A collection of memorable research [620608]

NOTABLE
ARTICLES
OF 2015
A collection of memorable research
of the past year as selected by NEJM editors

B Notable Articles of 2015
800.843.6356 | f: 781.891.1995 | [anonimizat]
860 winter street, waltham, ma 02451-1413
nejmgroup.org
January 2016
Dear Reader,
The face of medicine is constantly changing. In the past year, a number of studies published in the
New England Journal of Medicine challenged our ways of thinking. A trial on peanut allergy, published in
February, indicates that allergen avoidance is not the way to prevent allergy in young children. The
SPRINT trial on intensive blood pressure management, published in November, redefines blood-pres –
sure target goals. A third study, published in December, found that continuous chest compressions
during CPR don’t improve survival rates.
At NEJM we work to identify, vet, and publish the research that makes a difference in medicine. Each
year, from the thousands of submissions we receive, we publish about 200 research articles. We
choose these because we think these articles will change the face of medicine. This digital collection
represents the cream of the crop, the dozen studies from 2015 that we think will have the biggest influ –
ence on medicine. We hope that you enjoy this collection and that you will continue to join us as we
log medicine’s journey.
Jeffrey M. Drazen, M.D.
Editor-In-Chief, The New England Journal of Medicine
Distinguished Parker B. Francis Professor of Medicine
Harvard Medical School

ORIGINAL ARTICLE
A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke ………. 1
EDITORIAL: Interventional Thrombectomy for Major Stroke —
A Step in the Right Direction …………………………………….. 2
ORIGINAL ARTICLE
Tenofovir-Based Preexposure Prophylaxis for HIV Infection among
African Women ………………………………………………… 4
EDITORIAL: Preventing HIV in Women — Still Trying to Find Their VOICE …….. 5
ORIGINAL ARTICLE
Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy ….. 8
EDITORIAL: Preventing Peanut Allergy through Early Consumption —
through Early Consumption — Ready for Prime Time? ………………….. 9
ORIGINAL ARTICLE
Association of Improved Air Quality with Lung Development in Children ……… 11
EDITORIAL: Cleaner Air, Bigger Lungs ………………………………. 12
ORIGINAL ARTICLE
Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults …15
ORIGINAL ARTICLE
Idarucizumab for Dabigatran Reversal ………………………………. 16
EDITORIAL: Targeted Anti-Anticoagulants ……………………………. 17
ORIGINAL ARTICLE
Screening for Occult Cancer in Unprovoked Venous Thromboembolism ……… 19
EDITORIAL: Cancer Workup after Unprovoked Clot — Less Is More …………. 20
ORIGINAL ARTICLE
A Randomized Controlled Trial of Total Knee Replacement ……………….. 22
EDITORIAL: Parachutes and Preferences — A Trial of Knee Replacement ……… 23
ORIGINAL ARTICLE
Prospective Validation of a Multiparameter 21-Gene Assay in Breast Cancer …… 25
EDITORIAL: Biology before Anatomy in Early Breast Cancer — Precisely the Point ..26
ORIGINAL ARTICLE
A Randomized Trial of Intensive versus Standard Blood-Pressure Control …….. 28
EDITORIALS:
A SPRINT to the Finish ……………………………………….. 29
Redefining Blood-Pressure Targets — SPRINT Starts the Marathon ……….. 31TABLE OF CONTENTS
The New England Journal of Medicine is a publication of NEJM Group, a division of the Massachusetts Medical Society.
©2015 Massachusetts Medical Society, All rights reserved.(continued on next page)

ORIGINAL ARTICLE
Trial of Continuous or Interrupted Chest Compressions during CPR …………. 34
EDITORIAL: Continuous or Interrupted Chest Compressions for Cardiac Arrest …. 35
ORIGINAL ARTICLE
Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection ………. 37
EDITORIAL: Simple, Effective, but Out of Reach?
Public Health Implications of HCV Drugs ………………………….. 38 (continued from previous page)TABLE OF CONTENTS

Back to Table of Contents1 Notable Articles of 2015
nejm.org
n engl j med 372;1 nejm.org january 1 , 2015 11The new england
journal of medicine
established in 1812 january 1, 2015 vol. 372 no. 1
A Randomized Trial of Intraarterial Treatment for Acute
Ischemic Stroke
O.A. Berkhemer, P.S.S. Fransen, D. Beumer, L.A. van den Berg, H.F. Lingsma, A.J. Yoo, W.J. Schonewille, J.A. Vos,
P.J. Nederkoorn, M.J.H. Wermer, M.A.A. van Walderveen, J. Staals, J. Hofmeijer, J.A. van Oostayen,
G.J. Lycklama à Nijeholt, J. Boiten, P.A. Brouwer, B.J. Emmer, S.F. de Bruijn, L.C. van Dijk, L.J. Kappelle, R.H. Lo,
E.J. van Dijk, J. de Vries, P.L.M. de Kort, W.J.J. van Rooij, J.S.P. van den Berg, B.A.A.M. van Hasselt, L.A.M. Aerden,
R.J. Dallinga, M.C. Visser, J.C.J. Bot, P.C. Vroomen, O. Eshghi, T.H.C.M.L. Schreuder, R.J.J. Heijboer, K. Keizer,
A.V. Tielbeek, H.M. den Hertog, D.G. Gerrits, R.M. van den Berg-Vos, G.B. Karas, E.W. Steyerberg, H.Z. Flach,
H.A. Marquering, M.E.S. Sprengers, S.F.M. Jenniskens, L.F.M. Beenen, R. van den Berg, P.J. Koudstaal,
W.H. van Zwam, Y.B.W.E.M. Roos, A. van der Lugt, R.J. van Oostenbrugge, C.B.L.M. Majoie, and D.W.J. Dippel,
for the MR CLEAN Investigators*
ABSTRACT
The authors’ full names, academic de –
grees, and affiliations are listed in the Ap –
pendix. Address reprint requests to Dr.
Dippel at the Department of Neurology H643, Erasmus MC University Medical Center, PO Box 2040, Rotterdam 3000 CA, the Netherlands, or at d.dippel@erasmusmc.nl.
Drs. Berkhemer, Fransen, and Beumer and
Drs. van Zwam, Roos, van der Lugt, van Oostenbrugge, Majoie, and Dippel con –
tributed equally to this article.
* A complete list of investigators in the
Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) is provided in the Supple –
mentary Appendix, available at NEJM.org.
This article was published on December 17, 2014, and updated on January 1, 2015, at NEJM.org.
N Engl J Med 2015;372:11-20.
DOI: 10.1056/NEJMoa1411587
Copyright © 2014 Massachusetts Medical Society.Background
In patients with acute ischemic stroke caused by a proximal intracranial arterial
occlusion, intraarterial treatment is highly effective for emergency revasculariza –
tion. However, proof of a beneficial effect on functional outcome is lacking.
Methods
We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary out –
come was the modified Rankin scale score at 90 days; this categorical scale mea –
sures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecif ied prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower mod –
ified Rankin scores, as compared with usual care alone (shift analysis).
Results
We enrolled 500 patients at 16 medical centers in the Netherlands (233 assigned to in –
traarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before ran –
domization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differ –
ences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
Conclusions
In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours af –
ter stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.)
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved. ORIGINAL ARTICLE
Read Full Article at NEJM.org

Back to Table of Contents2 Notable Articles of 2015
nejm.org
n engl j med 372;1 nejm.org january 1 , 2015 75editorialsThe new england journal of medicine
Interventional Thrombectomy for Major Stroke —
A Step in the Right Direction
Werner Hacke, M.D., Ph.D.
Intravenous thrombolytic therapy is the only
proven treatment for acute ischemic stroke, but its use is limited by a brief time window of up to 4.5 hours after the onset of symptoms
1 a n d a
recanalization rate of less than 50%. Large clots in vessels such as the distal internal carotid ar –
tery or the first segment of the middle cerebral artery respond poorly to intravenous thromboly –
sis.
2 The need for a treatment for patients who
do not have a good response to intravenous treatment alone remains pressing.
On the basis of compelling anecdotal experi –
ence, stroke specialists had hoped that transvas –
cular recanalization would be an alternative to or a follow-on treatment after intravenous therapy for severe strokes with large-vessel occlusion. However, three randomized, controlled trials of intraarterial treatment, all reported in the Journal,
have had negative or ambiguous results.
3-5 These
trials were criticized for their use of older re –
canalization devices, which were associated with lower recanalization rates than those found with newer devices such as retrievable stents
6; for the
long interval between the onset of stroke and intervention; and for disappointingly low recruit –
ment rates, which suggested that many suitable patients had been treated outside the trials. Moreover, subgroup analyses suggested that there was a benefit for patients treated in shorter time windows.
7,8 P e r ha p s m o s t im p o rtan t, tw o
of the trials did not require evidence of an oc –
cluded vessel before randomization, thereby mak –
ing intracerebral treatment futile from the start.
The lessons of these studies were that trials
of intraarterial treatment should enroll patients with severe strokes, have proof of proximal ves -sel occlusion, initiate treatment as early as pos –
sible, and use modern thrombectomy devices.
9
The results of the first such trial now appear in the Journal .
10 The Multicenter Randomized Clini –
cal Trial of Endovascular Treatment of Acute Is –
chemic Stroke in the Netherlands (MR CLEAN) included patients with severe stroke and proxi –
mal-vessel occlusion. Almost 90% of the pa –
tients received intravenous thrombolysis first, and almost all the devices used were of the retrievable-stent variety, which have a track record
of successful recanalization. Thrombectomy im –
proved outcomes, with an absolute difference of 13.5 percentage points in the rate of functional independence, as assessed with the use of the modified Rankin scale. Most other prespecified clinical end points and the rate of recanalization favored transvascular treatment, although the re –
canalization rate with transvascular treatment was a little lower than expected. There were no significant differences in mortality or the occur –
rence of symptomatic intracranial hemorrhage.
Readers may wonder how the trialists from
a country with only 16.8 million inhabitants succeeded in enrolling 500 patients in just over 3 years, whereas other trials from much larger regions with similarly advanced medical systems struggled with recruitment. The well-established network of investigator-initiated stroke trials in the Netherlands contributed to the success of the trial, as did the relatively short distances be –
tween the 15 intervention centers in the coun –
try. In my view, however, the most important reason for success was the decision by the Dutch government to pay for the use of thrombectomy devices only in the context of a randomized trial,

Back to Table of Contents3 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 372;1 nejm.org january 1 , 2015 76thereby precluding treatment outside the trial.
This policy may be difficult to implement in other health systems, but imagine what prog –
ress the medical-device field would see if this strategy were the rule.
Finally, what does this first positive throm –
bectomy trial mean for interventional treatment? Is there any doubt left, or should thrombectomy now become the new standard treatment for se –
vere stroke with proximal large-vessel occlusion up to 6 hours after stroke onset? Several similar trials are ongoing; it is premature to conclude that there is no longer equipoise regarding thrombectomy. We need and will get results from other well-designed trials, not only to con –
firm or refute the results of MR CLEAN but also to look at effects in subgroups (according to stroke severity, occlusion site, or time to treat –
ment initiation), for which most single trials are underpowered. MR CLEAN is the first step in the right direction.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Neurology, University Hospital Heidel –
berg, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.This article was published on December 17, 2014, at NEJM.org.1. Emberson J, Lees KR, Lyden P, et al. Effect of treatment de –
lay, age, and stroke severity on the effects of intravenous throm –
bolysis with alteplase for acute ischaemic stroke: a meta-analysis
of individual patient data from randomised trials. Lancet 2014 August 5 (Epub ahead of print).
2. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R,
Deuschl G, Jansen O. The importance of size: successful recan –
alization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke 2011;42:1775-7.
3. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular
therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. [Errat um, N Engl J Med 2013;368:1265.]
4. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treat –
ment for acute ischemic stroke. N Engl J Med 2013;368:904-13.
5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging
selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23.
6. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration
device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012;380:1241-9.
7. Khatri P, Yeatts SD, Mazighi M, et al. Time to angiographic
reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial. Lancet Neurol 2014;13:567-74.
8. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-
reperfusion time on stroke mortality: a collaborative pooled analysis. Circulation 2013;127:1980-5.
9. Hacke W, Furlan AJ. (Here comes that) razors edge — endo –
vascular stroke therapy: the end, or only the beginning? Int J Stroke 2013;8:331-3.
10. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized
trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20
.
DOI: 10.1056/NEJMe1413346
Copyright © 2014 Massachusetts Medical Society.

Back to Table of Contents4 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 372;6 nejm.org February 5, 2015 509established in 1812 February 5, 2015 vol. 372 no. 6
The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr. Marrazzo at the Division of Infectious Diseases, Harborview Medical Center, 325 9th Ave., Mailbox 359932, Seattle, WA 98104, or at jmm2@ uw . edu.
*A complete list of members of the Vagi –
nal and Oral Interventions to Control the
Epidemic (VOICE) Study Team is provid –
ed in the Supplementary Appendix, avail –
able at NEJM.org.
N Engl J Med 2015;372:509-18.
DOI: 10.1056/NEJMoa1402269
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Reproductive-age women need effective interventions to prevent the acquisition of
human immunodeficiency virus type 1 (HIV-1) infection.
METHODS
We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir–emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed month –
ly, and plasma TFV levels were assessed quarterly.
RESULTS
Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was −49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), −4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with character –
istics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P = 0.004). We
observed no significant differences in the frequencies of other adverse events.
CONCLUSIONS
None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.)abstractTenofovir-Based Preexposure Prophylaxis for HIV Infection
among African Women
Jeanne M. Marrazzo, M.D., Gita Ramjee, Ph.D., Barbra A. Richardson, Ph.D., Kailazarid Gomez, M.P.A.,
Nyaradzo Mgodi, M.Med., Gonasagrie Nair, M.B., Ch.B., M.P.H., Thesla Palanee, Ph.D., Clemensia Nakabiito, M.Med.,
Ariane van der Straten, Ph.D., Lisa Noguchi, M.S.N., Craig W. Hendrix, M.D., James Y. Dai, Ph.D., Shayhana Ganesh, M.Med.,
Baningi Mkhize, M.B., Ch.B., Marthinette Taljaard, B.S., Urvi M. Parikh, Ph.D., Jeanna Piper, M.D., Benoît Mâsse, Ph.D.,
Cynthia Grossman, Ph.D., James Rooney, M.D., Jill L. Schwartz, M.D., Heather Watts, M.D., Mark A. Marzinke, Ph.D.,
Sharon L. Hillier, Ph.D., Ian M. McGowan, M.D., and Z. Mike Chirenje, M.D., for the VOICE Study Team*
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved. ORIGINAL ARTICLE
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Back to Table of Contents5 Notable Articles of 2015
nejm.org
n engl j med 372;6 nejm.org february 5 , 2015 563editorialsThe new england journal of medicine
Preventing HIV in Women — Still Trying to Find Their VOICE
Michael S. Saag, M.D.
The development and widespread use of potent
antiretroviral therapy has transformed HIV in –
fection from a near-certain death sentence to a chronic manageable condition, whereby patients who adhere fully to their medication regimen can have an almost normal life span.
1 Moreover,
those who take their medications as prescribed generally do not transmit the virus to others.
2 If
we could identify all persons infected with HIV, get them into care, successfully initiate antiret –
roviral therapy, and achieve and sustain suppres –
sion of the virus to undetectable levels, all pa –
tients would in theory have a near-normal life span and not transmit the virus to others — and the epidemic would end.
3 Despite the success of
antiretroviral therapy in dramatically prolonging life expectancy, we have not seen much progress in preventing new infections. In most areas around the world, including the United States, the number of new persons infected last year was roughly the same as in years before.
4 Most
experts indicate that “treatment as prevention” is an important approach, but we cannot treat our way out of the epidemic. Rather, multiple approaches to prevention are required.
One such approach is the use of preexposure
prophylaxis, whereby antiretroviral agents are used, either through systemic administration or as topical microbicides such as vaginal gels. Well-conducted, randomized studies have had mixed results. In a study conducted in resource-rich countries, involving men who have sex with men, preexposure prophylaxis reduced transmission by 44% overall and by 92% among those who took their medications regularly.
5 In contrast, in a
study conducted among women in sub-Saharan Africa (the Preexposure Prophylaxis Trial for HIV Prevention among African Women [FEM-PrEP]), the use of preexposure prophylaxis was ineffec –
tive, probably because of low levels of adherence to the medication regimen.
6 The use of vaginal
gels as microbicides has also had mixed efficacy outcomes.
In this issue of the Journal, Marrazzo and col –
leagues report the findings of the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, a placebo-controlled, randomized study of preexposure prophylaxis that was pro –
vided as oral antiretroviral therapy or as a vagi –
nal gel to women living in sub-Saharan Africa.
7
The study assessed five treatment groups (oral tenofovir alone, oral tenofovir with emtricitabine, oral placebo, vaginal tenofovir gel, and vaginal placebo gel). Although it was planned for a 36-month maximum follow-up, the data and safe –
ty monitoring board recommended terminat –
ing treatment in the oral tenofovir and tenofovir gel study groups early, owing to futility. The oral tenofovir–emtricitabine group continued to com –
pletion, but the treatment showed no efficacy. Therefore, the study yielded results similar to those of the FEM-PrEP trial. The likely reason
for the lack of efficacy can be gleaned from the pharmacokinetic data: approximately 30% of plasma samples in the VOICE study had detect –
able drug at the pharmacokinetic time points, which indicates that the majority of women in the trial were not taking their assigned medica –
tions regularly.
It is well established that medications don’t
work if they are not taken, which probably ex –
plains why no difference in efficacy was observed between the active-drug and placebo groups. On closer inspection, however, the striking finding

Back to Table of Contents6 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 372;6 nejm.org february 5 , 2015 564in the VOICE trial is the disconnect between re –
ported adherence and actual adherence to the
regimen. Although approximately 30% of plasma samples collected from the women had detect –
able drug, 90% and 88% of the women indicat –
ed that they had not missed a dose when asked by either a study interviewer or a computerized questionnaire, respectively. More striking, the medication reconciliation, in which returned un –
used tablets were counted to determine missed doses, revealed that 86% of medication was “taken.” This means that a large number of par –
ticipants actively removed unused medications from their allotment before returning to the study site in order to create the appearance of compliance with the protocol.
The question that emerges is this: why did
the participants go to such lengths to create the appearance that they were taking medications when they were not? To the study team’s credit, they investigated this question through a series of qualitative interviews with VOICE partici –
pants after the study results became known.
8,9
In a recently published report, van der Straten and colleagues identified several factors associ –
ated with poor adherence to the protocol.
8 A
common theme stemmed from fear of taking the medicine, because of concern either about adverse effects or about being falsely labeled as having HIV infection. The drugs used in the VOICE study are well known as anti-HIV agents. Despite detailed education provided by the study team, many of the participants feared that such potent treatment must have serious toxicity when used in uninfected people. In addition, because it is common knowledge within the community that antiretroviral therapy is associ –
ated with HIV infection, many women in the study were afraid that if they were seen taking HIV medications, they would be labeled as be –
ing infected. As a result, many of the women concealed their use of the products or hid the products out of a fear of stigma. The strong presence of stigma was identified among male partners and community members interviewed as part of the study, validating the concerns among the VOICE participants that their taking HIV pills would lead to gossip and rumor in
the community, workplace, and household. In –
further work, the researchers specifically stud –
ied participants with low levels of drug in the blood versus those with high levels.
9 The group with low levels had significantly more fear of the drug side effects and had less trust in the clinic and its staff. In contrast, those with high drug levels developed strategies to overcome concerns about stigma, valued advice from nurses, and were more likely to believe that the products worked.
9
At first glance, the VOICE study appears to
indicate that preexposure prophylaxis doesn’t work in women in Africa and that we should move on to explore other approaches to the pre –
vention of HIV transmission in high-risk set –
tings. On further review, the study indicates that much more work is needed, not so much in the realm of understanding the biologic basis of preexposure prophylaxis as a preventive treat –
ment but rather in the realm of understanding behavioral barriers in the setting of strong so –
cial stigma.
The “Declaration of Sentiments,” penned by
Elizabeth Cady Stanton at the Women’s Rights Convention in Seneca Falls, New York, in 1848, starts with the following statement: “When, in the course of human events, it becomes neces –
sary for one portion of the family of man to as –
sume among the people of the earth a position different from that which they have hitherto oc –
cupied . . . .”
10 This declaration represented the
formal beginning of the women’s rights move –
ment in the United States. As in the fight for women to find their voice in the United States against strong social stigma so long ago, victory in the battle to prevent HIV will require the women at risk for infection to find “a position different from that which they have hitherto oc –
cupied” in order for them to find their VOICE.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
This article was updated on February 5, 2015, at NEJM.org.
From the Center for AIDS Research, University of Alabama at Birmingham, Birmingham.
1. Nakagawa F, May M, Phillips A. Life expectancy living with
HIV: recent estimates and future implications. Curr Opin Infect Dis 2013;26:17-25.
2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1
infection with early antiretroviral therapy. N Engl J Med 2011;
365:493-505.
3. Thirty years of a disease: the end of AIDS? The Economist.
June 2, 2011 (http://www.economist.com/node/18774722).
4. Centers for Disease Control and Prevention. Estimated HIV
incidence in the United States, 2007–2010. HIV Surveillance Sup –
plemental Report 2012. Vol. 17. No. 4 (http://go.usa.gov/p8P4).
5. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemo –
prophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587-99.

Back to Table of Contents7 Notable Articles of 2015
nejm.org editorials
n engl j med 372;6 nejm.org february 5 , 2015 5656. Van Damme L, Corneli A, Ahmed K, et al. Preexposure pro –
phylaxis for HIV infection among African women. N Engl J Med
2012;367:411-22.
7. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-
based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015;372:509-18.
8. van der Straten A, Stadler J, Luecke E, Laborde N, Hartmann
M, Montgomery ET. Perspectives on use of oral and vaginal anti –
retrovirals for HIV prevention: the VOICE-C qualitative study in Johannesburg, South Africa. J Int AIDS Soc 2014;17:Suppl 2: 19146.9. van der Straten A, Musarea P, Etima J, et al. Disclosure of
PK drug results promotes open discourse on non-adherence during VOICE. Presented at the HIV Research for Prevention scientific meeting, Cape Town, South Africa, October 28–31, 2014. abstract.
10. The Declaration of Sentiments: Women’s Rights Convention
in Seneca Falls, New York, 1848. U.S. Constitution Online (http://www.usconstitution.net/sentiments.html#sent).
DOI: 10.1056/NEJMe1415750
Copyright © 2015 Massachusetts Medical Society.

Back to Table of Contents8 Notable Articles of 2015
nejm.org
n engl j med 372;9 nejm.org february 26, 2015 803The new england
journal of medicine
established in 1812 february 26, 2015 vol. 372 no. 9
Randomized Trial of Peanut Consumption
in Infants at Risk for Peanut Allergy
George Du Toit, M.B., B.Ch., Graham Roberts, D.M., Peter H. Sayre, M.D., Ph.D., Henry T. Bahnson, M.P.H.,
Suzana Radulovic, M.D., Alexandra F. Santos, M.D., Helen A. Brough, M.B., B.S., Deborah Phippard, Ph.D.,
Monica Basting, M.A., Mary Feeney, M.Sc., R.D., Victor Turcanu, M.D., Ph.D., Michelle L. Sever, M.S.P.H., Ph.D.,
Margarita Gomez Lorenzo, M.D., Marshall Plaut, M.D., and Gideon Lack, M.B., B.Ch., for the LEAP Study Team*
Abstract
From the Department of Pediatric Aller –
gy, Division of Asthma, Allergy and Lung
Biology, King’s College London and Guy’s and St. Thomas’ National Health Service Foundation Trust, London (G.D.T., S.R., A.F.S., H.A.B., M.B., M.F., V.T., G.L.), and the University of South –
ampton and National Institute for Health Research Respiratory Biomedical Re –
search Unit, Southampton and David Hide Centre, Newport, Isle of Wight (G.R.) — both in the United Kingdom; the Division of Hematology–Oncology, Department of Medicine (P.H.S.), and the Immune Tolerance Network (D.P.), University of California, San Francisco, San Francisco; Rho Federal Systems Divi –
sion, Chapel Hill, NC (H.T.B., M.L.S.); and the National Institute of Allergy and Infectious Diseases, Bethesda, MD (M.G.L., M.P.). Address reprint requests to Dr. Lack at the Children’s Allergy Unit, 2nd Fl., Stairwell B, South Wing, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Rd., London SE1 7EH, United Kingdom.
* A complete list of members of the
Learning Early about Peanut Allergy (LEAP) Study Team is provided in the Supplementary Appendix, available at NEJM.org.
This article was published on February 23, 2015, at NEJM.org.
N Engl J Med 2015;372:803-13.
DOI: 10.1056/NEJMoa1414850
Copyright © 2015 Massachusetts Medical Society.Background
The prevalence of peanut allergy among children in Western countries has doubled
in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy.
Methods
We randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was deter –
mined with the use of a skin-prick test — one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal mea –
suring 1 to 4 mm in diameter. The primary outcome, which was assessed indepen –
dently in each cohort, was the proportion of participants with peanut allergy at 60 months of age.
Results
Among the 530 infants in the intention-to-treat population who initially had nega –
tive results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = 0.004). There was no significant
between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy.
Conclusions
The early introduction of peanuts significantly decreased the frequency of the devel –
opment of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infec –
tious Diseases and others; ClinicalTrials.gov number, NCT00329784.)
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Back to Table of Contents9 Notable Articles of 2015
nejm.org
editorials
n engl j med 372;9 nejm.org february 26, 2015 874The new england journal of medicine
Preventing Peanut Allergy through Early Consumption —
Ready for Prime Time?
Rebecca S. Gruchalla, M.D., Ph.D., and Hugh A. Sampson, M.D.
Kids can’t take peanut butter to school. Some air –
lines no longer serve peanuts because of fear of
anaphylaxis among passengers. These develop –
ments are just the tip of the iceberg as the preva –
lence of peanut allergy among children continues to increase worldwide, especially in westernized countries. In the United States alone, the preva –
lence has more than quadrupled in the past 13 years, growing from 0.4% in 1997 to 1.4% in 2008
1 to more than 2% in 2010.2 Peanut allergy
has become the leading cause of anaphylaxis and death related to food allergy in the United States.
3
In 2000, largely in response to outcomes re –
ported in infant feeding trials conducted in Eu –
rope and the United States, the American Acad –
emy of Pediatrics (AAP) recommended that parents refrain from feeding peanuts to infants at risk for the development of atopic disease until the children reached 3 years of age.
4 However,
since the number of cases of peanut allergy con –
tinued to rise, many investigators and clinicians began questioning this advice. In 2008, after re –
viewing the published literature, the AAP retract –
ed its recommendation, stating that there was insufficient evidence to call for early food avoid –
ance.
5 S h o r tl y t h e r e a f t e r , D u T o i t e t a l .6 noted
that the prevalence of peanut allergy among Jewish children in London who were not given peanut-based products in the first year of life was 10 times as high as that among Jewish chil –
dren in Israel who had consumed peanut-based products before their first birthday. In addition, subsequent studies that evaluated the early intro –
duction of other allergenic foods, including egg
7
and cow’s milk,8 showed that earlier introduction of egg and milk into an infant’s diet was associ –
ated with a decrease in the development of allergy.
But since these studies were observational,
we needed data from controlled trials to provide reliable clinical guidance regarding the best time to introduce allergenic foods (e.g., milk, egg, peanuts, and tree nuts) to infants at high risk for the development of allergies (i.e., those from atopic families). Du Toit et al.
9 now address this
question in the Journal in their landmark study,
Learning Early about Peanut Allergy (LEAP). The investigators hypothesized that early introduc –
tion of peanut-based products (before 11 months o f a g e ) w o ul d l ea d to th e p rev e n ti o n o f pean u t allergy in high-risk infants. More than 500 in –
fants at high risk for peanut allergy were ran –
domly assigned to receive peanut products (con –
sumption group) or to avoid them (avoidance group). Approximately 10% of children, in whom a wheal measuring more than 4 mm developed after they received a peanut-specific skin-prick test, were excluded from the study because of concerns that they would have severe reactions. At 5 years of age, the children were given a pea –
nut challenge to determine the prevalence of pea –
nut allergy. The results are striking — overall, the prevalence of peanut allergy in the peanut-avoidance group was 17.2% as compared with 3.2% in the consumption group.
The trial was designed to examine two groups
— children who had negative results on the pea –
nut skin-prick test at enrollment (nonsensitized) and those who had “mild” sensitization at enroll –
ment (wheals with mean diameters of 1 to 4 mm in response to the test). In these two groups the

Back to Table of Contents10 Notable Articles of 2015
nejm.org editorials
n engl j med 372;9 nejm.org february 26, 2015 875results on the prevalence of peanut allergy were
equally striking. Among the children who ini –
tially had a negative result on the skin-prick test, the prevalence of peanut allergy was 13.7% in the avoidance group and 1.9% in the con –
sumption group, and among those who had mild sensitization the prevalence was 35.3% in the avoidance group versus 10.6% in the consump –
tion group. Thus, early consumption was effec –
tive not only in high-risk infants who showed no indication of peanut sensitivity at study entry (primary prevention) but also in infants who had slight peanut sensitivity (secondary prevention).
Du Toit et al. carefully defined their high-risk
population, which included children with severe eczema, egg allergy, or both. Moreover, they de –
termined whether these infants were sensitized to peanut at study entry and then challenged those in the peanut-consumption group to en –
sure that these children were unresponsive be –
fore sending them home to consume peanut-based products on a regular basis.
Given the results of this prospective, random –
ized trial, which clearly indicates that the early introduction of peanut dramatically decreases the risk of development of peanut allergy (approxi –
mately 70 to 80%), should the guidelines be changed? Should we recommend introducing peanuts to all infants before they reach 11 months of age? Unfortunately, the answer is not that simple, and many questions remain unan –
swered: Do infants need to ingest 2 g of peanut protein (approximately eight peanuts) three times a week on a regular basis for 5 years, or will it suffice to consume lesser amounts on a more intermittent basis for a shorter period of time? If regular peanut consumption is discontinued for a prolonged period, will tolerance persist? Can the findings of the LEAP study be applied to other foods, such as milk, eggs, and tree nuts?
These questions must be addressed, but we
believe that because the results of this trial are so compelling, and the problem of the increasing prevalence of peanut allergy so alarming, new guidelines should be forthcoming very soon. In the meantime, we suggest that any infant be –
tween 4 months and 8 months of age believed to be at risk for peanut allergy should undergo skin-prick testing for peanut. If the test results are negative, the child should be started on a diet that includes 2 g of peanut protein three times a week for at least 3 years, and if the re –
sults are positive but show mild sensitivity (i.e., the wheal measures 4 mm or less), the child should undergo a food challenge in which pea –
nut is administered and the child’s response observed by a physician who has experience per –
forming a food challenge. Children who are non –
reactive should then be started on the peanut-containing diet. Although other studies are urgently needed to address the many questions that remain, especially with respect to other foods, the LEAP study makes it clear that we can do something now to reverse the increasing prevalence of peanut allergy.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Departments of Internal Medicine and Pediatrics and
Division of Allergy and Immunology, University of Texas South –
western Medical Center, Dallas (R.S.G.); and Department of Pediatrics, Division of Allergy–Immunology, and Jaffe Food Al –
lergy Institute at the Icahn School of Medicine at Mount Sinai, New York (H.A.S.).
This article was published on February 23, 2015, at NEJM.org.
1. Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA.
US prevalence of self-reported peanut, tree nut, and sesame aller –
gy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1322-6.
2. Bunyavanich S, Rifas-Shiman SL, Platts-Mills TA, et al. Peanut
allergy prevalence among school-age children in a US cohort not
selected for any disease. J Allergy Clin Immunol 2014;134:753-5.
3. Sampson HA. Peanut allergy. N Engl J Med 2002;346:
1294-9.
4. American Academy of Pediatrics, Committee on Nutrition.
Hypoallergenic infant formulas. Pediatrics 2000;106:346-9.
5. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional
interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breast –
feeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008;121:183-91.
6. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of
peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008;122:984-91.
7. Koplin JJ, Osborne NJ, Wake M, et al. Can early introduction
of egg prevent egg allergy in infants? A population-based study.
J Allergy Clin Immunol 2010;126:807-13.
8. Katz Y, Rajuan N, Goldberg MR, et al. Early exposure to
cow’s milk protein is protective against IgE-mediated cow’s milk protein allergy. J Allergy Clin Immunol 2010;126:77-82.
9. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of
peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803-13.
DOI: 10.1056/NEJMe1500186
Copyright © 2015 Massachusetts Medical Society.

Back to Table of Contents11 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 372;10 nejm.org March 5, 2015 905established in 1812 March 5, 2015 vol. 372 no. 10
From the Department of Preventive Med –
icine, University of Southern California,
Los Angeles (W.J.G., R.U., E.A., K.B., R.M., E.R., R.C., F.G.) and Sonoma Tech –
nologies, Petaluma (F.L.) — both in Cali –
fornia. Address reprint requests to Dr. Gauderman at the Department of Pre –
ventive Medicine, University of Southern California, 2001 Soto St., 202-K, Los An –
geles, CA 90032, or at jimg@ usc . edu.
N Engl J Med 2015;372:905-13.
DOI: 10.1056/NEJMoa1414123
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Air-pollution levels have been trending downward progressively over the past sev –
eral decades in southern California, as a result of the implementation of air qual –
ity–control policies. We assessed whether long-term reductions in pollution were
associated with improvements in respiratory health among children.
METHODS
As part of the Children’s Health Study, we measured lung function annually in 2120 children from three separate cohorts corresponding to three separate calendar peri –
ods: 1994–1998, 1997–2001, and 2007–2011. Mean ages of the children within each cohort were 11 years at the beginning of the period and 15 years at the end. Linear-regression models were used to examine the relationship between declining pol –
lution levels over time and lung-function development from 11 to 15 years of age, measured as the increases in forced expiratory volume in 1 second (FEV
1) and
forced vital capacity (FVC) during that period (referred to as 4-year growth in FEV1
and FVC).
RESULTS
Over the 13 years spanned by the three cohorts, improvements in 4-year growth of both FEV
1 and FV C were associated with declining levels of nitrogen dioxide
(P<0.001 for FEV1 and FVC) and of particulate matter with an aerodynamic diameter
of less than 2.5 μm (P = 0.008 for FEV1 and P<0.001 for FVC) and less than 10 μm
(P<0.001 for FEV1 and FVC). These associations persisted after adjustment for sev –
eral potential confounders. Significant improvements in lung-function development were observed in both boys and girls and in children with asthma and children without asthma. The proportions of children with clinically low FEV
1 (defined as
<80% of the predicted value) at 15 years of age declined significantly, from 7.9% to 6.3% to 3.6% across the three periods, as the air quality improved (P = 0.001).
CONCLUSIONS
We found that long-term improvements in air quality were associated with statisti –
cally and clinically significant positive effects on lung-function growth in children. (Funded by the Health Effects Institute and others.)abstractAssociation of Improved Air Quality with Lung Development
in Children
W. James Gauderman, Ph.D., Robert Urman, M.S., Edward Avol, M.S., Kiros Berhane, Ph.D., Rob McConnell, M.D.,
Edward Rappaport, M.S., Roger Chang, Ph.D., Fred Lurmann, M.S., and Frank Gilliland, M.D., Ph.D.
The New England Journal of Medicine
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Back to Table of Contents12 Notable Articles of 2015
nejm.org
editorial
n engl j med 372;10 nejm.org march 5 , 2015 970The new england journal of medicine
Cleaner Air, Bigger Lungs
Douglas W. Dockery, Sc.D., and James H. Ware, Ph.D.
In the latter half of the 20th century, Los Angeles
had, by many measures, higher levels of photo –
chemical air pollutants than any other major city in the United States (Fig. 1). To address this problem, the California Air Resources Board and its partners became leaders in quantifying the health effects of air pollutants and in aggres –
sively implementing pollution-control strategies.
Even with these actions, air-pollution levels
remained high. In 1993, “Health Advisories” were issued on 92 days.
1 In that year , the pro –
spective Children’s Health Study was launched to examine the effects of air pollution on lung growth in children. Fourth-grade children were recruited from 12 communities in southern Cali –
fornia with varying exposures to the pollutants of concern (ozone, nitrogen dioxide, and partic-ulate matter). Repeated lung-function measure –
ments were taken for these children for 8 years, the period of life during which the greatest growth of lung function occurs.
In this first cohort, children living in more
polluted communities had lower cumulative lung growth during the follow-up period.
2 These re –
sults were important clinically because even modest reductions in attained lung function at maturity are predictive of respiratory disease, coronary heart disease, and reduced life expec –
tancy.
3
Of course, such an association does not prove
causality. However, the case for a causal relation –
ship can be strengthened by consistent evidence from repeated studies. To that end, Gauderman and his colleagues enrolled two additional co –
horts of children from the Children’s Health Study and found consistent associations be –
tween community air pollution and lung-function growth in the children recruited in 1993,
2 1997,4
and 2003.5
The consistency of findings in the three sepa –
rate cohorts is compelling. Moreover, the inves –
tigators sought to minimize the potential for confounding by controlling for known individual and community predictors of lung-function growth. Nevertheless, unmeasured or imperfectly measured characteristics of these communities, such as differences in ethnic background or socioeconomic status, may have confounded these analyses and produced a false positive association.
Although lung-function growth and potential
confounders were measured for each child, air-pollution exposures were based on community means. Such studies have been described as “semi-individual”
6 with respect to the exposure
variables. Thus, these analyses could also have been influenced by differences in community characteristics not captured in the individual data. A community is more than the aggregate of individual characteristics.
7
In this issue of the Journal, Gauderman et al.8
examine the association between improvements in air quality and changes in lung-function growth from 11 to 15 years of age across these three cohorts of children. They show that 4-year growth in forced expiratory volume in 1 second (FEV
1) and forced vital capacity (FVC) improved
as levels of air pollution (nitrogen dioxide and particulate matter with an aerodynamic diameter of <2.5 μm [PM
2.5] and <10 μm [PM10]) declined
in five of these communities.
This study provides corroborating informa –
tion because the analyses are based on compari –
sons within communities and thus are not con –
The New England Journal of Medicine
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Back to Table of Contents13 Notable Articles of 2015
nejm.org editorial
n engl j med 372;10 nejm.org march 5 , 2015 971founded by differences between communities.
The potential confounders of these temporal comparisons are characteristics of the commu-nities that changed during the period of study. Recall that, to be a confounder, a variable must be associated with both air-pollution levels and lung-function growth. The advantage of these complementary approaches is that characteris-tics of the communities are less likely to con-found both spatial and temporal comparisons.
In the original Children’s Health Study co-
hort design, communities were selected to repre-sent extremes of exposure to particulate matter, nitrogen dioxide, and ozone air pollution. For example, in 1994 mean concentrations of PM
2.5
ranged from 31.5 μg per cubic meter (in Mira Loma) to 6.7 μg per cubic meter (in Santa Maria), and the nitrogen dioxide level ranged from 36.4 ppb (in Long Beach) to 2.7 ppb (in Lompoc).
9
Between 1994 and 2010, the period analyzed by Gauderman et al., changes in PM
2.5 an d ni tr o-
gen dioxide levels within the five study commu-nities approached the between-community dif-ferences in 1994. For example, the mean PM
2.5
level improved from 31.5 μg per cubic meter (1994–1997) to 17.8 μg per cubic meter (2007–2010) in Mira Loma, and the nitrogen dioxide level improved from 34.4 ppb (1994–1997) to 20.3 ppb (2007–2010) in Long Beach. Temporal changes in ozone, however, were modest.
These results suggest that the children born
after air-pollution levels had declined in these communities had greater lung-function growth. These investigators had previously shown, in a relatively small number of children, that partici-pants who moved out of the study area to cleaner communities had improved lung-function growth, whereas those who moved to more polluted communities had reduced growth.
10 This raises
the possibility that some of the loss of lung function associated with exposure to air pollu-tion is reversible.
In recent years, much of the research on the
effects of community air pollution has focused on premature death and on clinical events such as myocardial infarctions or hospital admissions. Because these events occur primarily among older adults, there has been less interest in in-termediate physiological (subclinical) measures. Nevertheless, there is growing awareness of the effects of early life events on the risk of adult-onset chronic diseases. Reduced lung function is a powerful predictor not only of chronic respira-tory disease in adults but also of chronic cardio-vascular disease. The reported net deficits in lung function in children living in the more polluted communities may provide a partial explanation for the associations between air-pollution levels and mortality rates observed both in southern California
11 and nationally.12
Some have argued that the substantial im-
provements in air quality over the past 40 years are sufficient to protect public health and that there is little evidence to support more stringent standards. However, the current report and other studies suggest that further improvement in air quality may have beneficial public health effects.
A
B
Figure 1. Pollution in Los Angeles.
Los Angeles is shown in the late 1980s (Panel A) and in 2014 (Panel B).
Ted Spiegel/Corbis (Panel A), Ted Soqui/Corbis (Panel B)
The New England Journal of Medicine
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Back to Table of Contents14 Notable Articles of 2015
nejm.org editorial
n engl j med 372;10 nejm.org march 5 , 2015 972Four decades ago, most Americans were exposed
to much higher levels of air pollution than those observed today. At that time, it was difficult to find communities with little or no exposure, which limited the ability of investigators to deter –
mine a “no-effect level.” With the improvements in air quality, observational studies can now as –
sess the benefits of reductions in air-pollution exposure into the range below those historical levels. These new observational studies often show that there are health benefits associated with improvements in air quality even when the pollution levels are within a range previously thought to be safe.
Disclosure forms provided by the authors are available with the
full text of this article at NEJM.org.
From the Departments of Environmental Health (D.W.D.) and
Biostatistics (J.H.W.), Harvard T.H. Chan School of Public Health, Boston.
1. The Southland’s war on smog: f ifty years of progress toward
clean air (through May 1997). Diamond Bar, CA: South Coast Air Quality Management District (http://www.aqmd.gov/home/
library/public-information/publications/50-years-of-progress).
2. Gauderman WJ, Avol E, Gilliland F, et al. The effect of air
pollution on lung development from 10 to 18 years of age. N Engl J Med 2004;351:1057-67. [Erratum, N Engl J Med 2005;352:1276.]
3. Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Haw -thorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313:711-5.
4. Gauderman WJ, Gilliland GF, Vora H, et al. Association be –
tween air pollution and lung function growth in southern Cali –
fornia children: results from a second cohort. Am J Respir Crit Care Med 2002;166:76-84.
5. Urman R, McConnell R, Islam T, et al. Associations of chil-
dren’s lung function with ambient air pollution: joint effects of regional and near-roadway pollutants. Thorax 2014;69:540-7.
6. Künzli N, Tager IB. The semi-individual study in air pollu –
tion epidemiolog y: a valid design as compared to ecologic studies. Environ Health Perspect 1997;105:1078-83.
7. Diez-Roux AV. Bringing context back into epidemiology:
variables and fallacies in multilevel analysis. Am J Public Health 1998;88:216-22.
8. Gauderman WJ, Urman R, Avol E, et al. Association of im –
proved air quality with lung development in children. N Engl J Med 2015;372:905-13.
9. Peters JM, Avol E, Navidi W, et al. A study of twelve Southern
California communities with differing levels and types of air pollut ion. I. Prevalence of respirator y morbidit y. Am J Respir Crit Care Med 1999;159:760-7.
10. Avol EL, Gauderman WJ, Tan SM, London SJ, Peters JM. Re –
spiratory effects of relocating to areas of differing air pollution levels. Am J Respir Crit Care Med 2001;164:2067-72.
11. Jerrett M, Burnett RT, Ma R, et al. Spatial analysis of air pol –
lution and mortality in Los Angeles. Epidemiology 2005;16:727-36.
12. Pope CA III, Burnett RT, Thun MJ, et al. Lung cancer, cardio –
pulmonar y mort alit y, and long-term exposure to f ine part iculate air pollution. JAMA 2002;287:1132-41.
DOI: 10.1056/NEJMe1415785
Copyright © 2015 Massachusetts Medical Society.
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Back to Table of Contents15 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 373;5 nejm.org July 30, 2015 415The authors’ full names, academic degrees,
and affiliations are listed in the Appen –
dix. Address reprint requests to Dr. Jain at the Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS A-32, Atlanta, GA 30333, or at bwc8@ cdc . gov.
*A complete list of members of the Cen –
ters for Disease Control and Prevention
(CDC) Etiology of Pneumonia in the Community (EPIC) Study Team is pro –
vided in the Supplementary Appendix, available at NEJM.org.
This article was published on July 14, 2015, at NEJM.org.
N Engl J Med 2015;373:415-27.
DOI: 10.1056/NEJMoa1500245
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Community-acquired pneumonia is a leading infectious cause of hospitalization
and death among U.S. adults. Incidence estimates of pneumonia confirmed radio –
graphically and with the use of current laboratory diagnostic tests are needed.
METHODS
We conducted active population-based surveillance for community-acquired pneu –
monia requiring hospitalization among adults 18 years of age or older in five hospitals in Chicago and Nashville. Patients with recent hospitalization or severe immunosuppression were excluded. Blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and mo –
lecular diagnostic testing. Study radiologists independently reviewed chest radio –
graphs. We calculated population-based incidence rates of community-acquired pneumonia requiring hospitalization according to age and pathogen.
RESULTS
From January 2010 through June 2012, we enrolled 2488 of 3634 eligible adults (68%). Among 2320 adults with radiographic evidence of pneumonia (93%), the median age of the patients was 57 years (interquartile range, 46 to 71); 498 patients (21%) required intensive care, and 52 (2%) died. Among 2259 patients who had radio –
graphic evidence of pneumonia and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae
(in 5%). The annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults). For each pathogen, the incidence increased with age.
CONCLUSIONS
The incidence of community-acquired pneumonia requiring hospitalization was high –
est among the oldest adults. Despite current diagnostic tests, no pathogen was de –
tected in the majority of patients. Respiratory viruses were detected more frequently than bacteria. (Funded by the Influenza Division of the National Center for Immu –
nizations and Respiratory Diseases.)ABSTRACTCommunity-Acquired Pneumonia Requiring
Hospitalization among U.S. Adults
S. Jain, W.H. Self, R.G. Wunderink, S. Fakhran, R. Balk, A.M. Bramley, C. Reed,
C.G. Grijalva, E.J. Anderson, D.M. Courtney, J.D. Chappell, C. Qi, E.M. Hart,
F. Carroll, C. Trabue, H.K. Donnelly, D.J. Williams, Y. Zhu, S.R. Arnold,
K. Ampofo, G.W. Waterer, M. Levine, S. Lindstrom, J.M. Winchell, J.M. Katz,
D. Erdman, E. Schneider, L.A. Hicks, J.A. McCullers, A.T. Pavia, K.M. Edwards,
and L. Finelli, for the CDC EPIC Study Team* Original Article
The New England Journal of Medicine
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Back to Table of Contents16 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 373;6 nejm.org August 6, 2015 511From Pennsylvania Hospital, Philadel –
phia (C.V.P.); Boehringer Ingelheim Phar –
maceuticals, Ridgefield, CT (P.A.R., R.D.,
B.W.); McMaster University (J.E., J.I.W.) and Thrombosis and Atherosclerosis Re –
search Institute (J.I.W.) — both in Hamil –
ton, ON, Canada; Boehringer Ingelheim Pharma, Biberach (S.G., J.S.) and Ingel –
heim (J.K.), Klinikum Frankfurt Höchst, Frankfurt am Main, and Heidelberg Uni –
versity Hospital, Heidelberg (T.S.) — all in Germany; University of Leuven, Leu –
ven, Belgium (P.V.); Northwestern Uni –
versity, Chicago (R.A.B.); Leiden Univer –
sity Medical Center, Leiden (M.V.H.), and University Medical Center Groningen, Groningen, (P.W.K.) — both in the Neth –
erlands; Boston University School of Medicine, Boston (E.M.H.); Duke Univer –
sity Medical Center, Durham, NC (J.H.L.); Brown Medical School and Rhode Island Hospital, Providence, RI (F.W.S.); and Tuen Mun Hospital, Tuen Mun, NT, Hong Kong (C.-W.K.). Address reprint requests to Dr. Pollack at Thomas Jefferson University, Scott Memorial Li –
brary, 1020 Walnut St., Rm. 616, Philadel –
phia, PA 19107, or at charles . pollack@
jefferson . edu.
This article was published on June 22,
2015, at NEJM.org.
N Engl J Med 2015;373:511-20.
DOI: 10.1056/NEJMoa1502000
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lack –
ing. Idarucizumab, an antibody fragment, was developed to reverse the anticoagu –
lant effects of dabigatran.
METHODS
We undertook this prospective cohort study to determine the safety of 5 g of in –
travenous idarucizumab and its capacity to reverse the anticoagulant effects of
dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
RESULTS
This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute throm –
bin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who under –
went a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respec –
tively. One thrombotic event occurred within 72 hours after idarucizumab adminis –
tration in a patient in whom anticoagulants had not been reinitiated.
CONCLUSIONS
Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.)ABSTRACTIdarucizumab for Dabigatran Reversal
Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., John Eikelboom, M.B., B.S.,
Stephan Glund, Ph.D., Peter Verhamme, M.D., Richard A. Bernstein, M.D., Ph.D.,
Robert Dubiel, Pharm.D., Menno V. Huisman, M.D., Ph.D., Elaine M. Hylek, M.D.,
Pieter W. Kamphuisen, M.D., Ph.D., Jörg Kreuzer, M.D., Jerrold H. Levy, M.D.,
Frank W. Sellke, M.D., Joachim Stangier, Ph.D., Thorsten Steiner, M.D., M.M.E.,
Bushi Wang, Ph.D., Chak-Wah Kam, M.D., and Jeffrey I. Weitz, M.D. Original Article
The New England Journal of Medicine
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Back to Table of Contents17 Notable Articles of 2015
nejm.org
EditorialsThe new england journal of medicine
n engl j med 373;6 nejm.org August 6, 2015 568Targeted Anti-Anticoagulants
Kenneth A. Bauer, M.D.
Four direct oral anticoagulants have been ap –
proved for use in many countries. These drugs
are valuable alternatives to vitamin K antago –
nists, such as warfarin, for many patients re –
quiring anticoagulation to prevent stroke due to nonvalvular atrial fibrillation and to treat and prevent venous thromboembolism. The mecha –
nism of these agents is to selectively inhibit either thrombin or factor Xa, which are critical en –
zymes in the common pathway of blood coagu –
lation. Dabigatran etexilate inhibits thrombin, whereas apixaban, edoxaban, and rivaroxaban inhibit factor Xa.
Direct oral anticoagulants have several phar –
macologic advantages over vitamin K antagonists, including a wider therapeutic window, a rapid onset of action, and shorter half-lives that range between 7 hours and 14 hours in healthy persons. Direct oral anticoagulants are administered at fixed doses to adults without laboratory moni –
toring, which is more convenient than warfarin with its requirement for monitoring of the inter –
national normalized ratio and periodic dose ad –
justments. In randomized trials with good anti –
coagulation management (i.e., with international normalized ratios generally in the desired thera –
peutic range of 2 to 3 for >60% of the time), direct oral anticoagulants were noninferior, and in some cases superior, to dose-adjusted warfa –
rin for the prevention and treatment of throm –
bosis. As compared with warfarin, direct oral anticoagulants reduced the rate of major bleed –
ing by 28% and the rates of intracranial and fatal hemorrhage by 50%.
1
Despite the better bleeding profile of direct
oral anticoagulants, as compared with warfarin, some physicians and patients have been unwill –
ing to consider these drugs in the absence of an established way to reverse their anticoagulant activity. Although the anticoagulant activity of warfarin can be reversed with vitamin K, fresh-frozen plasma, and prothrombin complex con –
centrates, major bleeding events that occur in patients taking this drug often lead to poor outcomes; approximately 10% of patients who are hospitalized with warfarin-related bleeding die within 90 days,
2,3 and the mortality among
patients with intracranial hemorrhage can be as high as 50%.
4,5 The high mortality is attributable
in part to coexisting conditions in this patient population. Experimental data suggest that non –
specific reversal agents such as prothrombin com –
plex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa can re –
duce the anticoagulant effect of direct oral anti –
coagulants in vitro, in animal models, and in human volunteers.
6 However, these agents are of
unproven benefit in improving hemostasis in pa –
tients with bleeding related to direct oral antico –
agulant use, and they carry a risk of thrombosis; thus, they are currently reserved for patients with severe bleeding who cannot be treated with sup –
portive measures.
With the growing use of direct oral anticoagu –
lants, it would be advantageous to have reversal agents that can rapidly and completely neutral –
ize the anticoagulant activity of the drug and restore normal hemostasis. Specific reversal agents in clinical development include andexanet alfa, a recombinant factor Xa variant that spe –
cifically binds all the oral factor Xa inhibitors but lacks coagulant activity.
7 T h e r e i s a l s o a
nonspecific reversal agent in clinical develop –
ment, PER977, which binds to several of the di –
rect oral anticoagulants by means of electro –
static interactions.8 G i v e n t h a t t h e r e a r e n o

Back to Table of Contents18 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;6 nejm.org August 6, 2015 569established reversal strategies for the direct oral
anticoagulants, it is appropriate to undertake clinical trials of these agents without a control group.
Idarucizumab is a humanized monoclonal
antibody fragment with high affinity for the oral direct thrombin inhibitor dabigatran that selec –
tively and immediately neutralizes its anticoagu –
lant activity.
9 P o lla c k e t al .10 n o w r e p o rt in th e
Journal the results of an interim analysis of data
from 90 patients who were taking dabigatran and who presented with either serious bleeding or the need for urgent surgery or intervention and received intravenous idarucizumab. This multicenter observational study evaluated the effect of a single 5-g dose of antibody in eligible patients who were judged by the treating clini –
cian to require a reversal agent. The major end points of the study were pharmacodynamic as –
sessments of the ability of idarucizumab to neu –
tralize the anticoagulant activity of dabigatran. The data are convincing that the antidote effec –
tively and immediately neutralized the activity of dabigatran with a satisfactory safety profile. Normal hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of idarucizumab.
Without a control group, it is difficult to as –
sess the clinical benefit that is conferred by the administration of idarucizumab in patients with dabigatran-related bleeding. The mortality in the study population was high at 20%; half the deaths occurred more than 96 hours after the administration of the antidote and were attribut –
able to coexisting illness. Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neu –
tralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures? Major bleeding events in patients tak –
ing anticoagulants originate from anatomical lesions, and anticoagulation can lead to a rapid loss of blood from these sites. Thus, the location and size of the lesion along with the coexisting conditions of the patient may have a greater ef –
fect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking.
Laboratory measurements of the concentration
of dabigatran were performed centrally in this study and were not used to guide therapy. The results of one of these tests, the dilute thrombin time, were normal on study entry in nearly one quarter of the study population. This group of patients had little or no circulating anticoagu –
lant in their blood and would not be expected to benefit from the administration of idarucizumab. Thus, it will be useful to have activity measure –
ments available for the various direct oral anticoagulants in real time to help guide the
treatment of such patients and to prevent over –
utilization of what will surely be a costly medi –
cation.
The development of antidotes that are able to
neutralize the activity of the various direct oral anticoagulants rapidly and completely is an im –
portant advance. When they become available, guidelines and clinical pathways will need to be developed to care effectively for patients with, or at risk for, major bleeding related to direct oral anticoagulant use. Additional studies, however, will be required to determine in which situations the antidotes improve clinical outcomes.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From Harvard Medical School and Beth Israel Deaconess Med –
ical Center — both in Boston.
This article was published on June 22, 2015, at NEJM.org.
1. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The
impact of bleeding complications in patients receiving target-
specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124: 2450-8.
2. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembo –
lism, recurrent hemorrhage, and death after warfarin therapy
interruption for gastrointestinal tract bleeding. Arch Intern Med 2012; 172: 1484-91.
3. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleed –
ing in patients taking oral anticoagulant therapy for venous
thromboembolism: a meta-analysis. Ann Intern Med 2003; 139:
893-900.
4. Gomes T, Mamdani MM, Holbrook AM, Paterson JM,
Hellings C, Juurlink DN. Rates of hemorrhage during warfarin
therapy for atrial fibrillation. CMAJ 2013; 185(2): E121-E127.
5. Fang MC, Go AS, Chang Y, et al. Death and disability from
warfarin-associated intracranial and extracranial hemorrhages.
Am J Med 2007; 120: 700-5.
6. Bauer KA. Reversal of antithrombotic agents. Am J Hematol
2012; 87: Suppl 1: S119-S126.
7. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific anti –
dote for reversal of anticoagulation by direct and indirect in –
hibitors of coagulation factor Xa. Nat Med 2013; 19: 446-51.
8. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to
reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;
371: 2141-2.
9. Schiele F, van Ryn J, Canada K, et al. A specific antidote for
dabigatran: functional and structural characterization. Blood
2013; 121: 3554-62.
10. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for
dabigatran reversal. N Engl J Med 2015; 373: 511-20.
DOI: 10.1056/NEJMe1506600
Copyright © 2015 Massachusetts Medical Society.

Back to Table of Contents19 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;8 nejm.org August 20, 2015 697established in 1812 August 20, 2015 vol. 373 no. 8
From the Department of Medicine (M.C.,
K.D., G.L.G., P.S.W., M.A.R.) and the Clin –
ical Epidemiology Program (D.J.C., T.R., D.C.), Ottawa Hospital Research Insti –
tute, and Department of Diagnostic Imag –
ing (H.T.), University of Ottawa, Ottawa, Departments of Medicine (A.L.-L.), On –
cology (A.L.-L.), Epidemiology and Bio –
statistics (A.L.-L.), and Medical Imaging (Z.K.), University of Western Ontario, London, Department of Medicine, Dal –
housie University, Halifax, NS (S. Shiva –
kumar), Department of Medicine, Jewish General Hospital (V.T.), and Department of Medicine, Montreal General Hospital (S. Solymoss), McGill University, and De –
partment of Medicine, Sacre Coeur Hos –
pital, Université de Montréal (N.R., I.C.), Montreal, Department of Medicine, Univer –
sity of Manitoba, Winnipeg (R.Z.), Depart –
ment of Medicine, McMaster University, Hamilton, ON (J.D.), and the Department of Medicine, University of British Columbia, Vancouver (A.Y.L.) — all in Canada. Address reprint requests to Dr. Carrier at the Ottawa Hospital Research Institute, University of Ottawa, Ottawa Hospital General Campus, 501 Smyth Rd. Box 201a, Ottawa, ON K1H 8L6, Canada, or at mcarrier@ toh . on . ca.
* A complete list of investigators in the
Screening for Occult Malignancy in Pa –
tients with Idiopathic Venous Thrombo –
embolism (SOME) study is provided in the Supplementary Appendix, available at NEJM.org.
This article was published on June 22, 2015, at NEJM.org.
N Engl J Med 2015;373:697-704.
DOI: 10.1056/NEJMoa1506623
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Venous thromboembolism may be the earliest sign of cancer. Currently, there is a
great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed to –
mography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism.
METHODS
We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
RESULTS
Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P = 0.28). In the primary outcome analysis,
4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P = 1.0). There was no
significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P = 0.88) or in cancer-related mortality (1.4% and
0.9%, P = 0.75).
CONCLUSIONS
The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.)abstractScreening for Occult Cancer in Unprovoked Venous
Thromboembolism
Marc Carrier, M.D., Alejandro Lazo-Langner, M.D., Sudeep Shivakumar, M.D., Vicky Tagalakis, M.D.,
Ryan Zarychanski, M.D., Susan Solymoss, M.D., Nathalie Routhier, M.D., James Douketis, M.D.,
Kim Danovitch, C.C.R.P., Agnes Y. Lee, M.D., Gregoire Le Gal, M.D., Philip S. Wells, M.D., Daniel J. Corsi, Ph.D.,
Timothy Ramsay, Ph.D., Doug Coyle, Ph.D., Isabelle Chagnon, M.D., Zahra Kassam, M.D., Hardy Tao, M.D.,
and Marc A. Rodger, M.D., for the SOME Investigators*
The New England Journal of Medicine
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Back to Table of Contents20 Notable Articles of 2015
nejm.org
EditorialThe new england journal of medicine
n engl j med 373;8 nejm.org August 20, 2015 768Cancer Workup after Unprovoked Clot — Less Is More
Alok A. Khorana, M.D.
Consider this not unfamiliar scenario: a 56-year-
old educator presents with sudden onset of swelling and pain in the right thigh. She has no coexisting conditions except for well-controlled hypertension and has no family history of thrombophilia. She is admitted to the hospital after compression ultrasonography reveals the presence of a femoral-vein thrombosis. There are no provoking factors such as recent surgery or hospitalization. The phrase “possible cancer” is brought up on rounds, despite the patient’s re –
cent normal results on colonoscopy and mam –
mography. The patient is anxious about undiag –
nosed cancer and asks whether extensive imaging to rule out cancer is needed.
This important clinical question is at the
heart of a well-conducted randomized trial now reported in the Journal .
1 Unprovoked cases repre –
sent more than 40% of all venous thromboem –
bolisms.2 Epidemiologic studies have consis –
tently shown that a portion of unprovoked events are associated with undiagnosed cancer; an analysis of more than 500,000 Californians showed a standardized incidence ratio of 1.3 un –
provoked venous events (95% confidence inter –
val, 1.2 to 1.5) 1 year before cancer diagnosis.
3
A systematic review showed that the period prevalence of previously undiagnosed cancer in this context was 6.1% at baseline and 10.0% from baseline to 12 months.
4
Subjecting patients to an extensive diagnostic
workup could alter their clinical course: an ear –
lier cancer diagnosis might lead to earlier and more effective treatment and would also affect anticoagulant choice. Prior studies have investi –
gated the effect of extensive testing for cancer in this context but with suboptimal study design and sample sizes.
5,6 I n d e e d , a 2 0 1 5 C o c h r a n e systematic review was able to identify only two randomized or quasi-randomized studies involv –
ing a total of 396 patients.
7 I t c o n c l u d e d t h a t
there was insufficient evidence regarding the effectiveness of testing for undiagnosed cancer in reducing cancer-related and venous-thrombo –
embolism–related morbidity and mortality and that the results could be consistent with either harm or benefit.
In this context, the current report substan –
tially fills existing knowledge gaps. Carrier et al. randomly assigned patients across nine Canadian centers to either a limited screening strategy involving standard age- and sex-specific screen –
ing or to an extensive strategy that added com –
puted tomography (CT) of the abdomen and pelvis. It should be noted that the latter test was an enhanced version of the standard clinical scan and included a virtual colonoscopy and gastroscopy as well as parenchymal pancreatog –
raphy. Among 854 patients, 3.2% of the patients in the limited-screening group and 4.5% of the patients in the extensive-screening group had a new diagnosis of cancer between randomization and the 1-year follow-up — rates that were lower than anticipated. The primary outcome of the study was the number of cancers “missed” at the initial screening but diagnosed by the end of the 1-year follow-up period. Here, too, the num –
bers were encouraging: only 4 patients (0.93%) in the limited-screening group and 5 (1.18%) in the extensive-screening group had a cancer de –
tected after the completion of the initial screen –
ing. In other words, the risk of subsequent can –
cer was also quite low, and “doing more” did not lead to earlier cancer detection. Furthermore, secondary outcome analyses found no signifi –
cant between-group differences in the time to
The New England Journal of Medicine
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Back to Table of Contents21 Notable Articles of 2015
nejm.org Editorial
n engl j med 373;8 nejm.org August 20, 2015 769cancer diagnosis, overall mortality, or cancer-
related mortality.
One limitation of this study is generalizability:
the mean age of the study population was 54 years, whereas in the California study cited earlier, the mean age at cancer diagnosis was 66 years.
3 An
older study population would have had a greater prevalence of cancer. A second concern relates to whether the extensive screening was extensive enough. CT of the chest was not mandated; however, roughly 25% of patients had undergone such testing for diagnostic workup of pulmonary embolism, and no subsequent lung-cancer cases were diagnosed. Finally, the limited screening may have been too limited. Surprisingly, only 6.7% of the patients 50 years of age or older in the limited-screening group underwent colorectal-cancer screening, and no cancers were found; in contrast, the extensive screening strategy (which mandated virtual colonoscopy) identified three colorectal cancers. This limitation, however, supports the null hypothesis and if valid would only strengthen the conclusions of the study.
Thus, despite these concerns, the study re –
sults should do much to reassure our patient described above who has already had appropri –
ate screening that the risk of the subsequent discovery of cancer is roughly only 1% during the next year. Additional testing would be un –
likely to provide benefit and may cause harm by exposing the patient to unnecessary radiation. For decades, we have led ourselves to believe that doing more is doing better for our patients. In this context and many others, clinicians would do well to recall Robert Browning’s admonish –
ment, channeling the voice of the eponymous failed painter in his poem Andrea del Sarto : “Yet
do much less, so much less, . . . — so much
less! Well, less is more.”
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Taussig Cancer Institute, Cleveland Clinic, Cleveland. This article was published on June 22, 2015, at NEJM.org.
1. Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for
occult cancer in unprovoked venous thromboembolism. N Engl
J Med 2015;373:697-704.
2. Ageno W, Samperiz A, Caballero R, et al. Duration of antico –
agulation after venous thromboembolism in real world clinical practice. Thromb Res 2015; 135: 666-72.
3. White RH, Chew HK, Zhou H, et al. Incidence of venous
thromboembolism in the year before the diagnosis of cancer in
528,693 adults. Arch Intern Med 2005; 165: 1782-7.
4. Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rod –
ger MA. Systematic review: the Trousseau syndrome revisited:
should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008; 149: 323-33.
5. Piccioli A, Lensing AW, Prins MH, et al. Extensive screening
for occult malignant disease in idiopathic venous thromboem –
bolism: a prospective randomized clinical trial. J Thromb Hae –
most 2004; 2: 884-9.
6. Van Doormaal FF, Terpstra W, Van Der Griend R, et al. Is
extensive screening for cancer in idiopathic venous thromboem –
bolism warranted? J Thromb Haemost 2011; 9: 79-84.
7. Robertson L, Yeoh SE, Stansby G, Agarwal R. Effect of test –
ing for cancer on cancer- and venous thromboembolism (VTE)-
related mortality and morbidity in patients with unprovoked VTE. Cochrane Database Syst Rev 2015; 3: CD010837.
DOI: 10.1056/NEJMe1507506
Copyright © 2015 Massachusetts Medical Society.
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Back to Table of Contents22 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;17 nejm.org October 22, 2015 1597established in 1812 October 22, 2015 vol. 373 no. 17
From the Research Unit for Musculoskel –
etal Function and Physiotherapy, Institute
of Sports Science and Clinical Biome –
chanics, University of Southern Denmark, Odense (S.T.S., E.M.R.), Clinical Nursing Research Unit (S.T.S.) and Orthopedic Surgery Research Unit (S.T.S., M.B.L., O.S., S.R.), Aalborg University Hospital, and Center for Sensory-Motor Interac –
tion, Department of Health Science and Technology, Faculty of Medicine (S.T.S., M.B.L., M.S.R., L.A.-N., O.S., S.R.), and Department of Clinical Medicine (M.B.L., O.S., S.R.), Aalborg University, Aalborg — all in Denmark. Address reprint re –
quests to Dr. Skou at Aalborg University Hospital Science and Innovation Center, 15 Soendre Skovvej, 9000 Aalborg, Den –
mark, or at stskou@ health . sdu . dk.
N Engl J Med 2015;373:1597-606.
DOI: 10.1056/NEJMoa1505467
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
More than 670,000 total knee replacements are performed annually in the United
States; however, high-quality evidence to support the effectiveness of the proce –
dure, as compared with nonsurgical interventions, is lacking.
METHODS
In this randomized, controlled trial, we enrolled 100 patients with moderate-to-severe knee osteoarthritis who were eligible for unilateral total knee replacement. Patients were randomly assigned to undergo total knee replacement followed by 12 weeks of nonsurgical treatment (total-knee-replacement group) or to receive only the 12 weeks of nonsurgical treatment (nonsurgical-treatment group), which was delivered by physiotherapists and dietitians and consisted of exercise, educa –
tion, dietary advice, use of insoles, and pain medication. The primary outcome was the change from baseline to 12 months in the mean score on four Knee Injury and Osteoarthritis Outcome Score subscales, covering pain, symptoms, activities of daily living, and quality of life (KOOS
4); scores range from 0 (worst) to 100 (best).
RESULTS
A total of 95 patients completed the 12-month follow-up assessment. In the non –
surgical-treatment group, 13 patients (26%) underwent total knee replacement before the 12-month follow-up; in the total-knee-replacement group, 1 patient (2%) received only nonsurgical treatment. In the intention-to-treat analysis, the total-knee-replacement group had greater improvement in the KOOS
4 score than did the non –
surgical-treatment group (32.5 vs. 16.0; adjusted mean difference, 15.8 [95% confi –
dence interval, 10.0 to 21.5]). The total-knee-replacement group had a higher number of serious adverse events than did the nonsurgical-treatment group (24 vs. 6, P = 0.005).
CONCLUSIONS
In patients with knee osteoarthritis who were eligible for unilateral total knee re –
placement, treatment with total knee replacement followed by nonsurgical treatment resulted in greater pain relief and functional improvement after 12 months than did nonsurgical treatment alone. However, total knee replacement was associated with a higher number of serious adverse events than was nonsurgical treatment, and most patients who were assigned to receive nonsurgical treatment alone did not undergo total knee replacement before the 12-month follow-up. (Funded by the Obel Family Foundation and others; MEDIC ClinicalTrials.gov number, NCT01410409.)abstractA Randomized, Controlled Trial of Total Knee Replacement
Søren T. Skou, P.T., Ph.D., Ewa M. Roos, P.T., Ph.D., Mogens B. Laursen, M.D., Ph.D.,
Michael S. Rathleff, P.T., Ph.D., Lars Arendt-Nielsen, Ph.D., D.M.Sc., Ole Simonsen, M.D., D.M.Sc.,
and Sten Rasmussen, M.D., Ph.D.
The New England Journal of Medicine
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EditorialsThe new england journal of medicine
n engl j med 373;17 nejm.org October 22, 2015 1668Parachutes and Preferences — A Trial of Knee Replacement
Jeffrey N. Katz, M.D.
The term parachute trial entered the medical
lexicon to depict studies of treatments everyone already assumes to be effective. (In other words, do we need a trial to show that parachutes save the lives of persons who jump from airplanes?
1)
The parachute trial has been invoked to decry randomized trials of total joint replacement as senseless. After all, joint replacements are
among the most significant advances of the 20th century; don’t we already know they are suc –
cessful?
Nearly 1 million elective total knee and hip
replacements are performed annually in the United States; rates of total knee replacement tripled in the past 20 years and are projected to increase further.
2,3 M o r e t h a n 9 0 % o f t o t a l
knee replacements are performed for knee osteo –
arthritis, which affects approximately 14% of adults in the United States in their lifetimes.
4
Prior to the introduction of total knee replace –
ment in the 1970s, patients with advanced knee osteoarthritis frequently became housebound; now such patients can remain mobile. By all accounts, total knee replacement is a game changer. So why subject it to a randomized, con –
trolled trial?
First, total knee replacement poses risks. About
0.5 to 1% of patients die during the 90-day post –
operative period. The risks of deep venous thrombosis, pulmonary embolus, deep prosthetic infection, and periprosthetic fracture range from 0.1 to 1.0%,
5-7 w i t h h i g h e r r i s k s a m o n g o l d e r
persons and those with a higher number of co –
existing conditions.5,7 Second, the procedure is
not universally successful; approximately 20% of patients who undergo total knee replacement have residual pain 6 or more months after the procedure.
8 Third, there are alternatives. Clinical
trials have shown that physical therapy (includ –
ing exercises and manual therapies) can diminish pain and improve functional status in patients with advanced knee osteoarthritis.
9-11 Until now,
we have lacked rigorously controlled compar –
isons between total knee replacement and its alternatives.
Finally, an ideal treatment for one patient
may not be right for the next. Patients with knee osteoarthritis differ in the importance they at –
tach to pain relief, functional improvement, and risk of complications. Therefore, treatment deci –
sions should be shared between patients and their clinicians and anchored by the probabilities of pain relief and complications and the impor –
tance patients attach to these outcomes.
These considerations set the stage for the
carefully designed and executed trial by Skou et al., whose results are reported in this issue of the Journal .
12 I n t h i s r a n d o m i z e d , c o n t r o l l e d t r i a l ,
involving 100 patients with symptomatic knee osteoarthritis, patients were assigned to under –
go total knee replacement followed by a rigorous 12-week nonsurgical-treatment regimen (total-knee-replacement group) or to receive only the nonsurgical treatment (nonsurgical-treatment group), which consisted of supervised exercise, education, dietary advice, use of insoles, and pain medication. Total knee replacement proved markedly superior to nonsurgical treatment alone in terms of pain relief and functional improve –
ment. The percentage of patients who had an improvement of at least 15% (a clinically impor –
tant difference) in the score for pain after 1 year was 85% in the total-knee-replacement group and 68% in the nonsurgical-treatment group. In
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Back to Table of Contents24 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;17 nejm.org October 22, 2015 1669fact, 26% of patients in the nonsurgical-treatment
group elected to undergo total knee replacement
before the 12-month follow-up, and more patients are likely to cross over as follow-up extends further.
However, it is noteworthy that more than two
thirds of the patients in the nonsurgical-treat –
ment group had clinically meaningful improve –
ments in the pain score and that this group had a lower risk of complications. In the total-knee-replacement group, several severe adverse events occurred, including three episodes of deep ve –
nous thrombosis, one deep infection, one supra –
condylar fracture, and three episodes of stiffness requiring manipulation of the knee while the patient was anesthetized. The nonsurgical-treat –
ment group had one episode of stiffness requir –
ing manipulation of the knee while the patient was anesthetized and none of the other compli –
cations. In short, although total knee replace –
ment was clearly superior in terms of pain relief, these findings suggest that the decision for treatment with total knee replacement is no parachute at all. Patients face choices that are associated with different levels of symptomatic improvement and risk: as compared with non –
surgical treatment, total knee replacement is associated with a higher level of improvement and a higher risk of adverse events. Each patient must weigh these considerations and make the decision that best suits his or her values.
As with all good studies, this randomized,
controlled trial answers some questions and raises others. Sham-controlled trials have sug –
gested that both surgical therapy and physical therapy can have a potent placebo effect.
13,14 In
the absence of an untreated control group, some of the improvement that was seen in both groups may be attributable to placebo effects. Also, we do not know whether the benefit of non –
surgical treatment will be sustained over time. Finally, the study by Skou et al. was too small to examine the efficacy of total knee replacement in relevant subgroups, such as patients with mild baseline pain and dysfunction.
The trial by Skou et al. provides the first rigor –
ously controlled data to inform discussions be –
tween patients and their physicians about wheth –
er to undergo total knee replacement or rigorous nonsurgical therapy. For most patients, the dra –
matic pain relief associated with total knee re -placement provides a compelling rationale to
choose surgery. Other patients, particularly those who are more risk-averse, may prefer nonsurgi –
cal care. Since patients vary considerably in their preferences, physicians should present the rele –
vant data to their patients and then listen care –
fully.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Departments of Medicine and Orthopedic Surgery,
Brigham and Women’s Hospital and Harvard Medical School, Boston.
This article was updated on October 22, 2015, at NEJM.org.
1. Smith GCS, Pell JP. Parachute use to prevent death and major
trauma related to gravitational challenge: systematic review of
randomised controlled trials. BMJ 2003; 327: 1459-61.
2. Agency for Healthcare Research and Quality. Healthcare
Cost and Utilization Project database. 2012 (http://hcupnet .ahrq
.gov/ HCUPnet .jsp.)
3. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of
primary and revision hip and knee arthroplasty in the United
States from 2005 to 2030. J Bone Joint Surg Am 2007; 89: 780-5.
4. Losina E, Weinstein AM, Reichmann WM, et al. Lifetime
risk and age at diagnosis of symptomatic knee osteoarthritis in
the US. Arthritis Care Res (Hoboken) 2013; 65: 703-11.
5. Kennedy JW, Johnston L, Cochrane L, Boscainos PJ. Total
knee arthroplasty in the elderly: does age affect pain, function
or complications? Clin Orthop Relat Res 2013; 471: 1964-9.
6. Mahomed NN, Barrett JA, Katz JN, et al. Rates and outcomes
of primary and revision total hip replacement in the United
States medicare population. J Bone Joint Surg Am 2003; 85-A:
27-32.
7. SooHoo NF, Lieberman JR, Ko CY, Zingmond DS. Factors
predicting complication rates following total knee replacement.
J Bone Joint Surg Am 2006; 88: 480-5.
8. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P.
What proportion of patients report long-term pain after total
hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2012;
2(1): e000435.
9. Jansen MJ, Viechtbauer W, Lenssen AF, Hendriks EJ, de Bie
RA. Strength training alone, exercise therapy alone, and exercise
therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic re –
view. J Physiother 2011; 57: 11-20.
10. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI
guidelines for the non-surgical management of knee osteoar –
thritis. Osteoarthritis Cartilage 2014; 22: 363-88.
11. Skou ST, Roos EM, Simonsen O, et al. The efficacy of non-
surgical treatment on pain and sensitization in patients with
knee osteoarthritis: a pre-defined ancillary analysis from a ran –
domized controlled trial. Osteoarthritis Cartilage (in press).
12. Skou ST, Roos EM, Laursen MB, et al. A randomized, con –
trolled trial of total knee replacement. N Engl J Med 2015; 373:
1597-606.
13. Bennell KL, Egerton T, Martin J, et al. Effect of physical
therapy on pain and function in patients with hip osteoarthritis:
a randomized clinical trial. JAMA 2014; 311: 1987-97.
14. Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic
partial meniscectomy versus sham surgery for a degenerative
meniscal tear. N Engl J Med 2013; 369: 2515-24.
DOI: 10.1056/NEJMe1510312
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Back to Table of Contents25 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;21 nejm.org November 19, 2015 2005established in 1812 November 19, 2015 vol. 373 no. 21
The authors’ full names, academic degrees,
and affiliations are listed in the Appendix. Address reprint requests to Dr. Sparano at the Department of Oncology, Monte –
fiore Medical Center, 1695 Eastchester Rd., Bronx, NY 10461, or at jsparano@
montefiore . org.
This article was published on September 28,
2015, at NEJM.org.
N Engl J Med 2015;373:2005-14.
DOI: 10.1056/NEJMoa1510764
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
Prior studies with the use of a prospective–retrospective design including archival tumor
samples have shown that gene-expression assays provide clinically useful prognostic infor –
mation. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.
METHODS
We performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guide –
lines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was per –
formed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicat –
ing a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).
RESULTS
Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).
CONCLUSIONS
Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemo –
therapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine thera –
py alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)abstractProspective Validation of a 21-Gene Expression Assay
in Breast Cancer
J.A. Sparano, R.J. Gray, D.F. Makower, K.I. Pritchard, K.S. Albain, D.F. Hayes, C.E. Geyer, Jr., E.C. Dees, E.A. Perez,
J.A. Olson, Jr., J.A. Zujewski, T. Lively, S.S. Badve, T.J. Saphner, L.I. Wagner, T.J. Whelan, M.J. Ellis, S. Paik,
W.C. Wood, P. Ravdin, M.M. Keane, H.L. Gomez Moreno, P.S. Reddy, T.F. Goggins, I.A. Mayer, A.M. Brufsky,
D.L. Toppmeyer, V.G. Kaklamani, J.N. Atkins, J.L. Berenberg, and G.W. Sledge
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EditorialsThe new england journal of medicine
n engl j med 373;21 nejm.org November 19, 2015 2079Biology before Anatomy in Early Breast Cancer — Precisely the
Point
Clifford A. Hudis, M.D.
Building on a foundation of clinical and labora –
tory observations, translational research, broad
collaborations, and global education, adjuvant therapy for early-stage breast cancer has been an effective public health intervention. Standardiza –
tion and even a one-size-fits-all philosophy were supported by individual trials and the worldwide overviews that showed proportional reductions in risk with chemotherapy in particular. Because higher risk, identified anatomically on the basis of tumor size or the presence of ipsilateral axil –
lary nodal metastases, was associated with great –
er absolute therapeutic benefit, many clinical groups set risk thresholds, defined as a tumor size of 1 cm in the greatest dimension or any involved nodes, to guide chemotherapy use.
1
However, we also began to recognize that we
could take a different approach with both older (endocrine) and newer (anti–human epidermal growth factor receptor type 2 [HER2]) targeted treatments. Here we could be more biologically selective by using markers — which can be favor –
able or unfavorable prognostic factors — pri –
marily for their predictive usefulness.
2 Predictive
biomarkers can identify tumors that are more likely to respond to specific targeted treatments, and they allow us to avoid ineffective options. The inability to select similarly for or against chemotherapy use, coupled with the toxic effects, costs, and inconvenience of chemotherapy, has been a growing source of concern.
The initial publication in the Journal regard –
ing the 21-gene assay (Oncotype Dx, Genomic Health) described its prognostic performance but did not establish clinical usefulness.
3 The
world did not (and still does not) need yet an -other prognostic factor. Clinical usefulness was suggested later when this test was shown to be possibly predictive for chemotherapy benefit. The evidence came from two retrospective subgroup analyses of two different prospective, random –
ized clinical trials that tested combination chemo –
therapy added to standard endocrine treatment.
4,5
One study enrolled patients with node-negative disease, and the other enrolled patients with node-positive disease. All the patients received tamoxifen, and in both trials the patients with higher-score tumors (score of ≥31, on a scale from 0 to 100, with higher scores indicating a greater risk of recurrence) benefited from the addition of chemotherapy, whereas those with a score of less than 18 did not.
The limited validation provided by these ret –
rospective subgroup analyses across traditional risk strata (including node-negative and node-positive disease) distinguished this prognostic and would-be predictive test from many others in development that might be equally or even more useful. Prospective trials were then launched to refine our understanding of the clinical useful –
ness of the assay. The first results from any of these trials, limited to a key subgroup, are now reported in the Journal .
6 These results cannot
come soon enough, given the already widespread adoption of the test as a key component of guidelines and routine clinical decision making.
7-9
As described by Sparano et al., an arbitrary
and purposefully conservative decision was made in the first of these trials to limit any potential harms of omitting chemotherapy. This goal was accomplished by setting new, lower thresholds for risk-group assignment. Thus, we are con –
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nejm.org The new england journal of medicine
n engl j med 373;21 nejm.org November 19, 2015 2080fronted by a newly defined low-risk group of
patients with a score of 10 or less (instead of <18). As reported, the study included 1626 endo –
crine-treated patients with hormone-receptor–positive, HER2-negative, node-negative tumors that measured a median of 1.5 cm in the great –
est dimension. A very low event rate was seen, with a rate of freedom from recurrence of breast cancer at a distant site of 99.3% at 5 years. This result is numerically good enough to exclude any potentially meaningful benefit for additional chemotherapy.
For those seeking confirmation that this as –
say can identify a cohort of patients who should be spared chemotherapy, this result is both re –
assuring and frustrating. For patients in this new “lower risk” group, it is clearly helpful, if broadly anticipated. However, for the many phy –
sicians already using the test, the gap between this cutoff point of 10 and the higher “standard” cutoff point of 18 may be a concern. Some oth –
ers will wonder whether chemotherapy is benefi –
cial or indicated even in patients with scores up to 25. If chemotherapy is effective in this newly defined intermediate-risk group (score, 11 to 25), then examination of the subgroup of patients with scores of 11 to 17 will be critical, since there will be two conflicting guides to their treatment that need to be reconciled: the cutoff point used in this trial and the previously avail –
able cutoff point that is associated with the com –
mercial test.
This multigene assay is unlikely to be the
only test that can provide a prediction of chemo –
therapy benefit. A less expensive and broadly distributed test would be valuable globally. For now, however, this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive tests to select patients who should not receive chemo –
therapy. In that regard, it is one more step toward precision. There are more steps ahead.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Memorial Sloan Kettering Cancer Center and Weill
Cornell Medical College — both in New York.
This article was published on September 28, 2015, at NEJM.org.
1. Peto R, Davies C, Godwin J, et al. Comparisons between dif –
ferent polychemotherapy regimens for early breast cancer: meta-
analyses of long-term outcome among 100,000 women in 123
randomised trials. Lancet 2012; 379: 432-44.
2. Ballman KV. Biomarker: predictive or prognostic? J Clin On –
col 2015 September 21 (Epub ahead of print).
3.Paik S, Shak S, Tang G, et al. A multigene assay to predict
recurrence of tamoxifen-treated, node-negative breast cancer.
N Engl J Med 2004; 351: 2817-26.
4. Paik S, Tang G, Shak S, et al. Gene expression and benefit of
chemotherapy in women with node-negative, estrogen receptor-
positive breast cancer. J Clin Oncol 2006; 24: 3726-34.
5. Albain KS, Barlow WE, Shak S, et al. Prognostic and predic –
tive value of the 21-gene recurrence score assay in postmeno –
pausal women with node-positive, oestrogen-receptor-positive
breast cancer on chemotherapy: a retrospective analysis of a
randomised trial. Lancet Oncol 2010; 11: 55-65.
6.Sparano JA, Gray RJ, Makower DF, et al. Prospective valida –
tion of a 21-gene expression assay in breast cancer. N Engl J Med
2015; 373:2005-14.
7.Nguyen MT, Stessin A, Nagar H, et al. Impact of Oncotype
DX recurrence score in the management of breast cancer cases.
Clin Breast Cancer 2014; 14: 182-90.
8.Gradishar WJ, Anderson BO, Balassanian R, et al. Breast
cancer version 2.2015. J Natl Compr Canc Netw 2015; 13: 448-75.
9.Harris L, Fritsche H, Mennel R, et al. American Society of
Clinical Oncology 2007 update of recommendations for the use
of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287-
312.
DOI: 10.1056/NEJMe1512092
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The New England Journal of Medicine
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Back to Table of Contents28 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;22 nejm.org November 26, 2015 2103established in 1812 November 26, 2015 vol. 373 no. 22
The members of the writing committee
(Jackson T. Wright, Jr., M.D., Ph.D., Jeff D. Williamson, M.D., M.H.S., Paul K. Whelton, M.D., Joni K. Snyder, R.N., B.S.N., M.A., Kaycee M. Sink, M.D., M.A.S., Michael V. Rocco, M.D., M.S.C.E., David M. Reboussin, Ph.D., Mahboob Rahman, M.D., Suzanne Oparil, M.D., Cora E. Lewis, M.D., M.S.P.H., Paul L. Kimmel, M.D., Karen C. Johnson, M.D., M.P.H., David C. Goff, Jr., M.D., Ph.D., Lawrence J. Fine, M.D., Dr.P.H., Jeffrey A. Cutler, M.D., M.P.H., William C. Cush ­
man, M.D., Alfred K. Cheung, M.D., and Walter T. Ambrosius, Ph.D.) assume re ­
sponsibility for the overall content and integrity of the article. The affiliations of the members of the writing group are listed in the Appendix. Address reprint requests to Dr. Wright at the Division of Nephrology and Hypertension, Univer­sity Hospitals Case Medical Center, Case Western Reserve University, 1100 Euclid Ave. Cleveland, OH 44106 ­6053, or at
jackson . wright@ case . edu.
* A complete list of the members of the
Systolic Blood Pressure Intervention Trial (SPRINT) Research Group is pro ­
vided in the Supplementary Appendix, available at NEJM.org.
This article was published on November 9, 2015, at NEJM.org.
N Engl J Med 2015;373:2103-16.
DOI: 10.1056/NEJMoa1511939
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
The most appropriate targets for systolic blood pressure to reduce cardiovascular
morbidity and mortality among persons without diabetes remain uncertain.
METHODS
We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.
RESULTS
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The interven –
tion was stopped early after a median follow-up of 3.26 years owing to a signifi –
cantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of seri –
ous adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.
CONCLUSIONS
Among patients at high risk for cardiovascular events but without diabetes, target –
ing a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.)abstractA Randomized Trial of Intensive versus
Standard Blood-Pressure Control
The SPRINT Research Group*
The New England Journal of Medicine
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nejm.org
EditorialsThe new england journal of medicine
n engl j med 373;22 nejm.org November 26, 2015 2174A SPRINT to the Finish
Jeffrey M. Drazen, M.D., Stephen Morrissey, Ph.D., Edward W. Campion, M.D.,
and John A. Jarcho, M.D.
When investigators enroll patients in a clinical
study, they make an implicit contract with each participant. Through the data and safety moni –
toring board (DSMB) mechanism, they fulfill the first part of the contract — protecting the participant from avoidable harm that might re –
sult from participation in the trial. They fulfill the second part of the contract — the commit –
ment to honor the time at risk that the partici –
pant spent in the trial — by deriving the clearest and most clinically directive information possi –
ble from the data gathered during the trial. This task takes tremendous time and energy.
The SPRINT (Systolic Blood Pressure Interven –
tion Trial) investigators now report in the Journal
the results of a National Institutes of Health (NIH)–sponsored trial studying the impact on major cardiovascular events of a lower systolic blood-pressure target in adults with hyperten –
sion.
1 To the surprise of many, the trial was
stopped on September 11, 2015, years earlier than planned. The leadership of the National Heart, Lung, and Blood Institute (NHLBI) stopped the trial on the recommendation of the DSMB, which had identified a survival benefit in patients assigned to the lower blood-pressure target.
When the study was stopped, the NIH im –
mediately notified the participants that those in the low-target group had done better than those in the usual-care control group; the public was also notified, although a full report of the study was not yet available. The investigators, who were also taken by surprise, then hunkered down to the serious business of understanding the available data, knowing that the data set they had would change, since close-out visits are still ongoing.
Although unraveling the clinical messages
buried in a data set may sound like a simple task, it is not. Rarely does a trial’s clinically im –
portant message jump out fully formed. Instead, the process requires detailed analyses that weigh the risks and benefits of the study intervention as translated into a clinical care setting.
The trial investigators are uniquely qualified
to analyze the data, and their only agenda is a meticulous, fair, and informative reporting of the study results. Not only are they the ones who delineated the end points, crafted the inclusion and exclusion criteria, and collected the data, they are also the ones who best understand the adverse events. The process requires a deep knowledge of the study design and, most of all, time for scrupulous analysis and thoughtful re –
flection. Even in this rapid-fire information age, there is no substitute for serious thought, and that takes time.
We were therefore surprised by the call from
Topol and Krumholz for immediately “placing the data on the NIH website.”
2 We believe that it
is critical to give the investigators, on behalf of the study participants, who invested years of
their lives in the study, the opportunity to see what led the sponsor to stop the trial and then the opportunity to distill a clinical message from it. There are cogent reasons to follow this approach rather than put trial data in the public domain before those who gathered the data have had a chance to analyze it.
Although no one denies the importance of
treating hypertension, the clinical message from

Back to Table of Contents30 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;22 nejm.org November 26, 2015 2175SPRINT is a matter of public health urgency and
not an emergency. The subtleties of the clinical message need to be teased from the data. To put the issue in perspective, the investigators took about 8 weeks to prepare their study for publica-tion; they had previously spent over 250 weeks conducting the trial and perhaps another 50 to 100 weeks getting the trial ready to enroll pa –
tients at all. Through their perseverance and hard work, the data were accrued and an impor –
tant clinical question has been addressed. The investigators have spent the past 5 years think –
ing about and working on the study question, and they are the ones best qualified to under –
take the first interpretation of the data. Once their interpretation is in the public domain, scientific discourse on the strengths and weak –
nesses of the trial design, the gathered data, and the clinical directions should follow.
The manuscript reporting on SPRINT arrived
in our office 4 weeks after the trial was stopped. That manuscript was reviewed rapidly by multi –
ple outside peer reviewers, a statistical consul –
tant, and several editors. Their critiques and queries led to two rounds of substantial revision. After expedited editing of the manuscript and preparation of the figures, the report has been published to coincide with the investigators’ presentation at the meeting of the American Heart Association. Together with this important report, Journal readers have a pair of expert com -mentaries in an editorial and a Perspective arti –
cle. There is also a short Quick Take video sum –
mary of the article and a Clinical Decisions article in which readers can participate in a poll and comment on the key questions and clinical concerns raised by SPRINT.
This clinical trial will change practice, and
we are proud to publish it and to defend the importance of the expedited peer-review and publication process that it has undergone. The report is now in the public domain, and the in –
vestigators’ data interpretation, analysis, and clinical discussion are open to examination and comment. We understand that in the months ahead the underlying data from this taxpayer-funded trial will be put in the public domain by the NHLBI. We agree with the importance of making those data open and available to others. But with the article now published, physicians and the public have a detailed, critical, peer-reviewed report from the investigators who conducted the study and know it best.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
This article was published on November 9, 2015, at NEJM.org.
1. The SPRINT Research Group. A randomized trial of inten –
sive versus standard blood-pressure control. N Engl J Med 2015;
373:2103-16.
2. Topol EJ, Krumholz HM. Don’t sit on medical breakthroughs.
New York Times. September 18, 2015: A29.
DOI: 10.1056/NEJMe1513991
Copyright © 2015 Massachusetts Medical Society.

Back to Table of Contents31 Notable Articles of 2015
nejm.org
EditorialsThe new england journal of medicine
n engl j med 373;22 nejm.org November 26, 2015 2174Redefining Blood-Pressure Targets — SPRINT Starts
the Marathon
Vlado Perkovic, M.B., B.S., Ph.D., and Anthony Rodgers, M.B., Ch.B., Ph.D.
Blood pressure is a potent determinant of car –
diovascular risk, but the most appropriate tar –
gets for blood-pressure lowering have long been
debated. Observational studies with a low risk of confounding have shown a linear relationship between blood pressure and cardiovascular risk down to 115/75 mm Hg,
1 but some observa –
tional studies with a greater potential for con –
founding, involving persons at increased risk, have suggested a J-shaped curve — that is, below a given blood pressure, risk would increase. When trials of blood-pressure–lowering drugs have shown benefits in patients without hyper –
tension, these effects have often been ascribed to alternative mechanisms. The widespread un –
certainty about blood-pressure targets was in –
creased when the Action to Control Cardiovascu –
lar Risk in Diabetes (ACCORD) trial showed no significant overall difference in cardiovascular events between patients with type 2 diabetes as –
signed to a systolic blood-pressure target of less than 120 mm Hg and those assigned to a target of less than 140 mm Hg.
2
The eagerly awaited results of the Systolic
Blood Pressure Intervention Trial (SPRINT), now reported in the Journal ,
3 are certain to have far-
reaching implications. SPRINT randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardio –
vascular risk to a target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). People with difficult-to-control blood pressure were excluded and will require separate study. The mean blood pressure at baseline was 139.7/78.2 mm Hg in the intensive-treatment group and 139.7/78.0 mm Hg in the standard-treatment group, and the mean pressure at 1 year was 121.4/68.7 mm Hg and 136.2/76.3 mm Hg in the respective groups. Dur –
ing follow-up, the average difference in systolic pressure was 13.1 mm Hg, and the mean num –
ber of blood-pressure medications was 2.8 in the intensive-treatment group and 1.8 in the standard-treatment group.
The trial was stopped early, after a median
follow-up of 3.26 years. Overall, participants as –
signed to the intensive-treatment group, as com –
pared with those assigned to the standard-treatment group, had a 25% lower relative risk of major cardiovascular events (95% confidence interval [CI], 11 to 36), with consistent results across subgroups defined according to age, sex, race, medical history, and baseline blood pres –
sure. In addition, the intensive-treatment group had a 27% lower relative risk of death from any cause (95% CI, 10 to 40). Rates of some serious adverse events, including hypotension and acute kidney injury or failure, were higher in the inten –
sive-treatment group than in the standard-treat –
ment group, but these higher rates appear un –
likely to outweigh the benefits overall.
Are the results reliable? Small trials can over –
estimate benefits when stopped early,
4 but this is
unlikely for SPRINT, which had more than 500 primary outcome events. Lack of blinding is in –
evitable in trials involving blood-pressure targets,

Back to Table of Contents32 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;22 nejm.org November 26, 2015 2175but this was mitigated by structured assessment
of outcomes and adverse events. Some findings require further elucidation and follow-up, partic –
ularly the renal outcomes. The lack of effect on injurious falls will surprise many but is consis –
tent with the finding of the largest trial involving the elderly.
5
Are the results of SPRINT different from
those of the ACCORD trial? As shown in Fig. 1,
the effects on individual outcomes in SPRINT and the ACCORD trial are generally consistent. The main differences were that the ACCORD trial had less statistical power than SPRINT, and its primary outcome included a higher propor –
tion of events that are less sensitive to blood-pressure reduction. Previous trials have also shown similar-sized benefits in persons with dia –
betes and those without diabetes.
6 More broadly,
labeling trials as “positive” or “negative” is se –
ductive but ultimately counterproductive; it is more helpful to look at the totality of available data. Several previous large trials of blood-pressure lowering
7,8 included participants at high cardio –
vascular risk, about half of whom had a baseline systolic blood pressure below 140 mm Hg. These trials also showed benefits for people with a pressure of at least 140 mm Hg and those with a pressure below 140 mm Hg. The benefits seen in SPRINT are also consistent with those seen in previous trials of more intensive versus less in –
tensive blood-pressure control
9 and, more broad –
ly, in previous trials in which differences in blood pressure were achieved between groups.
1
SPRINT provides another cautionary reminder
about using data from nonrandomized trials or biologic plausibility to assess efficacy and safety. We are reminded that real-world data, such as J-curve associations, can be really wrong. Ran –
domized trials are required to reliably assess treatment effects. SPRINT also brings into focus approaches to synthesizing trial evidence for guidelines. The Eighth Joint National Committee took a targeted approach to consideration of previous trials and concluded that systolic blood-pressure targets should be below 140 mm Hg, or below 150 mm Hg in those 60 years of age or older. More inclusive trial reviews have indicated benefits of blood-pressure lowering in persons at high cardiovascular risk without hypertension.
1
Current guidelines and guideline processes re –
quire revision.Clearly, our current concept of hypertension
is insufficient to determine who benefits from blood-pressure lowering or how far to lower blood pressure.
10 SPRINT strongly supports pharmaco –
therapy decisions based on absolute risk levels, in a similar way to current recommendations for lipid lowering. For people at high cardiovascular risk, a systolic goal of less than 120 mm Hg is appropriate. Substantial effort and resources are required: initial combination therapy was the norm in SPRINT, with monthly visits until blood pressure was at the target level. Even with inten –
sive lifestyle modification and medical therapy, blood pressure will remain above target in many patients, which suggests the need for popula –
tion-level initiatives (e.g., reduced sodium con –
tent in food), new therapies, and multifactorial intervention. In SPRINT, less than half the pa –
tients were taking statins, 13% were still smok –
ing, and most were overweight or obese.
SPRINT redefines blood-pressure target goals
and challenges us to improve blood-pressure management. Success will require a marathon effort.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the George Institute for Global Health, University of Syd –
ney, Sydney.This article was published on November 9, 2015, at NEJM.org.
1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering
drugs in the prevention of cardiovascular disease: meta-analysis
of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665.
2. Cushman WC, Evans GW, Byington RP, et al. Effects of
intensive blood-pressure control in type 2 diabetes mellitus.
N Engl J Med 2010; 362: 1575-85.
3. The SPRINT Research Group. A randomized trial of inten –
sive versus standard blood-pressure control. N Engl J Med
2015;373:2103-16.
4. Bassler D, Briel M, Montori VM, et al. Stopping randomized
trials early for benefit and estimation of treatment effects: sys –
tematic review and meta-regression analysis. JAMA 2010; 303:
1180-7.
5. Peters R, Beckett N, Burch L, et al. The effect of treatment
based on a diuretic (indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age Ageing 2010; 39: 609-16.
6. Turnbull F, Neal B, Algert C, et al. Effects of different blood
pressure-lowering regimens on major cardiovascular events in
individuals with and without diabetes mellitus: results of pro –
spectively designed overviews of randomized trials. Arch Intern Med 2005; 165: 1410-9.
7. Brugts JJ, Ninomiya T, Boersma E, et al. The consistency of
the treatment effect of an ACE-inhibitor based treatment regi –
men in patients with vascular disease or high risk of vascular
disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J 2009; 30: 1385-94.

Back to Table of Contents33 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 373;22 nejm.org November 26, 2015 21768. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J.
Blood-pressure reduction and cardiovascular risk in HOPE
study. Lancet 2001; 358: 2130-1.
9. Lv JC, Neal B, Ehteshami P, et al. Effects of intensive blood
pressure lowering on cardiovascular and renal outcomes: a sys –
t emat ic re v ie w a nd met a-a na lysis. PL oS Med 2012; 9(8): e1001293.10. MacMahon S, Neal B, Rodgers A. Hypertension — time to
move on. Lancet 2005; 365: 1108-9.
DOI: 10.1056/NEJMe1513301
Copyright © 2015 Massachusetts Medical Society.

Back to Table of Contents34 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;23 nejm.org December 3, 2015 2203established in 1812 December 3, 2015 vol. 373 no. 23
The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr. Nichol at Box 359727, 325 Ninth Ave., Seattle, WA 98104, or at nichol@ uw . edu.
* A complete list of the Resuscitation
Outcomes Consortium (ROC) Investiga –
tors is provided in the Supplementary Appendix, available at NEJM.org.
This article was published on November 9, 2015, at NEJM.org.
N Engl J Med 2015;373:2203-14.
DOI: 10.1056/NEJMoa1509139
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
During cardiopulmonary resuscitation (CPR) in patients with out-of-hospital cardiac ar –
rest, the interruption of manual chest compressions for rescue breathing reduces blood
flow and possibly survival. We assessed whether outcomes after continuous compres –
sions with positive-pressure ventilation differed from those after compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations.
METHODS
This cluster-randomized trial with crossover included 114 emergency medical service (EMS) agencies. Adults with non–trauma-related cardiac arrest who were treated by EMS providers received continuous chest compressions (intervention group) or interrupted chest com –
pressions (control group). The primary outcome was the rate of survival to hospital dis –
charge. Secondary outcomes included the modified Rankin scale score (on a scale from 0 to 6, with a score of ≤3 indicating favorable neurologic function). CPR process was measured to assess compliance.
RESULTS
Of 23,711 patients included in the primary analysis, 12,653 were assigned to the interven –
tion group and 11,058 to the control group. A total of 1129 of 12,613 patients with available data (9.0%) in the intervention group and 1072 of 11,035 with available data (9.7%) in the control group survived until discharge (difference, −0.7 percentage points; 95% confidence interval [CI], −1.5 to 0.1; P = 0.07); 7.0% of the patients in the intervention group and 7.7%
of those in the control group survived with favorable neurologic function at discharge (dif –
ference, −0.6 percentage points; 95% CI, −1.4 to 0.1, P = 0.09). Hospital-free survival was
significantly shorter in the intervention group than in the control group (mean difference, −0.2 days; 95% CI, −0.3 to −0.1; P = 0.004).
CONCLUSIONS
In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions. (Funded by the National Heart, Lung, and Blood Institute and others; ROC CCC ClinicalTrials.gov number, NCT01372748.)abstractTrial of Continuous or Interrupted Chest Compressions
during CPR
Graham Nichol, M.D., M.P.H., Brian Leroux, Ph.D., Henry Wang, M.D., Clifton W. Callaway, M.D., Ph.D.,
George Sopko, M.D., Myron Weisfeldt, M.D., Ian Stiell, M.D., Laurie J. Morrison, M.D., Tom P. Aufderheide, M.D.,
Sheldon Cheskes, M.D., Jim Christenson, M.D., Peter Kudenchuk, M.D., Christian Vaillancourt, M.D.,
Thomas D. Rea, M.D., Ahamed H. Idris, M.D., Riccardo Colella, D.O., M.P.H., Marshal Isaacs, M.D., Ron Straight,
Shannon Stephens, Joe Richardson, Joe Condle, Robert H. Schmicker, M.S., Debra Egan, M.P.H., B.S.N.,
Susanne May, Ph.D., and Joseph P. Ornato, M.D., for the ROC Investigators*
The New England Journal of Medicine
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Copyright © 2015 Massachusetts Medical Society. All rights reserved. ORIGINAL ARTICLE
Read Full Article at NEJM.org

Back to Table of Contents35 Notable Articles of 2015
nejm.org
EditorialsThe new england journal of medicine
n engl j med 373;23 nejm.org December 3, 2015 2278Continuous or Interrupted Chest Compressions
for Cardiac Arrest
Rudolph W. Koster, M.D., Ph.D.
High-quality cardiopulmonary resuscitation (CPR)
is identified as a critical but often poorly per –
formed component of the rescue efforts for pa –
tients in cardiac arrest. Chest compressions have often been too shallow, and compression rates too low or too high. Prolonged interruptions of chest compressions have been observed during resuscitation both in the hospital and outside the hospital.
1,2 All prolonged pauses (not only
those for defibrillation) are associated with worse survival.
3 Interruptions of chest compres –
sions cause a rapid decline in coronary perfusion pressure, reducing myocardial blood f low, which has previously been shown with shorter inter –
ruptions for rescue breathing.
4 Experiments in
animals have suggested that the rate of survival may increase if CPR is performed with continu –
ous chest compressions, not interrupted for ventilations. Retrospective cohort studies have seemed to confirm this concept. A prospective statewide observational study in Arizona showed that training the population in continuous chest compressions until the arrival of emergency medical services (EMS) increased the rate of bystander-initiated CPR and increased the rate of survival to discharge from the hospital.
5
Randomized studies involving patients with
cardiac arrest are difficult and require consider –
able resources that are often not available. In the EMS setting, the concept of continuous chest compressions has been introduced and its po –
tential benefit has been studied in observational studies with historical controls. In the largest of these studies, several measures were introduced simultaneously as a “bundle of care.” In addition to three periods of 200 chest compressions each, which were interrupted only for rhythm analysis and defibrillation, this bundle of care included a single-shock scenario (three stacked shocks were allowed previously), no delay of chest compres –
sions for rhythm or pulse checks, deferred inser –
tion of an advanced-airway device, and passive oxygen insufflation replacing positive-pressure ventilation until 6 minutes had passed during which the three periods of 200 chest compres –
sions were delivered. The introduction of this bundle of care resulted in a significant increase in the rate of survival to discharge, from 1.8% to 5.4%; among patients with witnessed arrest and ventricular fibrillation, the rate increased from 4.7% to 17.6%.
6 On the basis of this study
and similar studies, the 2015 American Heart Association (AHA) guidelines for resuscitation included a new class IIb recommendation that it may be reasonable for EMS to initiate resuscita –
tion with three initial periods of 200 continuous chest compressions with passive oxygen insuf –
flation.
7 This recommendation was not made in
the concurrent 2015 guidelines for resuscitation from the European Resuscitation Council (ERC).
8
Bundles of care are a pragmatic way to intro –
duce and study new treatments. But if studies show higher rates of survival with the new tech –
niques, it is not clear which components of the bundle contributed to the improved survival. The results of a new randomized clinical trial from the Resuscitation Outcomes Consortium (ROC) have now been published in the Journal .
9 This
trial was designed as a cluster-randomized study of non–trauma-related cardiac arrest treated by
The New England Journal of Medicine
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Back to Table of Contents36 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;23 nejm.org December 3, 2015 2279EMS providers. Patients received either contin –
uous chest compressions or the standard ap –
proach of chest compressions that were inter –
rupted for positive-pressure ventilation in a ratio
of 30 compressions to two ventilations (termed “interrupted chest compressions”). In the group that received continuous chest compressions, asynchronous positive-pressure ventilations were given with a recommended rate of 10 ventila –
tions per minute. The primary outcome of the study was the rate of survival to hospital dis –
charge.
A total of 12,653 patients were included in the
group that received continuous chest compres –
sions (intervention group) and 11,058 in the group that received interrupted chest compres –
sions (control group). The overall rate of survival to hospital discharge was 9.0% in the interven –
tion group and 9.7% in the control group — a nonsignificant difference. Survival with favor –
able neurologic function at discharge, defined as a score of 3 or less on the modified Rankin scale (on which scores range from 0, indicating no symptoms, to 6, indicating death), did not differ significantly between the two groups. A pre –
specified per-protocol analysis that was based on strict adherence to the treatment algorithm showed significantly lower rates of survival among patients in the intervention group than among those in the control group (7.6% vs. 9.6%).
Why did this new large, randomized study
show no benefit from continuous chest com –
pressions, whereas previous observational stud –
ies showed a clear survival benefit among pa –
tients treated with this approach? First, in the bundle-of-care studies, measures other than the continuous chest compressions could be the changes that improved the rate of survival. Sec –
ond, in this study, the mean chest-compression fraction (the proportion of each minute during which compressions were given), which is an important marker of interruptions of chest com –
pressions, was already high (0.77) in the control group and was not much lower than the mean chest-compression fraction of 0.83 in the inter –
vention group. Both values were much higher than the target for chest-compression fraction of more than 0.60 that is recommended in the new AHA and ERC resuscitation guidelines.
7,8 Third, pauses for ventilation may be less critical, and less detrimental for survival, than is currently believed.
10 And of course, the randomized trial is
the best tool to investigate causality.
The new 2015 AHA resuscitation guidelines
were published only recently.7 If the results of
the current ROC study had been available, the guidelines committee might have decided to re –
tain the previous recommendation to give chest compressions interrupted for ventilations and perhaps even to upgrade that recommendation to a class IIa recommendation for EMS provid –
ers. Should the AHA reconsider their recommen –
dation?
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Cardiology, Academic Medical Center,
Amsterdam.
This article was published on November 9, 2015, at NEJM.org.
1. Abella BS, Alvarado JP, Myklebust H, et al. Quality of cardio –
pulmonar y resuscitation during in-hospital cardiac arrest. JAMA
2005; 293: 305-10.
2. Wik L, Kramer-Johansen J, Myklebust H, et al. Quality of
cardiopulmonary resuscitation during out-of-hospital cardiac
arrest. JAMA 2005; 293: 299-304.
3. Brouwer TF, Walker RG, Chapman FW, Koster RW. Associa –
tion between chest compression interruptions and clinical out –
comes of ventricular fibrillation out-of-hospital cardiac arrest.
Circulation 2015; 132: 1030-7.
4. Berg RA, Sanders AB, Kern KB, et al. Adverse hemodynamic
effects of interrupting chest compressions for rescue breathing
during cardiopulmonary resuscitation for ventricular fibrilla –
tion cardiac arrest. Circulation 2001; 104: 2465-70.
5. Bobrow BJ, Spaite DW, Berg RA, et al. Chest compression-
only CPR by lay rescuers and survival from out-of-hospital car-
diac arrest. JAMA 2010; 304: 1447-54.
6. Bobrow BJ, Clark LL, Ewy GA, et al. Minimally interrupted
cardiac resuscitation by emergency medical services for out-of-
hospital cardiac arrest. JAMA 2008; 299: 1158-65.
7. Kleinman ME, Brennan EE, Goldberger ZD, et al. Part 5:
adult basic life support and cardiopulmonary resuscitation qual –
ity: 2015 American Heart Association guidelines update for car –
diopulmonary resuscitation and emergency cardiovascular care.
Circulation 2015; 132: Suppl 2: S414-35.
8. Soar J, Nolan JP, Böttiger BW, et al. European Resuscitation
Council guidelines for resuscitation 2015: section 3. Adult ad –
vanced life support. Resuscitation 2015; 95: 100-47.
9. Nichol G, Leroux B, Wang H, et al. Trial of continuous or
interrupted chest compressions during CPR. N Engl J Med 2015;
373:2203-14.
10. Beesems SG, Wijmans L, Tijssen JG, Koster RW. Duration of
ventilations during cardiopulmonary resuscitation by lay rescu –
ers and first responders: relationship between delivering chest
compressions and outcomes. Circulation 2013; 127: 1585-90.
DOI: 10.1056/NEJMe1513415
Copyright © 2015 Massachusetts Medical Society.
The New England Journal of Medicine
Downloaded from nejm.org by MJ MEDAS on December 11, 2015. For personal use only. No other uses without permission.
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Back to Table of Contents37 Notable Articles of 2015
nejm.org The new england
journal of medicine
n engl j med 373;27 nejm.org December 31, 2015 2599established in 1812 December 31, 2015 vol. 373 no. 27
The authors’ full names, academic de –
grees, and affiliations are listed in the Ap –
pendix. Address reprint requests to Dr.
Feld at Toronto Western Hospital Liver Centre, 399 Bathurst St., 6B Fell Pavilion, Toronto, ON M5T 2S8, Canada, or at jordan . feld@ uhn . ca; or to Dr. Zeuzem at
the Johann Wolfgang Goethe University
Medical Center, Theodor Stern Kai 7, 60590 Frankfurt, Germany, or at zeuzem@ em
. uni-frankfurt . de.
* A complete list of investigators in the
ASTRAL-1 trial is provided in the Supple –
mentary Appendix, available at NEJM.org.
Drs. Feld and Zeuzem contributed equally
to this article.
This article was published on November 16,
2015, at NEJM.org.
N Engl J Med 2015;373:2599-607.
DOI: 10.1056/NEJMoa1512610
Copyright © 2015 Massachusetts Medical Society.BACKGROUND
A simple treatment regimen that is effective in a broad range of patients who are
chronically infected with the hepatitis C virus (HCV) remains an unmet medical need.
METHODS
We conducted a phase 3, double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low preva –
lence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir–velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
RESULTS
Of the 624 patients who received treatment with sofosbuvir–velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% geno –
type 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic re –
sponse among patients receiving sofosbuvir–velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir–velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir–velpatasvir group and none in the placebo group.
CONCLUSIONS
Once-daily sofosbuvir–velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.)abstractSofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5,
and 6 Infection
J.J. Feld, I.M. Jacobson, C. Hézode, T. Asselah, P.J. Ruane, N. Gruener, A. Abergel, A. Mangia, C.-L. Lai,
H.L.Y. Chan, F. Mazzotta, C. Moreno, E. Yoshida, S.D. Shafran, W.J. Towner, T.T. Tran, J. McNally, A. Osinusi,
E. Svarovskaia, Y. Zhu, D.M. Brainard, J.G. McHutchison, K. Agarwal, and S. Zeuzem,
for the ASTRAL-1 Investigators* ORIGINAL ARTICLE
Read Full Article at NEJM.org

Back to Table of Contents38 Notable Articles of 2015
nejm.org
EditorialsThe new england journal of medicine
n engl j med 373;27 nejm.org December 31, 2015 2678Simple, Effective, but Out of Reach? Public Health Implications
of HCV Drugs
John W. Ward, M.D., and Jonathan H. Mermin, M.D., M.P.H.
The results of four clinical trials showing the ex –
cellent safety and efficacy of a 12-week course of
sofosbuvir (an NS5B inhibitor licensed in the United States in 2013) and velpatasvir (a new NS5A inhibitor) in treating patients with hepati –
tis C infection (HCV) are reported now in the Journal .
1-3 In two of these studies, ASTRAL-1 and
ASTRAL-2, 97 to 100% of patients with HCV genotype 1a, 1b, 2, 4, 5, or 6 had a sustained virologic response at 12 weeks after the end of therapy, a marker that is indicative of virologic cure. Similar efficacy was observed among pa –
tients in whom previous treatment had failed and those with compensated cirrhosis, factors that have been associated with a reduced re –
sponse to the treatment of HCV infection.
4
In the ASTRAL-3 study, sofosbuvir–velpatas –
vir was 95% efficacious in achieving a sustained virologic response among patients with geno –
type 3 (the viral strain associated with a reduced treatment response).
4 Efficacy was 89 to 91% for
patients with cirrhosis or previous treatment failure.
In these three studies, sofosbuvir–velpatasvir
was associated with few serious adverse events, high study-completion rates, and rates of sus –
tained virologic response that were superior to those with selected study comparators. In addi –
tion, the data suggest that the pretreatment presence of NS5A resistance-associated variants was not a major factor in treatment outcomes but that more study is needed, particularly in patients with genotype 3.
For HCV-infected patients with decompen –
sated cirrhosis, ASTRAL-4 showed 94% efficacy with the addition of ribavirin, as compared with a sustained virologic response of 83% for the 12-week regimen of sofosbuvir–velpatasvir alone. The proportions of patients with serious adverse events were similar across treatment regimens (16 to 19%). Indicators of liver function im –
proved in nearly half the patients. Together, these studies indicate that this drug regimen can achieve high rates of HCV cure regardless of genotype.
The public health implications of simple, safe,
and curative HCV therapies could be profound. HCV chronically infects 2.7 million to 3.5 million persons in the United States and 130 million to 150 million persons globally,
5,6 causing more
than 700,000 deaths from cirrhosis or primary liver cancer worldwide every year.
6 In the United
States, the rate of new HCV infection has risen by more than 150% in recent years, fueled by increases in injection-drug use.
6 HCV treatment
could dramatically reverse these trends. A cure of HCV infection reduces the risk of liver cancer by 76% and of death from any cause by 50%. Theoretically, such a cure could reduce the force of infection and HCV transmission within a population.
7,8 Given the benefits of safe, simple,
and curative therapy, why are we still concerned about the public’s health with respect to HCV treatment?
Patients do not benefit from a drug they can –
not afford. Although studies by the Centers for Disease Control and Prevention have shown that treating all HCV-infected persons is cost-effec –
tive from a societal perspective,
9 the price of
current medications is a formidable barrier for many. Despite U.S. recommendations that all HCV-infected persons should receive treatment,
10
health plans and payers have responded to the cost of HCV medications ($83,000 to $153,000

Back to Table of Contents39 Notable Articles of 2015
nejm.org Editorials
n engl j med 373;27 nejm.org December 31, 2015 2679per course of treatment) by instituting restrictive
reimbursement policies. In 33 state Medicaid programs, only patients in whom the infection has progressed to severe liver disease qualify for HCV treatment.
11 Drug expenditures for the treat –
ment of HCV infection have declined as a result of mandated 23% rebates for Medicaid and pri –
vately negotiated prices by health plans, but in –
equities in patient access to such therapies persist.
In response, on November 5, 2015, the Cen –
ters for Medicare and Medicaid Services (CMS) notified state programs that limitations on drug coverage should not deny access to clinically ap –
propriate antiviral therapy for beneficiaries with chronic HCV infection. CMS also requested that manufacturers disclose value-based pricing agree –
ments so that states can participate in such arrangements.
6 Globally, a generic version of
sofosbuvir has been licensed for use in 91 low-resource countries.
12 A c c e s s t o t h e s e d r u g s i s
also a challenge in middle-income countries, in which more than 60% of HCV-infected persons reside.
13 Licensure of sofosbuvir–velpatasvir and
other HCV regimens that are now being studied creates opportunities for innovative pricing strategies that increase affordability of new HCV medications and of those already on the market.
Benefits of curative therapy can be realized
only for persons who have been tested and know they are infected with HCV. In the United States, HCV infection remains undiagnosed in at least half of all persons with the disease,
7 and the
proportions are even higher in other countries.14
A combination of testing strategies is recom –
mended to identify persons with ongoing trans –
mission risks (e.g., those who inject drugs) and those who were infected in the distant past who are at highest risk for dying from HCV infection. In the United States, even a modest increase in the capacity to implement HCV testing for all persons who were born from 1945 through 1965 could avert more than 320,000 deaths
9 but
only when testing is linked to care and curative treatment.
The progressive steps in HCV care from viral
detection to HCV cure are poor in the United States and in many other countries.
11,14 Educa –
tion for providers and creation of models for care improve quality.
6,7 Although currently licensed
therapies require that HCV-infected persons un –
dergo genotyping and disease staging before the initiation of treatment, most HCV-infected per –
sons do not receive this level of care. The sofos -buvir–velpatasvir regimen could simplify HCV management by reducing the need for these steps, paving the way for simple “test and cure” strategies appropriate for primary care and other settings, such as addiction-treatment programs.
The availability of simple, safe, and curative
regimens creates opportunities for improving the health of the millions of patients living with HCV infection. At a population level, the effect of HCV medications will be determined by afford –
ability and equitable access to HCV testing, care, and treatment. Only through these improve –
ments can our focus be directed to what matters most: reducing the morbidity and mortality as –
sociated with HCV infection, stopping HCV transmission, and ultimately eliminating HCV as a public health threat in the United States and worldwide.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Centers for Disease Control and Prevention, Atlanta.
This article was published on November 17, 2015, at NEJM.org.
1. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpa –
tasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med
2015;373:2599-607.
2. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and vel –
patasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015;
373:2608-17.
3. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpa –
tasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015;373:2618-28.
4. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and
ribavirin in HCV genot y pes 2 and 3. N Engl J Med 2014; 370: 1993-
2001.
5. World Health Organization. Hepatitis fact sheet no. 164.
April 2014 (http://www .who .int/ mediacentre/ factsheets/ fs164).
6. Centers for Disease Control and Prevention. Viral hepatitis
(http://www .cdc .gov/ hepatitis/ ).
7. Recommendations for the identification of chronic hepatitis C
virus infection among persons born during 1945-1965. MMWR
Recomm Rep 2012; 61(RR-4): 1-32.
8. Martin NK, Vickerman P, Grebely J, et al. Hepatitis C virus
treatment for prevention among people who inject drugs: model –
ing treatment scale-up in the age of direct-acting antivirals.
Hepatology 2013; 58: 1598-609.
9. Rein DB, Wittenborn JS, Smith BD, Liffmann DK, Ward JW.
The cost-effectiveness, health benefits, and financial costs of
new antiviral treatments for hepatitis C virus. Clin Infect Dis 2015; 61: 157-68.
10. American Association for the Study of Liver Diseases, Infec –
tious Diseases Society of America. Recommendations for testing,
managing, and treating hepatitis C (http://www .hcvguidelines
.org).
11. Canary LA, Klevens RM, Holmberg SD. Limited access to
new hepatitis C virus treatment under state Medicaid programs.
Ann Intern Med 2015; 163: 226-8.
12. World Health Organization. Patent situation of key prod –
ucts for treatment of hepatitis C. August 2014 (http://w w w .who
.int/ phi/ implementation/ ip_trade/ sofosbuvir_report_2014_09-02
.pdf ).
13. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H.

Back to Table of Contents40 Notable Articles of 2015
nejm.org The new england journal of medicine
n engl j med 373;27 nejm.org December 31, 2015 2680Global epidemiology and genotype distribution of the hepatitis C
virus infection. J Hepatol 2014; 61: Suppl: S45-S57.
14. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med 2013; 368: 1859-61.
DOI: 10.1056/NEJMe1513245
Copyright © 2015 Massachusetts Medical Society.

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