This document summarizes two studies that raised questions about the risks and benefits of testosterone therapy: 1. A retrospective study found that male veterans with low testosterone who received testosterone therapy had a higher risk of heart attack, stroke, or death compared to those not receiving therapy, even after adjusting for potential confounding factors. 2. A randomized trial found that adding testosterone to optimized sildenafil therapy for erectile dysfunction provided no additional improvement in erectile function compared to sildenafil alone. Together these studies highlight the need for more research on the long-term risks and benefits of testosterone therapy, as current understanding is limited despite its increasing use.

1. 2013
YEAR IN REVIEW
Original Perspectives on the Year’s
Most Important Clinical Topics in General Medicine,
from the Editors of NEJM Journal Watch

2. EDITOR-IN-CHIEF
Allan S. Brett, MD, Professor of Medicine
and Director, Division of General Internal
Medicine, University of South Carolina
School of Medicine
EXECUTIVE EDITOR
Charleen M. Hamilton, PhD
Massachusetts Medical Society
DEPUTY EDITOR
Thomas L. Schwenk, MD, Dean,
University of Nevada School of Medicine;
Vice President of Health Sciences,
University of Nevada
FOUNDING EDITOR
Anthony L. Komaroff, MD, Senior Physician,
Division of General Medicine, Brigham and
Women’s Hospital, Boston; Professor of
Medicine, Harvard Medical School
ASSOCIATE EDITORS
David 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, MA
Kirsten E. Fleischmann, MD, MPH,
Attending Physician, Medical Center
at the University of California,
San Francisco; Professor of Clinical
Medicine, University of California,
San Francisco
Patricia Anne Kritek, MD, EdM, Associate
Professor, Division of Pulmonary and
Critical Care Medicine, University of
Washington, Seattle
Jamaluddin Moloo, MD, MPH, Associate
Professor of Medicine, Department
of Medicine and Radiology, University
of Colorado Health Sciences Center
Paul S. Mueller, MD, MPH, FACP, Chair,
Division of General Internal Medicine,
Professor of Medicine, Mayo Clinic
College of Medicine, Rochester, MN
Bruce Soloway, MD, Associate Professor
and Vice Chair, Department of Family and
Social Medicine, Albert Einstein College
of Medicine and Montefiore Medical
Center, NY
Abigail Zuger, MD, Associate Professor
of Clinical Medicine, Columbia University
College of Physicians and Surgeons;
Senior Attending Physician, St. Luke’sRoosevelt Hospital Center, NY
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
CONTRIBUTING EDITOR
Robert W. Rebar, MD, Executive Director,
American Society for Reproductive
Medicine, Birmingham, AL
800.843.6356 | f: 781.891.1995 | nejmgroup@mms.org
860 winter street, waltham, ma 02451-1413
nejmgroup.org

3. YEAR IN REVIEW | 2013
TABLE OF CONTENTS
New Cholesterol Guidelines Spur Debate
4
New Data on Early Treatment of Stroke and
Transient Ischemic Attack
5
Restrictive Transfusion Strategy Lowers Mortality
in Patients with Upper Gastrointestinal Bleeding
6
Questions About Risks and Benefits
of Testosterone Therapy
7
Lung Cancer Screening with Computed Tomography —
Now Recommended
8
Renal Artery Stenting Receives the Death Knell
9
Proning? Yes. Gastric-Residual Monitoring? No.
Ongoing Battles with ICU Infections
11
Five-Day Prednisone Therapy Should Be the Norm
for Treating COPD Exacerbations
12
Dual Blockade of the Renin-Angiotensin-Aldosterone
System Doesn’t Benefit Anyone
13
Mediterranean Diet Tested in a Randomized Trial
14
Electronic Cigarettes: Increasingly Used,
Still Unregulated, Poorly Understood
The order of these stories is not
intended to reflect their relative
importance. All citations refer to
2013, unless otherwise noted.
10
15
Increasing Evidence That the Human Microbiome
Plays a Major Role in Health
16
NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society.
©2014 Massachusetts Medical Society. All rights reserved.

4. YEAR IN REVIEW | 2013
New Cholesterol Guidelines Spur Debate
The 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 ents new sex-specific equations, developed from multiple large cohorts, to
s
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 anklebrachial 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 ascular risk in adults (NEJM JW Gen Med Dec 15, p. 194, and J Am Coll Cardiol Nov 12; [e-pub ahead of
v
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
• atients with LDL cholesterol levels ≥190 mg/dL
P
• lder diabetic patients (age range, 40–75) with LDL cholesterol levels
O
of 70–189 mg/dL and without clinical ASCVD
• atients without clinical ASCVD or diabetes but with LDL cholesterol levels of 70–189 mg/dL and estimated
P
10-year ASCVD risk ≥7.5%
With few exceptions, use of lipid-modifying drugs other than statins is discouraged, and lifestyle modification 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 ­nstituting statin therapy in primary prevention is much lower than
i
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.
— irsten E. Fleischmann, MD, MPH
K
*The risk calculator is available at http://my.americanheart.org/cvriskcalculator free of charge.
4
Back to Table of Contents

5. YEAR IN REVIEW | 2013
New Data on Early Treatment of Stroke and Transient Ischemic Attack
Large 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 earchers conducted a randomized trial that involved 5170 patients with high-risk TIA or minor ischemic stroke
s
(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 aspirinalone 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 disruption 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 rd treatments in paa
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 receiving thrombolytic therapy, recent guidelines (Stroke Mar; 44:870) recommend treatment only when blood pressure 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 antihypertensive 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 randomized 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 ficial nor harmful for
e
ischemic stroke and might be beneficial for hemorrhagic stroke; (3) the efficacy of endovascular interventions
for anterior circulation strokes remains unproven.
— llan S. Brett, MD
A
*Information about the POINT trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00991029 free of charge.
5
Back to Table of Contents

6. YEAR IN REVIEW | 2013
Restrictive Transfusion Strategy Lowers Mortality in Patients
with Upper Gastrointestinal Bleeding
The 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 icular benefit in patients with mild-to-moderate cirrhotic disease
t
(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 decisionmaking. Both the lower transfusion rate and the clinical benefits are substantial. Patients with mild-to-moderate
cirrhotic disease ex­ erience particular benefits, presumably because they are protected against ­ncreases in
p
i
portal pressure.
— homas L. Schwenk, MD
T
6
Back to Table of Contents

7. YEAR IN REVIEW | 2013
Questions About Risks and Benefits of Testosterone Therapy
We 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 ver, in a short-term randomized trial published in 2010, the incidence of adverse cardiovascular
e
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 received 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 adverse events with testosterone therapy occurred regardless of the presence or absence of CAD. Analyses were adjusted 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 optimized sildenafil therapy and then were ran­ omized to add daily transdermal tes­ osterone (5–15 g) or placebo for
d
t
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 promotion 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.
— homas L. Schwenk, MD
T
7
Back to Table of Contents

8. YEAR IN REVIEW | 2013
Lung Cancer Screening with Computed Tomography —
Now Recommended
The 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 end­
m
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 ulator — which requires input of nine
c
demo­ raphic, clinical, and radiologic variables — is available online (NEJM JW Gen Med Oct 15, p. 157, and
g
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.
— llan S. Brett, MD
A
*The risk calculator is available at http://www.brocku.ca/lung-cancer-risk-calculator free of charge.
8
Back to Table of Contents

9. YEAR IN REVIEW | 2013
Renal Artery Stenting Receives the Death Knell
A 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.
— amaluddin Moloo, MD, MPH
J
9
Back to Table of Contents

10. YEAR IN REVIEW | 2013
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.
• atients with acute respiratory distress syndrome (ARDS) often develop consolidation of the dependent lung
P
regions. For many years, physicians have transitioned severely hypoxemic patients from supine to prone positions 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.
• n most hospitals, gastric residuals are monitored for all patients who receive enteral feeding. The theory
I
is that patients with larger residuals are at greater risk for vomiting, subsequent aspiration, and ventilatorassociated 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
10
Back to Table of Contents

11. YEAR IN REVIEW | 2013
Ongoing Battles with ICU Infections
Investigators 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 methicillinresistant Staphylococcus aureus (MRSA) or other resistant organisms and then placing colonized patients in contact 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 ted expanding use of contact precautions to all patients rather than just
a
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 improvement in clinical endpoints was found.
In other studies, researchers evalu­ ted the strategy of bolstering standard screening and isolation precaua
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 ointment, (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 cultures 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);
i
­ndeed, some ICUs have already implemented universal decontamination. Other commentators endorse building 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 topical 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).
— bigail Zuger, MD
A
11
Back to Table of Contents

12. YEAR IN REVIEW | 2013
Five-Day Prednisone Therapy Should Be the Norm
for Treating COPD Exacerbations
A 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 ilators, antibiotics, and systemic glucocorticoids. In a 1999 randomized trial, 2-week courses
d
of glucocorticoids (methyl­ rednisolone for 72 hours, followed by tapered oral prednisone) were as effective
p
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 (FEV1) 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.
— avid J. Amrol, MD
D
*The 2013 GOLD guidelines are available at http://www.goldcopd.org free of charge.
12
Back to Table of Contents

13. YEAR IN REVIEW | 2013
Dual Blockade of the Renin-Angiotensin-Aldosterone System
Doesn’t Benefit Anyone
Several 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 (composite 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, participants 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. Outcomes 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.
— aul S. Mueller, MD, MPH, FACP
P
13
Back to Table of Contents

14. YEAR IN REVIEW | 2013
Mediterranean Diet Tested in a Randomized Trial
This 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 pub­icized studies of 2013
l
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 ascular (CV) disease, inclusion criteria were either diabetes or
v
multiple non­ iabetes CV risk factors.
d
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.
— llan S. Brett, MD
A
14
Back to Table of Contents

15. YEAR IN REVIEW | 2013
Electronic Cigarettes: Increasingly Used, Still Unregulated, Poorly Understood
Among 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 documented 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 nicotine e-cigarettes abstained sig­ ifi­ antly longer than those in the other groups (medians: 35, 14, and 12 days,
n c
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 undermine 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.
— ruce Soloway, MD
B
15
Back to Table of Contents

16. YEAR IN REVIEW | 2013
Increasing Evidence That the Human Microbiome Plays a Major Role
in Health
The 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 iota from obese humans became obese mice, and those receiving microbiota from lean humans
b
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 definitive. But we might be witnessing the birth of a revolution in our understanding of human health and disease.
— Anthony L. Komaroff, MD
16
Back to Table of Contents

17. YEAR IN REVIEW | 2013
TIMELY. TRUSTED. ESSENTIAL.
To deliver the quality of care your patients deserve, you’ve got to remain current with the
latest research. But that’s daunting in today’s increasingly complex world of medicine.
That’s why every day, leading clinicians across the globe turn to NEJM Journal Watch.
NEJM Journal Watch is committed to delivering the rigorous quality and independent
perspective that define all NEJM Group products.
Our physician-editors continually survey over 250 journals, select the most important
research and guidelines, frame them in the proper context, and deliver them in formats
designed for today’s busy clinicians. NEJM Journal Watch keeps you clinically prepared
and confident.
Because time and trust are of the essence.
JWatch.org
Back to Table of Contents