YEAR IN REVIEW 2021

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, Clinical Professor of Medicine,
Dear Reader,
University of Colorado School of Medicine, Aurora
EXECUTIVE EDITOR In our annual review of important clinical research from the past
Charleen M. Hamilton, PhD
Massachusetts Medical Society year, we try to balance relevance to general medical practice and
MANAGING EDITOR recognition of landmark studies and key guidelines. By any measure,
Michael Kish
Massachusetts Medical Society the introduction of COVID-19 vaccination — and the ongoing pandemic
DEPUTY EDITOR despite the vaccines’ effectiveness — was the top medical story of
Thomas L. Schwenk, MD, Dean, University
of Nevada School of Medicine; Vice President
2021. But this narrative is well known to virtually all readers now,
of Health Sciences, University of Nevada, Reno and it is not easily compressed into a few hundred words. For this
FOUNDING EDITOR
Anthony L. Komaroff, MD, Senior Physician,
reason, we decided to omit COVID-19 vaccination from our 2021
Division of General Medicine, Brigham and Year in Review lineup.
Women’s Hospital; Professor of Medicine,
Harvard Medical School, Boston, MA
ASSOCIATE EDITORS The order of presentation of these summaries is not intended
David J. Amrol, MD, Associate Professor of
Clinical Internal Medicine, Director of the Division
to reflect their relative importance. All references are from 2021
of Allergy and Immunology, University of South unless otherwise noted.
Carolina School of Medicine, Columbia
Daniel D. Dressler, MD, MSc, MHM, FACP,
Director, Internal Medicine Teaching Services, — Allan S. Brett, MD
Emory University Hospital; Associate Program
Director, J Willis Hurst Internal Medicine Editor-in-Chief
Residency Program; Professor of Medicine, NEJM Journal Watch General 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
Rahul B. Ganatra, MD, MPH, Instructor in
Medicine, Harvard Medical School; Director of
Continuing Medical Education for the Medical
Service, VA Boston Healthcare System, Boston
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
Marie Claire O’Dwyer, MB BCh BAO, MPH,
Clinical Assistant Professor in Family Medicine,
University of Michigan Medical School, Ann
Arbor
Bruce Soloway, MD, Associate Professor
Emeritus of Family and Social Medicine, Albert
Einstein College of Medicine, Bronx, NY
Abigail Zuger, MD, former Associate Clinical
Professor of Medicine, Icahn School of Medicine
at Mount Sinai; former Senior Attending
Physician, Mount Sinai West and Mount Sinai
Morningside Hospitals, New York City, NY
NEJM JOURNAL WATCH EDITOR-IN-CHIEF
Allan S. Brett, MD
800.843.6356 | f: 781.891.1995 | nejmgroup@mms.org
860 winter street, waltham, ma 02451-1413
nejmgroup.org
YEAR IN REVIEW 2021
TABLE OF CONTENTS

Shoulder Pain and Immobility: Often, Less Is More 2

Empagliflozin and Heart Failure with Preserved Ejection Fraction 3

Stopping Antidepressants in Primary Care 4

Another GLP-1 Receptor Agonist for Weight Management 5

Once Again, Antibiotics Are Unnecessary for Acute Uncomplicated Diverticulitis 6

Mobile Stroke Units Bring the Treatment to the Patient 7

Sodium, Potassium, and Cardiovascular Disease 8

A Focus on the Adrenal Gland 9

Omega-3 Fatty Acids — Three More Negative Studies 10

Evidence Against Platelet-Rich Plasma Injections for Musculoskeletal Conditions 11

Asthma Guideline Update 12

Intravenous Contrast Media in Patients with Kidney Disease 13

Finally, Treatment for Outpatients with COVID-19 14

Immune Modulators Provide Some Additional Benefit to Patients with Severe COVID-19 15

A Synopsis of Other Important Research from 2021 16

NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society.
©2022 Massachusetts Medical Society. All rights reserved.
 YEAR IN REVIEW 2021

Shoulder Pain and Immobility: Often, Less Is More

For many patients with subacute or chronic shoulder problems, less-intensive options can
provide relief.
Subacute and chronic shoulder pain and immobility are common complaints in primary care
practice. Clinicians might recommend physical therapy (PT) or joint injection and, in more com-
plex cases, can refer patients for orthopedic consultation; however, limited evidence guides
these decisions. In several randomized trials, investigators compared various approaches.
U.K. researchers randomized 500 adults with unilateral adhesive capsulitis (i.e., “frozen
shoulder”) to manipulation under anesthesia or capsular release (each followed by as many as
12 sessions of PT), or to a single intra-articular steroid injection plus PT. One year later, manipu-
lation and PT yielded similar outcomes for shoulder pain and function. Capsular release was sta-
tistically, but not clinically, superior to the other approaches and was associated with excess seri-
ous adverse events (NEJM JW Gen Med Nov 15 2020 and Lancet 2020 Oct 3; 396:977).
In another U.K. study, investigators enrolled 700 primary care patients with shoulder pain of
shorter than 6 months’ duration attributed to rotator cuff disorders. Patients were randomized to
6 sessions with a physical therapist for progressive exercise or to 1 session for education only; pa-
tients also were randomized to receive a single subacromial steroid injection before therapy or
no injection. One year later, patients who received progressive exercise and those who received
a single education session had similar improvements in shoulder pain and disabil­ity. Patients
who received steroid injections had more improvement in pain, disabil­ity, and quality of life than
did the non­injection patients after 8 weeks; at 6 and 12 months, all groups had similar out-
comes (NEJM JW Gen Med Sep 1 and Lancet Jul 31; 398:416).
Finnish patients with at least 3 months of subacromial shoulder pain and rotator cuff tears
not attributable to high-energy trauma received 3 months of PT; 187 patients who did not have
satisfactory improvement (half with full-thickness tears on magnetic resonance imaging) were
randomized to receive continued conservative management or surgery. Two years later, patients
with partial-thickness tears had similar outcomes with or without surgery, but patients with full-
thickness tears had significantly greater pain relief with surgical than nonsurgical treatment
(NEJM JW Gen Med Jul 1 and Ann Rheum Dis Jun; 80:796).
Taken together, these studies suggest that, for many patients with subacute or chronic shoulder
pain or immobility, less-intensive interventions are as effective as more-intensive ones. Only for
full-thickness rotator cuff tears were outcomes better with surgery than with nonsurgical approaches.
— Bruce Soloway, MD

2
Back to Table of Contents
 YEAR IN REVIEW 2021

Empagliflozin and Heart Failure with Preserved Ejection

Fraction
This sodium–glucose cotransporter-2 inhibitor lowered the incidence of HF hospitalizations
significantly.
Prior to 2021, several sodium–glucose cotransporter (SGLT)-2 inhibitors had been shown to im-
prove cardiovascular (CV) outcomes in patients with heart failure with reduced ejection fraction
(HFrEF). In 2021, an industry-funded randomized trial extended these benefits to patients with
heart failure and preserved ejection fraction (HFpEF), regardless of diabetes status.
In the EMPEROR-Preserved trial, 6000 patients with class II–IV HFpEF, left ventricular ejection
fraction (LVEF) of >40%, and elevated natriuretic peptide levels received the SGLT-2 inhibitor
empagliflozin (10 mg daily) or placebo. During median follow-up of 26 months, empagliflozin
recipients were significantly less likely than placebo recipients to be hospitalized for HF (8.6%
vs. 11.8%) or to experience the composite outcome of HF hospitalization or CV-related death
(13.8% vs. 17.1%; NEJM JW Gen Med Oct 1 and N Engl J Med Oct 14; 385:1451). Empagli­f lo­zin
recipients had fewer hospitalizations that required intravenous vasoactive agents or intensive
care, and benefits were noted after only a few weeks of therapy. Benefits were consistent in
those with LVEF of 40% to 59% but were attenuated in those with LVEF ≥60%. Hypotension
and uncomplicated urinary tract infections and genital infections were more common with
empagliflozin (NEJM JW Cardiol Nov and Circulation Oct 19; 144:1284).
Investigators also reported effects of empagliflozin on health status using validated question-
naires. Although differences were modest, patients who received empagliflozin were more likely
to report improved health status and were less likely to experience deterioration (NEJM JW Gen
Med Dec 15 and Circulation Nov 15; [e-pub]).
Taken together, these data suggest that empagliflozin is an important potential new option
for HFpEF, a condition with few effective outcome-modifying treatments. Although empagliflozin
is not approved yet for this indication, the FDA has granted it “breakthrough therapy” status,
which will expedite its evalu­ation. Moreover, additional data are forthcoming from an ongoing
study of dapagliflozin in a similar patient popu­lation (DELIVER). Importantly, use of SGLT-2
inhibitors for indications other than diabetes has lagged in the face of unfamiliarity, concerns
about side effects, costs, and in some cases, confusion about whose role it is to initiate therapy.
Physicians will need to familiarize themselves with these agents and work together to identify
appropriate candidates for treatment.
— Kirsten E. Fleischmann, MD, MPH, FACC

Information about DELIVER is available at https://clinicaltrials.gov/ct2/show/NCT03619213 free of charge.

3
Back to Table of Contents
 YEAR IN REVIEW 2021

Stopping Antidepressants in Primary Care

A randomized trial provides information on relapse after stopping long-term antidepressant drug
therapy.
Questions about optimal duration of treatment with antidepressant medications arise almost
daily in primary care practice. But prior studies of antidepressant discontinuation have had limited
applicability for a variety of reasons: small sample sizes, short follow-up, or use of medications
no longer considered to be first line. A 2021 study of antidepressant discontinuation in U.K.
primary care practices can help patients and providers know what to expect when stopping
antidepressants.
Researchers enrolled 478 patients (75% women) with depression in remission who were taking
sertraline, fluoxetine, citalopram, or mirtazapine and who felt ready to discontinue their anti­
depressant. The majority reported at least three prior episodes of depression and had been tak-
ing antidepressants continuously for at least 3 years. Patients were randomized to continue their
current antidepressant or to taper over 2 months (using placebo pills to maintain blinding). At
1 year, relapse occurred in 39% of the maintenance group and in 56% of the discontinuation
group. By the end of the trial, most patients who relapsed in the discontinuation group had
resumed antidepressant medications. No suicides or suicide attempts were reported (NEJM
JW Gen Med Nov 1 and N Engl J Med Sep 30; 385:1257).
At first glance, this trial suggests that discontinuing antidepressants will result in relatively
short-term relapse in more than half of patients with longstanding depression who discontinue
antidepressants. However, more than one third of patients who continued medication also re-
lapsed. Therefore, relapse could be attributed to discontinuing antidepressants in only about
1 in 6 patients (the 17% difference between 39% and 56%); the other relapses presumably reflected
the natural history of recurrent depression. Of note, the largest differences between groups in
secondary outcomes like Patient Health Questionnaire (PHQ)–9 scores occurred soon after dis-
continuation, so some worsening symptoms in the discontinuation group could be attributable
to withdrawal rather than relapse.
Patients who are interested in discontinuation should be counseled about, and closely moni-
tored for, symptoms of withdrawal and relapse. Of note, referral for psychotherapy helps prevent
relapses in patients who discontinue medications (NEJM JW Psychiatry Nov 30 2020; [e-pub] and
Br J Psychiatry Oct; 219:538) and should be considered for such patients.
— Molly S. Brett, MD

Dr. Brett is an Instructor in Medicine at the University of Colorado.

4
Back to Table of Contents
 YEAR IN REVIEW 2021

Another GLP-1 Receptor Agonist for Weight Management

Obese patients without diabetes had substantial weight loss in several studies of semaglutide.
In studies of glucagon-like peptide-1 (GLP-1) receptor agonists for treating diabetes, weight loss
was a consistently observed — and welcome — secondary effect. In 2014, liraglutide was the
first GLP-1 agonist to be U.S. FDA approved for weight management in obese patients without
diabetes; in clinical trials, weight loss with a daily injection of liraglutide, compared with placebo,
averaged about 5 kg during 1 year. In 2021, the GLP-1 agonist semaglutide also was approved
for this indication, based on impressive weight loss in industry-sponsored studies.
In one study, nearly 2000 obese patients without diabetes (mean body-mass index [BMI],
38 kg/m2) were randomized to once-weekly subcutaneous injections of semaglutide or placebo,
in addition to receiving individual counseling on diet and exercise. At 16 months, weight reduc-
tion with semaglutide averaged nearly 13 kg versus no change with placebo, and half of semaglu-
tide recipients lost at least 15% of their baseline weight (NEJM JW Gen Med Mar 15 and N Engl J
Med Mar 18; 384:989). Results were similar in another study of the incremental effect of this drug
when it was added to a more-intensive dietary and behavioral intervention — again, in patients
without diabetes (NEJM JW Gen Med Apr 1 and JAMA Apr 13; 325:1403). A third study was con-
ducted in patients with type 2 diabetes (mean BMI, 36 kg/m2); weight loss with semaglutide
compared with placebo was less dramatic than that seen in the non­diabetes trials but still was
substantial at ≈6 kg (NEJM JW Gen Med Apr 1 and Lancet Mar 13; 397:971).
The target dose of semaglutide for weight reduction is 2.4 mg weekly, titrated over 4 months
from an initial dose of 0.25 mg. This target is much higher than the maximal approved dose for
diabetes treatment (1.0 mg), and unsurprisingly, the gastrointestinal side effects are not trivial.
In the first of the three trials ­summarized above, nausea, vomiting, and diarrhea were reported
by 44%, 25%, and 32% of semaglutide recipients, respectively — more than twice the incidence
of these side effects in placebo recipients. And cost is a huge concern: The current cash price of
each weekly dose is about US$400 — more than $20,000 annually.
Previously approved drug therapies for weight reduction have various limitations, including
considerable side effects and lack of data on long-term use. The same concerns apply to high-
dose GLP-1 receptor agonists in people without diabetes. To address these concerns, the manu-
facturer of semaglutide is conducting a several-years-long trial of the 2.4-mg weight-loss dose in
overweight or obese patients with established cardiovascular disease, but without diabetes.
— Allan S. Brett, MD

5
Back to Table of Contents
 YEAR IN REVIEW 2021

Once Again, Antibiotics Are Unnecessary

for Acute Uncomplicated Diverticulitis
More data confirm that antibiotics do not improve outcomes, and some guidelines move toward
limiting antibiotic use.
Although antibiotics traditionally have been used to treat all patients with diverticulitis, high-
quality evidence during the past decade suggests they are unnecessary for acute uncomplicated
cases. In 2021, a randomized outpatient study added new data to support this conclusion.
In past studies, inpatients with acute uncomplicated diverticulitis have been randomized to
receive antibiotics or not: Outcome data confirmed no differences in pain levels, complications
requiring surgery, duration of hospitalizations, or readmission rates (Br J Surg 2012 Apr; 99:532;
Br J Surg 2017 Jan; 104:52; NEJM JW Gen Med Jul 1 2020 and Clin Gastroenterol Hepatol Mar;
19:503).
However, the question of whether hos­pitalization itself affected these findings was never resolved —
in par­ticular, did liberal administration of intra­venous fluids affect study results? In the 2021 trial, re-
searchers randomized healthy outpatients with acute uncomplicated diverticulitis to oral amoxicillin/
clavulanate or no antibiotic and reported the same findings: No differences in hospitalization rates,
rates of emergency department visits, pain levels, or need for surgery (NEJM JW Gen Med Dec 1
and Ann Surg Nov; 274:435).
Whether these findings will change current practice is unclear. Some widely used clinical ref-
erences (e.g., UpToDate) continue to recommend that all diverticulitis patients receive oral or intra-
venous antibiotics. However, some guidelines now suggest that antibiotics be used “selectively
rather than routinely” in uncomplicated cases and be reserved for patients with serious comor-
bidities, high inflammatory mar­kers, or par­ticularly dramatic imaging (NEJM JW Gen Med Apr 1
and Gastroenterology Feb; 160:906).
Meanwhile, in another 2021 study, researchers retrospectively compared outcomes among
uncomplicated diverticulitis patients who received either metronidazole plus a quinolone or
amoxicillin/clavulanate alone (NEJM JW Gen Med Apr 1 and Ann Intern Med Jun; 174:737). No
differences in complications or outcomes were found, but among older patients (age, ≥65) the
quinolone combination was associated with significantly higher risk for Clostridioides difficile
­infection. Clinicians who are uncom­fortable abandoning their longstanding practice of adminis-
tering antibiotics to diverticulitis patients might at least consider de-escalating their coverage
to the safer drug.
— Abigail Zuger, MD

UpToDate can be accessed at https://www.uptodate.com/contents/acute-colonic-diverticulitis-medical-

management (subscription required).

6
Back to Table of Contents
 YEAR IN REVIEW 2021

Mobile Stroke Units Bring the Treatment to the Patient

Stroke patients treated in MSUs underwent thrombolysis sooner and had better outcomes than
patients treated at hospitals.
The importance of restoring perfusion as quickly as possible for patients experiencing ischemic
stroke is summarized aptly in the adage “time is brain.” Current stroke guidelines recommend
administering tissue plasminogen activator (tPA) to eligible patients within 4.5 hours of symptom
onset, with the best functional outcomes at discharge achieved by administration within 60 minutes.
How­ever, widespread timely access to com­prehensive stroke care has remained elusive.
In 2021, researchers performed a quasi-randomized trial to test whether stroke treatment
in mobile stroke units (MSUs; i.e., ambulances outfitted with computed tomography, laboratory
ca­pabilities, staff capable of administering tPA, and physicians available by remote access) im-
proved outcomes compared with transport to a hospital by emergency medical services (EMS).
About 1500 patients with potential stroke within 4.5 hours, and with physical examination find-
ings consistent with acute stroke, were allocated to MSU or to conventional EMS during alternating
weeks in seven large U.S. cities (77% were enrolled in Houston, Texas). Notably, of ≈10,500 patients
who were screened initially, nearly 9000 were excluded because they had nonqualifying strokes
or stroke mimics.
Among the 1047 patients who ultimately were eligible to receive tPA, the median time from
symptom onset to treatment was shorter in the MSU group than in the EMS group (72 vs. 108
minutes). Accordingly, more MSU patients received tPA within 60 minutes (33% vs. 3%). At 90 days,
MSU patients were more likely to have modified Rankin Scale scores of 0 or 1 (55% vs. 44%),
indicating no or minimal disability. Symptomatic intracerebral hemorrhage occurred in about
2% of patients in both groups (NEJM JW Gen Med Oct 15 and N Engl J Med Sep 9; 385:971).
This study builds on prior observational data (NEJM JW Neurol Apr and JAMA Feb 2; 325:454)
that supported improved clinical outcomes with MSUs. Developing comprehensive MSU systems
will generate various logistical challenges and concerns about cost-effectiveness. Nevertheless,
strategic deployment of MSUs in areas where people aren’t reasonably close to certified stroke
centers could be a game-changer in stroke care.
— Rahul B. Ganatra, MD, MPH

7
Back to Table of Contents
 YEAR IN REVIEW 2021

Sodium, Potassium, and Cardiovascular Disease

Several studies suggest that we should promote low-sodium, high-potassium diets — especially
in patients with hypertension.
Sodium restriction and generous potas­sium intake are associated with lower blood pressure
(BP), but the ultimate effect on cardiovascular (CV)-related morbidity is less clear. In 2021,
several studies addressed this issue and refocused attention on these dietary interventions.
In a trial from China, 21,000 people with histories of stroke or inadequately controlled hyper-
tension were randomized to replace regular salt with a salt substitute (75% sodium chloride,
25% potassium chloride) or to continue using regular salt; to further enhance sodium restric-
tion, intervention participants were instructed to use the salt substitute more sparingly than they
had used regular salt. At 5 years, rates of stroke, major adverse CV events, and mortality were
each significantly lower in the salt-substitute group — by roughly 2 or 3 events per 100 partici-
pants. According to 24-hour urine electrolyte measurements, the intervention lowered sodium in-
take by only about 10% but increased potassium intake by about 50% (NEJM JW Gen Med Oct 1
and N Engl J Med Sep 16; 385:1067).
In another study, researchers pooled data from 6 cohort studies in which people with no history
of CV or renal disease submitted multiple 24-hour urine collections for sodium and potassium
levels, reflecting dietary intake. At average follow-up of 9 years, those with sodium excretion of
≈2 g daily had 2 or 3 fewer CV events per 100 people, compared with those whose sodium ex-
cretion was ≈5 g daily. Conversely, people with high potassium excretion had 1 fewer CV event
per 100 people, compared with those whose potassium excretion was low. These findings were
adjusted for confounding factors, and they applied to people with or without diagnosed hyper-
tension (NEJM JW Gen Med Dec 15 and N Engl J Med Nov 13; [e-pub]).
Finally, a meta-analysis of 85 studies revealed a linear, dose-response relation between esti-
mated sodium intake and BP during 1 to 36 months of observation. At the extremes of intake
(6 g vs. 1 g of sodium intake), the systolic BP difference was ≈12 mm Hg; for diastolic BP, the
difference was ≈5 mm Hg (NEJM JW Gen Med Jun 1 and Circulation Apr 20; 143:1562).
Taken together, these studies suggest that we should redouble our efforts to promote low-
sodium, high-potassium diets for many patients, especially those with hypertension. A caveat
is that excessive potassium intake should be avoided in patients at risk for hyperkalemia (e.g.,
those with advanced renal disease).
— Allan S. Brett, MD

8
Back to Table of Contents
 YEAR IN REVIEW 2021

A Focus on the Adrenal Gland

Primary aldosteronism is underdiagnosed in hypertensive patients, and excess cortisol secretion
isn’t uncommon in patients with adrenal incidentalomas.
Several recent studies suggest that abnormal adrenal function — in particular, excess secretion
of aldosterone and cortisol — are more common than one might expect.
In a large 2020 study (>1000 patients), measurement of 24-hour urine aldosterone levels sug-
gested a much higher prevalence of primary aldosteronism in U.S. patients with hypertension
than had been reported previously: The prevalence was 16% in patients with stage 1 hyperten-
sion and ≈22% in those with stage 2 or resistant hypertension (NEJM JW Gen Med Jul 1 2020
and Ann Intern Med 2020 Jul 7; 173:10). These findings demonstrated that primary aldosteron-
ism likely has been underdiagnosed using traditional screening with aldosterone–renin ratio
(ARR). Underdiagnosis also was suggested in a 2021 cohort study of 270,000 U.S. veterans with
treatment-resistant hypertension: Fewer than 2% of these patients had been screened for hyper-
aldosteronism (NEJM JW Gen Med Feb 15 and Ann Intern Med Mar; 174:289).
A 2021 meta-analysis of 10 studies with variable quality and differing diagnostic thresholds,
including the aforementioned 2020 study, demonstrated highly variable ARR test sensitivities
(10%–100%) but reasonably high and more-consistent specificities (70%–100%). This analysis
confirmed that ARR has limitations as a screening test for primary aldosteronism (NEJM JW Gen
Med Sep 15 and J Clin Endocrinol Metab Aug; 106:2423). Although authorities disagree on the
optimal screening strategy, virtually everyone now agrees that hypertensive patients — especially
those with resistant hypertension — should be screened more liberally for primary aldosteronism.
Adrenal masses are common incidental findings on abdominal imaging done for other pur-
poses. Clinicians who encounter these “adrenal incidentalomas” should consider whether they
might be hormonally active. In a 2021 study of more than 1000 patients with benign adrenal inci-
dentalomas measuring ≥1 cm, about 20% had high cortisol levels (>3 µg/dL) after overnight dexa-
methasone suppression tests. These patients had more than twofold excess mortality during
median follow-up of 6 years (hazard ratio, 2.4; NEJM JW Gen Med Jul 1 and Ann Intern Med Aug;
174:1041). The findings align with guidelines that recommend screening for autonomous corti-
sol secretion in patients with adrenal incidentalomas (Endocr Pract 2009 Jul-Aug; 15:Suppl 1:1).
— Daniel D. Dressler, MD, MSc, MHM, FACP

9
Back to Table of Contents
 YEAR IN REVIEW 2021

Omega-3 Fatty Acids — Three More Negative Studies

New trials didn’t yield reductions in adverse cardiovascular events.
Most individual studies of omega-3 fatty acids (FAs) — generally combinations of eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA) — have failed to show significant reductions in ad-
verse cardiovascular (CV) events in primary and secondary prevention populations. Although
omega-3 FA supplementation is not recommended strongly in U.S. guidelines, many patients
continue to use them, and some clinicians recommend them. Three more negative randomized
trials were published in late 2020.
• 13,000 patients with known CV disease or high risk for CV disease received either 4 g daily of a
carbolic acid formulation of EPA/DHA or corn oil placebo. At 42 months, a composite CV end-
point occurred in about 12% of each group, but new-onset atrial fibrillation (AF) was signifi-
cantly more common in the omega-3 group (2.2% vs. 1.3%; NEJM JW Gen Med Dec 15 2020
and JAMA 2020 Dec 8; 324:2268).
• 1000 older patients (mean age, 75) with recent myocardial infarction received either EPA/DHA
(1.8 g daily) or placebo. At 2 years, the incidence of a composite CV endpoint was about
21% in each group, and again, new-onset AF was more frequent in the omega-3 group (7%
vs. 4%; NEJM JW Gen Med Dec 15 2020 and Circulation Feb 9; 143:528).
• 2200 healthy older adults were randomized both to EPA/DHA (1 g daily) or placebo and to
strength training or no training. EPA/DHA was not associated with any health benefit at
3 years (NEJM JW Gen Med Dec 15 2020 and JAMA 2020 Nov 10; 324:185).

Like the studies summarized above, most earlier individual studies also have been negative.
Nevertheless, in a recent meta-analysis of 38 trials, researchers concluded that omega-3 FAs con-
ferred modest r­ eductions in CV-related mortal­ity and coronary events; however, this conclusion
was driven heavily by one positive study (REDUCE-IT), which involved an EPA preparation alone
(icosapent ethyl) in a mainly secondary-prevention population of statin-treated patients with hyper-
triglyceridemia (NEJM JW Gen Med Jan 1 2019 and N Engl J Med 2019 Jan 3; 380:11). This observa-
tion led the meta-analysis authors (and other commentators) to suggest that potential benefits of
omega-3 FAs reside mainly in EPA alone and not in the EPA/DHA combination (EClinicalMedicine
Jul 8; 38:100997). Finally, both this and another recently published meta-analysis showed that
omega-3 FAs confer risk for atrial fib­rillation, particularly at doses >1 g daily (NEJM JW Gen Med
Dec 15 and Circulation Oct 6; [e-pub]).
Overall, omega-3 FAs might lower CV risk modestly — especially at higher doses and using
EPA alone — but also might confer excess risk for atrial fibrillation. Given that most recent trials
have been negative, and that the most convincingly positive recent trial (REDUCE-IT) was performed
in a highly selected population, broad use of omega-3 FAs isn’t justified.
— Thomas L. Schwenk, MD

10
Back to Table of Contents
 YEAR IN REVIEW 2021

Evidence Against Platelet-Rich Plasma Injections

for Musculoskeletal Conditions
Use of PRP continues to increase, despite negative results.
Use of platelet-rich plasma (PRP) injections for musculoskeletal conditions continues to increase,
based mostly on uncontrolled studies and anecdotal ex­perience. But in three rigorous randomized
trials in 2021, PRP was ineffective for patients with degenerative conditions of tendons and joints.
Based on the theoretical benefit of growth-promoting factors found in PRP, its use was examined
in a study of 240 patients (mean age, 52) with chronic mid-portion Achilles tendinopathy in whom
usual care had failed. Patients were randomized to single intratendinous injections of autologous
centrifuged PRP or dry sham injections just under the skin. The two groups scored similarly on
composite measures of pain and function at 2 weeks and at 3 and 6 months. In fact, more inter-
vention than control patients had injection site pain at follow-up (NEJM JW Gen Med Aug 15
and JAMA Jul 13; 326:137).
Dutch investigators randomized 100 patients with moderate-to-severe ankle osteoarthritis
(OA) to receive two tibiotalar PRP injections (6 weeks apart) or saline control injections. At
26 weeks, both groups improved by about 10 points on a validated 100-point composite meas­ure
of pain and function (NEJM JW Gen Med Dec 1 and JAMA Oct 26; 326:1595). Similarly, Australian
researchers randomized 288 patients with medial compartment knee OA to three weekly intra-
articular injections of PRP or saline. At 12 months, both groups had improved by about 2 points
on a validated 10-point pain scale; the two groups also had similar medial compartment cartilage
volume as determined by magnetic resonance imaging (NEJM JW Gen Med Jan 1 2022 and
JAMA Nov 23; 326:2021).
Despite the results of these and other controlled studies, use of PRP — often with large out-of-
pocket patient expense — likely will continue. Primary care clinicians have the opportunity and
respon­sibility to counsel patients about the mounting evidence of a lack of benefit for PRP in a
wide range of musculoskeletal conditions.
— Thomas L. Schwenk, MD

11
Back to Table of Contents
 YEAR IN REVIEW 2021

Asthma Guideline Update

As-needed inhaled steroids now are an option for many patients.
In December 2020, the U.S. National Asthma Education and Prevention Program (NAEPP) released
its first guideline update since 2007. While this was not a complete overhaul, it addresses several
issues relevant to primary care physicians and introduces as-needed use of inhaled steroids
(ICS) for some patients (NEJM JW Gen Med Jan 15 and JAMA 2020 Dec 8; 324:2301).

Key points for adolescent and adult patients (based on asthma severity) are as follows:

Step 1: As-needed short-acting β-agonists (SABAs), such as albuterol.

Step 2: For adolescent and adult patients, either daily low-dose ICS plus a SABA as needed, or
as-needed ICS only when a SABA is used (i.e., no daily maintenance ICS when asymptomatic).
In the U.S., no approved device contains both ICS and albuterol, so this protocol requires two
inhalers. An example is 2 to 4 puffs of albuterol, followed by 80 to 250 µg of beclomethasone
equivalent, every 4 hours, as needed.

Step 3: Low-dose ICS plus formoterol (a quick-onset but long-acting β-agonist [LABA]) in a single
inhaler used as maintenance and rescue therapy. An example is 2 puffs twice daily of budesonide/
formoterol (80/4.5), plus an additional 2 puffs as often as 4 times daily as a reliever; an alternative
would be fluticasone/salmeterol twice daily with a SABA as needed (since salmeterol is not quick
acting).

Step 4: Increase dose of ICS with a fixed-dose LABA.

Step 5: A long-acting antimuscarinic agent (LAMA) can be added to an ICS/LABA combination.

An example is 2 puffs daily of tiotropium (1.25 µg) or using fluticasone, umeclidinium, and
vilanterol in a single dry-powder inhaler.
Most patients with mild asthma do not use their controller medication daily, and even those
who do continue to have exacerbations. Using as-needed ICS/SABA for mild asthma and using an
ICS/bronchodilator combination for both maintenance and as-needed rescue therapy for moderate-
to-severe asthma can limit exacerbations by treating inflammation early. By the time moderate-
to-severe exacerbations start, increasing the ICS dose is ineffective. Rather, at the earliest
symptoms of worsening asthma, ICS must be given every time a rescue bronchodilator is used.
I prefer the Global Initiative for Asthma (GINA) approach: It recommends using intermittent ICS/
formoterol rather than ICS/SABA, since a single inhaler is more practical. But generic budesonide/
formoterol costs more than US$200, whereas albuterol is $30. And when using ICS/formoterol
for both maintenance and rescue, getting more than one inhaler approved monthly is difficult,
so patients run out if they need it frequently.
— David J. Amrol, MD

The GINA guidelines are available at https://ginasthma.org/gina-reports/free of charge.

12
Back to Table of Contents
 YEAR IN REVIEW 2021

Intravenous Contrast Media in Patients with Kidney Disease

These agents generally are safe, even in patients with impaired renal function.
In patients with kidney disease, risks associated with intravenous iodinated contrast media before
computed tomography (CT) or gadolinium-based contrast media before magnetic resonance im-
aging (MRI) are not as high as commonly perceived. A recent study and two evidence-based con-
sensus statements add to the evidence that these contrast agents are relatively safe.
Researchers assessed kidney function in 156,000 adult emergency department patients who
underwent d-dimer testing for suspected pulmonary embolism and did or did not undergo CT
pulmonary angiography (CTPA). Patients on either side of the d-dimer cut-off for CTPA (i.e.,
500 mg/mL) had similar characteristics except for undergoing CTPA and receiving contrast media.
After 6 months, exposure to contrast media was not associated with eGFR change, acute kidney
injury (AKI), need for renal replacement therapy, or death. Although the mean eGFR for the entire
population was 86 mL/minute/1.73 m2, no evidence of harm was noted in patients with baseline
eGFRs <45 mL/minute (NEJM JW Gen Med May 15 and JAMA Intern Med Jun; 181:767).
The American College of Radiology and the National Kidney Foundation published a consensus
statement regarding use of intravenous iodinated contrast media in patients with kidney disease.
Review of the evidence showed that risk for contrast-induced AKI is negligible in people with eGFRs
≥30 mL/minute. For patients with eGFRs <30 mL/minute, the authors recommend volume ex-
pansion with nor­mal saline and avoidance of nephrotoxic medications (e.g., nonsteroidal anti-
inflammatory drugs, aminoglycosides, diuretics) before iodinated contrast agents are administered.
Notably, the consensus statement does not address intra-arterial contrast media for coronary
artery angiography (NEJM JW Gen Med Mar 15 2020 and Radiology 2020 Mar; 294:660).
The same organizations also published a consensus statement regarding use of gadolinium-
based contrast media during MRI. These agents are classified into groups I, II and III: Nearly all
cases of nephrogenic systemic fibrosis have occurred in patients who received group I agents,
which are no longer available in the U.S. Risks for nephrogenic systemic fibrosis and nephrotoxicity
are extremely low following administration of a stand­ard dose of a group II agent. Only one group III
agent is available (i.e., gadoxetate sodium), and data on its effects are limited. The authors con-
clude that clinically indicated contrast-enhanced MRI using a group II agent should not be with-
held regardless of kidney function (NEJM JW Gen Med Feb 1 and Radiology Jan; 298:28).
In sum, currently available intra­venous contrast agents generally can be administered safely,
regardless of renal function. Not using these agents — when compelling clinical indications exist
to do so — risks misdiagnosis or delayed diagnosis.
— Paul S. Mueller, MD, MPH, FACP

13
Back to Table of Contents
 YEAR IN REVIEW 2021

Finally, Treatment for Outpatients with COVID-19

Three monoclonal antibody therapies have received approval for use in patients at high risk for
progression to severe illness.
In 2021, evidence-based treatment for COVID-19 finally became available for outpatients. Three
intravenous mono­clonal antibody therapies that target the v­ irus received emergency use authori­
zation for adult and adolescent outpatients (age, ≥12) with mild-to-moderate COVID-19 symptoms,
a positive test for SARS-CoV-2, and high risk for progression to severe illness; high-risk criteria include
age ≥65, obesity, pregnancy, and various under­lying medical conditions. Patients in the random-
ized treatment trials that led to emergency use authorization generally conformed to these criteria.

Key published trials for the three authorized treatments are as follows:
• In a study of the “cocktail” known as REGEN-COV (casirivimab plus imdevimab), the inci-
dence of hospitalization or death was significantly lower with REGEN-COV than with placebo
(1.0% vs. 3.2%) in the 1500-patient study arm that examined the authorized 1200-mg dose.
Nearly all these events were hospitalizations; only 1 patient died in each group (NEJM JW
Gen Med Nov 15 and N Engl J Med Dec 2; 385:81).
• In a study of bamlanivimab plus etesevimab that involved 1035 patients, the incidence of
hospitalization or death was significantly lower with this combination than with placebo
(2.1% vs. 7.0%). No deaths occurred in the antibody group, and 10 deaths occurred in the
placebo group (NEJM JW Infect Dis Sep and N Engl J Med Oct 7; 385:1382).
• In a study of sotrovimab that involved 583 patients, death or hospitalization was significantly
less likely with sotrovimab than with placebo (1% vs. 7%). As in the REGEN-COV study,
nearly all outcome events were hospitalizations and not deaths (NEJM JW Gen Med Dec 15
and N Engl J Med Nov 18; 385:1941).

REGEN-COV and bamlanivimab/etesevimab also are authorized for postexposure prophylaxis in

patients who are exposed to SARS-CoV-2 and at high risk for developing severe disease. Among
1500 such patients who received REGEN-COV or placebo sub­cutaneously, symptomatic COVID-19
­occurred in significantly fewer patients in the active treatment group — 1.5% vs. 7.8% (NEJM
JW Gen Med Sep 1 and N Engl J Med Sep 23; 385:1184).
Initially, access to monoclonal antibody therapy was spotty and disorganized in many areas of
the U.S. However, during the recent spike in COVID-19 cases, many healthcare facilities and state
health departments have expanded and streamlined access to this treatment — within both con-
ventional healthcare facilities and makeshift infusion centers. Several oral antiviral drugs for out-
patients with COVID-19 have been developed, but at the time of this writing, none have been
approved for use.
— Allan S. Brett, MD

14
Back to Table of Contents
 YEAR IN REVIEW 2021

Immune Modulators Provide Some Additional Benefit

to Patients with Severe COVID-19
Tocilizumab and baricitinib are recommended for selected severely ill patients.
During 2021, we learned that the cornerstone of therapy for patients with severe COVID-19 is
excellent supportive care. Supplemental oxygen, often via high-flow nasal cannula, is essential,
and patients who develop respiratory failure should be treated with evidence-based interventions
for acute respiratory distress syndrome (ARDS) including low tidal volume ventilation and prone
position. In addition, standard of care now includes treatment with dexamethasone for patients
who are receiving supplemental oxygen. Many clinicians treat hospitalized patients with remdesivir
(as we do across our health system), although how much additional benefit it confers is unclear,
particularly in critically ill patients.
In 2021, use of immune modulatory therapies (routinely used for patients with rheumatologic
diseases) was introduced into the care of hospitalized patients with COVID-19. The interleukin (IL)-6
inhibitor tocilizumab has become part of treatment guidelines from the U.S. NIH and the Infec-
tious Diseases Society of America.Early trials did not show a mortality benefit, but later, larger trials
(RECOVERY [NEJM JW Gen Med Jun 15 and Lancet May 1; 397:1637] and REMAP-CAP [NEJM JW
Gen Med Apr 1 and N Engl J Med Apr 22; 384:1503]) and a subsequent meta-analysis of 27 studies
dem­onstrated lower mortality among hospitalized patients treated with an IL-6 antagonist in
addition to steroids. The benefit seems to be greatest for patients early in the course of disease
with acutely worsening hypoxemia; any benefit is less clear among patients who are supported
by mechanical ventilation or extracorporeal membrane oxygenation at the time of treatment
(NEJM JW Infect Dis Aug and JAMA Aug 10; 326:499).
The newest therapy is baricitinib, a Janus kinase (Jak) inhibitor, which is being considered as
an alternative to tocilizumab. An early trial demonstrated more rapid recovery for hospitalized
patients treated with baricitinib (NEJM JW Infect Dis Feb and N Engl J Med Mar 4; 384:795) and
a subsequent larger trial showed slightly better 28-day survival in hospitalized patients (NEJM
JW Gen Med Nov 1 and Lancet Respir Med Dec; 9:1407). Interestingly, progression to need for
high-flow oxygen or mechanical ventilation was similar with or without baricitinib. Based on these
studies, the NIH and the Infectious Diseases Society of America recommend use of baricitinib
in select patients, although not in patients receiving mechanical ventilation (as ventilated patients
were excluded from the trials).
Although neither tocilizumab nor baricitinib is a blockbuster, it is likely that either one, when
used early and in conjunction with steroids, can incrementally improve outcomes in patients
with severe COVID-19.
— Patricia Kritek, MD

U.S. NIH COVID-19 guidelines are available at https://www.covid19treatmentguidelines.nih.gov and IDSA

guidelines are available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-
management, both free of charge.

15
Back to Table of Contents

A Synopsis of Other Important Research from 2021
In 2021, NEJM Journal Watch covered many studies that are not included in our detailed Year in
Review features but nevertheless are highly relevant for clinical practice. Here are brief synopses
of some of those studies.
Perioperative management
An international comparison of postdischarge
opioid prescribing after surgery showed a dra-
matic difference between the U.S. and other
countries: U.S. patients — including those
with minimal pain — were much more likely to
receive prescriptions for opioids than were sim-
ilar patients from many other countries
(NEJM JW Gen Med Jan 15 and J Am Coll Surg
2020 Dec; 231:639).
Overdose and respiratory complications were
more likely in patients who received gabapenti-
noids plus opioids for postoperative pain, com-
pared with opioids alone (NEJM JW Gen Med
Feb 15 and JAMA Netw Open 2020 Dec 29;
3:2031647).
Patients classified as frail or very frail had sub-
stantial post­operative mortality even after pro-
cedures that are considered to be low risk. The
authors note that “there is no such thing as a
low-risk procedure for frail patients” (NEJM
JW Gen Med Mar 1 and JAMA Surg Jan;
156:e205152).
In patients undergoing hip-fracture surgery, a
randomized comparison between spinal and
general anesthesia showed no sig­nificant dif-
ferences in complication rates (NEJM JW Gen
Med Dec 1 and N Engl J Med Nov 25;
385:2025).
Peripheral arterial disease
In an observational study of patients with in-
termittent claudi­cation — but no evidence of
16
Back to Table of Contents
YEAR IN REVIEW 2021
limb-threatening ischemia — those who under-
went revascularization had worse outcomes
than patients who were managed medically
(NEJM JW Gen Med Oct 15 and J Vasc Surg
Sep; 74:771).
In a randomized trial of patients with periph-
eral arterial disease, a high-intensity walking
exercise regimen (but not a low-intensity one)
improved 6-minute walking distance (NEJM
JW Gen Med May 1 and JAMA Apr 6;
325:1266).
Distal deep venous thrombosis (DVT)
In a retrospective study, patients with calf DVT
had better outcomes when they were antico­
agulated immediately than when they were
managed with serial ultrasound imaging
alone (NEJM JW Gen Med Aug 1 and Mayo
Clin Proc May; 96:1184).
Coffee and cardiac arrhythmias
In a large prospective study, habitual coffee
consumption (as many as 6 cups daily) was
not asso­ciated with excess risk for cardiac
arrhythmias (NEJM JW Gen Med Aug 15
and JAMA Intern Med Sep; 181:1185).
Bone-density monitoring
In a retrospective study of postmenopausal
women taking medication for osteoporosis,
researchers examined the results of serial
bone-density testing. Decreased bone density
after the first monitoring interval (≈3 years)
did not accurately predict long-term bone loss;

the findings raise questions about the value
of frequent bone densitometry (NEJM JW Gen
Med Oct 1 and J Clin Endocrinol Metab Sep;
106:2718).
Antihypertensive drugs in patients
with chronic kidney disease (CKD)
In an observational study of nondialyzed
patients with advanced CKD, those who took
angiotensin-converting–enzyme inhibitors or
angiotensin-receptor blockers were less likely
to progress to end-stage renal disease than
those who took calcium-channel blockers
(NEJM JW Gen Med Jun 15 and Am J Kidney
Dis May; 77:719).
Another observational study showed that
β-blocker use was associated with lower mor-
tality in dialyzed patients with heart failure; the
findings were particularly notable in patients
with preserved ejection fraction and in those
taking metoprolol (NEJM JW Gen Med Jun 15
and Am J Kidney Dis May; 77:704).
In a short-term randomized trial, chlorthalidone
lowered blood pressure in hypertensive patients
with stage 4 CKD — contradicting the conven-
tional wisdom that thiazides and thiazide-like
diuretics are ineffective in this setting (NEJM
JW Gen Med Dec 15 and N Engl J Med Nov 5;
[e-pub]).
A new guideline addressed management of
hypertension in CKD (NEJM JW Gen Med
Sep 1 and Ann Intern Med Sep; 174:1270).
17
Back to Table of Contents
YEAR IN REVIEW 2021
Guidelines from the U.S. Preventive
Services Task Force
For people at average risk for colorectal cancer,
the Task Force lowered the recommended age
for initial screening to 45; however, this recom-
mendation received a “B” grade, which is some-
what weaker than the “A” grade for screening
between ages 50 and 75 (NEJM JW Gen Med
Jun 15 and JAMA May 18; 325:1965).
Although screening for vitamin D deficiency
in healthy people is widespread, the Task Force
found insufficient evidence to recommend
this practice (NEJM JW Gen Med May 15
and JAMA Apr 13; 325:1436).
In a “draft recommendation” on aspirin for
primary prevention of cardiovascular disease,
routine use of aspirin was no longer advised
for any age group. For people between ages
40 and 59 whose predicted 10-year cardiovas-
cular risk exceeds 10%, the document suggests
an individualized approach based on profes-
sional judgment and patient preferences (a
“C” grade); for people 60 or older, the Task
Force recommended against aspirin prophy­
laxis (a “D” grade). The final version of the
document presumably will be published in
2022 (NEJM JW Gen Med Nov 15 and
USPSTF Oct 12; [e-pub]).
— Allan S. Brett, MD
 A journal for transforming
health care delivery
Practical innovations for health care leaders

NEJM Catalyst Innovations in Care Delivery provides practical help to health care professionals in meeting and
overcoming critical challenges. Here are just a few examples of applications of our content:
• Adapted in-depth strategic planning articles to • Shared Insights Interviews, reports, and
guide our health care executives in meeting proprietary data on response to Covid-19 that
financial viability, sustainability, and quality guided clinicians in navigating the “new normal”
improvement goals of care delivery
• Advanced health equity using case studies on • Stayed up to date and implemented new
equity, racism, and social determinants of health ways to combat clinician burnout and
that showed clinical leaders viable ways to meet increase engagement
community aspirations

Unlimited subscriber access to constantly updated

content, as well as easy navigation and discoverability,
keeps all our readers informed of knowledge critical to
the needs of their roles.

Subscribe today at STORE.NEJM.ORG/CATALYST