length of treatment were still debated. A 2011 Cochrane review showed no excess of treatment failures with regimens of ≤7 days versus >7 days, but data were insufficient to draw firm conclusions. The 2013 GOLD guidelines recommended prednisolone (30–40 mg for 10–14 days), citing level D evidence.*

In a 2013 Swiss trial, 314 patients with COPD exacerbations — most of whom were hospitalized — were randomized to 5 days or 14 days of prednisone (40 mg) in addition to other standard therapies. These patients had GOLD stage 3–4 COPD with an average forced expiratory volume in 1 second (FEV

1) 31% of predicted. About

10% of patients required home oxygen, and 30% were taking systemic steroids prior to the study. No difference between groups was noted in the primary endpoint (time to exacerbation within 180 days). Lung function, mortality, need for mechanical ventilation, and symptoms scores were similar between groups; adverse events, including hyperglycemia or hypertension, were rare and occurred equally in both groups. Hospital stays averaged 1 day shorter with the 5-day regimen (NEJM JW Gen Med Jul 15, p. 109, and JAMA Jun 5; 309:2223).

Patients with COPD exacerbations now should be treated with 40-mg prednisone for 5 days. Patients in the latest study had severe-to-very severe disease, so this short-course approach should be applicable to all patients. Because patients often experience several exacerbations annually, this approach could lower overall steroid exposure dramatically.

— David J. Amrol, MD

*The 2013 GOLD guidelines are available at http://www.goldcopd.org free of charge.







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Dual Blockade of the Renin-Angiotensin-Aldosterone System Doesn’t Benefit AnyoneSeveral new randomized trials and a meta-analysis all showed the same thing: No benefit and possible harm.

Compared with monotherapy (with angiotensin-converting–enzyme [ACE] inhibitors or angiotensin II–receptor blockers [ARBs]), dual blockade of the renin-angiotensin-aldosterone system results in lower blood pressure and less albuminuria. However, results of recent randomized, controlled trials and a meta-analysis indicate that dual blockade doesn’t benefit, and might harm, patients.

Three trials involved patients with type 2 diabetes. In one trial, 133 patients with diabetic nephropathy were randomized to receive an ACE inhibitor, an ARB, or dual blockade: After 32 months, the primary end-point (a composite of >50% increase in serum creatinine, progression to end-stage kidney disease [ESKD], and death) was about 30% in all three groups (NEJM JW Gen Med Apr 1, p. 55, and Am J Kidney Dis Feb; 61:211). In another trial, 8600 patients with type 2 diabetes who were taking an ACE inhibitor or an ARB were randomized to receive aliskiren (a renin inhibitor) or placebo: After 33 months, the primary outcome (composite of adverse cardiovascular- and kidney-associated outcomes) was about 18% in both groups, and adverse events were more common in the dual-blockade group (NEJM JW Gen Med Jan 1, p. 1, and N Engl J Med 2012 Dec 6; 367:2204). In another trial, 1450 patients with type 2 diabetes and reduced glomerular filtration rate (GFR) and proteinuria were randomized to receive an ARB plus an ACE inhibitor or placebo: After 2 years, the primary outcome (com-posite of decline in GFR >30 mL/minute/1.73 m2, ESKD, or death) was about 20% in both groups, and adverse events were more common in the dual-blockade group (NEJM JW Gen Med Dec 15, p. 190, and N Engl J Med Nov 14; 369:1892).

In a trial of more than 1600 patients with heart failure and reduced left ventricular ejection fraction, partici-pants received aliskiren or placebo in addition to standard medical therapy; 84% of patients were receiving an ACE inhibitor or an ARB. After 11 months, the primary endpoint (composite of cardiovascular-related death or heart-failure hospitalization) occurred in about 25% of each group, and adverse events (e.g., hypotension, kidney failure) were more common in the aliskiren group (NEJM JW Gen Med May 1, p. 69, and JAMA Mar 20; 309:1125).

Finally, in a meta-analysis of 33 randomized trials, researchers compared outcomes of dual blockade (ACE inhibitor plus ARB in 22 trials, ACE inhibitor or ARB plus aliskiren in 11 trials) with those of monotherapy. Out-comes were similar between the groups for all-cause death (about 15%), cardiovascular-related death (about 15%), and hospitalization for heart failure (about 10%); adverse events (e.g., hyperkalemia, hypotension, kidney failure) were more common with dual blockade (NEJM JW Gen Med Mar 15, p. 45, and BMJ Jan 28; 346:f360).

These results do not support use of dual therapy to block the renin-angiotensin system in patients with or without heart failure.

— Paul S. Mueller, MD, MPH, FACP







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Mediterranean Diet Tested in a Randomized TrialThis diet, supplemented generously with olive oil or nuts, was associated with fewer adverse cardiovascular events.

The so-called Mediterranean diet emphasizes olive oil, fruit, nuts, vegetables, and whole-grain cereals, as well as moderate intake of fish, poultry, and wine with meals. One of the most highly pub licized studies of 2013 was a large trial from Spain in which 7500 adults (age range, 55–80) were randomized to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil (at least 4 tablespoons daily), a Mediterranean diet supplemented with walnuts, almonds, and hazelnuts (30 g daily), or a low-fat control diet. Although participants had no clinically evident cardio vascular (CV) disease, inclusion criteria were either diabetes or multiple non diabetes CV risk factors.

During median follow-up of 5 years, rates of the primary outcome (myocardial infarction, stroke, or CV-related death) were significantly lower in both of the Mediterranean diet groups than in the control group (8 events per 1000 person-years in each Mediterranean group vs. 11 events per 1000 person-years in the control group); this translates into roughly 1 event prevented for every 70 Mediterranean-diet participants during the 5-year study. Most of the difference was attributable to lower stroke rates in the Mediterranean diet groups; neither myo-cardial infarction rates nor mortality differed by diet (NEJM JW Gen Med Apr 1, p. 53, and N Engl J Med Apr 4; 368:1279).

Because the low-fat control diet was not dramatically different from the Mediterranean diet, some observers believe that the supplemental olive oil and nuts were primarily responsible for this study’s outcome. Notably, about 50% of participants in each group were taking angiotensin-converting–enzyme inhibitors, 40% were taking statins, and 30% consumed at least one glass of wine daily. These background characteristics likely had some effect on the relatively low CV event rate in all groups.

Until now, most of the evidence favoring the Mediterranean diet was observational. We now have randomized-trial-level evidence that this diet — along with generous intake of extra-virgin olive oil and nuts — lowers cardiovascular risk to some extent.






15


Electronic Cigarettes: Increasingly Used, Still Unregulated, Poorly UnderstoodAmong adults and adolescents, e-cigarettes are the new trend.

Electronic cigarettes (e-cigarettes) — cigarette-shaped, battery-powered, nicotine-vapor delivery devices — are growing rapidly in popularity. They have been promoted as smoking-cessation aids, but we know little about their risks and benefits.

Two studies funded by the Centers for Disease Control and Prevention (CDC) and published in 2013 docu-mented the increasing popularity of e-cigarettes. In mail and Web-based surveys of adults in 2010 and 2011, awareness of e-cigarettes increased from 39% to 58%, and ever-use of e-cigarettes increased from 2.5% to 6.2%. Among current smokers, ever-use of e-cigarettes increased from 7.8% to 21.2% (Nicotine Tob Res Sep; 15:1623). In a school-based survey conducted in 2011 and 2012, similar trends were observed among youth, with ever-use of e-cigarettes increasing from 1.4% to 2.7% among middle-school students and from 4.7% to 10.0% among high-school students. Significantly, 20.3% of middle-school ever-users reported that they had never smoked conventional cigarettes (NEJM JW Gen Med Oct 15, p. 164, and MMWR Morb Mortal Wkly Rep Sep 6; 62:729).

The potential of e-cigarettes as smoking-cessation aids was explored in a New Zealand study: 657 adult smokers who wished to quit were randomized to ad lib use of e-cigarettes (containing either 16 mg of nicotine or placebo) or to daily 21-mg nicotine patches, for 13 weeks. At 6 months, all three groups had similar abstinence rates: 7.3% for nicotine e-cigarettes, 5.8% for patches, and 4.1% for placebo e-cigarettes. Participants using nico-tine e-cigarettes abstained sig nifi cantly longer than those in the other groups (medians: 35, 14, and 12 days, respectively; NEJM JW Gen Med Nov 15, p. 173, and Lancet Nov 16; 382:1629).

Many questions about e-cigarettes remain unanswered. Aside from addiction, what risks are incurred from inhaling nicotine vapor, particularly to the developing brains of children? Are other harmful substances present in e-cigarettes? Can nonusers be harmed by “second-hand vapor”? Will e-cigarettes be less harmful than smoking and aid in smoking cessation? Or will they encourage smoking initiation, deter smoking cessation, and under-mine antismoking campaigns?

E-cigarettes are currently classified as a tobacco product, but the FDA has not yet exercised its authority to regulate their marketing. Reportedly, it will issue preliminary rules soon (New York Times Oct 26). Clearly, we need more research to inform such regulations.

— Bruce Soloway, MD






16


Increasing Evidence That the Human Microbiome Plays a Major Role in HealthThe bacteria that live within us might influence everything from our weight to our cancer susceptibility.

We’ve known for more than a century that we are colonized by bacteria and that a few species benefit our health by synthesizing important vitamins and amino acids, degrading toxins, and helping digest plant material. However, we’ve assumed that most species that live on or within us don’t affect our health. An explosion of research is changing this view radically. We now know that our 13 trillion human cells coexist with 130 trillion bacterial cells. And, our 20,000 human genes coexist with 5 million to 8 million bacterial genes — what is called the “microbiome” or the “second human genome.”

Previously, the microbiome was linked to obesity (NEJM JW Gen Med Jan 15 2007, p. 16, and Nature 2006 Dec 21/28; 444:1027), inflammatory bowel disease (NEJM JW Gen Med Jul 15 2008, p. 112, and Nature 2008 May 29; 453:620), psoriasis, nonalcoholic fatty liver disease, asthma, and even autism. In 2013, investigators placed gut microbiota from obese and lean humans into the guts of average-weight mice: Those receiving the micro biota from obese humans became obese mice, and those receiving microbiota from lean humans remained lean (NEJM JW Gen Med Nov 15, p. 175, and Science Sep 6; 341:1079).

In 2011, the gut bug Fusobacterium nucleatum was linked to colorectal cancer (CRC) (NEJM JW Gen Med Dec 1 2011, p. 184, and Genome Res 2012 Feb; 22:292). But does F. nucleatum cause CRC, or does it secondarily colonize cancer cells? In 2013, researchers showed that the bacteria contain a unique receptor that binds to colorectal cells, stimulating both inflammation and carcinogenesis. When this bacterium was placed in the guts of CRC-susceptible mice, they developed excess numbers of CRCs (NEJM JW Gen Med Nov 1, p. 169, and Cell Host Microbe Aug 14; 14:195).

In 2013, several groups identified a “microbiome signature” that did a better job of predicting which people would develop type 2 diabetes mellitus than any human gene or behavior that has been linked to that disease (NEJM JW Gen Med Aug 1, p. 122, and Nature Jun 6; 498:99). Finally, several groups reported that gut bugs transform dietary lecithin and L-carnitine into a proatherogenic molecule, trimethylamine-N-oxide (TMAO). People with high blood levels of TMAO had excess risk for adverse cardiovascular events. In animal experiments, high blood levels of TMAO, caused by diets rich in lecithin or L-carnitine, and atherogenesis could be abolished by probiotic or antibiotic interventions (NEJM JW Gen Med Jun 15, p. 97, and N Engl J Med Apr 25; 368:1575 and NEJM JW Gen Med Jul 1, p. 103, and Nat Med May; 19:576).

None of the evidence that suggests an etiologic role for the microbiome in major human diseases is defini-tive. But we might be witnessing the birth of a revolution in our understanding of human health and disease.

— Anthony L. Komaroff, MD















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