Evidence Building Research Shedding Light On Clinical Uncertainty

Evidence-Building Research:
Shedding Light on
Clinical Uncertainty
A collection of research articles that add important evidence
in areas of clinical or policy uncertainty
March 2024
Dear Reader,
Just over two years since we launched, NEJM Evidence is publishing original research along the full spectrum of human
investigation, from first-in-human studies that offer insight into the safety and potential efficacy of novel therapeutics to the
late-stage confirmatory trials that solidify the evidence base that forms the foundation of clinical practice. But NEJM Evidence
seeks to go even further. Our goal is to contextualize rigorously conducted, cutting-edge research with novel article types
and commentary from physicians, scientists, statisticians, and clinical trial participants so that clinicians and investigators
can use or build upon that evidence to improve the care of patients.
This special collection from NEJM Evidence offers a selection of research articles that, through varied methodologic
approaches, each add to important areas of either clinical or policy uncertainty. We are also sharing related commentary
that contextualizes the work or sheds light on the methods utilized to generate the evidence. Each article in this collection
clarifies and builds on current medical evidence — answering previously open questions, challenging current clinical
practices, or creating dialogue around health policies where more evidence and study is required. Articles cover a broad
range of fields — neurology, oncology, cardiology, allergy, infectious disease, nephrology, and general medicine — and each
has relevance for practicing internists.
Here are a few highlights:
• Large language models, like ChatGPT and Bard, are increasingly making headlines. A 5-minute animated video, as part
of a series we call Stats, STAT!, explains the statistics behind these large language models. While these new tools may
seem remarkably intelligent, at their core they just assemble sentences based on statistics from large amounts of text.
• This collection includes three RCTs from the fields of neurology, allergy, and infectious diseases. When a person without
known atrial fibrillation has an embolic stroke from an unknown source, the optimal strategy to prevent recurrent stroke
has remained unclear. Prior trials have not demonstrated a benefit of oral anticoagulation over aspirin in this setting, but
investigators asked, would there be a benefit of oral anticoagulation among a population with specific risk factors for atrial
fibrillation or a patent foramen ovale? They conducted a trial to find out, and after an interim analysis, the Data and Safety
Monitor Board (DSMB) recommended stopping the trial for futility. Opting to stop a trial partway through enrollment is
not a decision made lightly. To help you understand the issues that a DSMB must consider in such circumstances, we
include an article from our DSMB mini-series that delves into the considerations about early termination of clinical trials.
• The next RCT in this collection continues the evolving story of how to best care for children with a peanut allergy, with a
trial that randomized peanut-allergic children who were between 1 to less than 4 years of age to receive a peanut allergen
powder-dnfp (PTAH) oral immunotherapy or placebo. After 12 months, 73.5% of participants who received the active
treatment tolerated a single dose of >600 mg peanut protein, compared with 6.3% in the placebo group.
• The third RCT takes a step in the effort to reduce the dosing burden for HPV vaccination by assessing 2 versus 3 doses of
a 9-valent HPV vaccine among 15–26-year-olds in the United States, for whom 3 doses is the current recommendation.
This trial is ongoing, but the article in this collection reports the interim results evaluating immunogenicity 1 month after
vaccination among female participants.
• We also include two observational studies. The first evaluates the association between hypertensive disorders
in pregnancy and the risk of stroke in later life among Black women in the U.S., a population that experiences a
disproportionate burden of stroke. The study used data from more than 40,000 participants in the longitudinal
(continued on next page)
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Black Women’s Health Study and found that hypertensive disorder in pregnancy was associated with an estimated 66%
increased long-term risk of stroke. The accompanying editorial delves into the clinical and population health implications
and makes a compelling case that the urgent need for primary prevention strategies that require action now are not
dependent on whether the identified association reflects a causal link.
• The second observational study tackles the common clinical question of how quickly or slowly to correct sodium in
patients with severe hyponatremia in order to avoid neurologic complications, including central pontine myelinolysis.
The data they present may surprise you.
• Finally, we close this collection with an article from our series that focuses on exploring the interface between clinical
practice and trial design. In this article, investigators provide a “new look” at P values in randomized trials by examining
results of more than 23,000 randomized trials. In their words, they hope to “guard medical researchers against naive
interpretations of the P value and overoptimistic effect sizes.”
NEJM Evidence is a platform for researchers, spanning all phases of their careers, and health care practitioners, whether
currently in training or seasoned clinicians, to discover the latest developments in medicine and explore the behind-the-
scenes process of generating evidence. We hope you enjoy reading this curated article collection and find that it informs
your own clinical decision-making. Comments or feedback you may have can be shared at editorial.evidence@nejm.org
and are always welcome!
Sincerely,
Chana A. Sacks, MD, MPH
Editor-in-Chief, NEJM Evidence
Table of Contents
STATS, STAT!
Large Language Models 1
Michael Fralick, MD, PhD, and Others
ORIGINAL ARTICLE
Apixaban versus Aspirin for Embolic Stroke of Undetermined Source 2
Tobias Geisler, MD, and Others
EDITORIAL
Power Considerations in Designing and Interpreting Adaptive Clinical Trials 3
Rui Wang, PhD, and Cyrus Mehta, PhD
CLINICAL TRIALS WORKSHOP | DSMB MINI-SERIES

Early Termination of Clinical Trials for Futility — Considerations for a Data
and Safety Monitoring Board 5
Susan S. Ellenberg, PhD, and Pamela A. Shaw, PhD
ORIGINAL ARTICLE
Oral Immunotherapy for Peanut Allergy in Children 1 to Less Than 4 Years of Age 6
George Du Toit, MB, BCh, and Others
EDITORIAL
Doing More with Less 7
Adora A. Lin, MD, PhD, and Patricia C. Fulkerson, MD, PhD
ORIGINAL ARTICLE
Immunogenicity of 2 or 3 Doses of 9vHPV Vaccine in U.S. Female Individuals
15 to 26 Years of Age 9
Abbey B. Berenson, MD, PhD, and Others
EDITORIAL
Reduced-Dose HPV Vaccination — Implications for Cancer Prevention Policy 10
Leeya F. Pinder, MD, MPH
ORIGINAL ARTICLE
Hypertensive Disorders of Pregnancy and Risk of Stroke in U.S. Black Women 12
Shanshan Sheehy, ScD, and Others
EDITORIAL
Hypertensive Disorders of Pregnancy in Black Women —
Where Do We Go from Here? 13
Kristian B. Filion, PhD, and Sonia M. Grandi, PhD
continued on next page
NEJM Evidence is a publication of NEJM Group, a division of the Massachusetts Medical Society.
©2024 Massachusetts Medical Society. All rights reserved.
continued from previous page
ORIGINAL ARTICLE
Severe Hyponatremia Correction, Mortality, and Central Pontine Myelinolysis 16
Harish Seethapathy, MD, and Others
ORIGINAL ARTICLE
A New Look at P Values for Randomized Clinical Trials 17
Erik van Zwet, PhD, and Others
NEJM Evidence is a publication of NEJM Group, a division of the Massachusetts Medical Society.
©2024 Massachusetts Medical Society. All rights reserved.
evidence.nejm.org Evidence-Building Research: Shedding Light on Clinical Uncertainty 1
Published July 25, 2023

NEJM Evid 2023; 2 (8)
DOI: 10.1056/EVIDstat23001
STATS, STAT!
Large Language Models

Michael Fralick, M.D., Ph.D., Chana A. Sacks, M.D., M.P.H., Daniel Muller, Tim Vining, Emily Ling, Jeffrey M. Drazen,
M.D., and C. Corey Hardin, M.D., Ph.D.
I
n the latest edition of Stats, STAT!, Fralick and colleagues explain the statistics behind large language models — used
in chat bots like ChatGPT and Bard. While these new tools may seem remarkably intelligent, at their core they just
assemble sentences based on statistics from large amounts of text.
Disclosures
Disclosure forms provided by the authors are available with the full text
of this article at evidence.nejm.org.
Author Affiliations
Michael Fralick, M.D., Ph.D.,Division of General Internal Medicine, Sinai Health System, Toronto.
Chana A. Sacks, M.D., M.P.H.,Massachusetts General Hospital, Boston, Massachusetts.
Watch Video
Jeffrey M. Drazen, M.D., Harvard Medical School, Boston, Massachusetts.
C. Corey Hardin, M.D., Ph.D., Massachusetts General Hospital, Boston, Massachusetts
at evidence.nejm.org
Back to Table of Contents

2 Evidence-Building Research: Shedding Light on Clinical Uncertainty evidence.nejm.org
Published
Published December
December 22,
22, 2023
2023
NEJM Evid 2023; 3 (1)
NEJM Evid 2023; 3 (1)
DOI: 10.1056/EVIDoa2300235
DOI: 10.1056/EVIDoa2300235
ORIGINAL ARTICLE
Apixaban versus Aspirin for Embolic Stroke of

Undetermined Source
Tobias Geisler, M.D.,1 Timea Keller, M.Sc.,1 Peter Martus, Ph.D.,2 Khouloud Poli, M.D.,3,4 Lina Maria Serna-Higuita, M.D.,2
Juergen Schreieck, M.D.,1 Meinrad Gawaz, M.D.,1 Johannes T€ unnerhoff, M.D.,3,4 Paula Bombach, M.D.,4,5
Thomas N€agele, M.D., Uwe Klose, Ph.D., Parwez Aidery, M.D.,1 Patrick Groga-Bada, M.D.,1 Andrea Kraft, M.D.,7
6 6
Frank Hoffmann, M.D.,7 Carsten Hobohm, M.D.,8 Katrin Naupold, M.D.,8 Ludwig Niehaus, M.D.,9 Marc Wolf, M.D.,10
Hansj€org B€azner, M.D.,10 Jan Liman, M.D.,11,12 Rolf Wachter, M.D.,13,14,15 Hubert Kimmig, M.D.,16 Werner Jung, M.D.,17
Roman Huber, M.D.,18 Regina Feurer, M.D.,18 Alfred Lindner, M.D.,19 Katharina Althaus, M.D.,20 Felix J. Bode, M.D.,21
Gabor C. Petzold, M.D.,21 Thanh N. Nguyen, M.D., Ph.D.,22,23 Brian Mac Grory, M.D., Ph.D.,24,25
Matthew Schrag, M.D., Ph.D.,26 Jan C. Purrucker, M.D.,27 Christine S. Zuern, M.D.,11,28 Ulf Ziemann, M.D.,3,4
Sven Poli, M.D.,3,4 for the ATTICUS Investigators*
Abstract
BACKGROUND Rivaroxaban and dabigatran were not superior to aspirin in trials of
patients with embolic stroke of undetermined source (ESUS). It is unknown whether
apixaban is superior to aspirin in patients with ESUS and known risk factors for
cardioembolism.
METHODS We conducted a multicenter, randomized, open-label, blinded-outcome trial

of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within Drs. Geisler and Poli contributed
equally to this article.
28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a
patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was *A complete list of the ATTICUS
Investigators is provided in the
switched to apixaban in case of atrial fibrillation detection. The primary outcome was any Supplementary Appendix,
new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow- available at evidence.nejm.org.
up. Secondary outcomes included major and clinically relevant nonmajor bleeding. The author affiliations are listed
at the end of the article.
RESULTS A total of 352 patients were randomly assigned to receive apixaban (178
Dr. Geisler can be contacted at
patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-
tobias.geisler@med.uni-tuebingen.
up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions de or at the Department of
Cardiology and Angiology,
occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%)
University Hospital T€ ubingen,
participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 Otfried-M€ uller-Str. 10, 72076
T€ubingen, Germany; and Dr. Poli
to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and
can be contacted at sven.poli@uni-
seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, tuebingen.de or at the Department
of Neurology & Stroke, University
0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per
Hospital T€ ubingen, Hoppe-Seyler-
100 person-years in those given apixaban and 45.7 per 100 person-years in those given Str. 3, 72076 T€ ubingen, Germany.
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Published December 26, 2023

NEJM Evid 2023; 3 (1)
NEJM Evid 2023; 3 (1)
DOI: 10.1056/EVIDe2300309
DOI: 10.1056/EVIDe2300309
EDITORIAL
Power Considerations in Designing and

Interpreting Adaptive Clinical Trials
Rui Wang, Ph.D.,1,2 and Cyrus Mehta, Ph.D.2,3
A
daptive clinical trials allow researchers to make preplanned modifications based
on accumulating data from an ongoing trial while preserving the trial’s integrity
and validity. These modifications may include early termination in cases of suc-
cesses or lack of efficacy, refining the sample size, altering treatments or doses, or focusing
recruitment efforts on individuals most likely to benefit.
In this issue of NEJM Evidence, Geisler et al.1 report results from the Apixaban for Treatment
of Embolic Stroke of Undetermined Source (ATTICUS) trial, a multicenter randomized trial
of apixaban compared with aspirin in patients with cardioembolism risk factors. The primary
outcome was any new ischemic lesion on brain magnetic resonance imaging during a
12-month follow-up. The trial utilized an adaptive design with a recruitment target of a maxi-
mum of 600 participants, allowing for early termination for futility or efficacy based on data
from the first 200 participants. At the interim analysis, the one-sided P value for the primary
end point was 0.63; the trial was stopped for new recruitment due to futility.
The adaptive trial design offers greater flexibility than a single-stage fixed design. However,
there is a cost for repeated analyses using data from the same trial. Sample size determina-
tion needs to take the design choices (e.g., the number of interim looks and futility boundary)
into account.2 The trial design of Geisler et al.1 followed the method described by Bauer and
Ko€hne3: at the interim analysis, the trial will be stopped for efficacy if the one-sided P value
is smaller than a1=0.0131 and for futility if it is larger than a0=0.3. Bauer and Ko€hne3 noted
that the loss of power for an a0>0.5 is very small, but the loss increases as a0 decreases
(i.e., a more aggressive futility boundary). Specifically, if a0=1 (no futility boundary), a trial
with a sample size of 480 participants has 90% power to detect a 7.5-percentage-point abso-
lute drop in the appearance of new lesions during a 12-month follow-up period, decreasing
from 10% in the control group to 2.5% on the experimental arm, with a one-sided type 1
error of 0.025. The power drops to 89.2% if a0=0.5, and to 86.1% if a0=0.3.
In the design stage, sample size calculations rely on assumptions about the trial end point
and the hypothesized treatment effect, both of which may be associated with substantial The author affiliations are listed
uncertainty. In Geisler et al.,1 the sample size calculations assumed 10% of participants
would have any new ischemic lesion in the aspirin group and an absolute reduction of Dr. Wang can be contacted at
7.5 percentage points in the apixaban group (i.e., to 2.5% of participants). From the actual rwang@hsph.harvard.edu or at
Harvard Medical School, 401
trial data, the percentage of patients in the aspirin group with a new lesion was 16% and the Park Dr., Suite 401, Boston,
observed risk difference from the apixaban group was 2.4 percentage points. For a binary MA 02215.
outcome, both a higher event proportion in the control group confidence intervals all included the null value of 1. Over-
(up to 50%) and a smaller risk difference would result in a all, the trial did not provide sufficient evidence demonstrat-
decrease in a trial’s power. If the true proportion of patients ing the superiority of apixaban over aspirin. The adaptive
with new lesions on imaging in the aspirin group were 16%, design allowed the trial team to save resources by stopping
as observed (i.e., higher than the assumed 10%), the neces- the trial early. Based on the observed data at the interim
sary sample size would have to rise from 480 to 852 to main- analysis in support of futility, it is likely that similar conclu-
tain 90% power to detect the same 7.5 percentage point sions would have been reached even if the trial had contin-
difference between the trial groups. Furthermore, if the true ued to the end with the planned maximum sample size.
difference in percentages of patients with new lesions The authors cautioned in their Discussion that the small
between the groups were 2.4 percentage points, the sample sample size of ATTICUS and its associated low power could
size would have to increase to 9364 to maintain 90% power. provide a possible explanation of the lack of statistical sig-
For ATTICUS, this was not feasible, because the practical nificance in favor of apixaban for a small true effect.
constraints limited the maximum sample size to 600.
Disclosures
Sample size reassessment methods are available to help Author disclosures are available at evidence.nejm.org.
address uncertainty about the essential input parameters
in sample size calculations. Distinctions are made when Author Affiliations
1
such modifications are based on estimates of the nuisance Department of Population Medicine, Harvard Pilgrim Health Care
Institute and Harvard Medical School, Boston
parameters (e.g., event proportion in the control group for 2
Department of Biostatistics, Harvard T.H. Chan School of Public Health,
a binary outcome) or the parameter of interest (e.g., the Boston
treatment effect).4 In Geisler et al.,1 the investigators 3
Cytel Corporation, Cambridge, MA
acknowledged the uncertainty regarding the assumptions,
considered a difference of 7.5 percentage points clinically
References
relevant, and planned a sample size re-estimation at the
1. Geisler T, Keller T, Martus P. Apixaban versus aspirin for embolic
interim analysis if the trial did not stop for efficacy or futil-
stroke of undermined source. NEJM Evid 2024;3(1). DOI: 10.1056/
ity. This flexibility allows the trial team to stop the recruit-
EVIDoa2300235.
ment earlier if the required sample size is smaller than the
2. Jennison C, Turnbull BW. Group sequential methods with applica-
planned maximum recruitment target, which was chosen
tions to clinical trials. New York: Routledge, 1999. DOI: 10.1201/
for practical reasons. Alternatively, one can start with a
9780367805326.
smaller sample size that is adequately powered to detect a
treatment effect that is somewhat larger than the minimum 3. Bauer P, K€
ohne K. Evaluation of experiments with adaptive interim
analyses. Biometrics 1994;50:1029-1041. DOI: 10.2307/2533441.
clinically meaningful improvement and then repower the
trial at the interim analysis if the observed data fall within a 4. Proschan MA. Sample size re-estimation in clinical trials. Biom J
promising zone.5-7 2009;51:348-357. DOI: 10.1002/bimj.200800266.
5. Hsiao ST, Liu L, Mehta CR. Optimal promising zone designs. Biom J
Finally, standard methods for effect estimation following 2018;61:1175-1186. DOI: 10.1002/bimj.201700308.
early termination may be subject to bias.8 Without account- 6. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim
ing for early stopping, trials that stop early for benefits may results are promising: a practical guide with examples. Stat Med
overestimate the true treatment effect, whereas those that 2010;30:3267-3284. DOI: 10.1002/sim.4102.
stop early for futility may have a downward bias (i.e., 7. Jennison C, Turnbull BW. Adaptive sample size modification in clini-
underestimate the true treatment effect). Depending on cal trials: start small then ask for more? Stat Med 2015;34:3793-3810.
the imputation approaches used for handling missing out- DOI: 10.1002/sim.6575.
come data, the estimated odds ratios for the primary out- 8. Marschner IC, Schou M, Martin AJ. Estimation of the treatment effect
come in Geisler et al.1 ranged from 0.65 to 0.86, all in the following a clinical trial that stopped early for benefit. Stat Methods
direction of favoring the apixaban group, but the 95% Med Res 2022;31:2456-2469. DOI: 10.1177/09622802221122445.
NEJM EVIDENCE 2
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Published
PublishedJune
June28,
28, 2022
2022
NEJM
NEJM Evid 2022;11(7)
Evid 2022; (7)
DOI: 10.1056/EVIDctw2100020
DOI: 10.1056/EVIDctw2100020
CLINICAL TRIALS WORKSHOP | DSMB MINI-SERIES
Early Termination of Clinical Trials for

Futility — Considerations for a Data and Safety
Monitoring Board
Susan S. Ellenberg, Ph.D.,1 and Pamela A. Shaw, Ph.D.2
Abstract
Clinical trials may be stopped for futility if there is little or no chance of demonstrating Scott R. Evans, Ph.D.,
the hoped-for effect. Reasons include evidence of no treatment effect, substantial missing DSMB Mini-Series Editor
data that would unacceptably undermine trial conclusions, or event rates too low to sup- Jeffrey Drazen, M.D.,
port meaningful comparisons. An example of the last type of futility can be seen in the Editor
Covid-19 epidemic. ACTIV-4b (Accelerating COVID-19 Therapeutic Interventions and
Vaccines) was a placebo-controlled trial testing antithrombotic agents given prophylacti-
cally to people with Covid-19 who had not yet been hospitalized. Antithrombotic agents
prevent clots which were common in patients with Covid-19, but they also increase the
risk of bleeding. As the trial progressed, the DSMB noted that the overall rate of throm-
botic events was far too low to ever observe a treatment benefit and too low to justify the
use of anticoagulant or antiplatelet therapy; only three events had been documented
among the 558 participants. By making this decision, the DSMB not only protected the
patients who had enrolled in the trial, they conserved community and financial resources.
The authors use this and other examples to illustrate the thinking that members of the
DSMB use when examining data from an ongoing trial.
Introduction
I
n the early 2000s, epidemiologic data indicated a strong association between a
The author affiliations are listed
patient’s “inflammatory status,” as measured by the serum level of C-reactive protein, at the end of the article.
and the risk of a major adverse cardiovascular event such as myocardial infarction,
Dr. Ellenberg can be contacted at
stroke, and other vascular events. Was inflammation a root cause of this cardiovascular dis-
sellenbe@pennmedicine.upenn.edu
ease? To address this question, the National Institutes of Health sponsored the Cardiovascu- or at Department of Biostatistics,
lar Inflammation Reduction Trial (CIRT), assessing whether low-dose methotrexate, an Epidemiology, and Informatics,
anti-inflammatory agent long used in the treatment of rheumatoid arthritis, could prevent Perelman School of Medicine,
University of Pennsylvania, 423
cardiovascular events in a population at elevated risk for such events.1 The trial protocol Guardian Dr., Room 611,
included a statistical plan for early termination for “futility,” should the emerging data Philadelphia, PA 19104.
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Published October 23, 2023

NEJM Evid 2023; 2 (11)
NEJM Evid 2023; 2 (1)
DOI: 10.1056/EVIDoa2300145
DOI: 10.1056/EVIDoa2300145
ORIGINAL ARTICLE
Oral Immunotherapy for Peanut Allergy in

Children 1 to Less Than 4 Years of Age
George Du Toit, M.B., B.Ch.,1 Kari R. Brown, M.D.,2 Andrea Vereda, M.D., Ph.D.,3 Anne-Marie Irani, M.D.,2
Stephen Tilles, M.D.,2 Anoshie Ratnayake, M.D.,2 Stacie M. Jones, M.D.,4 and Brian P. Vickery, M.D.,5
for the POSEIDON Study Group*
Abstract
BACKGROUND Peanut allergy is a common childhood allergy, and the only approved
treatment for children 4 to 17 years of age is peanut allergen powder-dnfp (PTAH) oral
immunotherapy.
METHODS For this phase 3, randomized, double-blind, placebo-controlled trial, we

enrolled peanut-allergic children 1 to <4 years of age who experienced dose-limiting
symptoms from 300 mg peanut protein during a screening double-blind, placebo-
controlled food challenge (DBPCFC). Participants received PTAH or placebo, randomized
in a 2:1 ratio, for approximately 12 months. At the trial conclusion, all participants under-
went an exit BDPCFC. The primary end point was desensitization (i.e., tolerating a
600-mg single dose of peanut protein with only mild allergy symptoms).
RESULTS In the PTAH-treated group (n=98), 73.5% of participants tolerated a single dose
of 600 mg peanut protein at exit DBPCFC compared with 6.3% in the placebo group
*A complete list of investigators in
(n=48). Most participants experienced an adverse event (98.0% of PTAH-treated and the POSEIDON Study Group is
provided in the Supplementary
97.9% of placebo-treated participants), which was mild or moderate in grade for 93.2%
Appendix, available at evidence.
of participants (92.9% in PTAH-treated and 93.8% in placebo-treated participants). nejm.org.
Treatment-related adverse events, which were mild to moderate, were experienced by
75.5% of PTAH-treated and 58.3% of placebo-treated participants. Three treatment- at the end of the article.
related systemic allergic reactions, none of which were severe or serious in grade, were Dr. Du Toit can be contacted at
noted in two PTAH-treated participants (2%). georgedutoit@gmail.com or at
Guy’s and St. Thomas’ National
CONCLUSIONS In peanut-allergic children 1 to <4 years of age treated with PTAH for Health Service Foundation
Trust, Evelina London Children’s
approximately 12 months, the majority tolerated all peanut protein dose levels assessed. Hospital, St Thomas’
PTAH-treated patients had more treatment-related adverse events, which were mild to Hospital, Westminster Bridge Rd,
London SE1 7EH, United
moderate severity. (Funded by Aimmune Therapeutics; ClinicalTrials.gov number, Kingdom.
NCT03736447.)
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NEJM Evid 2023; 2 (11)
DOI: 10.1056/EVIDe2300223
EDITORIAL
Doing More with Less

Adora A. Lin, M.D., Ph.D.,1 and Patricia C. Fulkerson, M.D., Ph.D.1
P
eanut allergy affects 1 to 3% of children in Western countries and is increasing in
prevalence in Africa and Asia. In most patients, peanut allergy develops early in
life and continues into adulthood. Peanut allergy is the most common cause of
food-related anaphylaxis and death and creates significant medical, financial, and psycho-
social burdens on patients and their families.1-3 Until recently, the mainstay of treatment
for peanut and other food allergies was strict avoidance of peanut and carrying injectable
epinephrine in case of accidental exposure. In 2020, the Food and Drug Administration
approved the use of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) oral immuno-
therapy for patients 4 to 17 years of age. This remains the only approved treatment for pea-
nut or any other food allergy, and there is no approved treatment for children <4 years old.
In this issue of NEJM Evidence, Du Toit et al. report the findings of the POSEIDON (Peanut
Oral Immunotherapy Study of Early Intervention for Desensitization, NCT03736447) trial,
a phase 3, international, randomized, double-blind, placebo-controlled trial of PTAH oral
immunotherapy in children 1 to <4 years of age. The trial found that 73.5% of peanut-
allergic children receiving 300 mg (equivalent to about one peanut kernel) per day of
PTAH for 12 to 24 weeks achieved the primary end point of desensitization, that is, tolerat-
ing at least a cumulative dose of 1000 mg of peanut protein. In the placebo group, only
6.3% of the participants reached this end point.4 Among the PTAH-treated children, 61.2%
were able to tolerate 4043 mg of peanut protein (equivalent to approximately 1 tablespoon
of peanut butter). These results add to the body of evidence that oral immunotherapy is
efficacious in children <4 years of age. Importantly, this trial also suggests that clinically
significant results can be seen with much lower doses and shorter durations than used in
previous trials for this age group.
Efficacy of oral immunotherapy in young children is not surprising, given what has been
learned from studies of food introduction. Early introduction of peanut into the diet can
substantially reduce the development of peanut allergy,5,6 suggesting that early immune
pathways leading to food allergy instead of tolerance can be influenced by timely introduc-
tion to, and regular consumption of, allergenic foods. In the DEVIL (Determining the Effi-
cacy and Value of Immunotherapy on the Likelihood of Peanut Tolerance, NCT00932828) The author affiliation is listed at
trial, peanut-reactive children <3 years of age were given at least 300 mg and up to the end of the article.
3000 mg of peanut protein daily for a median of 29 months. In the IMPACT (Oral Immu- Dr. Fulkerson can be contacted at
notherapy for Induction of Tolerance in Peanut-Allergic Children, NCT03345160) trial, patricia.fulkerson@nih.gov or at
peanut-reactive children 1 to <4 years of age were treated with up to 2000 mg of peanut National Institute of Allergy and
Infectious Diseases, 5601 Fishers
protein (or placebo) daily for approximately 26 months. After completing treatment, more Lane #6B56, Bethesda, MD
than 70% of participants in both trials were able to safely consume 5000 mg of peanut 20892.
protein (equivalent to approximately 16 peanuts),7,8 dem- with its predecessors, creates a strong argument to support
onstrating a remarkable increase in the amount of peanut the use of oral immunotherapy in infants and young chil-
that the children could tolerate, although this effect was dren with peanut allergy.
not examined until at least 2 years of peanut oral immuno-
therapy were completed. Younger age at trial entry was
Disclosures
associated with more favorable outcomes. Author disclosures are available at evidence.nejm.org.
The DEVIL and IMPACT trials showed that peanut-specific Author Affiliation
1
National Institute of Allergy and Infectious Diseases, Bethesda, MD
IgE (psIgE) levels quickly and significantly decrease over the
course of treatment, whereas peanut-specific IgG4 (psIgG4)
levels increase. In general, peanut avoidance results in References
increasing psIgE in peanut-allergic young children. In these 1. Bock SA, Mu~
noz-Furlong A, Sampson HA. Fatalities due to anaphy-
trials, lower psIgE levels at baseline were associated with lactic reactions to foods. J Allergy Clin Immunol 2001;107:191-193.
more favorable response to therapy. Rapid decreases in DOI: 10.1067/mai.2001.112031.
psIgE and elevated psIgG4 levels were observed in the 2. King RM, Knibb RC, Hourihane JO. Impact of peanut allergy on
POSEIDON trial even though the children consumed lower quality of life, stress and anxiety in the family. Allergy 2009;64:
doses of peanut protein and had a much shorter duration of 461-468. DOI: 10.1111/j.1398-9995.2008.01843.x.
treatment. Notably, the changes observed in peanut-specific 3. Avery NJ, King RM, Knight S, Hourihane JO. Assessment of quality
immune parameters in the participants in these studies and of life in children with peanut allergy. Pediatr Allergy Immunol
the advantageous results in younger patients imply that 2003;14:378-382. DOI: 10.1034/j.1399-3038.2003.00072.x.
even after development of peanut sensitization and clinical 4. Du Toit G, Brown KR, Vereda A, et al. Oral immunotherapy for
reactivity, early treatment with oral exposure can disrupt peanut allergy in children 1 to less than 4 years of age. NEJM Evid
further immune progression in peanut allergy and induce at 2023;2(11). DOI: 10.1056/EVIDoa2300145.
least desensitization to peanut, if not remission of their pea- 5. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut
nut allergy. consumption in infants at risk for peanut allergy. N Engl J Med
2015;372:803-813. DOI: 10.1056/NEJMoa1414850.
The POSEIDON trial provides evidence that the commer- 6. Perkin MR, Logan K, Tseng A, et al. Randomized trial of introduc-
cially available PTAH immunotherapy is effective at desen- tion of allergenic foods in breast-fed infants. N Engl J Med 2016;
sitizing peanut-allergic children under 4 years of age and 374:1733-1743. DOI: 10.1056/NEJMoa1514210.
increasing their tolerance threshold to peanut, with a safety 7. Vickery BP, Berglund JP, Burk CM, et al. Early oral immunotherapy
profile that is similar to that in prior studies in this age in peanut-allergic preschool children is safe and highly effective.
group and better with regard to reaction frequency and J Allergy Clin Immunol 2017;139:173-181.e8. DOI: 10.1016/j.jaci.
2016.05.027.
severity compared with PTAH trials in children 4 years
and older.9,10 The ability to minimize the therapeutic dose 8. Jones SM, Kim EH, Nadeau KC, et al. Efficacy and safety of oral
and duration needed to achieve some protection against immunotherapy in children aged 1–3 years with peanut allergy (the
Immune Tolerance Network IMPACT trial): a randomised placebo-
accidental exposure may make this treatment option more
controlled study. Lancet 2022;399:359-371. DOI: 10.1016/S0140-
attractive to caregivers of young and picky eaters, who
6736(21)02390-4.
may have trouble ingesting larger quantities of peanut and
9. Vickery BP, Vereda A, Nilsson C, et al. Continuous and aildy oral
recognizing peanut-containing foods outside the home.
immunotherapy for peanut allergy: results from a 2-year open-label
However, questions regarding the durability of protection
follow-on study. J Allergy Clin Immunol Pract 2021;9:1879-1889.e13.
remain unanswered. In addition, questions regarding just DOI: 10.1016/j.jaip.2020.12.029.
how much (or how little) peanut protein young children
10. Hourihane JO, Beyer K, Abbas A, et al. Efficacy and safety of oral
need to consume and how often it needs to be consumed
immunotherapy with AR101 in European children with a peanut
to prevent serious allergic reactions or promote tolerance allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-
likely inhibit robust implementation of these practices by controlled phase 3 trial. Lancet Child Adolesc Health 2020;4:728-739.
families with young children. Nonetheless, this trial, along DOI: 10.1016/S2352-4642(20)30234-0.
NEJM EVIDENCE 2
Published January 23, 2024

Published January 23, 2024
NEJM Evid 2024; 3 (2)
NEJM Evid 2024; 3 (2)
DOI: 10.1056/EVIDoa2300194
DOI: 10.1056/EVIDoa2300194
ORIGINAL ARTICLE
Immunogenicity of 2 or 3 Doses of 9vHPV Vaccine

in U.S. Female Individuals 15 to 26 Years of Age
Abbey B. Berenson, M.D., Ph.D.,1,2 Gitika Panicker, Ph.D.,3 Elizabeth R. Unger, M.D., Ph.D.,3 Richard E. Rupp, M.D.,2,4
and Yong-Fang Kuo, Ph.D.2,5
Abstract
BACKGROUND Within the United States, a 9-valent human papillomavirus (9vHPV) vac-
cine (HPV-6/11/16/18/31/33/45/52/58) is recommended as a two-dose series among
individuals 9 to 14 years of age and a three-dose series among those 15 to 26 years of age.
Data comparing two versus three doses of 9vHPV vaccine among individuals 15 to
26 years of age are limited.
METHODS We report on an ongoing, single-blinded, randomized noninferiority trial of

the 9vHPV vaccine among individuals 15 to 26 years of age in the United States. Partici-
pants were randomly assigned to a two-dose (0 and 6 months) or three-dose (0, 2, and 6
months) schedule. Blood draws to assess antibody titers were planned before the first
vaccination and at 1 and 6 months after the final vaccination. The primary outcome was
the rate of seroconversion at 1 month after final vaccination. The secondary outcome was
the two-dose versus three-dose ratio of antibody geometric mean titers (GMTs) for each
of the 9vHPV genotypes at 1 and 6 months after final vaccination. This interim analysis
reports results of female participants at 1 month after final vaccination.
RESULTS Of 860 participants screened, 438 were enrolled and randomly assigned to the
two-dose (n=217) or three-dose (n=221) group. At 1 month after the final vaccine dose, the
seroconversion rate for each of the nine HPV genotypes in the vaccine was 100% among
participants in the two-dose group and 99% in the three-dose group. The point estimates of
the two-dose versus three-dose ratios of antibody GMTs for eight of the nine HPV genotypes
were above unity; the ratio for HPV-45 was 0.86 (95% confidence interval [CI], 0.66 to
1.13). This was also the smallest value for the lower bound of the 95% CI for all nine ratios at the end of the article.
(ratios above 1 favor the two-dose schedule). No serious adverse events were observed.
Dr. Berenson can be contacted at
abberens@utmb.edu or at Center
CONCLUSIONS In this unplanned interim analysis of U.S. female participants 15 to
for Interdisciplinary Research in
26 years of age, two doses of 9vHPV vaccine appear to elicit responses similar to three Women’s Health, The University
of Texas Medical Branch, 301
doses at 1 month postvaccination. We await final results at 6 months following the last
University Blvd., Galveston,
vaccine dose. (ClinicalTrials.gov number, NCT03943875.) TX 77555.
Read Full Article

Published
PublishedJanuary
January23,
23, 2024
2024
NEJM Evid 2024; 3 (2)
NEJM Evid 2024; 3 (2)
DOI: 10.1056/EVIDe2300336
DOI: 10.1056/EVIDoa2300194
EDITORIAL
Reduced-Dose HPV Vaccination — Implications

for Cancer Prevention Policy
Leeya F. Pinder, M.D., M.P.H.1
H
uman papillomaviruses (HPVs), of which there are over 200 types, typically
infect cells of the skin and mucosa. Most infections are cleared by the immune
system without any intervention; however, in a small percentage of infected
individuals, the virus persists, resulting in a variety of disorders. More specifically,
13 HPV types have been characterized as oncogenic because of their central role in the
development of premalignant and malignant lesions of the oropharynx (mouth and
throat), lower gastrointestinal tract (anus), and genital organs (uterine cervix, vagina,
vulva, and penis). Worldwide, HPV infections contribute to approximately 5% of all
cancers, with an estimated 625,000 women and 69,000 men affected annually by HPV-
related cancers.1,2 The fourth most common female cancer in the world is cancer of
the cervix, the obligate cause of which is persistent infection with an oncogenic HPV.
Annually, over 600,000 women are diagnosed with and over 300,000 die from this
preventable disease.3
In 2018, the World Health Organization (WHO) Director General, Dr. Tedros Ghebreyesus,
announced a call to action to eliminate cervical cancer as a public health problem. One of
three key strategies to eliminate cervical cancer is primary prevention with HPV vaccina-
tion.4 The overarching goal of this strategy is to achieve 90% vaccination coverage by 2030
for adolescent girls.1 Although HPV vaccination typically focuses on the adolescent popula-
tion, approval of HPV vaccination in the United States has recently expanded to include per-
sons up to 45 years of age, which directly benefits high-risk adult populations and the
previously unvaccinated. A schedule of two doses 6 months apart is recommended for those
21 years of age and older by the WHO; however, in the United States, three doses are still
recommended for those 15 to 45 years of age by the Centers for Disease Control and Pre-
vention (CDC).5 In 2021, only 59% of U.S. adolescents 13 to 15 years of age had received
two or three doses of the HPV vaccine.5 Given the low overall rates of vaccination, a
reduced-dose HPV vaccination catch-up strategy in older populations may contribute to
achieving the goal of eliminating not only cervical cancer but other HPV-related diseases. The author affiliation is listed at
the end of the article.
Hesitancy in support for a reduced-dose HPV vaccination schedule in persons over 15 years
Dr. Pinder can be contacted at
of age centers on the lack of immunogenic evidence to support this strategy. Berenson et al.6 pinderl@ucmail.uc.edu or at
designed a prospective, randomized clinical trial investigating the noninferiority of a two- the University of Cincinnati,
dose schedule compared with a three-dose schedule of the nine-valent human papillomavi- Department of Obstetrics and
Gynecology, ML 0526, 231 Albert
rus (9vHPV) vaccine to fill this knowledge gap. In this issue of NEJM Evidence, the authors Sabin Way, Cincinnati, OH
present data from an unplanned interim analysis of their ongoing trial of 438 female 45229.
participants randomized to receive either a two-dose (0 required to end the needless suffering from cervical can-
and 6 months) or three-dose (0, 2, and 6 months) vaccina- cer and other HPV-related diseases.
tion regimen. The primary outcome was the rate of HPV
type–specific antibody development (seroconversion) at Disclosures
1 month after final vaccination. In this unplanned interim Author disclosures are available at evidence.nejm.org.
analysis, the seroconversion rate for each of the nine HPV
genotypes contained in the vaccine was 100% among par- Author Affiliation
ticipants in the two-dose group and 99% in the three-dose 1
Division of Gynecologic Oncology, University of Cincinnati, Cincinnati
group, consistent with noninferiority of the two-dose
schedule. On the basis of this interim analysis, the authors References
conclude that in female participants 15 to 26 years of age, 1. World Health Organization. Cervical cancer. Geneva, Switzerland:
two doses of 9vHPV vaccine appear to stimulate HPV anti- World Health Organization, November 17, 2023 (https://www.who.
body responses similar to those achieved with three doses int/news-room/fact-sheets/detail/cervical-cancer#:~:text=Globally%
at 1 month postvaccination. We await the final results of 2C%20cervical%20cancer%20is%20the,%2D%20and%20middle%
this study to further confirm noninferiority. 2Dincome%20countries).
2. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global

In 2016, the CDC modified its recommendation for the burden of cancer attributable to infections in 2018: a worldwide
HPV vaccine schedule for persons under 15 years of age incidence analysis. Lancet Glob Health 2020;8:e180-e190. DOI:
on the basis of noninferiority data of the two- versus three- 10.1016/S2214-109X(19)30488-7.
dose schedule in this population. Should the final analysis 3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:
continue to demonstrate the same noninferiority in 15- to GLOBOCAN estimates of incidence and mortality worldwide for
26-year-old participants, the CDC should adjust their 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.
recommendations to be in line with the WHO and other DOI: 10.3322/caac.21660.
countries. Australia, for example, is on the path to elimi- 4. Gultekin M, Morice P, Concin N, Querleu D. ESGO contribution to
nate cervical cancer by 2035 with a two-dose 9vHPV the WHO initiative on elimination of cervical cancer. Int J Gynecol
vaccination schedule combined with a national cervical Cancer 2020;30:434-435. DOI: 10.1136/ijgc-2020-001286.
cancer screening program.7 If the United States is commit- 5. National Cancer Institute. HPV vaccination. Washington, DC:
ted to the goal of eliminating cervical cancer, we cannot National Cancer Institute, August 2023 (https://progressreport.
continue with the status quo three-dose HPV vaccination cancer.gov/prevention/hpv_immunization).
schedule and cumbersome processes for screening and 6. Berenson AB, Panicker G, Unger ER, Rupp RE, Kuo Y-F. Immuno-
treatment of cervical preinvasive disease.8,9 genicity of 2 or 3 doses of 9vHPV vaccine in U.S. female indivi-
duals 15 to 26 years of age. NEJM Evid 2024;3(2). DOI: 10.1056/
I applaud the authors for closing this knowledge gap in EVIDoa2300194.
HPV vaccine immunogenicity; however, we also must 7. Hall MT, Simms KT, Lew JB, et al. The projected timeframe until cervi-
acknowledge that simplification of the HPV vaccination cal cancer elimination in Australia: a modelling study. Lancet Public
schedule is only one barrier that providers and the scien- Health 2019;4:e19-e127. DOI: 10.1016/S2468-2667(18)30183-X.
tific community must overcome. Lack of knowledge about 8. Ginsburg O, Bray F, Coleman MP, et al. The global burden of
HPV, concerns about vaccine safety, its necessity, and its women’s cancers: a grand challenge in global health. Lancet 2017;
potential impact on fertility, and the perception of influ- 389:847-860.
ence on adolescent sexual behaviors are all factors that 9. Wingrove BK. Excess cervical cancer mortality: a marker for low
contribute to vaccine hesitancy.10,11 Although scientists access to health care in poor communities. Bethesda, MD: National
continue to prove the safety and efficacy of HPV vaccina- Cancer Institute, Center to Reduce Cancer Health Disparities, May
tion, public health specialists need to increase HPV and 2005 (http://purl.fdlp.gov/GPO/gpo13462).
HPV-related cancer education efforts and reduce barriers 10. Osazuwa-Peters N, Rohde RL, Boakye EA. HPV vaccination is
to accessing not only HPV vaccination but also other cervi- safe — you don’t have to whisper it. JAMA Netw Open 2021;4:
cal cancer prevention services, especially in high-risk e2125124-e190. DOI: 10.1001/jamanetworkopen.2021.25124.
populations. Providers also bear responsibility for initiat- 11. Beavis AL, Meek K, Moran MB, Fleszar L, Adler S, Rositch AF.
ing discussions on cancer prevention, including vaccina- Exploring HPV vaccine hesitant parents’ perspectives on decision-
tion. A successful HPV vaccination strategy that increases making and motivators for vaccination. Vaccine X 2022;12:100231.
vaccine coverage is only one tool in the armamentarium DOI: 10.1016/j.jvacx.2022.100231.
NEJM EVIDENCE 2

NEJM Evid 2023; 2 (10)
NEJM Evid 2023; 2 (10)
DOI: 10.1056/EVIDoa2300058
DOI: 10.1056/EVIDoa2300058
ORIGINAL ARTICLE
Hypertensive Disorders of Pregnancy and Risk of

Stroke in U.S. Black Women
Shanshan Sheehy, Sc.D.,1,2 Hugo J. Aparicio, M.D., M.P.H.,2,3,4 Nuo Xu, M.S.P.H.,1 Kimberly A. Bertrand, Sc.D.,1,2
Yvonne Page Robles, M.P.H.,1 Vasileios-Arsenios Lioutas, M.D.,5,6 Julie G. Shulman, M.D.,2,3 Lynn Rosenberg, Sc.D.,1
and Julie R. Palmer, Sc.D.1,2
Abstract
BACKGROUND Black women have a disproportionately higher burden of both pre-
eclamptic pregnancy and stroke compared with White women, but virtually all existing
evidence on this possible association has been generated from women of European
ancestry.
METHODS In the Black Women’s Health Study, a prospective cohort of U.S. Black women
who enrolled in 1995, 42,924 participants were parous and free of cardiovascular disease
at baseline. Biennial questionnaires included questions on preeclampsia, gestational hyper-
tension, and stroke. We sought the medical records for participants who reported a stroke,
and we reviewed them blinded to reproductive history. Cox proportional-hazards models,
with control for potential confounders, were used to estimate hazard ratios and 95% confi-
dence intervals (CIs).
RESULTS Over a median of 22 years of follow-up, there were 1555 incident strokes,
including 310 among 4938 women with a history of hypertensive disorders of pregnancy
(HDOP). The multivariable hazard ratio for stroke for women with any HDOP compared
with those who had never experienced HDOP was 1.66 (95% CI, 1.46 to 1.89). Compara-
ble hazard ratios were 1.53 (95% CI, 1.29 to 1.82) for preeclampsia and 1.81 (95% CI, 1.53
to 2.13) for gestational hypertension only. Associations were similar among women under
age 55 years and those aged 55 years and older. The author affiliations are listed
CONCLUSIONS In this prospective study of Black women, a history of HDOP was associ- Dr. Sheehy can be contacted at
ated with an estimated 66% increased long-term risk of stroke. This association may con- shl607@bu.edu or at Slone
Epidemiology Center, Boston
tribute to the disproportionately higher stroke incidence in Black women given the higher
University, 72 East Concord St.,
prevalence of HDOP in this population. (Funded by the U.S. National Institutes of L-7, Boston, MA 02118.
Health.)
Read Full Article
Published September 26, 2023

NEJM Evid 2023; 2 (10)
DOI: 10.1056/EVIDe2300138
EDITORIAL
Hypertensive Disorders of Pregnancy in Black

Women — Where Do We Go from Here?
Kristian B. Filion, Ph.D.,1,2,3 and Sonia M. Grandi, Ph.D.4,5
I
n this issue of NEJM Evidence, Sheehy et al.1 report the results of a prospective cohort
study that examined the association between hypertensive disorders of pregnancy
(HDOP) and the risk of stroke among Black women in the United States. Using data
from 42,924 participants in the Black Women’s Health Study (BWHS) who were free of
cardiovascular disease at baseline, they compared the rates of stroke between women with
HDOP and those who did not have HDOP over a median follow-up of 22 years. The
authors found that HDOP was associated with a 66% increased rate of stroke (hazard ratio,
1.66; 95% confidence interval, 1.46 to 1.89). Similar increased rates were observed with
preeclampsia and gestational hypertension. Overall, 7% of strokes in this population were
attributable to HDOP.
This study1 has several strengths. These include addressing an urgent question that is
important clinically and at a population level, particularly as rates of pregnancy-related
complications increase over time due to shifts in underlying risk factors (e.g., obesity,
increasing maternal age). Furthermore, with its long follow-up duration and large sample
size, the BWHS is a well-suited data source to study this question among Black women.
The inclusion of case validation by neurologists blinded to exposure status represents
another key strength.
This study also has some limitations, many of which are acknowledged by the authors and
addressed in some sensitivity analyses.1 First, 86% of included women were already parous
at the time of enrollment. As acknowledged by the authors, there is the potential for a
depletion of susceptible women from the study universe, in which women at an elevated
risk for preeclampsia and early stroke would have been excluded because of the occurrence
of an event before enrollment. Second, the authors were unable to measure prepregnancy
cardiovascular risk factor levels because these data were not available before study onset. at the end of the article.
With analyses only adjusted for age, age at first birth, body mass index at 18 years of age,
Dr. Filion can be contacted at
educational attainment, and parental history of stroke, residual confounding is likely.
kristian.filion@mcgill.ca or at
Third, the study relied on self-reported measures of exposure and outcome, and although McGill University, Centre for
blinded case ascertainment was performed by neurologists, the investigators were only Clinical Epidemiology, Lady Davis
Institute, Jewish General Hospital,
able to obtain appropriate medical records for 31% of self-reported strokes. Although this
5750 Cote-des-Neiges, Suite H410.
limitation was partially mitigated by a sensitivity analysis restricted to confirmed strokes, 1, Montreal, Quebec H3T 1E2,
the use of self-report remains a potential limitation. Canada.
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society. Back to Table of Contents
The study by Sheehy et al.1 leads to the question, “Is this and ethnic disparities in obstetric and perinatal out-
association causal?” Unfortunately, this question remains comes.9 In addition, trials are needed to compare vari-
unanswered. The authors provide a clear summary of the ous multicomponent, cardiovascular disease prevention
cardiometabolic changes that occur in pregnancy and with strategies among women with a history of HDOP, with
preeclampsia that may lead to an increased risk of stroke. targeted interventions developed for high-risk popula-
However, the literature now recognizes pregnancy as a tions such as Black women.
physiological stress that may bring underlying diseases to
the surface,2 and preeclampsia and maternal cardiovascu- The study by Sheehy et al.1 has provided crucial evidence
lar disease share several risk factors, including hyperten- regarding the clinical and population health consequences
sion, diabetes, obesity, and inflammatory diseases.3 There of HDOP among Black women and identified an oppor-
also seems to be a strong genetic factor, with recent evi- tune time to initiate cardiovascular disease prevention
dence suggesting that genes related to hypertension, kid- strategies. Doing so may help reduce disparities in health
ney function, and placental development are associated in a high-risk population both during and after pregnancy.
with the development of preeclampsia.4 Studies to date
are limited in their ability to fully adjust for cardiovascular Disclosures
risk factor levels due to unavailable data; the need Author disclosures are available at evidence.nejm.org.
remains therefore to more fully understand the mecha-
nism underlying the relationship between HDOP and Author Affiliations
1
maternal cardiovascular outcomes. Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General
Hospital, Montreal
2
Department of Epidemiology, Biostatistics and Occupational Health,
Fortunately, the clinical implications of the study by McGill University, Montreal
Sheehy et al.1 are not dependent upon whether this associ- 3
Department of Medicine, McGill University, Montreal
ation is causal. Given the long-term clinical consequences 4
Child Health Evaluative Sciences, The Hospital for Sick Children,
of HDOP,5 this work underscores the need for cardiovas- Toronto
5
cular risk assessment and the implementation of primary Division of Epidemiology, Dalla Lana School of Public Health, Univer-
sity of Toronto, Toronto
prevention strategies6 among women of childbearing age,
particularly among those planning to conceive. The imple-
References
mentation of such strategies is essential in Black women
given the results of the study by Sheehy et al.1 The Ameri- 1. Sheehy S, Aparicio HJ, Xu N, et al. Hypertensive disorders of preg-
nancy and risk of stroke in U.S. Black women. NEJM Evid 2023;2(10).
can Heart Association and the American College of Obste-
DOI: 10.1056/EVIDoa2300058.
tricians and Gynecologists have called for the inclusion of
obstetricians and gynecologists as part of this endeavor, 2. Brown HL, Warner JJ, Gianos E, et al. Promoting risk identification
and reduction of cardiovascular disease in women through collabo-
because many women of childbearing age view them as
ration with obstetricians and gynecologists: a Presidential Advisory
their primary care physician.2 Furthermore, regular blood
from the American Heart Association and the American College of
pressure screening during pregnancy is needed for the early Obstetricians and Gynecologists. Circulation 2018;137:e843-e852.
identification and treatment of HDOP, despite the incon- DOI: 10.1161/CIR.0000000000000582.
sistency across treatment guidelines regarding the opti-
3. Vigil-De Gracia P, Vargas C, S
anchez J, Collantes-Cubas J. Pre-
mal blood pressure cutoff at which antihypertensive drugs eclampsia: narrative review for clinical use. Heliyon 2023;9:e14187.
should be initiated.7 In addition, increased efforts should DOI: 10.1016/j.heliyon.2023.e14187.
be made to optimize the use of low-dose aspirin among
4. Tyrmi JS, Kaartokallio T, Lokki AI, et al. Genetic risk factors associ-
women at high risk for preeclampsia.8 Finally, the find- ated with preeclampsia and hypertensive disorders of pregnancy.
ings of the study by Sheehy et al.1 underscore the impor- JAMA Cardiol 2023;8:674-683. DOI: 10.1001/jamacardio.2023.1312.
tance of timely and continual follow-up of Black women
5. Grandi SM, Filion KB, Yoon S, et al. Cardiovascular disease-related mor-
with HDOP for regular assessment and management of
bidity and mortality in women with a history of pregnancy complications.
their cardiovascular risk factors. Circulation 2019;139:1069-1079. DOI: 10.1161/CIRCULATIONAHA.
118.036748.
Although Sheehy et al.1 have addressed an important 6. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guide-
knowledge gap, future studies are needed to assess both line on the Primary Prevention of Cardiovascular Disease: a report
clinical risk factors as well as social determinants of of the American College of Cardiology/American Heart Association
health and quality of care given the established racial Task Force on Clinical Practice Guidelines [published corrections
NEJM EVIDENCE 2
appear in J Am Coll Cardiol 2019;74:1429-1430 and J Am Coll 8. Davidson KW, Barry MJ, Mangione CM, et al. Aspirin use to prevent
Cardiol 2020;75:840]. J Am Coll Cardiol 2019;74:e177-e232. DOI: preeclampsia and related morbidity and mortality: US Preventive
10.1016/j.jacc.2019.03.010. Services Task Force Recommendation Statement. JAMA 2021;326:
1186-1191. DOI: 10.1001/jama.2021.14781.
7. Sinkey RG, Battarbee AN, Bello NA, Ives CW, Oparil S, Tita ATN.
Prevention, diagnosis, and management of hypertensive disorders of 9. Howell EA, Zeitlin J. Quality of care and disparities in obstetrics.
pregnancy: a comparison of international guidelines. Curr Hypertens Obstet Gynecol Clin North Am 2017;44:13-25. DOI: 10.1016/j.ogc.
Rep 2020;22:66. DOI: 10.1007/s11906-020-01082-w. 2016.10.002.
NEJM EVIDENCE 3
Published
PublishedSeptember
September26,
26, 2023
2023
NEJM
NEJMEvid 2023;
Evid 2 (10)
2023; 2 (1)
DOI: 10.1056/EVIDoa2300107
DOI: 10.1056/EVIDoa2300107
ORIGINAL ARTICLE
Severe Hyponatremia Correction, Mortality, and

Central Pontine Myelinolysis
Harish Seethapathy, M.D.,1 Sophia Zhao, Ph.D.,1 Tianqi Ouyang, M.P.H.,1 Christie Passos, B.A.,1 Adviti Sarang, B.S.A.,1
Pui W. Cheung, M.D., M.S.,1 Sushrut S. Waikar, M.D., M.P.H.,2 David J.R. Steele, M.D.,1 Sahir Kalim, M.D., M.M.Sc.,1
Andrew S. Allegretti, M.D., M.Sc.,1 Juan Carlos Ayus, M.D.,3 and Sagar U. Nigwekar, M.D., M.M.Sc.1
Abstract
BACKGROUND In clinical practice, sodium correction rates are frequently limited in
patients with severe hyponatremia to prevent neurologic complications. The implications
of correction rates on overall mortality and length of hospital stay are unclear.
METHODS In this multicenter observational study, we evaluated the association of

sodium correction rates with mortality, length of stay, and central pontine myelinolysis
(CPM) in patients hospitalized with severe hyponatremia (admission serum sodium level
less than 120 mEq/l).
RESULTS The cohort included 3274 patients. A correction rate of less than
6 mEq/l/24 hours was observed in 38%, 6 to 10 mEq/l/24 hours was observed in 29%,
and greater than 10 mEq/l/24 hours was observed in 33%. Compared with 6 to 10 mEq/
l/24 hours, a correction rate of less than 6 mEq/l/24 hours exhibited higher in-hospital
mortality in multivariable-adjusted and propensity score–weighted analyses. Compared
with 6 to 10 mEq/l/24 hours, a correction rate of greater than 10 mEq/l/24 hours was
associated with lower in-hospital mortality and shorter length of stay in multivariable
analyses. Seven patients with CPM were identified, with five of seven developing CPM
despite a sodium correction rate of less than or equal to 8 mEq/l/24 hours. Six of seven
patients who developed CPM had alcohol use disorder, malnutrition, hypokalemia, or
hypophosphatemia. at the end of the article.
CONCLUSIONS Limiting the sodium correction rate was associated with higher mor- Dr. Nigwekar can be contacted at
snigwekar@mgh.harvard.edu or at
tality and longer length of stay. Whether the sodium correction rate influences neurologic
165 Cambridge St., Suite 302,
complications needs further evaluation. Boston, MA 02114.
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NEJM Evid 2023; 3 (1)
NEJM Evid 2024; 3 (1)
DOI: 10.1056/EVIDoa2300003
DOI: 10.1056/EVIDoa2300003
ORIGINAL ARTICLE | INTERFACE SERIES
A New Look at P Values for Randomized

Clinical Trials
Erik van Zwet, Ph.D.,1 Andrew Gelman, Ph.D.,2,3 Sander Greenland, M.D., Ph.D.,4,5 Guido Imbens, Ph.D.,6
Simon Schwab, Ph.D.,7 and Steven N. Goodman, M.D., Ph.D.8
Abstract
BACKGROUND We have examined the primary efficacy results of 23,551 randomized
clinical trials from the Cochrane Database of Systematic Reviews.
METHODS We estimate that the great majority of trials have much lower statistical
power for actual effects than the 80 or 90% for the stated effect sizes. Consequently,
“statistically significant” estimates tend to seriously overestimate actual treatment
effects, “nonsignificant” results often correspond to important effects, and efforts to repli-
cate often fail to achieve “significance” and may even appear to contradict initial results.
To address these issues, we reinterpret the P value in terms of a reference population of
studies that are, or could have been, in the Cochrane Database.
RESULTS This leads to an empirical guide for the interpretation of an observed P value
from a “typical” clinical trial in terms of the degree of overestimation of the reported
effect, the probability of the effect’s sign being wrong, and the predictive power of the trial.
CONCLUSIONS Such an interpretation provides additional insight about the effect under
study and can guard medical researchers against naive interpretations of the P value and
overoptimistic effect sizes. Because many research fields suffer from low power, our
results are also relevant outside the medical domain. (Funded by the U.S. Office of Naval
Research.)

Introduction
H
Dr. van Zwet can be contacted at
ow should researchers and clinicians interpret the P value for the null hypothe- E.W.van_Zwet@lumc.nl or at
Biomedical Data Sciences, Leiden
sis of no effect from a randomized clinical trial (RCT)? This P value is com-
University Medical Center,
monly defined as the probability, under the null hypothesis and an assumed Einthovenweg 20, 2333 ZC Leiden,
statistical model, that an appropriate test statistic would be as or more extreme than what The Netherlands.
was observed. Here, we will consider the absolute z statistic as a test statistic. We wish to
This article was updated
reinterpret the resulting two-sided P value in light of background information about studies on January 16, 2024 at
with similar statistical properties. The Cochrane Database of Systematic Reviews contains evidence.nejm.org.
Read Full Article

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CLINICAL TRIALS WORKSHOP | DSMB MINI-SERIES

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Published July 25, 2023

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Severe Hyponatremia Correction, Mortality, and

METHODS In this multicenter observational study, we evaluated the association of

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Published December 22, 2023

ORIGINAL ARTICLE | INTERFACE SERIES

A New Look at P Values for Randomized

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NEJM Evidence gives you an insider’s view on how clinical

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“ With NEJM Evidence, we'll publish original

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