YEAR IN REVIEW 2019

Original Perspectives on the Year’s

Most Important Clinical Topics
in General Medicine from the
Editors of NEJM Journal Watch
EDITOR-IN-CHIEF
Allan S. Brett, MD, Professor of Medicine
Dear Reader,
and Director, Division of General Internal
Medicine, University of South Carolina
School of Medicine, Columbia
In our annual review of important clinical research from the past year,
EXECUTIVE EDITOR the editors of NEJM Journal Watch General Medicine try to balance
Charleen M. Hamilton, PhD relevance to general medicine and recognition of landmark studies
Massachusetts Medical Society
DEPUTY EDITOR and key guidelines. The order of presentation of these summaries is
Thomas L. Schwenk, MD, Dean, not intended to reflect their relative importance. All references are
University of Nevada School of Medicine;
Vice President of Health Sciences, from 2019 unless otherwise noted.
University of Nevada, Reno
FOUNDING EDITOR
Anthony L. Komaroff, MD, Senior Physician,
Division of General Medicine, Brigham and — Allan S. Brett, MD
Women’s Hospital; Professor of Medicine,
Harvard Medical School, Boston, MA Editor-in-Chief
ASSOCIATE EDITORS NEJM Journal Watch General Medicine
David J. Amrol, MD, Associate Professor
of Clinical Internal Medicine, Director of
the Division of Allergy and Immunology,
University of South Carolina School of
Medicine, Columbia
Jonathan S. Coblyn, MD, Associate
Professor, Harvard Medical School;
Vice Chair of Medicine and Director of
Clinical Rheumatology; Brigham and
Women’s Hospital, Boston, MA
Daniel D. Dressler, MD, MSc, SFHM, FACP,
Director, Internal Medicine Teaching
Services, Emory University Hospital;
Associate Program Director, J Willis Hurst
Internal Medicine Residency Program;
Professor of Medicine, Emory University
School of Medicine, Atlanta, GA
Kirsten E. Fleischmann, MD, MPH, FACC,
Attending Physician, Medical Center at the
University of California, San Francisco;
Professor of Clinical Medicine, University
of California, San Francisco
Patricia Kritek, MD, Professor of Medicine,
Division of Pulmonary and Critical Care
Medicine, University of Washington, Seattle
Paul S. Mueller, MD, MPH, FACP, Regional
Vice President — Southwest Wisconsin,
Mayo Clinic Health System; Professor of
Medicine and Biomedical Ethics, Mayo
Clinic College of Medicine and Science,
La Crosse, WI
Bruce Soloway, MD, Associate Professor
of Family Medicine and Attending Family
Physician, Montefiore Medical Center, Albert
Einstein College of Medicine, Bronx, NY
Abigail Zuger, MD, Associate Clinical
Professor of Medicine, Icahn School of
Medicine at Mount Sinai; Senior Attending
Physician, Mount Sinai Roosevelt and Mount
Sinai St. Luke’s Hospitals, New York City, NY

800.843.6356 | f: 781.891.1995 | nejmgroup@mms.org

860 winter street, waltham, ma 02451-1413
nejmgroup.org
Year in Review 2019

TABLE OF
CONTENTS

Common Guidelines for Bacterial Pneumonia Have Been Updated 2

Are As-Needed Inhaled Steroids Effective for Mild Asthma? 3

Secondary Prevention After Stroke 4

Important New Studies on Managing Atrial Fibrillation 5

New Studies on Managing Severe Aortic Stenosis 6

A New Cholesterol  Treatment Guideline 7

Follow-up Colonoscopy in Patients with Small Nonadvanced Adenomas 8

Proton-Pump Inhibitors Are Probably Safe for at Least 3  Years of Chronic Use 9

Preventing Venous  Thromboembolism in Intensive Care Patients 10

Overtreatment of Blood Pressure in Hospitalized Patients 11

E-Cigarette or Vaping-Associated Lung Injury 12

Alternatives to Opioids for Pain Management 13

NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society.
©2020 Massachusetts Medical Society. All rights reserved.
 YEAR IN REVIEW 2019

Common Guidelines for Bacterial Pneumonia

Have Been Updated
Influential clinical protocols have changed to include fewer rules and require more thought.
2019 saw seismic changes in recommendations for preventing and treating bacterial pneumonia.
First, the CDC no longer supports routine administration of the 13-valent conjugate pneumo-
coccal vaccine (Prevnar) to older adults (age, ≥65; NEJM JW Gen Med Aug 15 and Clin Infect Dis
Jul 1; 69:34). Effective pediatric immunization has dramatically lowered rates of adult pneumonia
caused by this vaccine’s serotypes. The vaccine still is recommended for immunocompromised
older adults and those with cerebrospinal fluid leak or cochlear implants. Everyone else is advised
to discuss pros and cons with their clinicians, presumably focusing on any substantial comorbid-
ities and general care preferences (NEJM JW Gen Med Aug 15). Routine immunization with the
23-valent vaccine (Pneumovax) still is recommended for all adults older than 65 (MMWR Morb
Mortal Wkly Rep Nov 22; 68:1069).
The widely respected joint IDSA/ATS treatment guidelines for community-acquired pneumonia
(CAP) were updated for the first time in 12 years. The most substantial change is the elimination
of the “healthcare-associated pneumonia” category. These patients were once thought to be at
such high risk for nosocomial pathogens like methicillin-resistant Staphylococcus aureus (MRSA)
or Pseudomonas aeruginosa that aggressive empirical treatment was warranted. Good evidence now
suggests this practice does not improve clinical outcomes and leads to massive overuse of broad-
spectrum agents. The new guidelines urge clinicians to use other criteria for deploying these drugs
before cultures are available. The single greatest risk for a CAP with MRSA or P. aeruginosa is
having had a previous episode. Other risks have been more difficult to pin down, and the guidelines
urge clinicians to consider local patterns to create sensible policies for their own practices
(NEJM JW Gen Med Dec 1 and Am J Respir Crit Care Med Oct; 200:45).
The guidelines recommend against using steroids in patients without refractory septic shock,
against using procalcitonin as a marker of illness severity, and against routine posttreatment chest
imaging. Past enthusiasm for macrolides as go-to drugs for nonsevere CAP has been moderated
because of increasing resistance targeting some communities. Both amoxicillin and doxycycline
are alternatives for healthy outpatients, whereas outpatients with substantial comorbidities might
receive amoxicillin/clavulanate or an oral cephalosporin (both in combination with a macrolide)
or a respiratory quinolone alone. New evidence suggests that a macrolide/β-lactam combination
might be superior to a uinolone/β-lactam combination in patients with severe CAP. The guidelines
endorse a minimum of 5 days’ treatment for all patients, whereas other studies this year strongly
suggest that 5 days is all stable patients really need (NEJM Gen Med Aug 15 and Ann Intern Med
Jul 9; 171:153).
Clinicians might well be frustrated by these changes, which remove familiar algorithms and
substitute the need for case-by-case decision making. But, alas, such is infectious disease practice
these days, as both sensible vaccine policy and profligate antibiotic overuse continue to change
the spectrum of human pathogens.
— Abigail Zuger, MD

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 YEAR IN REVIEW 2019

Are As-Needed Inhaled Steroids Effective

for Mild Asthma?
As-needed budesonide/formoterol appears to be at least as effective as daily inhaled steroids.
U.S. guidelines from the National Asthma Education and Prevention Program (NAEPP) — last
updated in 2007 — recommend as-needed short-acting β-agonists (e.g., albuterol) for patients with
mild intermittent asthma and daily inhaled corticosteroids (ICS) for those with mild persistent
asthma. However, most patients in the latter category don’t use their asthma controller inhalers daily.
Because even patients with mild asthma can have severe exacerbations, in recent studies researchers
have examined whether patients with mild asthma could benefit from as-needed use of ICS
combined with a quick-onset but long-acting β-agonist (e.g., budesonide plus formoterol).
Two such studies were published in 2019.
In one unblinded, randomized trial, patients with mild asthma received daily budesonide
(plus as-needed albuterol), as-needed budesonide/formoterol (i.e., no daily ICS), or as-needed
albuterol only. Both budesonide groups had similarly fewer exacerbations compared with the
albuterol-only group, although daily symptom scores were slightly better with daily budesonide
than with as-needed budesonide/formoterol (NEJM JW Gen Med Jul 1 and N Engl J Med May 19;
380:2020). In another open-label, randomized trial, as-needed budesonide/formoterol (compared
with daily budesonide plus as-needed short-acting β-agonist) was associated with 30% fewer se-
vere exacerbations and with less cumulative exposure to ICS (NEJM JW Gen Med Oct 15 and Lan-
cet Sep 14; 394:919). Several previous trials yielded similar outcomes. In all these studies, a dry-
powder budesonide/formoterol Turbohaler was used.
These findings led the largely European 2019 Global Initiative for Asthma (GINA) to discourage
as-needed albuterol monotherapy in any patient. Instead, GINA now recommends as-needed
ICS/formoterol for intermittent asthma, and either daily ICS or as-needed ICS/formoterol for
mild persistent asthma. In the U.S., an update of the NAEPP guideline finally will be released in
2020. An early draft suggests that NAEPP also will permit the option of as-needed ICS for mild
persistent asthma — but in combination with albuterol rather than formoterol. (Note: This will
require separate ICS and albuterol inhalers.)
Because albuterol is much cheaper than metered-dose budesonide/formoterol in the U.S.,
I still use albuterol alone for very mild intermittent asthma. But for mild persistent asthma, I believe
it’s appropriate to use as-needed ICS-containing therapy. For now, I offer the option of as-needed
therapy with the metered-dose version of budesonide/formoterol, ensuring that patients under-
stand that this represents off-label use. Many of my patients have opted for this regimen, with
good results. Two final caveats: First, this regimen has not been studied in children younger than
12. Second, ICS/salmeterol combinations cannot be used in this manner, as salmeterol has
slower onset than formoterol.
— David Amrol, MD
The NAEPP and GINA guidelines are available at https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthsumm.pdf and
https://ginasthma.org/gina-reports/, respectively, free of charge.

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 YEAR IN REVIEW 2019

Secondary Prevention After Stroke

Researchers examined lipid targets, blood pressure targets, and antithrombotic therapy after
embolic stroke of unknown source.
In 2019, data were published from three large randomized trials in which several facets of
secondary prevention after stroke were examined.
One trial addressed antithrombotic therapy to prevent recurrence in patients with embolic
stroke of unknown source (ESUS). About 5400 patients with ESUS received either dabigatran or
aspirin; during average follow-up of 19 months, researchers noted no significant difference in in-
cidence of recurrent stroke in the two groups (NEJM JW Gen Med Aug 1 and N Engl J Med May 16;
380:1906). In a similar study, published in 2018, investigators compared rivaroxaban and aspirin
and reached a similar conclusion — no difference between groups (NEJM JW Gen Med Jun 15
2018 and N Engl J Med 2018 Jun 7; 378:2191). Thus, although the idea of anticoagulation rather
than antiplatelet therapy for ESUS patients is intriguing, trial results don’t support that move.
The widely prescribed fixed dose of 80-mg atorvastatin for secondary stroke prevention comes
from a single trial (SPARCL) published in 2006 (N Engl J Med 2006 Aug 10; 355:549). The 80-mg
atorvastatin dose reduced the incidence of recurrent stroke from 13% to 11% during 5 years of
follow-up, but the result was barely statistically significant. In 2019, another group examined
lipid-lowering therapy in nearly 3000 patients with recent ischemic stroke or transient ischemic
attack (TIA) of presumed atherosclerotic origin. Patients were randomized to an LDL cholesterol
target of <70 mg/dL or 90 to 110 mg/dL; treating physicians were permitted to use any statin
and to add ezetimibe if necessary. During average follow-up of 3.5 years, incidence of the primary
endpoint (including both recurrent stroke and coronary events) was slightly lower in the lower-
target group (8.5% vs. 10.9%; P=0.04). These results support more flexibility in choosing lipid-
lowering therapy after ischemic stroke; many patients in the lower-target group required only
moderate-intensity statins (NEJM JW Gen Med Dec 15 and N Engl J Med Nov 18; [e-pub]).
Finally, what is the optimal long-term blood pressure target in patients with recent stroke
or TIA? In a Japanese study, 1300 patients were randomized to long-term targets of either
<120/80 mm Hg or <140/90 mm Hg (NEJM JW Gen Med Dec 15 and JAMA Neurol Nov 15;
76:1309). During 4 years of follow-up, a small difference in incidence of recurrent stroke did not
reach significance (6% and 8%; P=0.15). In the only previous large trial in which this question
was examined directly (but conducted exclusively in patients with lacunar stroke), results were simi-
lar — a small but nonsignificant reduction in recurrent stroke in a lower-target group (Lancet
2013 Aug 10; 382:507). My take: A target of roughly 120 mm Hg is reasonable, as
long as the patient tolerates treatment without adverse effects.
— Allan S. Brett, MD

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 YEAR IN REVIEW 2019

Important New Studies on Managing Atrial Fibrillation

Randomized trials addressed antithrombotic therapy and timing of cardioversion.
Atrial fibrillation (AF) and coronary artery disease (CAD) often coexist, but how do we best use
anticoagulants and antiplatelet agents to balance efficacy and bleeding risk? To address this
question in patients with recently symptomatic CAD, researchers enrolled 4600 patients with AF
and acute coronary syndrome or percutaneous coronary intervention (PCI) during the previous
2 weeks. In addition to receiving a P2Y12 inhibitor (most often clopidogrel), patients were random­
ized twice — to apixaban or a vitamin K antag­onist (VKA), and to aspirin or placebo. Both clinically
significant bleeding and a composite endpoint of hospitalization or death were less common with
apixaban than with VKA, and aspirin led to more bleeding without significantly improving cardio­
vascular outcomes. Thus, two-drug therapy with apixaban plus a P2Y12 inhibi­tor offered the best
benefit-harm balance; triple therapy led to more bleeding without conferring cardiovascular benefit,
although an editorialist believes that triple therapy still might be appropriate for selected high-
risk patients (NEJM JW Gen Med May 1 and N Engl J Med Apr 18; 380:1509, 1580).
In another randomized trial, researchers examined antithrombotic therapy in 2200 AF patients
with chronic stable CAD (coronary bypass surgery or PCI at least 1 year earlier or medically treated
disease). Patients received either rivaroxaban alone or rivaroxaban plus an antiplatelet drug
(clinicians’ choice of aspirin or P2Y12 inhibitor). At 2 years, rivaroxaban monotherapy was
associated with fewer adverse cardiovascular events and deaths and with less major bleeding,
compared with two-drug therapy, suggesting that monotherapy with a direct-acting oral antico-
agulant is sufficient for AF patients with chronic stable CAD (NEJM JW Gen Med
Oct 1 and N Engl J Med Sep 19; 381:1103).
In 2019, investigators examined another facet of AF treatment — the timing of cardioversion
— in 437 hemodynamically stable patients who presented to emergency departments with sympto­
matic AF of <36 hours onset. Patients were randomized to early pharmacologic or electrical
cardioversion or to delayed cardioversion at 48 hours after symptom onset. The rate of sinus
rhythm at 4 weeks was similar in the early and delayed groups (94% and 91%). In the early
group, 16% of patients converted to sinus rhythm before cardioversion and 78% converted with
cardioversion. In the delayed group, 69% converted to sinus rhythm sponta­neously and 28%
converted after delayed cardioversion. This study suggests that waiting until 48 hours to
cardiovert hemodynamically stable patients with symptomatic AF is a reasonable option
(NEJM JW Gen Med Apr 15 and N Engl J Med Apr 18; 380:1499).
— Kirsten E. Fleischmann, MD, MPH, FACC

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 YEAR IN REVIEW 2019

New Studies on Managing Severe Aortic Stenosis

Use of transcatheter aortic valve replacement is expanding to lower-risk patients.
Until recently, transcatheter aortic valve replacement (TAVR) was reserved for patients in whom
conventional valve replacement was considered to be too high risk. But in 2019, two studies
shed light on outcomes with TAVR in low-risk patients.
In the one study, 1000 patients at low surgical risk were randomized to surgical aortic valve
replacement (SAVR) or TAVR. Death, stroke, or rehospitalization at 1 year was significantly lower
in the TAVR group (8.5% vs. 15.1%). TAVR also conferred lower 30-day rates of death, stroke,
and new atrial fibrillation and also was asso­ciated with shorter index hospitalization, although
new left bundle branch block and paravalvar regurgitation were more common with TAVR
(NEJM JW Gen Med May 1 and N Engl J Med May 2; 380:1695).
In a second study, researchers randomized more than 1400 patients (mean age, 74) to TAVR
with a self-expanding bioprosthesis or to SAVR. Interim results suggest TAVR is noninferior and
that death or disabling stroke is nonsignificantly less common in the TAVR group (estimated
24-month incidence, 5.3% vs. 6.7%; NEJM JW Gen Med May 1 and N Engl J Med May 2;
380:1706).
Aortic valve replacement for aortic stenosis generally is reserved for symptomatic patients.
But in a new study from Korea, 145 asymptomatic patients with very severe aortic stenosis were
randomized to surgery or conservative management. The average age of patients was approxi­
mately 64, and about 60% had bicuspid aortic valves. A composite endpoint of 30-day postoperative
mortality and cardiovascular-related mortality during the follow-up period (median, 6 years) oc-
curred significantly less often in the surgical group (1% vs. 15%; NEJM JW Gen Med Jan 1 2020
and N Engl J Med Nov 16; [e-pub]).
The first two studies demonstrate the intense interest in expanding indications for TAVR to
patients at low surgical risk. Correspondents note the younger age of these lower-risk patients,
the relatively short follow-up time, and the lack of long-term durability results. Nonetheless, when
the time comes to consider valve replacement, more and more of my patients are asking about
TAVR, even if they are good candidates for surgery. Findings from the Korean study suggest better
outcomes with earlier surgical intervention for asymptomatic patients with very severe aortic
stenosis, but with some caveats: Study participants were relatively young, and the incidence of
bicuspid valve disease was high. Therefore, these findings might not be generalizable to typical
older patients.
— Kirsten E. Fleischmann, MD, MPH, FACC

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 YEAR IN REVIEW 2019

A New Cholesterol Treatment Guideline

For primary prevention, the guideline is somewhat less aggressive about statin therapy than its
2013 predecessor.
A 2013 guideline from the American College of Cardiology and American Heart Association
(ACC/AHA) sug­gested statin therapy for primary pre­vention if a patient’s 10-year risk for cardio­
vas­cular (CV) events — as calcu­lated on an ACC/AHA risk calculator — exceeded 7.5%. But in an
update published during the past year, the guideline committee revised its approach to primary
prevention somewhat. For middle-aged adults (age range, 40–75) with LDL cholesterol levels
between 70 and 189 mg/dL and with 10-year risk ≥20%, statins are recommended unequivocally.
However, the authors created a broad new “intermediate risk” category, defined as 10-year risk
between 7.5% and 19.9%. For these patients, the guideline states that statin therapy “should be
considered during risk discussion of treatment options,” and that the decision should be informed
by patient preferences, presence of “risk-enhancing factors” (e.g., metabolic syndrome, strong
family history), and in some cases, coronary artery calcium scoring. This less dogmatic approach,
which gives clinicians more discretion in whether to prescribe statins, stems in part from recognition
that the ACC/AHA calculator overestimates risk in some patients (NEJM JW Gen Med Feb 1 and
J Am Coll Cardiol Jun 25; 73:e285).
A controversial modeling study on primary preventive statin therapy also was published in
2019. The model, which included data from randomized and observational studies, incorporated
hypothetical patient preferences and gave considerable weight to adverse effects of statins (some
of which likely were overestimated). The 10-year predicted CV risk above which the model
predicted net benefit from statins ranged from 14% for men in their 40s to 21% for men in their
70s, and from 17% for women in their 40s to 22% for women in their 70s (NEJM JW Gen Med
Feb 15 and Ann Intern Med Jan 1; 170:1).
Another debated topic is whether primary preventive statin therapy is warranted in older
patients. In a new meta-analysis that involved 15,000 older randomized trial participants
(age, ≥75) without vascular disease, statin therapy did not significantly lower the incidence
of major vascular events. The ACC/AHA guideline nevertheless states that selective use of
statins, depending on patient preferences, “may be reasonable” for primary prevention in this
age group (NEJM JW Gen Med Mar 15 and Lancet Feb 2; 393:407).
— Allan S. Brett, MD

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 YEAR IN REVIEW 2019

Follow-up Colonoscopy in Patients

with Small Nonadvanced Adenomas
Patients with 1 or 2 small adenomas probably need only routine follow-up screening.
Many average-risk patients who undergo screening colonoscopy have a few small tubular
adenomas without high-grade dysplasia. Although the 2012 multisociety guideline that has
served as a U.S. practice standard recommends a 5- to 10-year surveillance interval for patients
with 1 or 2 tubular adenomas measuring <10 mm (Gastroenterology 2012 Sep; 143:844), many
are asked to return for repeat colonoscopy every 5 years. In 2019, a host of new studies added
information particularly relevant to such patients. For example:
• In a study from Japan, patients with 1 or 2 unresected diminutive adenomas (<5 mm) were
not more likely than patients with no adenomas to develop advanced colorectal neoplasia —
defined as adenoma ≥10 mm, adenoma with high-grade dysplasia or villous histology, or
carcinoma — at 5-year follow-up colonoscopy; 5-year risk for new advanced lesions was only
1% in both groups (NEJM JW Gastroenterol Aug and Am J Gastroenterol Jun; 114:964).
• In a U.S. study, the cumulative 10-year incidence of advanced neoplasia among patients with 1
or 2 small (<10 mm) adenomas at baseline was similar to that of patients with no adenomas —
about 5% in both groups (NEJM JW Gastroenterol Aug 13; [e-pub] and Gastroenterology Jul 31;
[e-pub]).
• In a huge study from Poland, researchers used the endpoint of development of colorectal
cancer (rather than the surrogate endpoint of advanced polyp). During as long as 14 years
of follow-up, the only findings on screening colonoscopy that predicted subsequent colorectal
cancer were adenoma size >20 mm or adenoma of any size with high-grade dysplasia (NEJM
JW Gen Med Dec 1 and Gastroenterology Sep 26; [e-pub]).
• In another U.S. study, 10-year colorectal cancer risk among patients with nonadvanced
conventional adenomas at baseline screening was similar to that of patients with no adeno-
mas (NEJM JW Gen Med Sep 1 and Gastroenterology Jul 11; [e-pub]).
Recommended surveillance intervals after abnormal screening colonoscopy are based on
imperfect observational data and expert consensus. Although these new studies also have
limitations, taken together, they suggest that the longer 10-year interval could be applicable to a
broader range of patients. The evidence for a longer interval is strongest for patients with 1 or 2
diminutive adenomas (≤5 mm), but some studies suggest that less-intensive surveillance also
could be applied safely to a larger subgroup of patients with nonadvanced adenomas. The study
from Poland is particularly provocative, suggesting that a relatively small proportion of patients
with adenomas ultimately benefit from short-interval repeat screening. An updated version of
the 2012 multisociety U.S. guideline will be released shortly; it will be interesting to see whether
recommended surveillance interval recommendations are revised in the new iteration.
— Allan S. Brett, MD, and Charles J. Kahi, MD, MS, NEJM Journal Watch Gastroenterology

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 YEAR IN REVIEW 2019

Proton-Pump Inhibitors Are Probably Safe for at Least

3 Years of Chronic Use
A randomized trial showed no association between pantoprazole and various purported
adverse outcomes.
Proton-pump inhibitors (PPIs) are very effective for reducing gastric acid secretion, and many
patients take them chronically for relief of dyspepsia or heartburn. But observational studies,
some widely publicized, have suggested that long-term PPI use might be associated with excess
risk for pneumonia, fracture, enteric infections, Clostridioides difficile–related diarrhea, cerebro­
vas­cular events, chronic renal failure, dementia, and all-cause mortality. Guidelines advise that
long-term treatment with PPIs be avoided wherever possible, and patients who rely on these
drugs sometimes express concerns about their safety.
In the COMPASS trial, researchers randomized 27,000 patients with stable atherosclerotic
disease to take rivaroxaban, aspirin, or both, and, in addition, 17,000 of these patients who were
not taking PPIs at baseline were randomized again to receive either pantoprazole (40 mg) or
placebo daily. The rivaroxaban/ aspirin arm of the study was terminated early, and cardiovascular
outcomes were reported in 2017 (NEJM JW Gen Med Oct 1 2017 and N Engl J Med 2017 Oct 5;
377:1319). But patients continued taking pantoprazole or placebo for a mean of 3 years, providing
some of the first randomized data on long-term efficacy and safety of PPIs, which were reported
this year.
Pantoprazole and placebo were not significantly different for the primary efficacy outcome,
which was a composite of upper gastrointestinal (GI) clinical events. This finding was unsurprising,
given that patients who were perceived to be at high risk for bleeding were excluded from the
pantoprazole arm of the study (NEJM JW Gen Med Sep 15 and Gastroenterology Aug; 157:403).
Of greater interest were the prospective safety data, which demonstrated modestly more non-
Clostridioides enteric infections in the pantoprazole group (1.4% vs. 1.0%) but no associations
between pantoprazole and any of the other purported adverse safety outcomes (NEJM JW Gen Med
Sep 15 and Gastroenterology Sep; 157:682).
Excess enteric infections in patients who take PPIs plausibly can be attributed to reduced
ability of gastric acid to disable ingested pathogens. The absence of other adverse effects during
3 years of PPI use should be broadly reassuring to patients and clinicians, although adverse
effects with longer use cannot be excluded. Despite more confidence in their long-term safety,
PPIs still should be used only when clinically indicated and should not be re­prescribed indefi-
nitely when indi­cations are no longer present (NEJM JW Gen Med Sep 15).
— Bruce Soloway, MD

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 YEAR IN REVIEW 2019

Preventing Venous Thromboembolism

in Intensive Care Patients
Patients generally don’t benefit from adding pneumatic compression to pharmacologic
prophylaxis.
Quite often, we keep doing things simply because we’ve always done them that way. In many
intensive care units (ICU), one of those practices is “dual therapy” for preventing venous
thromboembolism (VTE): pharmacologic prophylaxis plus pneumatic compression devices.
In 2019, a large multinational study put this practice to the test.
A total of 2000 ICU patients were randomized to receive pharmacologic prophylaxis alone
(with a choice of unfractionated heparin or low-molecular-weight heparin) or in conjunction with
intermittent pneumatic compression. Patients most commonly were admitted to the ICU for
nonsurgical and non–trauma-related issues, and data on high-risk states (e.g., malignancy) were
not reported. Adherence to use of pneumatic compression was good (median, 22 hours daily).
All patients underwent lower-extremity ultrasound assessment for deep venous thrombosis
(DVT) twice weekly, with evaluation for possible pulmonary embolism (PE) at the discretion of
the treating team. Incidence of new VTE was rare (DVT, 4%; PE, 1%) and similar between groups.
Incidences of pressure ulcers and skin injury were similar in the two groups (NEJM JW Gen Med
Apr 1 and N Engl J Med Apr 4; 380:1305).
Most patients find pneumatic compression devices to be uncomfortable. They disrupt sleep
and tether patients to their beds. As we work to prioritize early mobility in the ICU, as well as
minimize factors that contribute to delirium, using pneumatic compression devices only when we
really need them makes sense. For patients who can receive pharmacologic prophylaxis (and
aren’t at particularly high risk), my default practice now is to go with heparin or low-molecular-
weight heparin alone and forego compression devices.
— Patricia Kritek, MD

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 YEAR IN REVIEW 2019

Overtreatment of Blood Pressure in Hospitalized Patients

Aggressive management of BP is associated with worse outcomes.
Although evidence-based recommendations exist for outpatient management of hypertension,
guidelines for treating inpatients with elevated blood pressure (BP) are lacking. Recent data
suggest that a less-intensive approach is best.
In two studies, researchers aimed at lower use of intravenous (IV) hydralazine or labetalol in
asymptomatic inpatients with elevated BP. In a study of 2000 hospitalized adults, an educational
campaign and electronic medical record intervention (changing BP notification parameters from
>160/90 mm Hg to >180/90 mm Hg) reduced use of antihypertensive medications (from 11%
of patients to 7%), without a change in patient-centered outcomes (NEJM JW Gen Med Jun 1 and
J Hosp Med Mar; 14:144). In another study, nurses were empowered to identify culprits of likely
transient BP elevations (e.g., pain, agitation, withholding home BP medications) and communicate
them to covering physicians; this intervention resulted in a subsequent 60% decrease in IV anti­
hypertensive use and a proportional reduction in adverse events (NEJM JW Gen Med Jun 1 and
J Hosp Med Mar; 14:151).
Hospitalized patients with elevated BP often have their outpatient antihypertensive regimens
titrated up at discharge. In one study, researchers analyzed the rec­ords of 4000 older hypertensive
patients, half of whom received up-titration of anti­hypertensive medications at hospital discharge
after admission for one of several noncardiac conditions. At 30 days, patients who received intensi­
fication of their antihypertensive regimens had significant excess risks for readmission (21% vs.
18%) and serious adverse events (4.5% vs. 3.1%; NEJM JW Gen Med Oct 15 and JAMA Intern
Med Nov; 179:1528). And in another study, more than half of patients whose BP medications were
titrated up had well-controlled preadmission BP (<140 mm Hg systolic; <90 mm Hg diastolic;
NEJM JW Gen Med Nov 15 2018 and BMJ 2018 Sep 12; 362:k3503).
These studies highlight a common clinical inpatient scenario: Clinicians often feel compelled to
act on elevated BP readings in stable hospitalized patients, but these results suggest we should
do otherwise. IV antihypertensives essentially have no role in asymptomatic patients who can
tolerate oral medication. Additionally, oral medication should be titrated up during hospitalization
only if BP elevation is substantial, persistent, and not triggered by readily identifiable causes
(e.g., agitation, pain, IV fluids). In general, the most prudent and safe strategy is communicating
concerns to primary care practitioners and ensuring close outpatient follow-up.
— Neil H. Winawer, MD, SFHM, NEJM Journal Watch Hospital Medicine

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 YEAR IN REVIEW 2019

E-Cigarette or Vaping-Associated Lung Injury

The CDC has established criteria to define EVALI.
More than 1300 cases of electronic cigarette (e-cigarette, or vaping) product use–associated
lung injury (EVALI) have been reported, and now we have some insights into the etiology and
natural history of EVALI. Criteria from the CDC include use of e-cigarettes within 90 days of
symptom onset, opacities on chest imaging, no evidence of infection on a viral panel and by in-
fluenza testing, and no evidence of plausible alternative causes (NEJM JW Gen Med Oct 15 and
N Engl J Med Sep 6; [e-pub]).
Patients are most commonly young men who have used a mixture of nicotine and tetrahydro­
cannabinol (THC) products. Symptoms include constitutional, respiratory, and gastrointestinal
complaints; clinicians should ask about vaping in any patient who presents with this constellation
of symptoms. Although many patients in the first cohort were critically ill, subsequent publications
have revealed milder presentations, with patients receiving only outpatient care.
Evaluation with bronchoalveolar lavage (BAL) is uncommon, but when it is performed, lipid-
laden macrophages are consistent findings (NEJM JW Gen Med Oct 15 and N Engl J Med Sep 6; [e-
pub]; NEJM JW Gen Med Jan 1 2020 and Lancet Nov 8; [e-pub]). The CDC has reported that BAL
fluid from 29 patients with EVALI (across 10 states) revealed vitamin E acetate in all samples and
did not demonstrate other concerning substances (e.g., oils, petroleum products). Vitamin E
might be added by some illicit manufacturers to dilute THC or to thicken vaping liquids. Whether
vitamin E acetate is the causative agent is not yet established (NEJM JW Gen Med Dec 15 and
MMWR Morb Mortal Wkly Rep Nov 15; 68:1040).
In the reported case series, nearly all patients were treated with antibiotics and glucocorti­coids.
Because improvement often was noted in conjunction with steroid treatment, the CDC recommends
considering steroids along with supportive care for patients with suspected EVALI. Although
deaths have occurred, most patients improve with supportive care. In a report of short-term
follow-up, chest imaging and pulmonary function tests were persistently abnormal 2 weeks after
hospital discharge (NEJM JW Gen Med Jan 1 2020 and Lancet Nov 8; [e-pub]). Continued heightened
awareness of EVALI is essential, as is further investigation into causative agents.
— Patricia Kritek, MD

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 YEAR IN REVIEW 2019

Alternatives to Opioids for Pain Management

Studies show that gabapentinoids, tramadol, and topical agents are not necessarily the answer.
Concern about overuse of conventional opioids for pain management has pushed clinicians to
substitute other medications that are thought to be effective and safe, including gabapentinoids
and tramadol. In 2019, researchers addressed this issue in several studies and reviews, with mostly
discouraging findings.
Some clinicians might not realize that gabapentin’s only FDA-approved pain indication is
postherpetic neuralgia; for pregabalin, FDA-approved pain indications are postherpetic neuralgia,
diabetic neuropathy, fibromyalgia, and spinal cord injury. The increasing use of gabapentinoids
for non–FDA-approved indications led to a review of 34 randomized trials in which researchers
examined off-label use for non-cancer, non-postoperative pain. Weak evidence supported
gabapentin use for fibromyalgia, diabetic neuropathy, or “unspecified neuropathy,” and no
evidence supported gabapentin use for low back pain (with or without radiculopathy) or
acute zoster pain (NEJM JW Gen Med May 1 and JAMA Intern Med May 1; 179:695).
Gabapentinoids also are prescribed increasingly to reduce postoperative opioid use, with mixed
results. In a trial of 80 patients randomized to pregabalin or placebo for postoperative pain (following
donor nephrectomy), pregabalin recipients used modestly less opioids, but had significantly
more errors in several domains of cognitive function at 24 hours (NEJM JW Gen Med Feb 15
and Anesthesiology Jan; 130:63).
Risks associated with tramadol, a weak opioid agonist and inhibitor of serotonin and
norepine­phrine reuptake, were assessed in two observational studies. In a study of patients
with osteoarthritis, mortality was significantly higher in those using tramadol than in those using
nonsteroidal anti-inflammatory drugs (NEJM JW Gen Med Apr 15 and JAMA Mar 12; 321:969).
And in a study of pain control in opioid-naive surgical patients, those who received tramadol as
their primary analgesic were significantly more likely to receive an additional opioid prescription
than were those who initially received hydrocodone or oxycodone (NEJM JW Gen Med Jul 1 and
BMJ May 14; 365:l1849).
In an attempt to avoid systemic pain medications, compounded creams have been promoted
that contain various combinations of drugs, including ketamine, gabapentin, clonidine, lidocaine,
baclofen, diclofenac, and cyclobenzaprine. In a randomized trial that involved 400 adults,
researchers found no difference between specially compounded pain creams and placebo
creams for any pain measurement (NEJM JW Gen Med Mar 1 and Ann Intern Med Mar 5; 170:309).
Another approach is to avoid drugs entirely. A 2019 meta-analysis of nonpharmacologic
approaches showed that meditation, cognitive-behavioral therapy, hypnosis, and nonhypnotic
therapeutic suggestion demonstrated clinically important benefits (NEJM JW Gen Med Dec 15 and
JAMA Intern Med Nov 4; [e-pub]).

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 YEAR IN REVIEW 2019

In sum, the growing interest in minimizing use of conventional opioids for pain management
is certainly appropriate, but commonly prescribed alternative medications — gabapentinoids,
tramadol, and topical agents — are not necessarily the answer. The search for effective
alternatives continues, but meanwhile, we must guard against undertreatment of patients with
legitimate need for effective pain management.
— Thomas L. Schwenk, MD

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