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NOTABLE��ARTICLESOF�2016�A collection of important studies from the past year as selected by NEJM editors

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December 2016

Dear Reader,

In 2016, the Journal published trials that sought to answer complicated questions. One such study looked at whether men with early prostate cancer should undergo prostatectomy, radiation, or “watchful waiting” to achieve the best outcome at 10 years. This study found that men with low-risk or intermediate-risk prostate cancer had low prostate-cancer–specific mortality after 10 years, irrespective of the treatment assigned. Importantly, these data helped with the conundrum of treating prostate cancer. Since this is a disease of older men, the study balanced the competing issues of aggressive treatment of a redolent disease with the reality that other factors may claim the life of the patient before he suc-cumbs to prostate cancer. It provided solid landmarks for men wrestling with what to do when they were diagnosed with low-intermediate risk prostate cancer.

Another study examined whether inducing labor at 39 weeks in pregnant women 35 years of age or older, compared to expectant management, reduced stillbirth. While the study was underpowered to assess differences in perinatal outcomes, it found no effect between the two groups on the rate of caesarean section. This trial makes an important contribution to our current medical knowledge, and helps build the foundation for larger, forthcoming studies. And even without larger studies, the data presented helped pregnant women and their physicians visualize the risks and benefits of inducing labor.

As the medical information published in NEJM is regularly used in daily practice, we ensure each paper published meets exacting standards for editorial quality, clinical relevance, and impact on patient out-comes. Among all papers published in 2016, this “most notable” collection was selected by the editors as being the most meaningful in improving medical practice and patient care. We hope that you will take valuable insights from these articles as you continue along your path of lifelong learning.

Jeffrey�M.�Drazen,�M.D.Editor-In-Chief, The New England Journal of MedicineDistinguished Parker B. Francis Professor of MedicineHarvard Medical School

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contents

original articleIncidence of Dementia over Three Decades in the Framingham Heart Study ............................................ 1 perspective

Is Dementia in Decline? Historical Trends and Future Trajectories ....................................... 2

original articleEffects of Testosterone Treatment in Older Men .......................................................................................... 5 editorial

Establishing a Framework — Does Testosterone Supplementation Help Older Men? ......... 6

original articleNational Cluster-Randomized Trial of Duty-Hour Flexibility in Surgical Training ....................................... 8 editorial

Surgical Resident Duty-Hour Rules — Weighing the New Evidence ...................................... 9 perspective

Leaping without Looking — Duty Hours, Autonomy,and the Risks of Research and Practice .............................................................................................................................11

original articleRandomized Trial of Labor Induction in Women 35 Years of Age or Older .............................................. 14 editorial

Induction of Labor and Cesarean Delivery ............................................................................. 15

original articlesRandomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis ........................................ 17Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis ................................. 18 editorial

Endarterectomy, Stenting, or Neither for Asymptomatic Carotid-Artery Stenosis ............... 19

original articlesBlood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease ........................ 21Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease .............................. 22Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease ........................... 23 editorial

More HOPE for Prevention with Statins ................................................................................. 24

original articleEfficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older .................................. 27 editorial

Preventing Shingles and Its Complications in Older Persons ............................................... 28

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The New England Journal of Medicine is a publication of NEJM Group, a division of the Massachusetts Medical Society.©2016 Massachusetts Medical Society, All rights reserved.

contents

original articles10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer ................ 30original articlePatient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer ................. 31 editorial

Treatment or Monitoring for Early Prostate Cancer ............................................................... 32

original articleGuillain–Barré Syndrome Associated with Zika Virus Infection in Colombia ............................................ 34 editorial

Zika Getting on Your Nerves? The Association with the Guillain–Barré Syndrome ............. 35

original articleA Randomized Trial of Long-term Oxygen for COPD with Moderate Desaturation ................................. 37 editorial

Clinical Usefulness of Long-Term Oxygen Therapy in Adults ................................................ 38

perspectiveZika Virus in the Americas — Yet Another Arbovirus Threat .................................................................... 40

perspectiveReducing the Risks of Relief — The CDC Opioid-Prescribing Guideline .................................................. 44

perspectiveRethinking the Primary Care Workforce — An Expanded Role for Nurses ................................................ 48

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nejm.org 1 Notable Articles of 2016T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 374;6 nejm.org February 11, 2016 523

From the Boston University Schools of Medicine (C.L.S., A.S.B., V.C., S.S.) and Public Health (A.S.B.), Boston, and the Framingham Heart Study, Framingham (C.L.S., A.S.B., V.C., S.S.) — all in Mas-sachusetts; and Inserm Unité 1219 and CIC 1401-EC (Clinical Epidemiology) and University of Bordeaux, ISPED (Bordeaux School of Public Health) — both in Bor-deaux, France (G.C., C.D.). Address re-print requests to Dr. Seshadri at the Bos-ton University School of Medicine, Department of Neurology, 72 E. Concord St., B602, Boston, MA 02118, or at suseshad@ bu . edu.

N Engl J Med 2016;374:523-32.DOI: 10.1056/NEJMoa1504327Copyright © 2016 Massachusetts Medical Society.

BACKGROUNDThe prevalence of dementia is expected to soar as the average life expectancy in-creases, but recent estimates suggest that the age-specific incidence of dementia is declining in high-income countries. Temporal trends are best derived through continuous monitoring of a population over a long period with the use of consis-tent diagnostic criteria. We describe temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study.

METHODSParticipants in the Framingham Heart Study have been under surveillance for in-cident dementia since 1975. In this analysis, which included 5205 persons 60 years of age or older, we used Cox proportional-hazards models adjusted for age and sex to determine the 5-year incidence of dementia during each of four epochs. We also explored the interactions between epoch and age, sex, apolipoprotein E ε4 status, and educational level, and we examined the effects of these interactions, as well as the effects of vascular risk factors and cardiovascular disease, on temporal trends.

RESULTSThe 5-year age- and sex-adjusted cumulative hazard rates for dementia were 3.6 per 100 persons during the first epoch (late 1970s and early 1980s), 2.8 per 100 persons during the second epoch (late 1980s and early 1990s), 2.2 per 100 persons during the third epoch (late 1990s and early 2000s), and 2.0 per 100 persons during the fourth epoch (late 2000s and early 2010s). Relative to the incidence during the first epoch, the incidence declined by 22%, 38%, and 44% during the second, third, and fourth epochs, respectively. This risk reduction was observed only among persons who had at least a high school diploma (hazard ratio, 0.77; 95% confi-dence interval, 0.67 to 0.88). The prevalence of most vascular risk factors (except obesity and diabetes) and the risk of dementia associated with stroke, atrial fibril-lation, or heart failure have decreased over time, but none of these trends com-pletely explain the decrease in the incidence of dementia.

CONCLUSIONSAmong participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified. (Funded by the National Institutes of Health.)

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Incidence of Dementia over Three Decades in the Framingham Heart Study

Claudia L. Satizabal, Ph.D., Alexa S. Beiser, Ph.D., Vincent Chouraki, M.D., Ph.D., Geneviève Chêne, M.D., Ph.D., Carole Dufouil, Ph.D., and Sudha Seshadri, M.D.

Original Article

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PERSPECTIVE

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Is Dementia in Decline?

n engl j med 374;6 nejm.org February 11, 2016


History of Medicine

Is Dementia in Decline? Historical Trends and Future TrajectoriesDavid S. Jones, M.D., Ph.D., and Jeremy A. Greene, M.D., Ph.D.

Related article, p. 523

In 2005, researchers from the Duke Center for Demographic

Studies reported a “surprising trend”: data from the National Long-Term Care Surveys showed that the prevalence of severe cog-nitive impairment in the Medi-care population had decreased significantly between 1982 and 1999.1 At a time when baby-boomer demographics led to pre-dictions of a looming dementia crisis, this finding offered hope. Since that time, other reports have similarly shown that the in-cidence or prevalence of demen-tia is decreasing in various popu-lations. Researchers have offered many possible explanations, in-cluding increased wealth, better education, control of vascular risk factors, and use of statins, anti-hypertensive agents, and nonste-roidal antiinflammatory drugs.1,2 However, even as researchers de-scribe their “cautious optimism” about specific populations, they still project a quadrupling of global prevalence over the com-ing decades.3

In this issue of the Journal, Satizabal and colleagues report more “robust evidence” of demen-tia’s decline (pages 523–32). Using surveillance data collected from the Framingham Heart Study from 1975 to the present, they found a 20% decrease in demen-tia incidence each decade, even as average body-mass index, dia-betes prevalence, and population age have increased. Can we now conclude that the tide has turned

in the dementia epidemic? The potential decline of dementia, seen in light of the rise and fall of other major diseases, raises an even more tantalizing prospect: Can we control our burden of disease?

This is not the first time that the medical profession and the public health community have struggled to interpret reports of an unexpected reversal of a chronic-disease epidemic.4 In 1964, Cali-fornia health officials reported that rates of coronary artery dis-ease (CAD) had begun to de-crease. This finding, which defied the widespread belief that the CAD epidemic would only worsen as life expectancy grew, garnered scant attention. Even a decade later, most health officials as-sumed that CAD was still on the rise. It was only in 1974 that re-searchers began taking the pros-pect of decline seriously. By 1978, they had accepted that CAD’s na-tional decline had begun in the mid-1960s. Similar decreases were soon reported in many other high-income countries, from Australia to Finland. This recognition trig-gered debate over the contribu-tion of medical and public health interventions, in hopes that knowl-edge of the causes of decline would guide policies and resource allocation and ensure continua-tion of these health benefits.

The history of the debate on CAD decline carries important lessons for emerging reports of dementia’s decline. First, it can

be extremely difficult to produce timely and convincing data about the trajectories of chronic dis-eases.4 When physicians began to debate CAD trends in 1974, they had to rely on government data that were 5 years out of date. It took 4 years of concerted effort to reach consensus about an in-flection that had occurred more than a decade earlier. Even though better and timelier data are now available, dementia researchers must still be resourceful in seek-ing convincing data. As Satizabal et al. indicate, each existing re-port has limitations. Their new data, which overcome many of these limitations, demonstrate the value of investments in long-term, longitudinal epidemiologic re-search such as the Framingham Heart Study. But the data still re-flect only one population sample. Whether they are accepted as conclusive evidence of a broad-based reduction in dementia in-cidence will become clear only over time.

Second, since trajectories of chronic-disease incidence reflect complex interactions of many causal factors, it will almost al-ways be uncertain whether de-creases will continue or reverse. Even as consensus about interna-tional CAD reduction consolidat-ed between the 1970s and the 1990s, worrisome evidence about countervailing trends also ap-peared.4 Enthusiasm for anti-CAD public health campaigns has been fragile, even in countries like

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Finland that demonstrated their promise so well. The widespread increases in obesity and diabetes could fuel CAD resurgences. Many researchers have warned that CAD’s decline could stall or even reverse — something that has happened among young adults and other subpopulations in Europe, Australia, and the United States. Other countries, such as China, continue to see increases in CAD with no evi-dence of plateau or reversal.

All these countervailing trends could affect dementia as well. Rocca and colleagues have warned that increases in obesity, diabetes, and hypertension could under-mine the gains achieved through improved education, wealth, and control of vascular risk factors. Even if a dementia decline has begun, it might not last: the out-come depends on the balance of diverging trends.2,3

Third, these ambiguities open up a battleground for conflicting interpretations by interested par-ties. Policymakers can use the same data to tell vastly different stories about public health. Fore-casts of CAD’s future continue to swing between narratives of tri-umph and catastrophe.4 The good news is that more and more countries are reporting evidence of decline. The bad news is the evidence of the fragility of these gains.

Narratives of dementia remain similarly malleable. In the early

1980s, even after CAD’s decline had been accepted and despite knowledge that dementia shares many risk factors with CAD, phy-sicians began to warn about an exploding dementia epidemic.5 The decrease in prevalence that surprised Manton and colleagues in 2005 could have been predict-ed decades earlier. But dementia will remain a problem despite these decreases. The prevalence of dementia can increase, even if the incidence falls, if global pop-

ulations live longer. The absolute number of people with dementia can increase, even if both inci-dence and prevalence fall, if the size of the elderly population grows. That explains why, 10 years into the era of reports of decreas-ing dementia in selected popula-tions, Satizabal and colleagues still write that the “prevalence of dementia is expected to soar as our societies age.” Even research-ers rigorously examining the evi-dence of decreases continue to worry about what the future will bring.

History offers reasons for hope. Evidence of dementia’s de-cline shows once again that our burden of disease is malleable. This lesson has been hard won. Mid-19th-century physicians saw cholera and tuberculosis as in-evitable scourges of urban envi-ronments. But those epidemics yielded to sanitary reform, im-proved standards of living, and eventually medical care. As con-

trol of infectious disease led to dramatic gains in life expectancy, physicians in the early 20th cen-tury came to see CAD and cancer as the inevitable scourges of long lives. Over recent decades, that pessimism has largely given way as well: CAD and many forms of cancer are increasingly prevent-able and curable. The burden of disease of the 20th century, like that of the 19th, was not an in-evitable fact of life, but a product of lives lived amid specific — and malleable — conditions.

What should we expect as can-cer and heart disease come under control? Many people think that we can live even longer lives — but lives compromised by demen-tia, vision loss, and hearing loss. Whether that fate is inevitable or whether these, too, are malleable scourges remains to be seen. Such questions are better left to futurists and geriatricians than to historians. Yet Satizabal et al. believe there’s cause for “cautious hope.” Primary and secondary pre-vention might diminish the mag-nitude of the long-feared dementia epidemic. Something else might save our vision and hearing.

Faced with choices between equally defensible epidemiologic projections, physicians and re-searchers must think carefully about what stories they empha-size to patients and policymak-ers. The implications, especially for investment in long-term care facilities, are enormous. Our ex-planations of decline are equally important, since they guide in-vestments in behavior change, medications, and other treat-ments.

With this latest contribution, optimism about dementia is more justified than ever before. Even if death and taxes remain inevita-

History offers reasons for hope. Evidence of dementia’s decline shows once again that our burden of disease

is malleable.

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ble, cancer, CAD, and dementia may not. But cautious optimism should not become complacency. If we can elucidate the changes that have contributed to these improvements, perhaps we can ex-tend them. Today, the dramatic reductions in CAD-related mor-tality are under threat. The incipi-ent improvements in dementia are presumably even more fragile. The burden of disease, ever mal-leable, can easily relapse.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

From the Department of Global Health and Social Medicine, Harvard Medical School, Boston (D.S.J); the Department of the His-tory of Science, Harvard University, Cam-bridge, MA (D.S.J.); and the Division of General Internal Medicine and the Depart-ment of the History of Medicine, Johns Hopkins University School of Medicine, Baltimore (J.A.G.).

1. Manton KC, Gu XL, Ukraintseva SV. De-clining prevalence of dementia in the U.S. el-derly population. Adv Gerontol 2005; 16: 30-7.2. Larson EB, Yaffe K, Langa KM. New in-

sights into the dementia epidemic. N Engl J Med 2013; 369: 2275-7.3. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cog-nitive impairment in the United States. Al-zheimers Dement 2011; 7: 80-93.4. Jones DS, Greene JA. The decline and rise of coronary heart disease: understand-ing public health catastrophism. Am J Pub-lic Health 2013; 103: 1207-18.5. Beck JC, Benson DF, Scheibel AB, Spar JE, Rubenstein LZ. Dementia in the elderly: the silent epidemic. Ann Intern Med 1982; 97: 231-41.

DOI: 10.1056/NEJMp1514434Copyright © 2016 Massachusetts Medical Society.Is Dementia in Decline?

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The new england journal of medicine


established in 1812 February 18, 2016 vol. 374 no. 7

The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Snyder at [email protected].

* A complete list of investigators in the Testosterone Trials is provided in the Supplementary Appendix, available at NEJM.org.

Drs. Bhasin, Cunningham, Matsumoto, Stephens-Shields, and Ellenberg contrib-uted equally to this article.


BACKGROUNDSerum testosterone concentrations decrease as men age, but benefits of raising testos-terone levels in older men have not been established.

METHODSWe assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vital-ity Trial. The primary outcome of each of the individual trials was also evaluated in all participants.

RESULTSTestosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with sig-nificantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking dis-tance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P = 0.003). Tes-tosterone had no significant benefit with respect to vitality, as assessed by the Func-tional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received tes-tosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.

CONCLUSIONSIn symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking dis-tance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)

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Effects of Testosterone Treatment in Older MenP.J. Snyder, S. Bhasin, G.R. Cunningham, A.M. Matsumoto, A.J. Stephens-Shields, J.A. Cauley, T.M. Gill,

E. Barrett-Connor, R.S. Swerdloff, C. Wang, K.E. Ensrud, C.E. Lewis, J.T. Farrar, D. Cella, R.C. Rosen, M. Pahor, J.P. Crandall, M.E. Molitch, D. Cifelli, D. Dougar, L. Fluharty, S.M. Resnick, T.W. Storer, S. Anton, S. Basaria,

S.J. Diem, X. Hou, E.R. Mohler III, J.K. Parsons, N.K. Wenger, B. Zeldow, J.R. Landis, and S.S. Ellenberg, for the Testosterone Trials Investigators*


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E d i t o r i a l

T h e n e w e ngl a nd j o u r na l o f m e dic i n e


Establishing a Framework — Does Testosterone Supplementation Help Older Men?

Eric S. Orwoll, M.D.

Aging is variably but inevitably accompanied by declines in health; concomitantly, in men, circu-lating sex-steroid levels fall with age.1 To what extent these two processes are causally linked and whether testosterone therapy can prevent or ameliorate important age-related problems have been major issues in men’s health. In 2003, a com-mittee assembled by the Institute of Medicine (IOM) found a paucity of randomized, placebo-controlled clinical trials involving older men and noted a lack of definite evidence that testoster-one therapy conferred benefits.2 The committee recommended that clinical trials be initiated, first to evaluate the efficacy of testosterone supplementation in older men and then to assess long-term benefits and risks through large-scale trials.

Little has changed to alter the conclusions of that report; if anything, the issue of testosterone supplementation has become more controversial.3 However, in this issue of the Journal, Snyder et al.4 describe the long-awaited initial results of the National Institutes of Health–sponsored Testos-terone Trials, which were designed to address the key issues identified by the IOM. Their re-port is important, not only because it deals with an essential public health issue but also because the investigators have succeeded in conducting the kind of generally well-conceived studies that are sorely needed in the field. The findings be-gin to provide a basis for more rational clinical decisions about testosterone use as well as for additional research.

The overall design of the Testosterone Trials is complex.5 It includes seven independent, double-blind, placebo-controlled trials intended to ad-dress specific outcomes that are postulated to be related to testosterone deficiency (sexual function, vitality, physical function, cognitive function,

anemia, bone density, and cardiovascular status). The trials are knitted together by common methods and some shared measures, thus maxi-mizing the power of the overall investigation. This inaugural report describes the findings of the three main studies (with primary outcomes related to sexual function, physical function, and vitality).

The results show that testosterone therapy did yield certain benefits, but at this point their clinical importance is uncertain. Therapy was not a panacea, and the findings alone might be insufficient to support a decision to initiate tes-tosterone therapy in symptomatic older men. The study confirmed that testosterone supplementa-tion can yield improvements in sexual function, but the benefits were modest, tended to wane in the latter months of the treatment period, and, as the authors note, were not as robust as those of phosphodiesterase type 5 inhibitors.6 There were only small gains in physical performance and in indexes of mood and depression; overall vitality was no better with testosterone therapy than with placebo. For each of the outcomes, some older men may have a more vigorous re-sponse to testosterone therapy and thus could be more attractive candidates for supplementation; however, it was not possible to confidently iden-tify them by the testosterone levels achieved with therapy. As expected, estradiol levels also increased; those levels have been linked to key health variables in men (e.g., sexual function).7 It’s not yet clear whether responses (or the lack thereof) in the Testosterone Trials may be due to changes in estradiol levels.

There is considerable controversy about pos-sible adverse effects of testosterone therapy in older men, and these studies do not resolve this controversy. Although there were minor effects

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nejm.org 7 Notable Articles of 2016Editorial


on hemoglobin and prostate-specific antigen levels, and, reassuringly, no apparent major toxic effects, larger and more extended trials would be needed to determine whether therapy has negative effects on outcomes such as pros-tate or cardiovascular health.

Importantly, the study participants were re-cruited on the basis of stringent criteria (age ≥65 years, total testosterone levels below the normal range in men 19 to 40 years of age [<275 ng per deciliter], symptoms related to predetermined outcomes, and no contraindications to partici-pation). Only 1.5% of those screened (790 of 51,085 men) were eligible and enrolled. The aver-age participant was 72 years of age; almost 90% of participants were white, most were obese, most had hypertension, more than one third had diabetes, and almost 20% had sleep apnea. The select nature of the participants reflects the sci-entific rigor of the trials (and the causes of low testosterone levels) but also clearly limits the generalizability of the conclusions. We should not assume that the benefits, lack of benefits, or adverse-event profile observed in these studies would be similar in younger men (most testos-terone prescriptions are written for middle-aged men3), men with higher testosterone levels, or those with different demographic or clinical characteristics.

The report by Snyder et al. is likely to stimu-

late controversy and to engender additional re-search questions — as did the Women’s Health Initiative with respect to estrogen-replacement therapy. Nevertheless, it is a landmark study in the field of men’s health and no doubt a bell-wether for additional important contributions from the Testosterone Trials.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the Department of Medicine, Oregon Health and Science University, Portland.

1. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testoster-one levels in healthy men. J Clin Endocrinol Metab 2001; 86: 724-31.2. Liverman C, Blazer D, eds. Testosterone and aging: clinical research directions. Washington, DC: National Academies Press, 2004.3. Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and “age-related hypogonadism” — FDA concerns. N Engl J Med 2015; 373: 689-91.4. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testos-terone treatment in older men. N Engl J Med 2016; 374: 611-24.5. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testos-terone Trials: seven coordinated trials of testosterone treatment in elderly men. Clin Trials 2014; 11: 362-75.6. Spitzer M, Basaria S, Travison TG, et al. Effect of testoster-one replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med 2012; 157: 681-91.7. Finkelstein JS, Yu EW, Burnett-Bowie SA. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369: 2455-7.

DOI: 10.1056/NEJMe1600196Copyright © 2016 Massachusetts Medical Society.

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established in 1812 February 25, 2016 vol. 374 no. 8

From the Surgical Outcomes and Quality Improvement Center (SOQIC), Depart-ment of Surgery and Center for Health-care Studies, Feinberg School of Medicine and Northwestern Medicine, Northwest-ern University (K.Y.B., J.W.C., A.R.D., R.L., A.D.Y., D.M.M., D.D.O., J.J.S.), and the American College of Surgeons (K.Y.B., M.E.C., D.B.H., C.Y.K.), Chicago, the De-partment of Statistics, Northwestern Uni-versity, Evanston (L.V.H.), and the De-partment of Surgery, Southern Illinois University, Springfield ( J.D.M.) — all in Illinois; the Department of Surgery, Vanderbilt University, Nashville ( J.L.T.); the Department of Surgery and the Cen-ter for Surgery and Health Economics, Perelman School of Medicine, University of Pennsylvania (R.R.K.), and the Ameri-can Board of Surgery (F.R.L.) — both in Philadelphia; and the Department of Sur-gery, University of California, Los Ange-les, School of Medicine, Los Angeles (C.Y.K.). Address reprint requests to Dr. Bilimoria at the Surgical Outcomes and Quality Improvement Center (SOQIC), Department of Surgery, Feinberg School of Medicine and Northwestern Medicine, Northwestern University, 633 N. St. Clair St., 20th Fl., Chicago, IL 60611, or at k-bilimoria@ northwestern . edu.

This article was published on February 2, 2016, at NEJM.org.


BACKGROUNDConcerns persist regarding the effect of current surgical resident duty-hour policies on patient outcomes, resident education, and resident well-being.

METHODSWe conducted a national, cluster-randomized, pragmatic, noninferiority trial involving 117 general surgery residency programs in the United States (2014–2015 academic year). Programs were randomly assigned to current Accreditation Council for Graduate Medical Education (ACGME) duty-hour policies (standard-policy group) or more flexible policies that waived rules on maximum shift lengths and time off between shifts (flexible-policy group). Outcomes included the 30-day rate of postoperative death or serious complica-tions (primary outcome), other postoperative complications, and resident perceptions and satisfaction regarding their well-being, education, and patient care.

RESULTSIn an analysis of data from 138,691 patients, flexible, less-restrictive duty-hour policies were not associated with an increased rate of death or serious complications (9.1% in the flexible-policy group and 9.0% in the standard-policy group, P = 0.92; unadjusted odds ratio for the flexible-policy group, 0.96; 92% confidence interval, 0.87 to 1.06; P = 0.44; noninferiority criteria satisfied) or of any secondary postoperative outcomes studied. Among 4330 residents, those in programs assigned to flexible policies did not report significantly greater dissatisfaction with overall education quality (11.0% in the flexible-policy group and 10.7% in the standard-policy group, P = 0.86) or well-being (14.9% and 12.0%, respectively; P = 0.10). Residents under flexible policies were less likely than those under standard policies to perceive negative effects of duty-hour policies on multiple aspects of patient safety, continuity of care, professionalism, and resident education but were more likely to perceive negative effects on personal activities. There were no sig-nificant differences between study groups in resident-reported perception of the effect of fatigue on personal or patient safety. Residents in the flexible-policy group were less likely than those in the standard-policy group to report leaving during an operation (7.0% vs. 13.2%, P<0.001) or handing off active patient issues (32.0% vs. 46.3%, P<0.001).

CONCLUSIONSAs compared with standard duty-hour policies, flexible, less-restrictive duty-hour policies for surgical residents were associated with noninferior patient outcomes and no signifi-cant difference in residents’ satisfaction with overall well-being and education quality. (FIRST ClinicalTrials.gov number, NCT02050789.)

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National Cluster-Randomized Trial of Duty-Hour Flexibility in Surgical Training

Karl Y. Bilimoria, M.D., M.S.C.I., Jeanette W. Chung, Ph.D., Larry V. Hedges, Ph.D., Allison R. Dahlke, M.P.H., Remi Love, B.S., Mark E. Cohen, Ph.D., David B. Hoyt, M.D., Anthony D. Yang, M.D., John L. Tarpley, M.D.,

John D. Mellinger, M.D., David M. Mahvi, M.D., Rachel R. Kelz, M.D., M.S.C.E., Clifford Y. Ko, M.D., M.S.H.S., David D. Odell, M.D., M.M.Sc., Jonah J. Stulberg, M.D., Ph.D., M.P.H., and Frank R. Lewis, M.D.


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Surgical Resident Duty-Hour Rules — Weighing the New Evidence

John D. Birkmeyer, M.D.

Surgical training has always been hard on resi-dents. During my own residency more than 20 years ago, 100-hour workweeks and in-house call every other night were routine. A resident’s life outside the hospital was simply not a priority. Residency may be even harder on patients. A large body of research has linked sleep deprivation in resident physicians to poor performance in neu-robehavioral testing and, more alarmingly, to higher rates of attention failure in patient care.1,2

Reacting to concerns about both resident well-being and patient safety, the Accreditation Coun-cil for Graduate Medical Education (ACGME) implemented duty-hour reforms in 2003 that constrained resident workweeks to 80 hours, among other changes. A 2011 update added new limits to the length of individual shifts (24 hours plus 4 hours for transition) and guaranteed a minimum amount of time off between 24-hour shifts (14 hours). Although they are not nearly as stringent as standards set in other occupations in which performance has implications for pub-lic safety (e.g., airline pilots), the ACGME rules were nonetheless criticized by many in the medi-cal community. Surgeons in particular were concerned that the new duty-hour rules would paradoxically increase medical errors as a result of increased handoffs — residents signing out their sickest patients to providers who are not familiar with their cases. In other words, the safety benefits of reducing resident fatigue would be offset by harms associated with disrupting continuity of care.

Extending the results of a previous national study based on Medicare claims data,3 a very ambitious, scientifically robust study by Bilimoria et al. now published in the Journal should help allay these concerns.4 By random assignment, 59

general-surgery training programs were required to adhere to the ACGME rules about maximum shift length and minimum time off between 24-hour shifts. Another 59 programs were granted “flexibility” and did not have to adhere to those rules. Both groups adhered to ACGME require-ments for total workweek hours. Residents who were not required to adhere to the duty-hour rules were less likely to report dissatisfaction with continuity of care and hand-offs. After 1 year, however, the two groups of teaching hospitals had virtually indistinguishable rates of death, overall complications, and specific types of com-plications, on the basis of data on risk-adjusted clinical outcomes from the American College of Surgeons National Surgical Quality Improvement Program.

It is not surprising that outcomes did not vary according to whether programs adhered to ACGME requirements on maximum shift length and time off between shifts. The patients most likely to be affected by resident handoffs — those with acute or deteriorating clinical condi-tions — represent only a small percentage of surgical patients at teaching hospitals. More important, teaching hospitals have become far less reliant on surgical residents than they used to be. In earlier eras, surgical residents had con-siderable autonomy. During my own residency, surgical residents often operated independently, particularly at night and on weekends. Today, they operate almost exclusively in the presence of an attending surgeon. Intensive care units, which house the sickest surgical patients, are increasingly “closed” and staffed by board-certi-fied intensivists. Postoperative care is delivered by multidisciplinary teams staffed with associate providers as well as residents.

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The Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial also assessed the effects of ACGME duty-hour restrictions on resi-dent perceptions of educational quality and well-being, with the use of survey data collected annually by the American Board of Surgery. Residents in the two groups of teaching hospi-tals had similarly high rates of satisfaction with the quality of their training. Although residents in programs not required to adhere to the ACGME duty-hour rules were more likely to be dissatis-fied with time for rest, there were no significant differences in overall resident well-being and morale between the two groups.

What do the results of the FIRST Trial mean for ACGME policy on resident duty hours? The authors conclude, as will many surgeons, that surgical training programs should be afforded more flexibility in applying work-hour rules. This interpretation implicitly places the burden of proof on the ACGME. Thus, because the FIRST Trial found no evidence that removing restrictions on resident shift length and time off between shifts was harmful to patients, programs should have more autonomy to train residents as they choose.

I reach a different conclusion. The FIRST Trial effectively debunks concerns that patients will suffer as a result of increased handoffs and breaks in the continuity of care. Rather than backtrack on the ACGME duty-hour rules, surgi-

cal leaders should focus on developing safe, re-silient health systems that do not depend on overworked resident physicians. They should also recognize the changing expectations of post-millennial learners. To many current residents and medical students, 80-hour (or even 72-hour) workweeks and 24-hour shifts probably seem long enough. Although few surgical residents would ever acknowledge this publicly, I’m sure that many love to hear, “We can take care of this case without you. Go home, see your family, and come in fresh tomorrow.”


From the Dartmouth–Hitchcock Medical Center and the Dart-mouth Institute for Health Policy and Clinical Practice — both in Lebanon, NH.


1. Veasey S, Rosen R, Barzansky B, Rosen I, Owens J. Sleep loss and fatigue in residency training: a reappraisal. JAMA 2002; 288: 1116-24.2. Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns’ weekly work hours on sleep and attentional failures. N Engl J Med 2004; 351: 1829-37.3. Volpp KG, Rosen AK, Rosenbaum PR, et al. Mortality among hospitalized Medicare beneficiaries in the first 2 years following ACGME resident duty hour reform. JAMA 2007; 298: 975-83.4. Bilimoria KY, Chung JW, Hedges LV, et al. National cluster-randomized trial of duty-hour f lexibility in surgical training. N Engl J Med 2016;374:713-27.


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Perspective

The NEW ENGLAND JOURNAL of MEDICINE

February 25, 2016


In 2014, Facebook users were furious to discover that they’d unwittingly been experimented on.1 Researchers had randomly assigned users to news

feeds with reduced “positive” content or reduced

“negative” content and found that happy posts beget happy posts and that grim ones beget grim ones.2 Although that may now seem obvious, previous evidence had suggested that because we tend to compare ourselves to oth-ers, exposure to positive content compromises users’ well-being. There was thus no reason to be-lieve that the status quo — news feeds curated by an algorithm tailored to users’ viewing habits — was any “safer” than the experi-mental interventions. And given Facebook’s reach, there were com-pelling reasons to find out. Never-theless, the results triggered out-rage that 700,000 users had been exposed to potential emotional damage without their consent.

Similar accusations have been

leveled at investigators who are comparing the 2011 duty-hour restrictions imposed by the Ac-creditation Council for Graduate Medical Education (ACGME) with more flexible shift lengths for residents. The Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial, whose re-sults are now reported by Bilimo-ria et al. in the Journal, compared 59 surgical training programs randomly assigned to an ACGME-compliant schedule with 58 grant-ed flexibility in designing shift lengths (still within an 80-hour workweek). The ongoing Individ-ualized Comparative Effectiveness of Models Optimizing Safety and Resident Education (iCOMPARE) trial involves internal medicine programs. Both used cluster

randomization at the residency-program level, and neither required consent of residents or patients. That consent waiver has drawn criticism from Public Citizen and the American Medical Student Association, which in open letters to the Office for Human Research Protections (OHRP) accuse the in-vestigators of “egregious ethical and regulatory violations.”3,4

The allegations, focused pri-marily on “serious health risks” to residents from long shifts, are dizzyingly tautological. The critics claim it’s unethical not to obtain residents’ consent; but because pressure on residents to conform makes seeking their consent akin to coercion, that’s unethical too. Thus, there’s no ethical way to study the duty-hour rules in a randomized fashion. But that’s fine, because we already know they’re beneficial; we know that because the ACGME made the rules in the first place. And if the trials found otherwise, their re-

Leaping without Looking — Duty Hours, Autonomy, and the Risks of Research and PracticeLisa Rosenbaum, M.D.

Related article, p. 713

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sults challenging the status quo would be suspect because the in-vestigators, who have publicly ac-knowledged the need for data to inform policy, are consequently too biased to generate those data.

To unpack these allegations, it’s important to understand that even if the trials are considered

human-subjects research, there are circumstances under which federal rules deem it ethical to waive consent. The key one here is that the incremental risk posed by the research should be, at most, minimal. For trials like these that evaluate a standard practice, the question becomes: Is there equipoise between the status quo and investigational groups in terms of possible risks? Though the letters to OHRP claim otherwise, the answer is un-equivocally yes. The complaints ignore a considerable body of re-search suggesting, as Bilimoria et al. point out, that duty-hour re-forms have not improved patient safety; some trials have even raised concerns that they’ve actu-ally worsened quality of care and patient outcomes.

As for risks to residents, the letters cite data suggesting that fatigue causes harms such as in-creased motor vehicle accidents, needlesticks, and burnout. Yet there’s little evidence to suggest that shorter hours have reduced occupational hazards or burnout rates. Though I suspect that these findings partly reflect the emo-

tional toll of “work compression” and the reality that many trainees don’t actually sleep more, they also speak to a fundamental challenge in improving care: the factors affecting physicians’ per-formance are so numerous and interdependent that no single vari-able, such as sleep, can be under-

stood or targeted in isolation. Be-cause of the unknown real-life consequences of such myriad in-teractions, no drug would be ap-proved solely on the basis of lab-oratory evidence. Yet we require neither consideration of complex-ity nor rigorous studies before implementing policies with simi-larly broad implications. Why?

Bioethicist and legal scholar Michelle Meyer has described our “tendency to view a field experi-ment designed to study the ef-fects of an existing or proposed practice as more morally suspi-cious than an immediate, univer-sal implementation of an untest-ed practice.” She argues that people in power often rely on in-tuition in creating and imple-menting wide-reaching policies. Indeed, neither residents nor pa-tients consented to the ACGME rules, yet no one finds this omis-sion ethically suspect. Moreover, intuition seems particularly sa-lient to debates over duty hours, since everyone knows how it feels to be tired. Unfortunately, few people know how it feels to see a patient through illness, spend a fifth of your time en-

gaged in hand-offs, leave halfway through an operation because your shift’s up, or perceive resent-ment in your supervisors who think you have it easier than they did. Given such trade-offs and uncertainties, it’s not just ethical but laudable to comparatively evaluate duty-hours policies. The question then becomes: Can the research be accomplished if con-sent is required?

The Facebook experiment’s re-sults would have been invalid had consent been sought, since we couldn’t determine how much users adjusted their emotional content because they knew it was being monitored. Similarly, requir-ing residents’ consent in duty-hour trials would render the re-sults uninterpretable, given the selection bias that would be intro-duced if those preferring longer hours were more likely to par-ticipate.

The challenges with regard to patients are more pragmatic. Con-sider, for instance, caring for a man with a myocardial infarc-tion. After obtaining his consent for percutaneous coronary inter-vention, you’d have to add, “I also need your consent to be cared for by residents who are working longer hours.” If he said no, would you have to transfer him, as heart muscle continued to die, to a nonteaching hospital? Surely here the risk posed by seeking consent is greater than that from the research itself.

Moreover, as we examine the implications for efforts to develop “learning health systems,” a corol-lary of this hypothetical situation is worth considering. Imagine tell-ing a patient, “I need your per-mission to care for you at a hos-pital where we’re using a new electronic health record, are bas-ing your doctor’s reimbursement

No drug would be approved solely on the basis of laboratory evidence. Yet we require neither consideration of complexity nor rigorous studies before implementing policies with broad implications. Why?

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on whether you stay healthy, and are under pressure to discharge you quickly and make sure you don’t come back. We don’t really know how all this will affect your health, but we believe it’s for the better. Can you sign here?”

The point is that our approach to human-subjects research per-petuates a misleading distinction between risks posed by research and those posed by practice, de-manding greater scrutiny for in-vestigative efforts while assum-ing that untested practice is safe. In describing this phenomenon, Meyer cites the moratorium that the OHRP imposed on a study assessing a checklist designed to reduce catheter-related blood-stream infections because re-searchers hadn’t obtained physi-cians’ or patients’ consent. The OHRP explained that its regula-tions don’t apply when institu-tions are merely “implementing” practices aiming to improve care, but if they’re “planning research activities examining the effective-ness of interventions to improve the quality of care, then the reg-ulatory protections are important to protect the rights and welfare of human research subjects.” This double standard leaves us, para-doxically, with unregulated prac-tices that may be ineffective and unsafe because we can’t surmount the regulatory hurdles to conduct-ing research to improve them.

To address this problem, we

must understand the values of the people we’re professing to pro-tect. In one relevant study, Hal-pern and colleagues asked patients undergoing dialysis to imagine two hypothetical scenarios.5 In the “research scenario,” patients in a trial are randomly assigned to a prespecified dialysis dura-tion of 4.5 hours or a duration at the physician’s discretion (both approaches are within the stan-dard of care). In the “clinical care scenario,” patients receive di-alysis for a duration determined by a protocol (also common prac-tice). Participants were more will-ing in the research than the practice setting to give up their own decision-making autonomy, including written informed con-sent. They recognized the value of research and didn’t perceive the hypothetical study as posing higher risk than ordinary care. But they expressed deep reserva-tions about compromising physi-cians’ autonomy to individualize treatment absent compelling rea-sons for doing so.

This last finding highlights the ultimate irony of both duty-hour restrictions and objections to studying them: we’ve created an educational system that com-promises trainees’ freedom to judge for themselves when their patients need them. The value that physicians and patients place on such autonomy is not measur-able in mortality rates or hours

slept but should remain foremost in our discussions. An essential contribution of the duty-hour trials is that, in assessing flexi-bility itself, they remind us that autonomy is an ethical concept that matters to both doctors and patients — in research and in practice.


Dr. Rosenbaum is a national correspondent for the Journal.

This article was published on February 2, 2016, and updated on February 4, 2016, at NEJM.org.

1. Meyer MN. Two cheers for corporate ex-perimentation: the A/B illusion and the vir-tues of data-driven innovation. Colo Tech L J 2015; 13(2): 273.2. Kramer ADI, Guillory JE, Hancock JT. Experimental evidence of massive-scale emo-tional contagion through social networks. Proc Natl Acad Sci U S A 2014; 111: 8788-90.3. Carome MA, Wolfe SM, Almashat S, Hall DV. Letter to Jerry Menikoff, director, and Kristina Borror, director, Division of Compliance Oversight, Office for Human Research Protections, Department of Health and Human Services, regarding iCOMPARE trial. November 19, 2015 (http://www .citizen .org/ documents/ 2283 .pdf).4. Carome MA, Wolfe SM, Almashat S, Hall DV. Letter to Jerry Menikoff, director, and Kristina Borror, director, Division of Compliance Oversight, Office for Human Research Protections, Department of Health and Human Services, regarding FIRST trial. November 19, 2015 (http://www .citizen .org/ documents/ 2284 .pdf).5. Kraybill A, Dember LM, Joffe S, et al. Patient and physician views about proto-colized dialysis treatment in randomized tri-als and clinical care. AJOB Empirical Bioeth-ics 2015 October 23 (Epub ahead of print).

DOI: 10.1056/NEJMp1600233Copyright © 2016 Massachusetts Medical Society.Leaping without Looking

Pharmaceutical Policy Reform

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established in 1812 March 3, 2016 vol. 374 no. 9

From the Division of Child Health, Ob-stetrics and Gynaecology, School of Clin-ical Sciences (K.F.W., M.M., C.M., J.G.T.), and Nottingham Clinical Trials Unit (L.B.), and the University of Nottingham, the Division of Obstetrics and Gynaecology, Nottingham University Hospitals NHS Trust (G.J.B., N.G.), Nottingham, Still-birth and Neonatal Death Charity, Lon-don (C.W.), and the Department of Ob-stetrics and Gynaecology and National Institute for Health Research Biomedical Research Centre, Cambridge University, Cambridge (G.C.S.S.) — all in the United Kingdom. Address reprint requests to Dr. Thornton at the Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Hucknall Rd., Nottingham NG5 1PB, United Kingdom, or at jim . thornton@ nottingham . ac . uk.

* A complete list of investigators in the 35/39 Trial Group is provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.


BACKGROUNDThe risk of antepartum stillbirth at term is higher among women 35 years of age or older than among younger women. Labor induction may reduce the risk of stillbirth, but it also may increase the risk of cesarean delivery, which already is common in this older age group.

METHODSWe conducted a randomized, controlled trial involving primigravid women who were 35 years of age or older. Women were randomly assigned to labor induction between 39 weeks 0 days and 39 weeks 6 days of gestation or to expectant management (i.e., waiting until the spontaneous onset of labor or until the development of a medical problem that mandated induction). The primary outcome was cesarean delivery. The trial was not designed or powered to assess the effects of labor induction on stillbirth.

RESULTSA total of 619 women underwent randomization. In an intention-to-treat analysis, there were no significant between-group differences in the percentage of women who underwent a cesarean section (98 of 304 women in the induction group [32%] and 103 of 314 women in the expectant-management group [33%]; relative risk, 0.99; 95% confidence interval [CI], 0.87 to 1.14) or in the percentage of women who had a vaginal delivery with the use of forceps or vacuum (115 of 304 women [38%] and 104 of 314 women [33%], respectively; relative risk, 1.30; 95% CI, 0.96 to 1.77). There were no maternal or infant deaths and no significant between-group differences in the women’s experience of childbirth or in the frequency of adverse maternal or neonatal outcomes.

CONCLUSIONSAmong women of advanced maternal age, induction of labor at 39 weeks of gestation, as compared with expectant management, had no significant effect on the rate of cesarean section and no adverse short-term effects on maternal or neonatal out-comes. (Funded by the Research for Patient Benefit Programme of the National Insti-tute for Health Research; Current Controlled Trials number, ISRCTN11517275.)

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Randomized Trial of Labor Induction in Women 35 Years of Age or Older

Kate F. Walker, M.R.C.O.G., George J. Bugg, M.D., Marion Macpherson, M.D., Carol McCormick, M.Sc., Nicky Grace, M.A., Chris Wildsmith, B.A., Lucy Bradshaw, M.Sc., Gordon C.S. Smith, D.Sc.,

and James G. Thornton, M.D., for the 35/39 Trial Group*


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n engl j med 374;9 nejm.org March 3, 2016880

Induction of Labor and Cesarean Delivery

William A. Grobman, M.D.

At the heart of obstetrical care is a seemingly simple calculus: when are the benefits of deliv-ery greater than the benefits of continued preg-nancy? However, making this determination is anything but straightforward, given the poten-tially conflicting needs of the mother and the needs of her offspring, which must both be taken into account to maximize maternal and perinatal health.

In the absence of maternal or fetal complica-tions, current consensus favors the consideration of delivery between 41 weeks 0 days and 42 weeks 0 days of gestation. In addition, for these women, delivery is recommended after 42 weeks 0 days and no later than 42 weeks 6 days of gestation, given the increase in perinatal morbidity and mortality at these gestational ages.1 Thus, induc-tion before 41 weeks 0 days of gestation in the absence of complications is considered not to be medically indicated.

One consideration that traditionally has tipped the balance toward continuing pregnancy is the concern that labor induction may increase the risk of cesarean delivery, particularly among nulliparous women. This belief is based on the findings of multiple observational studies in which outcomes in women who underwent in-duction were compared with those of women who had spontaneous labor.2 However, sponta-neous labor is not a clinical “strategy,” and thus it is not the appropriate comparison.

Observational studies in which outcomes in women who underwent induction were compared with those in women who received expectant management generally have not shown an in-creased risk of cesarean delivery among women who underwent induction.3-6 However, trials that have explored whether, in the absence of compli-cations, labor induction before 41 weeks 0 days of gestation is associated with adverse maternal

or perinatal outcomes have been too small to guide clinical practice.7

In this issue of the Journal, Walker et al.8 have attempted to rectify this gap in evidence. They report the results of a trial in which more than 600 women who were at least 35 years of age were randomly assigned to labor induction be-tween 39 weeks 0 days and 39 weeks 6 days of gestation or to expectant management. This study was powered to detect at least a 36% rela-tive difference between the two groups in the frequency of cesarean delivery. A total of 32% of the women assigned to the induction group, as compared with 33% of the women assigned to the expectant-management group, underwent a cesarean delivery (relative risk, 0.99; 95% confi-dence interval, 0.87 to 1.14). There were no sig-nificant differences between the groups in other adverse maternal or perinatal outcomes, but such outcomes were uncommon.

On the basis of the results of this trial, it would be premature to alter recommendations regarding the timing of delivery in uncomplicated pregnancies. Although the study did not show evidence of harm from induction at 39 weeks of gestation, it also did not show evidence of benefit, and one could argue that medical inter-ventions in general, and intervention in the natural progress of gestation specifically, should be performed only when benefit has been shown.

Because this trial was not designed or ade-quately powered to assess differences in perinatal outcomes, whether labor induction at 39 weeks of gestation affects these outcomes remains un-known. We do not know whether the findings of this trial are generalizable to women younger than 35 years of age or whether the results would differ according to whether or not women require cervical ripening. Finally, women in this trial received care in the United Kingdom, which

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has a health delivery system that differs from that of the United States in ways that could af-fect the relationship between labor induction and cesarean delivery; these differences include a higher rate of operative vaginal delivery in the United Kingdom.9

The authors note the need for “a larger trial to test the effects of induction on stillbirth and uncommon adverse neonatal outcomes.” I am the principal investigator of such a trial (Clinical-Trials.gov number, NCT01990612), which is currently under way within the Maternal–Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This trial, which has a targeted enrollment of 6000 women, is designed to identify differences in perinatal outcomes among nulliparous women with uncomplicated singleton pregnancies who are randomly as-signed to induction between 39 weeks 0 days and 39 weeks 4 days of gestation or to expectant management. The trial is more than halfway complete.

Although the trial by Walker et al. was not designed to assess the effect of labor induction on stillbirth and adverse neonatal outcomes, it makes an important contribution to medical knowledge. It is the largest trial of its type to be completed, and it suggests that a belief that guides decisions about the timing of delivery — namely, that induction of labor at term increases the risk of cesarean delivery — may not be true after all.


From the Northwestern University Feinberg School of Medi-cine, Chicago.

1. American College of Obstetricians and Gynecologists. Prac-tice bulletin no. 146: Management of late-term and postterm pregnancies. Obstet Gynecol 2014; 124: 390-6.2. Maternal and neonatal outcomes of elective induction of labor. Rockville, MD: Agency for Healthcare Research and Quality, October 2014 (http://www .ahrq .gov/ research/ findings/ evidence-based-reports/ eiltp .html).3. Osmundson S, Ou-Yang RJ, Grobman WA. Elective induction compared with expectant management in nulliparous women with an unfavorable cervix. Obstet Gynecol 2011; 117: 583-7.4. Gibson KS, Waters TP, Bailit JL. Maternal and neonatal out-comes in electively induced low-risk term pregnancies. Am J Obstet Gynecol 2014; 211(3): 249.e1-249.e16.5. Stock SJ, Ferguson E, Duffy A, Ford I, Chalmers J, Norman JE. Outcomes of elective induction of labour compared with ex-pectant management: population based study. BMJ 2012; 344: e2838.6. Cheng YW, Kaimal AJ, Snowden JM, Nicholson JM, Caughey AB. Induction of labor compared to expectant management in low-risk women and associated perinatal outcomes. Am J Obstet Gynecol 2012; 207(6): 502.e1-8.7. Saccone G, Berghella V. Induction of labor at full term in uncomplicated singleton gestations: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet Gy-necol 2015; 213: 629-36.8. Walker KF, Bugg GJ, Macpherson M, et al. Randomized trial of labor induction in women 35 years of age or older. N Engl J Med 2016; 374:813-22.9. Kyser KL, Lu X, Santillan D, et al. Forceps delivery volumes in teaching and nonteaching hospitals: are volumes sufficient for physicians to acquire and maintain competence? Acad Med 2014; 89: 71-6.


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established in 1812 March 17, 2016 vol. 374 no. 11

From Massachusetts General Hospital, Boston (K.R., M.R.J.); the University of Wisconsin, Madison (J.S.M.); the University of Miami, Miami (S.C.); NYU Langone School of Medicine, New York (T.R.); Ohio Health System, Columbus (G.M.A.); Wellmont Cardiovascular Associates Heart Institute, Kingsport, TN (D.C.M.); the University of Pittsburgh Medical Center, Pittsburgh (L.W.); and the Main Line Health System, Philadelphia (W.G.). Address reprint requests to Dr. Rosenfield at the Division of Cardiology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

* A complete list of the Asymptomatic Carotid Trial (ACT) I Investigators is provided in the Supplementary Appendix, available at NEJM.org.

Drs. Rosenfield and Matsumura contributed equally to this article.



BACKGROUNDPrevious clinical trials have suggested that carotid-artery stenting with a device to capture and remove emboli (“embolic protection”) is an effective alternative to carotid endarterectomy in patients at average or high risk for surgical complications.

METHODSIn this trial, we compared carotid-artery stenting with embolic protection and ca-rotid endarterectomy in patients 79 years of age or younger who had severe carotid stenosis and were asymptomatic (i.e., had not had a stroke, transient ischemic attack, or amaurosis fugax in the 180 days before enrollment) and were not considered to be at high risk for surgical complications. The trial was designed to enroll 1658 pa-tients but was halted early, after 1453 patients underwent randomization, because of slow enrollment. Patients were followed for up to 5 years. The primary composite end point of death, stroke, or myocardial infarction within 30 days after the pro-cedure or ipsilateral stroke within 1 year was tested at a noninferiority margin of 3 percentage points.

RESULTSStenting was noninferior to endarterectomy with regard to the primary composite end point (event rate, 3.8% and 3.4%, respectively; P = 0.01 for noninferiority). The rate of stroke or death within 30 days was 2.9% in the stenting group and 1.7% in the endar-terectomy group (P = 0.33). From 30 days to 5 years after the procedure, the rate of freedom from ipsilateral stroke was 97.8% in the stenting group and 97.3% in the endarterectomy group (P = 0.51), and the overall survival rates were 87.1% and 89.4%, respectively (P = 0.21). The cumulative 5-year rate of stroke-free survival was 93.1% in the stenting group and 94.7% in the endarterectomy group (P = 0.44).

CONCLUSIONSIn this trial involving asymptomatic patients with severe carotid stenosis who were not at high risk for surgical complications, stenting was noninferior to endarterectomy with regard to the rate of the primary composite end point at 1 year. In analyses that included up to 5 years of follow-up, there were no significant differences between the study groups in the rates of non–procedure-related stroke, all stroke, and survival. (Funded by Abbott Vascular; ACT I ClinicalTrials.gov number, NCT00106938.)

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Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis

Kenneth Rosenfield, M.D., M.H.C.D.S., Jon S. Matsumura, M.D., Seemant Chaturvedi, M.D., Tom Riles, M.D., Gary M. Ansel, M.D., D. Chris Metzger, M.D., Lawrence Wechsler, M.D., Michael R. Jaff, D.O.,

and William Gray, M.D., for the ACT I Investigators*


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From the Mayo Clinic, Jacksonville, FL (T.G.B., J.F.M.); the University of Alabama at Birmingham (G.H., V.J.H.) and Cardiovas-cular Associates of the Southeast (G.S.R.) — both in Birmingham; Centre Hospitalier Universitaire de Québec–Université Laval, Quebec, QC (A.M.), and the University of Calgary, Calgary, AB (M.D.H.) — both in Canada; Baptist Health Lexington, KY (W.B.); the University of California, Los Angeles, Los Angeles (W.S.M.); Mercy Hospital St. Louis, St. Louis (V.A.M.); Oregon Health and Sci-ence University, Portland (W.M.C.); the Uni-versity of Texas Southwestern Medical Cen-ter, Dallas (C.H.T); Novant Health Clinical Research, Winston-Salem, NC (D.H.); the Providence Sacred Heart Medical Center and Children’s Hospital, Spokane, WA (P.P.L.); Rutgers New Jersey Medical School, Newark (A.J.S., R.W.H.); the University of Miami Miller School of Medicine, Miami (S.C.); the University of Maryland Medical Center, Balti-more (B.K.L.); and the Medical University of South Carolina, Charleston (J.H.V.). Address reprint requests to Dr. Brott at the Mayo Clinic, Griffin Bldg. 1st Fl., Rm. 170, 4500 San Pablo Rd. S, Jacksonville, FL 32224, or at brott . thomas@ mayo . edu.

* Deceased.

†A complete list of investigators in the Carotid Revascularization Endarterec-tomy versus Stenting Trial (CREST) is provided in the Supplementary Appen-dix, available at NEJM.org.



BACKGROUNDIn the Carotid Revascularization Endarterectomy versus Stenting Trial, we found no significant difference between the stenting group and the endarterectomy group with respect to the primary composite end point of stroke, myocardial in-farction, or death during the periprocedural period or any subsequent ipsilateral stroke during 4 years of follow-up. We now extend the results to 10 years.

METHODSAmong patients with carotid-artery stenosis who had been randomly assigned to stenting or endarterectomy, we evaluated outcomes every 6 months for up to 10 years at 117 centers. In addition to assessing the primary composite end point, we assessed the primary end point for the long-term extension study, which was ipsilateral stroke after the periprocedural period.

RESULTSAmong 2502 patients, there was no significant difference in the rate of the pri-mary composite end point between the stenting group (11.8%; 95% confidence interval [CI], 9.1 to 14.8) and the endarterectomy group (9.9%; 95% CI, 7.9 to 12.2) over 10 years of follow-up (hazard ratio, 1.10; 95% CI, 0.83 to 1.44). With respect to the primary long-term end point, postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4 to 9.7) of the patients in the stent-ing group and in 5.6% (95% CI, 3.7 to 7.6) of those in the endarterectomy group; the rates did not differ significantly between the groups (hazard ratio, 0.99; 95% CI, 0.64 to 1.52). No significant between-group differences with respect to either end point were detected when symptomatic patients and asymptomatic patients were analyzed separately.

CONCLUSIONSOver 10 years of follow-up, we did not find a significant difference between patients who underwent stenting and those who underwent endarterectomy with respect to the risk of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. The rate of postprocedural ipsilateral stroke also did not differ between groups. (Funded by the National Institutes of Health and Abbott Vascular Solutions; CREST ClinicalTrials.gov number, NCT00004732.)

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Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery StenosisThomas G. Brott, M.D., George Howard, Dr.P.H., Gary S. Roubin, M.D., Ph.D.,

James F. Meschia, M.D., Ariane Mackey, M.D., William Brooks, M.D., Wesley S. Moore, M.D., Michael D. Hill, M.D., Vito A. Mantese, M.D., Wayne M. Clark, M.D., Carlos H. Timaran, M.D., Donald Heck, M.D.,

Pierre P. Leimgruber, M.D., Alice J. Sheffet, Ph.D., Virginia J. Howard, Ph.D., Seemant Chaturvedi, M.D., Brajesh K. Lal, M.D., Jenifer H. Voeks, Ph.D.,

and Robert W. Hobson II, M.D.,* for the CREST Investigators†

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Endarterectomy, Stenting, or Neither for Asymptomatic Carotid-Artery Stenosis

J. David Spence, M.D., and A. Ross Naylor, M.D.

Important data from two large, randomized trials comparing early and late outcomes after carotid endarterectomy and carotid-artery stent-ing have now been published in the Journal.1,2 In common with every other large, multicenter, ran-domized trial to date, the Asymptomatic Carotid Trial (ACT I) and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed that after the perioperative period, there was no difference in the rate of late ipsilateral stroke after endarterectomy or stenting. In ACT I, which included asymptomatic patients who were deemed to be at average risk, the 5-year rate of ipsilateral stroke (excluding the perioperative period) was 2.2% after stenting (i.e., 0.4% per year) and 2.7% after endarterectomy (0.5% per year).1 In CREST, which included symptomatic and asymptomatic patients who were deemed to be at average risk, the estimated 10-year rate of ipsilateral stroke (excluding the perioperative period) was 6.9% after stenting (i.e., 0.7% per year) and 5.6% (0.6% per year) after endarterectomy.2

The fact that there is near-unanimous con-sensus within randomized trials that after the perioperative period the rates of late ipsilateral stroke after stenting do not differ significantly from those after endarterectomy should dispel any lingering concerns about the durability of stenting. That issue has now surely been resolved. What has not been resolved, however, is the issue of the generalizability of randomized-trial find-ings into routine clinical practice, and, more importantly, the vexed question of how best to treat the asymptomatic patient. No one should harbor any illusions that ACT I and CREST have resolved the latter issue.

CREST and ACT I both used credentialing to ensure that only the best interventionists and surgeons performed stenting or endarterectomy within the trials. The commendably low rates of death and stroke during the procedure in ACT I

and CREST attest to this. It therefore remains to be seen whether these findings can be translated into routine clinical practice, if guidelines are changed to further liberalize indications for stenting, especially in asymptomatic patients. This is an important point, because a recent systematic review showed that 9 of 21 large ad-ministrative data-set registries (43%) reported rates of death and stroke in excess of the 3% risk threshold that is recommended by the American Heart Association in asymptomatic patients undergoing stenting, as compared with 1 of 21 registries (5%) after endarterectomy.3 Further-more, the 3% risk threshold is clearly too high, given the reduction of risk with intensive medi-cal therapy. Discrepancies between randomized-trial data (i.e., from ACT I and CREST) and real-world practice are nothing new and, in this case, are probably attributable to the fact that many real-world practitioners in the United States are performing two or fewer procedures annually in asymptomatic patients, with poorer outcomes than their more experienced colleagues.4

The magnitude of the initial procedural risk will ultimately determine whether endarterectomy or stenting is preferable in recently symptomatic patients, and this will be determined by recency of symptoms, age of the patient, and coexisting conditions. However, there is a major concern that the data from these two trials will be un-critically interpreted to mean that stenting is equivalent to endarterectomy and so further ex-acerbate the situation in the United States, where more than 90% of carotid-artery interven-tions are performed in asymptomatic patients, even though evidence suggests that up to 90% of them will undergo an ultimately unnecessary and potentially harmful procedure.5,6 By contrast, the percentage of interventions that are per-formed for asymptomatic stenoses is approxi-mately 60% in Germany and Italy, 15% in Canada

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and Australia, and 0% in Denmark.7 Such dis-crepancies call into question the appropriateness of advocating routine interventions for asymp-tomatic carotid-artery stenosis.

The ACT I authors conceded that in hindsight it would have been preferable to have included a medical group in their trial.1 However, the de-bate about how improvements in modern medi-cal therapy may have lowered the annual risk of stroke had not reached its zenith when ACT I was conceived. It is certainly a highly topical and controversial issue in the current era, because data from both randomized trials and nonran-domized studies suggest that the annual rate of stroke among medically treated asymptomatic patients has declined over the past two decades, regardless of the severity of stenosis at baseline.8 Evidence now suggests that the annual rate of ipsilateral stroke may be as low as 0.5 to 1%8 — a rate that is very similar to that observed in ACT I and CREST after successful stenting or endarterectomy.1,2

Accordingly, contemporary guidelines, which recommend that interventions may be appropri-ate if they can be performed with a risk of less than 3%, are based on historical data from ran-domized trials that were completed decades ago and that should now be considered obsolete. Outside clinical trials, endarterectomy and stent-ing should be reserved for patients with symp-tomatic severe stenosis or for asymptomatic pa-tients who are shown to be at higher risk for stroke with medical therapy than with interven-tion. Such patients (approximately 10 to 15% of patients with asymptomatic stenosis of 70 to 99%) may be identified by an algorithm that incorporates information about microemboli de-tected by means of transcranial Doppler,6,9,10 and in the future by imaging strategies that identify the vulnerable plaque.11

It is hoped that the Carotid Revascularization and Medical Management for Asymptomatic Ca-rotid Stenosis Trial (CREST-2; ClinicalTrials.gov number, NCT02089217), which includes a medi-cal group, will help settle this issue. Unfortu-nately, the Stent-Protected Angioplasty in Asymp-tomatic Carotid Artery Stenosis vs. Endarterectomy (SPACE-2; Current Controlled Trials number, ISRCTN78592017) trial (which also had a third group receiving medical therapy) has now been

abandoned because of poor recruitment. Pend-ing the completion of CREST-2, we think that it would be desirable for interventionists and sur-geons to forgo stenting and endarterectomy in low-risk asymptomatic patients outside that trial. This restraint would not only spare patients from procedures that may be unnecessary, but it should also facilitate early completion of the trial (and so avoid the fate of SPACE-2), so that it may be possible to identify which patients will benefit from an intervention rather than medical therapy alone in an evidence-based rather than an eminence-based manner.


From the Stroke Prevention and Atherosclerosis Research Cen-tre, Robarts Research Institute, Western University, London, ON, Canada (J.D.S.); and the Vascular Surgery Group, Division of Cardiovascular Sciences, Leicester Royal Infirmary, Leicester, United Kingdom (A.R.N.).


1. Rosenfield K, Matsumura JS, Chaturvedi S, et al. Random-ized trial of stent versus surgery for asymptomatic carotid steno-sis. N Engl J Med 2016; 374:1011-20.2. Brott TG, Howard G, Roubin GS, et al. Long-term results of stenting versus endarterectomy for carotid-artery stenosis. N Engl J Med 2016; 374:1021-31.3. Paraskevas KI, Kalmykov EL, Naylor AR. Stroke/death rates following carotid artery stenting and carotid endarterectomy in contemporary administrative dataset registries: a systematic re-view. Eur J Vasc Endovasc Surg 2016; 51: 3-12.4. Choi JC, Johnston SC, Kim AS. Early outcomes after carotid artery stenting compared with endarterectomy for asymptom-atic carotid stenosis. Stroke 2015; 46: 120-5.5. Bogiatzi C, Cocker MS, Beanlands R, Spence JD. Identifying high-risk asymptomatic carotid stenosis. Expert Opin Med Diagn 2012; 6: 139-51.6. Spence JD, Tamayo A, Lownie SP, Ng WP, Ferguson GG. Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis. Stroke 2005; 36: 2373-8.7. Vikatmaa P, Mitchell D, Jensen LP, et al. Variation in clinical practice in carotid surgery in nine countries 2005-2010: lessons from VASCUNET and recommendations for the future of na-tional clinical audit. Eur J Vasc Endovasc Surg 2012; 44: 11-7.8. Naylor AR. Why is the management of asymptomatic carotid disease so controversial? Surgeon 2015; 13: 34-43.9. Spence JD, Coates V, Li H, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptom-atic carotid stenosis. Arch Neurol 2010; 67: 180-6.10. Markus HS, King A, Shipley M, et al. Asymptomatic emboli-sation for prediction of stroke in the Asymptomatic Carotid Em-boli Study (ACES): a prospective observational study. Lancet Neurol 2010; 9: 663-71.11. Naylor AR, Schroeder TV, Sillesen H. Clinical and imaging features associated with an increased risk of late stroke in pa-tients with asymptomatic carotid disease. Eur J Vasc Endovasc Surg 2014; 48: 633-40.DOI: 10.1056/NEJMe1600123Copyright © 2016 Massachusetts Medical Society.

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established in 1812 May 26, 2016 vol. 374 no. 21

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Lonn at the Population Health Research Institute and Hamilton Health Sciences, 237 Barton St. E., Hamilton ON L8L 2X2, Canada, or at eva . lonn@ phri . ca.

* Deceased.

†A complete list of the Heart Outcomes Prevention Evaluation (HOPE)–3 trial investigators is provided in the Supple‑mentary Appendix, available at NEJM.org.

This article was published on April 2, 2016, at NEJM.org.


BACKGROUNDAntihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear.METHODSIn one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 par-ticipants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years.RESULTSThe mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 par-ticipants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 partici-pants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P = 0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second copri-mary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P = 0.02 and P = 0.009, respectively, for trend in the two outcomes).CONCLUSIONSTherapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardio-vascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)

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Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease

Eva M. Lonn, M.D., Jackie Bosch, Ph.D., Patricio López‑Jaramillo, M.D., Ph.D., Jun Zhu, M.D., Lisheng Liu, M.D., Prem Pais, M.D., Rafael Diaz, M.D., Denis Xavier, M.D., Karen Sliwa, M.D., Ph.D., Antonio Dans, M.D.,

Alvaro Avezum, M.D., Ph.D., Leopoldo S. Piegas, M.D., Ph.D., Katalin Keltai, M.D., Ph.D., Matyas Keltai, M.D., Ph.D., Irina Chazova, M.D., Ph.D., Ron J.G. Peters, M.D., Ph.D., Claes Held, M.D., Ph.D., Khalid Yusoff, M.D.,

Basil S. Lewis, M.D., Petr Jansky, M.D., Alexander Parkhomenko, M.D., Ph.D., Kamlesh Khunti, M.D., Ph.D., William D. Toff, M.D., Christopher M. Reid, Ph.D., John Varigos, B.Sc., Lawrence A. Leiter, M.D.,

Dora I. Molina, M.D., Robert McKelvie, M.D., Ph.D., Janice Pogue, Ph.D.,* Joanne Wilkinson, B.A., Hyejung Jung, M.Sc., Gilles Dagenais, M.D., and Salim Yusuf, M.B., B.S., D.Phil., for the HOPE‑3 Investigators†


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The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Yusuf at the Population Health Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at yusufs@ mcmaster . ca.

*Deceased.

†A complete list of the Heart Outcomes Prevention Evaluation (HOPE)–3 trial in‑vestigators is provided in the Supplemen‑tary Appendix, available at NEJM.org.



BACKGROUNDPrevious trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease.

METHODSIn one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 partici-pants in 21 countries who did not have cardiovascular disease and were at intermedi-ate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome addi-tionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years.

RESULTSThe overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P = 0.002). The results for the second coprimary outcome were consistent with the re-sults for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P = 0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P = 0.005).

CONCLUSIONSTreatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE-3 ClinicalTrials.gov number, NCT00468923.)

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Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease

S. Yusuf, J. Bosch, G. Dagenais, J. Zhu, D. Xavier, L. Liu, P. Pais, P. López‑Jaramillo, L.A. Leiter, A. Dans, A. Avezum, L.S. Piegas, A. Parkhomenko,

K. Keltai, M. Keltai, K. Sliwa, R.J.G. Peters, C. Held, I. Chazova, K. Yusoff, B.S. Lewis, P. Jansky, K. Khunti, W.D. Toff, C.M. Reid, J. Varigos,

G. Sanchez‑Vallejo, R. McKelvie, J. Pogue,* H. Jung, P. Gao, R. Diaz, and E. Lonn, for the HOPE‑3 Investigators†

Original Article


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Original Article

BACKGROUNDElevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially.METHODSIn a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at inter-mediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revas-cularization. The median follow-up was 5.6 years.RESULTSThe decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the com-bined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P = 0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P = 0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of dis-continuation of the trial regimen was similar in the two groups.CONCLUSIONSThe combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hy-drochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)

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Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease

Salim Yusuf, M.B., B.S., D.Phil., Eva Lonn, M.D., Prem Pais, M.D., Jackie Bosch, Ph.D., Patricio López‑Jaramillo, M.D., Ph.D., Jun Zhu, M.D., Denis Xavier, M.D., Alvaro Avezum, M.D., Ph.D., Lawrence A. Leiter, M.D.,

Leopoldo S. Piegas, M.D., Ph.D., Alexander Parkhomenko, M.D., Ph.D., Matyas Keltai, M.D., Ph.D., Katalin Keltai, M.D., Ph.D., Karen Sliwa, M.D., Ph.D.,

Irina Chazova, M.D., Ph.D., Ron J.G. Peters, M.D., Ph.D., Claes Held, M.D., Ph.D., Khalid Yusoff, M.D., Basil S. Lewis, M.D., Petr Jansky, M.D.,

Kamlesh Khunti, M.D., Ph.D., William D. Toff, M.D., Christopher M. Reid, Ph.D., John Varigos, B.Sc., Jose L. Accini, M.D., Robert McKelvie, M.D., Ph.D.,

Janice Pogue, Ph.D.,* Hyejung Jung, M.Sc., Lisheng Liu, M.D., Rafael Diaz, M.D., Antonio Dans, M.D., and Gilles Dagenais, M.D., for the HOPE‑3 Investigators†

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Yusuf at the Population Health Re‑search Institute, 237 Barton St. E., Hamil‑ton, ON L8L 2X2, Canada, or at yusufs@ mcmaster . ca .

*Deceased.

†A complete list of the Heart Outcomes Prevention Evaluation (HOPE)–3 trial in‑vestigators is provided in the Supplemen‑tary Appendix, available at NEJM.org.




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More HOPE for Prevention with Statins

William C. Cushman, M.D., and David C. Goff, Jr., M.D., Ph.D.

In view of the worldwide burden of cardiovascu-lar disease and the high cost of and poor adher-ence to medication regimens for the prevention of cardiovascular disease, the concept of a “polypill” — a single pill that combines several medica-tions — is an attractive public health approach. However, evidence that each component of a polypill would independently reduce the risk of cardiovascular events and that the combination of agents would be safe is lacking. The primary results of the Heart Outcomes Prevention Evalu-ation (HOPE)–3 trial are now reported in three articles in the Journal.1-3 HOPE-3 was a double-blind, randomized, placebo-controlled trial with a 2-by-2 factorial design, in which 12,705 inter-mediate-risk men (≥55 years of age) and women (≥60 years of age) who did not have cardiovascu-lar disease were randomly assigned to receive cholesterol-lowering treatment with rosuvastatin at a dose of 10 mg per day or placebo and were also randomly assigned to receive blood-pressure–lowering treatment with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo for a median of 5.6 years. Treatment with rosuvastatin resulted in a 24% lower risk of cardiovascular events than that with placebo (absolute difference, 1.1 per-centage points), but the antihypertensive therapy did not result in a significantly lower risk of cardiovascular events. The HOPE-3 trial provides evidence to reinforce some current guideline recommendations and to influence future guide-lines.

The cholesterol-lowering component of the trial1 produced results consistent with a meta-analysis of randomized trials of statin therapy, which showed that a reduction of 1 mmol per liter in the low-density lipoprotein (LDL) choles-terol level was associated with a 25% lower risk of cardiovascular events in a primary-prevention

population.4 Furthermore, the rate of cardiovas-cular events that was observed in the placebo group (4.8% over a period of 5.6 years) was within the range of the rates that were observed among the lowest-risk groups shown to have a benefit from statin therapy in the meta-analysis. The trial participants who had high-sensitivity C-reactive protein (CRP) levels higher than 2 mg per deciliter and those who had levels lower than 2 mg per deciliter had similar rates of cardiovas-cular events and a similar benefit from rosuva-statin. Hence, these results support a risk-based approach to statin use, which has been recom-mended in recent guidelines,5 rather than an approach that is based primarily on LDL choles-terol levels, and the results add to the evidence supporting statin use for primary prevention.

The blood-pressure–lowering component of the trial2 showed no significant benefit of anti-hypertensive therapy in reducing the risk of cardiovascular events. The observed difference between the active-treatment group and the pla-cebo group in the decrease in blood pressure over the course of the trial (6.0/3.0 mm Hg) was small, and the 95% confidence interval for the estimated hazard ratio did not exclude the bene-fit one might expect (on the basis of the results from the meta-analysis) from this degree of blood-pressure lowering.6 Neither of the drugs for blood-pressure lowering that were used in the trial have been shown to reduce the risk of cardiovascular events at such low doses. If higher doses had been used, the risk of cardiovascular events might have been significantly reduced, whether from greater blood-pressure lowering, additional effects of the antihypertensive drugs, or both. Hydrochlorothiazide, even at a dose of 25 mg per day, has been less effective in reduc-ing the risk of cardiovascular events than has a full dose of amlodipine,7 whereas chlorthalidone

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at a dose of 25 mg per day has been effective in reducing the risk of cardiovascular events in a placebo-controlled trial8 and has been at least as effective as amlodipine.9 These observations suggest that the use of chlorthalidone could have been more effective than the use of hydro-chlorothiazide in HOPE-3.

The trial population was at a lower cardiovas-cular risk than the populations in previous hyper-tension trials. The observed rate of cardiovascu-lar events in the dual-placebo group was 5.0% over a period of 5.6 years. Since most previous trials of blood-pressure lowering have used in-clusion criteria that are designed to increase the level of cardiovascular risk in order to increase trial efficiency, those trials have included few low-risk adults. Meta-analyses of such trials pro-vide evidence of cardiovascular benefit from the use of blood-pressure–lowering medications in adults with an average systolic blood pressure higher than 130 mm Hg and either clinical car-diovascular disease or a high cardiovascular risk (defined as a 5-year risk of cardiovascular events of ≥6.5%).6 In addition, the Systolic Blood Pres-sure Intervention Trial (SPRINT) provides support for the use of blood-pressure–lowering medica-tions in patients who do not have cardiovascular disease but who have a systolic blood pressure higher than 130 mm Hg; in SPRINT, the risks of cardiovascular events and death from any cause were significantly reduced with the use of regi-mens for blood-pressure lowering that were more intensive than the regimen used in this trial.10 However, the SPRINT participants who did not have clinical cardiovascular disease at baseline were required to have subclinical cardiovascular disease or a 10-year cardiovascular risk (on the basis of the Framingham risk score) that was higher than 15%. The difference in systolic blood pressure between the active-treatment and control groups that was seen in SPRINT was twice the difference seen in HOPE-3 because the treatment regimen was more intensive.

The overall null results of the blood-pressure–lowering component of HOPE-3 could be due to insufficient dosing of antihypertensive medica-tions, treatment of a relatively low-risk group, or chance. Setting aside the play of chance, we may take from these results new insight regarding the initiation threshold and treatment targets for blood-pressure–lowering medications. Although no benefit of blood-pressure lowering was ob-

served overall, a prespecified subgroup analysis showed a 27% lower risk of cardiovascular events with blood-pressure–lowering therapy in the subgroup of participants who were in the upper third of systolic blood pressure levels (>143.5 mm Hg). Among the patients in that subgroup who received placebo, the rate of car-diovascular events was 6.5% over a period of 5.6 years. This rate is within the range of rates reported in the previously mentioned meta-analysis. However, the rates of cardiovascular events in the subgroups of participants in the lower and middle thirds of systolic blood pres-sure levels who received placebo were lower than the rates among the lowest-risk groups shown to have benefit from blood-pressure lowering in previous trials. Blood-pressure–lowering treat-ment with low doses of the two drugs used in HOPE-3 may not be effective over the period studied in this trial among patients with low levels of systolic blood pressure and low levels of cardiovascular risk. These results may help to define the combined threshold of systolic blood pressure (<140 mm Hg) and cardiovascular risk (<5.0%) below which the use of blood-pressure–lowering medications may not be useful in the short term. However, these results do not rule out the possibility of a benefit with longer-term treatment in a portion of this relatively low-risk population.

The results of the comparison of the effects of the combined intervention (rosuvastatin and candesartan plus hydrochlorothiazide) with pla-cebo3 generally agreed with the results for the separate interventions. There was no evidence of harm or synergy between the two interventions. Although the addition of blood-pressure lower-ing to rosuvastatin therapy appeared to provide more benefit than that observed with rosuva-statin alone in the subgroup of participants who were in the upper third of systolic blood pres-sure levels, the P value for interaction was not significant.

The results of the HOPE-3 trial suggest that rosuvastatin at a dose of 10 mg per day is more effective in preventing cardiovascular events than is candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day in this relatively low-risk population. Although these results do not exclude the possibility that more effective therapy for blood-pressure lower-ing might be beneficial in a relatively low-risk,

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nejm.org 26 Notable Articles of 2016Editorials


older population, they provide support for the use of statins as a safe and effective intervention to prevent cardiovascular events in such patients.

The opinions expressed in this article do not necessarily repre-sent the official views of the Department of Veterans Affairs or the U.S. government.


From the Preventive Medicine Section, Veterans Affairs Medi-cal Center, Memphis, TN (W.C.C.); and the Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora (D.C.G.).


1. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: 2021-31.2. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: 2009-20.3. Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016; 374: 2032-43.4. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people

at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581-90.5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the Amer-ican College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: Suppl 2: S1-45.6. The Blood Pressure Lowering Treatment Trialists’ Collabo-ration. Blood pressure-lowering treatment based on cardiovas-cular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591-8.7. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: 2417-28.8. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255-64.9. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major out-comes in high-risk hypertensive patients randomized to angio-tensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288: 2981-97.10. The SPRINT Research Group. A randomized trial of inten-sive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103-16.DOI: 10.1056/NEJMe1603504Copyright © 2016 Massachusetts Medical Society.

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n engl j med 375;11 nejm.org September 15, 2016 1019

established in 1812 September 15, 2016 vol. 375 no. 11

The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Heineman at Genocea Biosciences, Cam-bridge Discovery Park, 100 Acorn Park Dr., 5th Floor, Cambridge, MA 02140, or at thomas . heineman@ genocea . com.

* A complete list of investigators in the Zoster Efficacy Study in Adults 70 Years of Age or Older (ZOE-70) Study Group is provided in the Supplementary Appen-dix, available at NEJM.org.

Drs. Cunningham and Lal contributed equally to this article. Authors from Dr. Godeaux to Dr. Zahaf (listed alphabeti-cally) also contributed equally, as did au-thors from Dr. Ahonen to Dr. Yeo (listed alphabetically).


BACKGROUNDA trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella–zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70).

METHODSThis randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.

RESULTSIn ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in partici-pants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated dis-eases, and deaths occurred with similar frequencies in the two study groups.

CONCLUSIONSIn our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neu-ralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229.)

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Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older

A.L. Cunningham, H. Lal, M. Kovac, R. Chlibek, S.-J. Hwang, J. Díez-Domingo, O. Godeaux, M.J. Levin, J.E. McElhaney, J. Puig-Barberà, C. Vanden Abeele, T. Vesikari, D. Watanabe, T. Zahaf, A. Ahonen, E. Athan,

J.F. Barba-Gomez, L. Campora, F. de Looze, H.J. Downey, W. Ghesquiere, I. Gorfinkel, T. Korhonen, E. Leung, S.A. McNeil, L. Oostvogels, L. Rombo, J. Smetana, L. Weckx, W. Yeo, and T.C. Heineman, for the ZOE-70 Study Group*


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Preventing Shingles and Its Complications in Older Persons

Kathleen M. Neuzil, M.D., M.P.H., and Marie R. Griffin, M.D., M.P.H.

In the United States each year, herpes zoster, or shingles, develops in half a million people 60 years of age or older. Although the symptoms are often mild in younger persons, the risk for serious complications of herpes zoster, including postherpetic neuralgia, ocular involvement, and central nervous system disease, increases with advancing age.1 The rising age-specific incidence of shingles and the aging population in the United States are likely to contribute to additional shingles-associated morbidity in coming years.2 The prevention of herpes zoster and its compli-cations in older persons will improve quality of life and should be a public health priority.

Since 2008, the U.S. Advisory Committee on Immunization Practices has recommended that all immunocompetent persons 60 years of age or older receive a single dose of a live attenu-ated herpes zoster vaccine (Zostavax).1 In a large, placebo-controlled trial, the efficacy of this vaccine against herpes zoster was 51.3%, and the efficacy against postherpetic neuralgia was 66.5%.3 Further follow-up of participants and postmarketing studies have confirmed the effec-tiveness of the vaccine and have documented declines in the efficacy of the vaccine over time.4 Among 176,078 members of Kaiser Permanente who were 60 years of age or older and matched controls, the effectiveness of the live attenuated vaccine against herpes zoster decreased from 68.7% (95% confidence interval [CI], 66.3 to 70.9) in the first year after vaccination to 4.2% (95% CI, −24.0 to 25.9) in the eighth year.5 These data, coupled with information on the immuno-genicity of booster doses of the vaccine, will in-form recommendations regarding the need for a subsequent dose or doses.6

In this issue of the Journal, Cunningham et al. report on the efficacy of two doses of an investi-gational, adjuvanted herpes zoster subunit vaccine (HZ/su) in immunocompetent persons 70 years

of age or older.7 This trial, involving 13,900 per-sons, was conducted concurrently with a previ-ously reported trial involving persons 50 years or age or older in which the same vaccine and schedule were used.8 The vaccine contains a recombinant varicella–zoster virus (VZV) glyco-protein E with a novel adjuvant (AS01B) designed to improve CD4+ T-cell–mediated immune re-sponses, which are thought to be important in preventing the reactivation of latent VZV. A lower dose of this adjuvant is used in a malaria vaccine that was approved in 2015 by the European Medicines Agency for children living in areas in which malaria is endemic.

In 2015, the efficacy of HZ/su against herpes zoster was reported as 97.2% (95% CI, 93.7 to 99.0) among participants 50 years of age or older and as 97.9% (95% CI, 87.9 to 100.0) among participants 70 years of age or older dur-ing a mean follow-up period of 3.2 years.8 In the current trial, during a mean follow-up period of 3.7 years, the efficacy against herpes zoster was 89.8% (95% CI, 84.2 to 93.7) in persons 70 years of age or older. Efficacy was similar among par-ticipants who were 70 to 79 years of age and those who were 80 years of age or older, and it was maintained for the duration of the trial. For the outcome of postherpetic neuralgia, the investiga-tors included the participants who were 70 years of age or older from both trials, and they report an efficacy of 88.8% (95% CI, 68.7 to 97.1).

Given the limited efficacy and duration of Zostavax, newer vaccine formulations with im-proved efficacy are welcome. Although the higher point estimates of efficacy with the HZ/su vaccine are encouraging, the direct comparison of results from different trials is problematic. For example, in the pivotal trial evaluating Zostavax, the inci-dence of postherpetic neuralgia in the control group was higher than that in the control group in the HZ/su trial, which may indicate that the

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n engl j med 375;11 nejm.org September 15, 20161080

Zostavax efficacy trial included a more frail population, more active surveillance, or the use of a more sensitive case definition. A major benefit of the HZ/su vaccine as compared with Zostavax appears to be retention of high efficacy against herpes zoster and postherpetic neuralgia in the oldest age groups and over time. Continued fol-low-up of the vaccinated cohorts is warranted.

Although the safety profile regarding serious adverse events reported in the trials of HZ/su was reassuring, a full understanding of less common serious side effects will be known only as larger and more diverse populations are vac-cinated. This is particularly pertinent given the new adjuvant included in this vaccine. It is worth noting that the short-term reactogenicity with this adjuvanted vaccine is higher than with other adult vaccines. In the first 7 days after vaccina-tion, 79.0% of vaccine recipients, versus 29.5% of placebo recipients, reported local or systemic re-actions, and 11.9% of vaccine recipients, versus 2.0% of placebo recipients, reported that their reactions were severe enough to prevent normal activity. It is remarkable that few participants declined the second injection, but whether ad-herence would be similar in a different popula-tion, especially one that included more frail older adults, is unknown.

Policy deliberations regarding the HZ/su vac-cine will need to include consideration of how these trial data will translate into routine condi-tions of use. The HZ/su trials reported data on participants who received two doses of vaccine — therefore, the efficacy of a single dose, or of two doses given on a different schedule, is not known. Persons with a history of herpes zoster or of herpes zoster vaccination were excluded from these trials, so the benefit of the vaccine in those populations is uncertain. Ultimately, HZ/su may provide an option for immunocompromised persons who are at high risk for herpes zoster and its complications and are unable to receive the live attenuated vaccine. This would be a ma-jor advance in efforts to prevent herpes zoster.

Despite the 2008 recommendations for the zoster vaccine, by 2014 only 27.9% of adults 60 years of age or older reported being vaccinated.9 In the early years after vaccine approval, supply

constraints limited uptake. In more recent years, the supply has been sufficient, and the reasons for the continued poor uptake include provider challenges (e.g., cost, storage of the frozen formu-lation, and complex Medicare reimbursement), limited public awareness of the disease and vac-cine, a lack of requirements for adult vaccina-tion, and the focus on acute medical care over prevention among practitioners caring for adult patients.10 Although HZ/su may address some of these issues, such as easier storage requirements for a nonreplicating product, it will have its own challenges, including the two-dose schedule and the higher reactogenicity. Thus, the full public health value of herpes zoster vaccines will not be realized unless we identify and address barriers to delivery and uptake.

Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.

From the Center for Vaccine Development, University of Mary-land School of Medicine, Baltimore (K.M.N.); and the Depart-ments of Health Policy and Medicine, Vanderbilt University Medical Center, Nashville (M.R.G.).

1. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immuni-zation Practices (ACIP). MMWR Recomm Rep 2008; 57(RR-5): 1-30.2. Kawai K, Yawn BP, Wollan P, Harpaz R. Increasing incidence of herpes zoster over a 60-year period from a population-based study. Clin Infect Dis 2016; 63: 221-6.3. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to pre-vent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352: 2271-84.4. Morrison VA, Johnson GR, Schmader KE, et al. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 2015; 60: 900-9.5. Tseng HF, Harpaz R, Luo Y, et al. Declining effectiveness of herpes zoster vaccine in adults aged ≥60 years. J Infect Dis 2016; 213: 1872-5.6. Levin MJ, Schmader KE, Pang L, et al. Cellular and humoral responses to a second dose of herpes zoster vaccine adminis-tered 10 years after the first dose among older adults. J Infect Dis 2016; 213: 14-22.7. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the her-pes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med 2016; 375: 1019-32.8. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015; 372: 2087-96.9. Williams WW, Lu PJ, O’Halloran A, et al. Surveillance of vaccination coverage among adult populations — United States, 2014. MMWR Surveill Summ 2016; 65: 1-36.10. Hurley LP, Bridges CB, Harpaz R, et al. Physician attitudes toward adult vaccines and other preventive practices, United States, 2012. Public Health Rep 2016; 131: 320-30.DOI: 10.1056/NEJMe1610652Copyright © 2016 Massachusetts Medical Society.

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The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Hamdy at the Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Bldg., Roosevelt Dr., Headington, Oxford OX3 7DQ, United Kingdom, or at freddie . hamdy@ nds . ox . ac . uk.

* A complete list of investigators in the Prostate Testing for Cancer and Treatment (ProtecT) trial is provided in the Supplementary Appendix, available at NEJM.org.

Drs. Hamdy, Donovan, Lane, and Neal contributed equally to this article.

This article was published on September 14, 2016, at NEJM.org.


BACKGROUNDThe comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain.

METHODSWe compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths.

RESULTSThere were 17 prostate-cancer–specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P = 0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P = 0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P = 0.004 for the overall comparison). Higher rates of disease progression were seen in the active-mon-itoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison).

CONCLUSIONSAt a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treat-ment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

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10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

F.C. Hamdy, J.L. Donovan, J.A. Lane, M. Mason, C. Metcalfe, P. Holding, M. Davis, T.J. Peters, E.L. Turner, R.M. Martin, J. Oxley, M. Robinson, J. Staffurth, E. Walsh, P. Bollina, J. Catto, A. Doble, A. Doherty, D. Gillatt,

R. Kockelbergh, H. Kynaston, A. Paul, P. Powell, S. Prescott, D.J. Rosario, E. Rowe, and D.E. Neal, for the ProtecT Study Group*


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The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Donovan at the School of Social and Community Medicine, University of Bris-tol, Canynge Hall, 39 Whatley Rd., Bristol BS8 2PS, United Kingdom, or at jenny . donovan@ bristol . ac . uk.

* A complete list of investigators in the Prostate Testing for Cancer and Treat-ment (ProtecT) Study Group is provided in the Supplementary Appendix, avail-able at NEJM.org.

Drs. Donovan, Hamdy, Lane, and Neal contributed equally to this article.

This article was published on September 14, 2016, at NEJM.org.


BACKGROUNDRobust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes.

METHODSWe compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific ef-fects on quality of life, anxiety and depression, and general health. Cancer-related qual-ity of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle.

RESULTSThe rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function de-clined gradually in the active-monitoring group. Bowel function was worse in the radio-therapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life.

CONCLUSIONSIn this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and as-sociated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

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Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer

J.L. Donovan, F.C. Hamdy, J.A. Lane, M. Mason, C. Metcalfe, E. Walsh, J.M. Blazeby, T.J. Peters, P. Holding, S. Bonnington, T. Lennon, L. Bradshaw, D. Cooper, P. Herbert, J. Howson, A. Jones, N. Lyons, E. Salter, P. Thompson,

S. Tidball, J. Blaikie, C. Gray, P. Bollina, J. Catto, A. Doble, A. Doherty, D. Gillatt, R. Kockelbergh, H. Kynaston, A. Paul, P. Powell, S. Prescott, D.J. Rosario, E. Rowe, M. Davis, E.L. Turner, R.M. Martin, and D.E. Neal, for the ProtecT Study Group*

Original Article


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Treatment or Monitoring for Early Prostate CancerAnthony V. D’Amico, M.D., Ph.D.

The “best” initial approach to early (low-risk or intermediate-risk)1 prostate cancer remains un-known. Specifically, does active monitoring with the use of prostate-specific antigen (PSA) testing as opposed to treatment lead to increased metas-tasis and death from prostate cancer? If yes, then which treatment, radical prostatectomy or radia-tion with or without short-term (3 to 6 months) androgen-suppression therapy, minimizes metas-tasis and death from prostate cancer?

Hamdy and colleagues now report in the Jour-nal the results of a randomized comparison of three of these four approaches after a median follow-up of 10 years,2 and Donovan and col-leagues present data on patient-reported health-related quality of life at 6 years of follow-up.3 Men were screened with PSA testing and pre-sented at a median age of 62 years with favorable clinical characteristics: 76% had stage T1c (PSA-detected) disease, 77% and 21% had tumors with Gleason scores of 6 and 7, respectively (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and the median PSA level was 4.6 ng per milliliter. Although a median follow-up of 10 years was too short to evaluate the primary outcome of prostate-cancer mortal-ity in this favorable cohort (death from prostate cancer occurred in 8 of the 545 men assigned to active monitoring, 5 of the 553 men assigned to surgery, and 4 of the 545 men assigned to ra-diotherapy), it was adequate to evaluate the sec-ondary outcome of the incidence of metastatic disease, defined as bony, visceral, or lymph-node metastasis on imaging or a PSA level above 100 ng per milliliter.

Several important observations were made. First, men assigned to active monitoring were significantly more likely to have metastatic dis-ease than those assigned to treatment (P = 0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death

from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence inter-val [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring. Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was estab-lished. The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong in-termittent androgen-deprivation therapy), which are not inconsequential.4

Second, within the prerandomization stratum of age, a near-significant interaction (P = 0.09 for interaction) was observed given that men 65 years of age or older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment. This finding prob-ably reflects the fact that advancing age is associ-ated with higher-grade disease than disease iden-tified at an initial biopsy5 owing to sampling error, resulting in undergrading, the risk of which rises with the increasing prostate-gland volume6 that occurs with advancing age.7 Should the in-teraction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to moni-toring to otherwise healthy men 65 years of age or older with early prostate cancer who today are increasingly being placed on active surveillance,8 given that the reduction in death from prostate cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09) in the Prostate Cancer Intervention versus Ob-servation Trial (PIVOT) only trended toward significance (P = 0.09).9 However, the increasing use of surveillance is already of potential con-cern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into

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nejm.org 33 Notable Articles of 2016Editorials


the Surveillance, Epidemiology, and End Results database.10

Finally, a trend favoring radiation and short-course androgen-deprivation therapy over surgery was observed. Specifically, the point estimate for the hazard ratio for death from prostate cancer when comparing these two treatments was 0.80 (95% CI, 0.22 to 2.99). If this trend becomes significant, then one may consider radiation and androgen-deprivation therapy as a preferred op-tion for otherwise healthy men 65 years of age or older with early prostate cancer for whom treatment as compared with monitoring may be more effective (P = 0.09 for interaction) in reduc-ing death from prostate cancer.

For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as com-pared with treatment of early prostate cancer, leads to increased metastasis. Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shorten-ing coexisting disease such that his life expec-tancy is less than the 10-year median follow-up of the current study.2 In addition, given no sig-nificant difference in death due to prostate can-cer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and with-out fear of possibly selecting a less effective can-cer therapy.

Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.

From the Department of Radiation Oncology, Brigham and Women’s Hospital and Dana–Farber Cancer Institute, Boston.

This editorial was published on September 14, 2016, at NEJM.org.

1. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate can-cer, version 1.2016. J Natl Compr Canc Netw 2016; 14: 19-30.2. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016; 375:1415-24.3. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported out-comes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016; 375:1425-37.4. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation ther-apy for prostate cancer. JAMA 2005; 294: 238-44.5. Anderson CB, Sternberg IA, Karen-Paz G, et al. Age is asso-ciated with upgrading at confirmatory biopsy among men with prostate cancer treated with active surveillance. J Urol 2015; 194: 1607-11.6. Moussa AS, Kattan MW, Berglund R, Yu C, Fareed K, Jones JS. A nomogram for predicting upgrading in patients with low- and intermediate-grade prostate cancer in the era of extended prostate sampling. BJU Int 2010; 105: 352-8.7. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132: 474-9.8. Cooperberg MR, Carroll PR. Trends in management for pa-tients with localized prostate cancer, 1990-2013. JAMA 2015; 314: 80-2.9. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203-13.10. Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial man-agement of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 2014; 113: 43-50.DOI: 10.1056/NEJMe1610395Copyright © 2016 Massachusetts Medical Society.

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From the Department of Microbiology (B.P., A.F.Z.-V.), the Department of Inter-nal Medicine, Hospital Universitario del Valle (A.F.Z.-V., G.Z.), and Escuela de Salud Publica (L.O.), Universidad del Valle, Cali, Hospital Universitario Erasmo Meoz, Universidad de Pamplona, Cucuta (J.L.), Universidad de Antioquia, Clinica Leon XIII, Neuroclinica, Medellin ( J.A.J.-A., R.L.-G.), Universidad Surcolombiana, Hos-pital Universitario de Neiva (G.G.-M., C.L.B.), and Clinica Medilaser ( J.A.A.), Neiva, Clinica La Misericordia Internacio-nal, Barranquilla (J.V., K.H.R., M.T.M.), and Instituto Nacional de Salud, Bogota (O.P., M.L.O.) — all in Colombia; and the Departments of Neurology (A.K., D.R.C., L.S.M., P.B., C.A.P.) and Pathology (C.A.P.), Johns Hopkins University School of Med-icine, Baltimore. Address reprint requests to Dr. Pardo at Johns Hopkins University School of Medicine, 600 N. Wolfe St., 627 Pathology Bldg., Baltimore, MD 21287, or at cpardov1@ jhmi . edu.

This article was published on October 5, 2016, at NEJM.org.


BACKGROUNDZika virus (ZIKV) infection has been linked to the Guillain–Barré syndrome. From No-vember 2015 through March 2016, clusters of cases of the Guillain–Barré syndrome were observed during the outbreak of ZIKV infection in Colombia. We characterized the clini-cal features of cases of Guillain–Barré syndrome in the context of this ZIKV infection outbreak and investigated their relationship with ZIKV infection.

METHODSA total of 68 patients with the Guillain–Barré syndrome at six Colombian hospitals were evaluated clinically, and virologic studies were completed for 42 of the patients. We per-formed reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays for ZIKV in blood, cerebrospinal fluid, and urine, as well as antiflavivirus antibody assays.

RESULTSA total of 66 patients (97%) had symptoms compatible with ZIKV infection before the onset of the Guillain–Barré syndrome. The median period between the onset of symp-toms of ZIKV infection and symptoms of the Guillain–Barré syndrome was 7 days (inter-quartile range, 3 to 10). Among the 68 patients with the Guillain–Barré syndrome, 50% were found to have bilateral facial paralysis on examination. Among 46 patients in whom nerve-conduction studies and electromyography were performed, the results in 36 pa-tients (78%) were consistent with the acute inflammatory demyelinating polyneuropathy subtype of the Guillain–Barré syndrome. Among the 42 patients who had samples tested for ZIKV by RT-PCR, the results were positive in 17 patients (40%). Most of the positive RT-PCR results were in urine samples (in 16 of the 17 patients with positive RT-PCR re-sults), although 3 samples of cerebrospinal fluid were also positive. In 18 of 42 patients (43%) with the Guillain–Barré syndrome who underwent laboratory testing, the presence of ZIKV infection was supported by clinical and immunologic findings. In 20 of these 42 patients (48%), the Guillain–Barré syndrome had a parainfectious onset. All patients tested were negative for dengue virus infection as assessed by RT-PCR.

CONCLUSIONSThe evidence of ZIKV infection documented by RT-PCR among patients with the Guillain–Barré syndrome during the outbreak of ZIKV infection in Colombia lends support to the role of the infection in the development of the Guillain–Barré syndrome. (Funded by the Bart McLean Fund for Neuroimmunology Research and others.)

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Guillain–Barré Syndrome Associated with Zika Virus Infection in Colombia

Beatriz Parra, Ph.D., Jairo Lizarazo, M.D., Jorge A. Jiménez-Arango, M.D., Andrés F. Zea-Vera, M.D., Ph.D., Guillermo González-Manrique, M.D., José Vargas, M.D., Jorge A. Angarita, M.D., Gonzalo Zuñiga, M.D., Reydmar Lopez-Gonzalez, M.D., Cindy L. Beltran, M.D., Karen H. Rizcala, M.D., Maria T. Morales, M.D., Oscar Pacheco, M.D., Martha L. Ospina, M.D., Anupama Kumar, M.B., B.S., David R. Cornblath, M.D.,

Laura S. Muñoz, M.D., Lyda Osorio, M.D., Ph.D., Paula Barreras, M.D., and Carlos A. Pardo, M.D.


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Zika Getting on Your Nerves? The Association with the Guillain–Barré Syndrome

Jennifer A. Frontera, M.D., and Ivan R.F. da Silva, M.D., Ph.D.

Parra and colleagues1 report in the Journal the results of a prospective study of 68 Colombian patients who had a syndrome consistent with the Guillain–Barré syndrome, 66 of whom had previously had symptoms of Zika virus (ZIKV) infection. Major strengths of this study include the documentation of a temporal relationship between the Guillain–Barré syndrome and ZIKV infection (marked by a substantial increase in the incidence of the Guillain–Barré syndrome after the introduction of ZIKV, from 20 to 90 cases per month throughout Colombia), the cri-teria applied for the diagnosis of the Guillain–Barré syndrome, and the molecular and sero-logic f lavivirus data from analyses of serum, cerebrospinal fluid (CSF), and urine.

However, the difficulties related to diagnos-ing ZIKV infection are multifold. First, the symp-toms associated with ZIKV infection are similar to those caused by dengue virus (DENV) and chikungunya virus, both of which are endemic in Colombia. Second, the serologic cross-reactivity among flaviviruses (including yellow fever virus, West Nile virus, DENV, and Japanese encephalitis virus) have been well described.2 Although the Centers for Disease Control and Prevention (CDC) recommends neutralizing antibody testing with a plaque-reduction neutralization test to distinguish among flaviviruses,3 this testing is expensive, requires cell culture, and is also sus-ceptible to cross-reactivity.4 Polymerase-chain-reaction (PCR) testing can definitively identify ZIKV, but molecular studies of serum are usu-ally sensitive only during the first week after infection. Because the Guillain–Barré syndrome has been linked to microbial pathogens through a molecular mimicry mechanism, it is typically diagnosed 1 week or longer after an infection.

Indeed, Parra et al. observed that the median time to onset of the Guillain–Barré syndrome was 7 days after ZIKV infection.

The authors deal with these diagnostic dilem-mas by showing that ZIKV PCR testing of other body fluids (particularly urine) may remain sen-sitive for a longer duration than does testing of serum. Indeed, in 13 patients, ZIKV PCR results were positive only in urine, whereas serum, CSF, or both were PCR-negative when tested in a similar time frame. IgM antibody testing of CSF for both ZIKV and DENV may be another diag-nostic strategy, since the IgM pentamer is too large to cross the blood–brain barrier.5 There-fore, CSF that is positive for ZIKV IgM and negative for DENV IgM would be suggestive of a primary central nervous system ZIKV infection. Of the patients who tested positive for ZIKV by PCR and underwent CSF IgM testing, 8 were PCR-positive but ZIKV IgM–negative in CSF, which suggested that ZIKV PCR testing of urine may be more sensitive than serologic testing of CSF.

The difficulties in diagnosing ZIKV infection are borne out in this study, as only 17 patients had definitive laboratory evidence of recent ZIKV infection. On the basis of Table S5 in the Parra et al. Supplementary Appendix, of these 17 pa-tients, only 14 had electrophysiological data con-sistent with the Guillain–Barré syndrome and therefore could have met Brighton level 1 diag-nostic criteria for the syndrome, although the actual number of patients meeting level 1 criteria may have been smaller because we do not know the corresponding results of CSF testing for these patients.6 Because of these limitations in diagnostic certainty for both ZIKV infection and the Guillain–Barré syndrome, a strong associa-tion was identified in approximately 20% of pa-

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tients in this cohort (14 of 68). Among the 25 ZIKV PCR–negative patients, DENV IgG antibod-ies were present in the CSF of 12 patients and in the serum of 10 patients, and serum DENV IgM test results were positive in 1. These data raise the possibility of primary DENV infection and false positive ZIKV serologic test results due to cross-reactivity. In addition, data on yellow fever vaccination or infection were not provided; yel-low fever is also endemic in much of Colombia and may complicate the interpretation of the ZIKV serologic results.

As is true with most clinical studies, proving a causal relationship between ZIKV infection and the Guillain–Barré syndrome is challenging. In keeping with Hill criteria for causality,7 the au-thors show a consistent, specific, temporal rela-tionship, which is analogous to relationships between ZIKV infection and the Guillain–Barré syndrome observed in other countries.8,9 What is more difficult to demonstrate is pathophysiolog-ical plausibility. The authors point out that 20 pa-tients had neurologic symptoms immediately after the viral syndrome (only 9 of 20 had defi-nite laboratory-proven ZIKV) and speculate that other mechanisms, including a hyperacute im-mune response or direct viral neuropathic mech-anisms, may be in effect, rather than postinfec-tious molecular mimicry. Although studies using human neural progenitor cells have shown that ZIKV infection increases cell death and dysregu-lates cell-cycle progression,10 evidence of direct neurotropism in adult neuronal cells is still lack-ing. A recent study showed that there is a high peptide overlap between the ZIKV polyprotein and human proteins related to myelin and axons, which suggests that an immune-mediated mech-anism may be more likely.11 Although protein epitopes and antibodies that are normally in-volved in the genesis of the Guillain–Barré syn-drome seem not to be highly involved in one cohort with ZIKV-associated acute motor axonal neuropathy,8 it is possible that differences in sub-types of the Guillain–Barré syndrome and host genetic factors may lead to varying immune-mediated mechanisms in different populations.

Overall, the study by Parra and colleagues supports the association between ZIKV and the Guillain–Barré syndrome, although confirmation in another cohort would strengthen this asser-tion. Although high rates of seropositivity may prove protective against further waves of ZIKV-related Guillain–Barré syndrome in Central and South America, the ZIKV pandemic is just begin-ning in North America and Africa, and an in-crease in the incidence of the Guillain–Barré syndrome may follow.

Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.

From the Cerebrovascular Center of the Neurological Institute, Cleveland Clinic, Cleveland (J.A.F.); and the Neurology Depart-ment, Universidade Federal Fluminense, Niteroi (I.R.F.S.), and the Neurocritical Care Department, Americas Medical City, Rio de Janeiro (I.R.F.S.) — both in Brazil.

This article was published on October 5, 2016, at NEJM.org.

1. Parra B, Lizarazo J, Jiménez-Arango JA, et al. Guillain–Barré syndrome associated with Zika virus infection in Colombia. N Engl J Med 2016; 375:1513-23.2. Mansfield KL, Horton DL, Johnson N, et al. Flavivirus- induced antibody cross-reactivity. J Gen Virol 2011; 92: 2821-9.3. Update on interim Zika virus clinical guidance and recom-mendations: Clinician Outreach and Communication Activity (COCA) call. Atlanta: Centers for Disease Control and Preven-tion, February 25, 2016 (http://emergency .cdc .gov/ coca/ ppt/ 2016/ 03_3_16_zika_update .pdf).4. Laboratory testing for Zika virus infection. Geneva: World Health Organization, March 23, 2016 (http://apps .who .int/ iris/ bitstream/ 10665/ 204671/ 1/ WHO_ZIKV_LAB_16 .1_eng .pdf?ua=1).5. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Dis-eases Society of America. Clin Infect Dis 2008; 47: 303-27.6. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collec-tion, analysis, and presentation of immunization safety data. Vaccine 2011; 29: 599-612.7. Hill AB. The environment and disease: association or causa-tion? Proc R Soc Med 1965; 58: 295-300.8. Cao-Lormeau VM, Blake A, Mons S, et al. Guillain-Barré syn-drome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016; 387: 1531-9.9. da Silva IR, Frontera JA, Moreira do Nascimento OJ. News from the battlefront: Zika virus-associated Guillain-Barré syn-drome in Brazil. Neurology 2016 July 15 (Epub ahead of print).10. Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016; 18: 587-90.11. Lucchese G, Kanduc D. Zika virus and autoimmunity: from microcephaly to Guillain-Barré syndrome, and beyond. Autoim-mun Rev 2016; 15: 801-8.


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The members of the writing committee (Richard K. Albert, M.D., David H. Au, M.D., Amanda L. Blackford, Sc.M., Richard Casaburi, M.D., Ph.D., J. Allen Cooper, Jr., M.D., Gerard J. Criner, M.D., Philip Diaz, M.D., Anne L. Fuhlbrigge, M.D., Steven E. Gay, M.D., Richard E. Kanner, M.D., Neil MacIntyre, M.D., Fernando J. Martinez, M.D., Ralph J. Panos, M.D., Steven Piantadosi, M.D., Ph.D., Frank Sciurba, M.D., David Shade, J.D., Thomas Stibolt, M.D., James K. Stoller, M.D., Robert Wise, M.D., Roger D. Yusen, M.D., James Tonascia, Ph.D., Alice L. Stern-berg, Sc.M., and William Bailey, M.D.) as-sume responsibility for this article. The affiliations of the members of the writing committee are listed in the Appendix. Ad-dress reprint requests to Dr. Wise at the Johns Hopkins Asthma and Allergy Cen-ter, 4B.72, Division of Pulmonary and Critical Care, 5501 Hopkins Bayview Cir-cle, Baltimore, MD 21224, or at rwise@ jhmi . edu.

* A complete list of investigators in the Long-Term Oxygen Treatment Trial (LOTT) Research Group is provided in the Supplementary Appendix, available at NEJM.org.


BACKGROUNDLong-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation.

METHODSWe originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin satu-ration as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the ran-domization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked.

RESULTSA total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = 0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes.

CONCLUSIONSIn patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198.)

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A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation

The Long-Term Oxygen Treatment Trial Research Group*


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Clinical Usefulness of Long-Term Oxygen Therapy in Adults

Magnus Ekström, M.D., Ph.D.

The fact that we all need oxygen to survive might make the benefit of supplemental oxygen in hypox-emia seem obvious. It is not. Long-term oxygen therapy was the first treatment to improve prog-nosis in patients with chronic obstructive pulmo-nary disease (COPD) and chronic severe hypox-emia.1,2 However, the question of whether long-term oxygen therapy is beneficial in moder-ate hypoxemia has been floating in the air.

The literature on the efficacy of long-term oxygen therapy requires no librarian. The current indications for its use are based on two un-blinded, randomized trials that were conducted in the 1970s and involved a total of 290 patients.1,2 Long-term oxygen therapy given for 15 hours or more per day prolonged survival, as compared with only nocturnal use or no such therapy.1,2 Par-ticipants had COPD and chronic severe hypox-emia (a partial pressure of arterial oxygen [Pao2] of ≤55 mm Hg or an oxyhemoglobin saturation level as measured by pulse oximetry [Spo2] of approximately 88%) or moderate hypoxemia (Pao2 of 56 to 59 mm Hg or Spo2 between 88% and 90%) with signs of heart failure on the right side or polycythemia.1,2 These characteristics have since been the clinical eligibility criteria for long-term oxygen therapy.3 Of note, patients in the trials were younger and had fewer coexisting conditions than patients starting long-term oxy-gen therapy in current practice.4 A survival benefit was not seen in two smaller trials in the 1990s of nocturnal oxygen (in 76 patients)5 or long-term oxygen therapy (in 135)6 among patients with mild-to-moderate hypoxemia.

But does long-term oxygen therapy reduce breathlessness or improve quality of life? With regard to patients who have COPD with mild-to-moderate hypoxemia, some data suggest that supplemental oxygen decreases breathlessness

during exercise testing or structured training,7 but evidence of efficacy with regard to symp-toms and quality of life in the home setting is lacking.3,8,9 In patients with severe hypoxemia, the effect of long-term oxygen therapy on patient-reported outcomes has not been studied.9

Thus, despite frequent prescription, relatively high costs, and the potential burden on patients of long-term oxygen therapy, quality evidence regarding its clinical usefulness in patients with COPD and moderate hypoxemia has been lack-ing.3 Until now.

As published in this issue of the Journal, the Long-Term Oxygen Treatment Trial (LOTT)10 ran-domly assigned 738 participants with COPD (73% of whom were men) and mild-to-moderate hypox-emia at rest or during a 6-minute walk test to receive either long-term supplemental oxygen or no long-term supplemental oxygen. The supple-mental oxygen was prescribed as 2 liters of oxy-gen per minute continuously in participants with resting hypoxemia (57% of the participants) and as an adjusted oxygen dose during exercise and 2 liters of oxygen per minute during sleep in participants with exertional hypoxemia only (43%). During a median follow-up of 18.4 months, there was no significant between-group differ-ence in the rate of death or first hospitalization in the time-to-event analysis (primary outcome) or in mortality and the rate of hospitalizations separately, COPD exacerbations, quality of life, anxiety, depression, or functional status.

This landmark study is the largest to date with regard to long-term oxygen therapy. It evalu-ated clinically relevant patient outcomes in daily life. Owing to slow recruitment, there were early changes in the trial; from two separate trials, one involving patients with resting desaturation and one involving patients with exercise desatu-

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ration, the investigators created a composite trial that included both types of patients. Although this change added complexity, the trial met its target sample size and included clinically rele-vant subgroups of patients and treatment strate-gies for which evidence is needed. Similar to previous trials,1,2,5,6 the LOTT was unblinded, which may have confounded the effect of long-term oxygen therapy to seem more beneficial (e.g., because of a placebo effect or more clinical contacts in the supplemental-oxygen group, es-pecially for patient-reported outcomes) or less beneficial (e.g., a lower threshold for seeking or providing care in people in the no-supplemental-oxygen group). The validity of the findings is supported by the consistent lack of effect across outcomes, which was not modified by type of oxygen prescription, desaturation profile, oxygen use, sex, smoking status, and lung function.

I believe that on the basis of all available cur-rent data, long-term oxygen therapy should be prescribed to prolong survival among patients with COPD who have chronic (>3 weeks) severe resting hypoxemia (Pao2 of ≤55 mm Hg or Spo2 of <88%) while they are breathing ambient air. Since a lack of evidence of effect is not evidence of a lack of any clinical effectiveness, a trial of oxygen use might still be appropriate in selected patients with moderate exertional hypoxemia and intractable breathlessness despite appropriate evidence-based treatment. I think that the oxy-gen treatment should be evaluated by means of blinded exercise tests while the patient is breath-ing ambient air or oxygen and discontinued if the patient perceives no benefit during the test or within a day or two after it.8 If there is benefit, these selected patients should be prescribed oxy-gen, and I think that this treatment should be

covered by insurance payers. However, long-term oxygen therapy should not be routinely prescribed in patients with mild or moderate hypoxemia at rest or during exercise.

Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.

From the Department of Clinical Sciences, Division of Respira-tory Medicine and Allergology, Lund University, Lund, and the Department of Medicine, Blekinge Hospital, Karlskrona — both in Sweden.

1. Nocturnal Oxygen Therapy Trial Group. Continuous or noc-turnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93: 391-8.2. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema: report of the Medical Research Council Working Party. Lancet 1981; 1: 681-6.3. Hardinge M, Annandale J, Bourne S, et al. British Thoracic Society guidelines for home oxygen use in adults. Thorax 2015; 70: Suppl 1: i1-43.4. Ekström MP, Wagner P, Ström KE. Trends in cause-specific mortality in oxygen-dependent chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011; 183: 1032-6.5. Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmo-nary disease patients. Eur Respir J 1999; 14: 1002-8.6. Górecka D, Gorzelak K, Sliwiński P, Tobiasz M, Zieliński J. Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxae-mia. Thorax 1997; 52: 674-9.7. Uronis HE, Ekström MP, Currow DC, McCrory DC, Samsa GP, Abernethy AP. Oxygen for relief of dyspnoea in people with chronic obstructive pulmonary disease who would not qualify for home oxygen: a systematic review and meta-analysis. Thorax 2015; 70: 492-4.8. Abernethy AP, McDonald CF, Frith PA, et al. Effect of pallia-tive oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010; 376: 784-93.9. Cranston JM, Crockett AJ, Moss JR, Alpers JH. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005; 4: CD001744.10. The Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med 2016; 375: 1617-27.DOI: 10.1056/NEJMe1611742Copyright © 2016 Massachusetts Medical Society.

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Perspective


February 18, 2016


The explosive pandemic of Zika virus infection occurring throughout South America, Central America, and the Caribbean (see map) and

potentially threatening the United States is the most

recent of four unexpected arrivals of important arthropod-borne vi-ral diseases in the Western Hemi-sphere over the past 20 years. It follows dengue, which entered this hemisphere stealthily over decades and then more aggres-sively in the 1990s; West Nile vi-rus, which emerged in 1999; and chikungunya, which emerged in 2013. Are the successive migra-tions of these viruses unrelated, or do they reflect important new patterns of disease emergence? Furthermore, are there secondary health consequences of this arbo-virus pandemic that set it apart from others?

“Arbovirus” is a descriptive term applied to hundreds of pre-dominantly RNA viruses that are transmitted by arthropods, notably

mosquitoes and ticks. Arboviruses are often maintained in complex cycles involving vertebrates such as mammals or birds and blood-feeding vectors. Until recently, only a few arboviruses had caused clinically significant human dis-eases, including mosquito-borne alphaviruses such as chikungunya and flaviviruses such as dengue and West Nile. The most histori-cally important of these is yellow fever virus, the first recognized viral cause of deadly epidemic hemorrhagic fever.

Zika, which was discovered in-cidentally in Uganda in 1947 in the course of mosquito and pri-mate surveillance,1 had until now remained an obscure virus con-fined to a narrow equatorial belt running across Africa and into

Asia. The virus circulated pre-dominantly in wild primates and arboreal mosquitoes such as Aedes africanus and rarely caused recog-nized “spillover” infections in hu-mans, even in highly enzootic areas.2 Its current explosive pan-demic reemergence is therefore truly remarkable.3 Decades ago, African researchers noted that aedes-transmitted Zika epizootics inexplicably tended to follow aedes-transmitted chikungunya epizo-otics and epidemics. An analogous pattern began in 2013, when chi-kungunya spread pandemically from west to east, and Zika later followed. Zika has now circled the globe, arriving not only in the Americas but also, in September, in the country of Cape Verde in West Africa, near its presumed ancient ancestral home.

With the exception of West Nile virus, which is predominantly spread by culex-species mosqui-toes, the arboviruses that recently reached the Western Hemisphere

Zika Virus in the Americas — Yet Another Arbovirus ThreatAnthony S. Fauci, M.D., and David M. Morens, M.D.

Zika Virus in the Americas

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have been transmitted by aedes mosquitoes, especially the yellow fever vector mosquito A. aegypti. These viruses started to emerge millennia ago, when North Afri-can villagers began to store wa-ter in their dwellings. Arboreal A. aegypti then adapted to deposit their eggs in domestic water-containing vessels and to feed on humans, which led to adaptation of arboreal viruses to infect hu-mans. The yellow fever, dengue, and chikungunya viruses evolved entirely new maintenance cycles of human–A. aegypti–human trans-mission.4 Now, 5000 years later, the worst effects of this evolu-tionary cascade are being seen in the repeated emergence of arbo-viruses into new ecosystems in-volving humans. Moreover, arbo-viruses transmitted by different mosquitoes have, in parallel, adapted to humans’ domestic an-imals, such as horses in the case of Venezuelan equine encephalitis and pigs in the case of Japanese encephalitis virus, or to verte-brate hosts and non-aedes mos-

quitoes found in areas of human habitation, as West Nile virus did. The possibility that Zika may yet adapt to transmission by A. albop-ictus, a much more widely distrib-uted mosquito found in at least 32 states in the United States, is cause for concern.

Through early epidemiologic surveillance and human challenge studies, Zika was characterized as a mild or inapparent dengue-like disease with fever, muscle aches, eye pain, prostration, and maculopapular rash. In more than 60 years of observation, Zika has not been noted to cause hemor-rhagic fever or death. There is in vitro evidence that Zika virus mediates antibody-dependent en-hancement of infection, a phe-nomenon observed in dengue hemorrhagic fever; however, the clinical significance of that find-ing is uncertain.

The ongoing pandemic con-firms that Zika is predominantly a mild or asymptomatic dengue-like disease. However, data from French Polynesia documented a

concomitant epidemic of 73 cases of Guillain–Barré syndrome and other neurologic conditions in a population of approximately 270,000, which may represent complications of Zika. Of greater concern is the explosive Brazilian epidemic of microcephaly, mani-fested by an apparent 20-fold in-crease in incidence from 2014 to 2015, which some public health officials believe is caused by Zika virus infections in pregnant women. Although no other flavi-virus is known to have terato-genic effects, the microcephaly epidemic has not yet been linked to any other cause, such as in-creased diagnosis or reporting, increased ultrasound examina-tions of pregnant women, or other infectious or environmental agents. Despite the lack of defini-tive proof of any causal relation-ship,5 some health authorities in afflicted regions are recommend-ing that pregnant women take meticulous precautions to avoid mosquito bites and even to delay pregnancy. It is critically impor-

Countries with Past or Current Evidence of Zika Virus Transmission (as of December 2015).

For countries with serosurvey data only, evidence of Zika virus transmission is derived from studies that detected Zika virus anti-bodies in healthy people. Outlined areas, all with locally acquired cases or virus isolation, include Cape Verde, Cook Islands, Easter Island, Federated States of Micronesia, French Polynesia, Martinique, New Caledonia, Puerto Rico, Solomon Islands, and Vanuatu. Data are from the Centers for Disease Control and Prevention (http://www . cdc . gov/ zika).

Locally acquired cases or virus isolation

Serosurvey data only

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tant to confirm or dispel a causal link between Zika infection of pregnant women and the occur-rence of microcephaly by doing intensive investigative research, including careful case–control and other epidemiologic studies as well as attempts to duplicate this phenomenon in animal models.

In a “pure” Zika epidemic, a diagnosis can be made reliably on clinical grounds. Unfortunate-ly, the fact that dengue and chi-kungunya, which result in simi-lar clinical pictures, have both been epidemic in the Americas confounds clinical diagnoses. Spe-cific tests for dengue and chi-kungunya are not always avail-able, and commercial tests for Zika have not yet been developed. Moreover, because Zika is closely related to dengue, serologic sam-ples may cross-react in tests for either virus. Gene-detection tests such as the polymerase-chain-reaction assay can reliably distin-guish the three viruses, but Zika-specific tests are not yet widely available.

The mainstays of management are bed rest and supportive care. When multiple arboviruses are co-circulating, specific viral diagno-sis, if available, can be important in anticipating, preventing, and managing complications. For ex-ample, in dengue, aspirin use should be avoided and patients should be monitored for a rising hematocrit predictive of impend-ing hemorrhagic fever, so that potentially lifesaving treatment can be instituted promptly. Pa-tients with chikungunya virus in-fection should be monitored and treated for acute arthralgias and postinfectious chronic arthritis.

There are no Zika vaccines in advanced development, although a number of existing flavivirus vaccine platforms could presum-

ably be adapted, including flavi-virus chimera or glycoprotein sub-unit technologies. Zika vaccines would, however, face the same problem as vaccines for chikun-gunya,4 West Nile, St. Louis en-cephalitis, and other arboviruses: since epidemics appear sporadi-cally and unpredictably, preemp-tively vaccinating large popula-tions in anticipation of outbreaks may be prohibitively expensive and not cost-effective, yet vaccine stockpiling followed by rapid deployment may be too slow to counter sudden explosive epi-demics. Although yellow fever has historically been prevented entirely by aggressive mosquito control, in the modern era vector control has been problematic be-cause of expense, logistics, pub-lic resistance, and problems posed by inner-city crowding and poor sanitation. Among the best pre-ventive measures against Zika vi-rus are house screens, air-condi-tioning, and removal of yard and household debris and containers that provide mosquito-breeding sites, luxuries often unavailable to impoverished residents of crowd-ed urban locales where such epi-demics hit hardest.

With its recent appearance in Puerto Rico, Zika virus forces us to confront a potential new disease-emergence phenomenon: pandem-ic expansion of multiple, heretofore relatively unimportant arboviruses previously restricted to remote ecologic niches. To respond, we urgently need research on these viruses and the ecologic, entomo-logic, and host determinants of viral maintenance and emergence. Also needed are better public health strategies to control arbo-viral spread, including vaccine platforms for flaviviruses, alpha-viruses, and other arbovirus groups that can be quickly modi-

fied to express immunogenic an-tigens of newly emerging viruses. With respect to treatment, the arbovirus pandemics suggest that the one-bug–one-drug approach is inadequate; broad-spectrum antiviral drugs effective against whole classes of viruses are ur-gently needed.

As was realized more than 50 years ago, when enzootic Zika vi-rus spread was linked to human activity, arboviruses continually evolve and adapt within ecologic niches that are increasingly be-ing perturbed by humans. Zika is still a pandemic in progress, and many important questions about it, such as that of terato-genicity, remain to be answered. Yet it has already reinforced one important lesson: in our human-dominated world, urban crowd-ing, constant international travel, and other human behaviors com-bined with human-caused micro-perturbations in ecologic balance can cause innumerable slumber-ing infectious agents to emerge unexpectedly. In response, we clearly need to up our game with broad and integrated research that expands understanding of the complex eco systems in which agents of future pandemics are aggressively evolving.


From the National Institute of Allergy and Infectious Diseases, Bethesda, MD.

This article was published on January 13, 2016, at NEJM.org.

1. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 1952; 46: 509-20.2. Pierson TC, Diamond MS. Flaviviruses. In: Knipe DM, Howley PM, Cohen IC, et al., eds. Fields virology. 6th ed. Vol. 1. Philadel-phia: Wolters Kluwer, 2014: 746-94.3. Marcondes CB, Ximenes MF. Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes. Rev Soc Bras

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Med Trop 2015 December 22 (Epub ahead of print).4. Morens DM, Fauci AS. Chikungunya at the door — déjà vu all over again? N Engl J Med 2014; 371: 885-7.5. European Centre for Disease Prevention

and Control. Microcephaly in Brazil poten-tially linked to the Zika virus epidemic: ECDC assesses the risk. Solna, Sweden: European Centre for Disease Prevention and Control, November 25, 2015 (http://ecdc .europa .eu/ en/ press/ news/ _layouts/ forms/

News_DispForm .aspx?ID=1329&List= 8db7286c-fe2d-476c-9133-18ff4cb1b568 &Source=http%3A%2F%2Fecdc .europa .eu%2Fen%2FPages%2Fhome .aspx).DOI: 10.1056/NEJMp1600297Copyright © 2016 Massachusetts Medical Society.Zika Virus in the Americas

How Employers Are Responding to the ACA

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Perspective


April 21, 2016

n engl j med 374;16 nejm.org April 21, 2016 1501

Deaths from prescription-opioid overdose have increased dramatically in the United States, quadrupling in the past 15 years. Efforts to

improve pain management resulted in quadrupled

rates of opioid prescribing, which propelled a tightly correlated epi-demic of addiction, overdose, and death from prescription opioids that is now further evolving to in-clude increasing use and overdoses of heroin and illicitly produced fentanyl.

The pendulum of opioid use in pain management has swung back and forth several times over the past 100 years. Beginning in the 1990s, efforts to improve treat-ment of pain failed to adequately take into account opioids’ addic-tiveness, low therapeutic ratio, and lack of documented effectiveness in the treatment of chronic pain. Increased prescribing was also fueled by aggressive and some-times misleading marketing of

long-acting opioids to physicians.1 It has become increasingly clear that opioids carry substantial risks and uncertain benefits, especially as compared with other treat-ments for chronic pain.

On March 15, 2016, the Cen-ters for Disease Control and Pre-vention (CDC) released a “Guide-line for Prescribing Opioids for Chronic Pain” to chart a safer, more effective course.2 The guide-line is designed to support clini-cians caring for patients outside the context of active cancer treat-ment or palliative or end-of-life care. More research is needed to fill in critical evidence gaps re-garding the effectiveness, safety, and economic efficiency of long-term opioid therapy. However,

given what we know about the risks associated with long-term opioid therapy and the availability of effective nonpharmacologic and nonopioid pharmacologic treat-ment options, the guideline uses the best available scientific data to provide information and recom-mendations to support patients and clinicians in balancing the risks of addiction and overdose with the limited evidence of ben-efits of opioids for the treatment of chronic pain.

Most placebo-controlled, ran-domized trials of opioids have lasted 6 weeks or less, and we are aware of no study that has com-pared opioid therapy with other treatments in terms of long-term (more than 1 year) outcomes re-lated to pain, function, or quality of life.2 The few randomized tri-als to evaluate opioid efficacy for longer than 6 weeks had consis-tently poor results. In fact, several studies have showed that use of

Reducing the Risks of Relief — The CDC Opioid-Prescribing GuidelineThomas R. Frieden, M.D., M.P.H., and Debra Houry, M.D., M.P.H.

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the cdc opioid-prescribing guideline

n engl j med 374;16 nejm.org April 21, 2016

opioids for chronic pain may ac-tually worsen pain and function-ing, possibly by potentiating pain perception. A 3-year prospective

observational study of more than 69,000 postmenopausal women with recurrent pain conditions showed that patients who had re-

ceived opioid therapy were less likely to have improvement in pain (odds ratio, 0.42; 95% con-fidence interval [CI], 0.36 to 0.49) and had worsened function (odds ratio, 1.25; 95% CI, 1.04 to 1.51).3 An observational case–control study of patients under-going orthopedic surgery showed that those receiving long-term opioid therapy had significantly higher levels of preoperative hy-peralgesia.4 After surgery, patients who had received long-term opi-oid therapy reported higher pain intensity (a rating of 7.6 vs. 5.5 out of 10) in the recovery room than patients who had not been tak-ing opioids.

Whereas the benefits of opi-oids for chronic pain remain un-certain, the risks of addiction and overdose are clear. Although partial agonists such as buprenor-phine may carry a lower risk of dependence, prescription opioids that are full mu-opioid–receptor agonists — nearly all the prod-ucts on the market — are no less addictive than heroin. Although abuse-deterrent formulations may reduce the likelihood that pa-tients will inject melted pills, these formulations are no less addictive and do not prevent opioid abuse or fatal overdose through oral intake.

The prevalence of opioid de-pendence may be as high as 26% among patients in primary care receiving opioids for chronic non–cancer-related pain.2 Risk-stratifi-cation tools do not allow clinicians to predict accurately whether a patient will become addicted to opioids, although persons with a history of mental illness or addiction are at higher risk.2 Overdose risk increases in a dose–response manner, at least dou-bling at 50 to 99 morphine milli-

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected ben-efits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate.

2. Before starting opioid therapy for chronic pain, clinicians should establish treat-ment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically mean-ingful improvement in pain and function that outweighs risks to patient safety.

3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and provider responsibilities for managing therapy.

4. When starting opioid therapy for chronic pain, clinicians should prescribe imme-diate-release opioids instead of extended-release/long-acting (ER/LA) opioids.

5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dos-age to ≥50 morphine milligram equivalents (MME) per day, and should avoid increasing dosage to ≥90 MME per day or carefully justify a decision to titrate dosage to ≥90 MME per day.

6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than need-ed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed.

7. Clinicians should evaluate benefits and harms with patients within 1–4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid ther-apy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids.

8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorpo-rate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use are present.

9. Clinicians should review the patient’s history of controlled substance prescrip-tions using state prescription drug monitoring program (PDMP) data to deter-mine whether the patient is receiving opioid dosages or dangerous combina-tions that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically dur-ing opioid therapy for chronic pain, ranging from every prescription to every 3 months.

10. When prescribing opioids for chronic pain, clinicians should use urine drug test-ing before starting opioid therapy and consider urine drug testing at least annu-ally to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.

11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.

12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with be-havioral therapies) for patients with opioid-use disorder.

The CDC Opioid-Prescribing Guideline.

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gram equivalents (MME) per day and increasing by a factor of up to 9 at 100 or more MME per day, as compared with doses of less than 20 MME per day.2 Over-all, 1 of every 550 patients start-ed on opioid therapy died of opioid-related causes a median of 2.6 years after the first opioid prescription; the proportion was as high as 1 in 32 among pa-tients receiving doses of 200 MME or higher.5 We know of no other medication routinely used for a nonfatal condition that kills pa-tients so frequently.

The new CDC guideline em-phasizes both patient care and safety. We developed the guide-line using a rigorous process that included a systematic review of the scientific evidence and input from hundreds of leading experts and practitioners, other federal agencies, more than 150 profes-sional and advocacy organiza-tions, a wide range of key patient and provider groups, a federal advisory committee, peer review-ers, and more than 4000 public comments.

Three key principles underlie the guideline’s 12 recommenda-tions (see box). First, nonopioid therapy is preferred for chronic pain outside the context of active cancer, palliative, or end-of-life care. Opioids should be added

to other treatments for chronic pain only when their ex-pected benefits for

both pain and function are likely to outweigh the substantial risks inherent in this class of medi-cation.

Nonpharmacologic therapies can ameliorate chronic pain while posing substantially less risk to patients. In some instances, other therapies result in better out-

comes than opioids. These ther-apies include exercise therapy, weight loss, psychological thera-pies such as cognitive behavioral therapy, interventions to improve sleep, and certain procedures. The evidence review conducted in developing the guideline re-vealed that exercise therapy helped improve, and sustain im-provements in, pain and function in patients with osteoarthritis. It did not find evidence that opi-oids were more effective for pain reduction than nonopioid treat-ments such as nonsteroidal anti-inflammatory drugs for low back pain or antidepressants for neu-ropathic pain, but it did find that nonopioid treatments could be better tolerated and superior for improving physical function while conferring little or no risk of addiction and substantially lower risks of overdose and death.2

Second, when opioids are used, the lowest possible effective dose should be prescribed to reduce the risks of opioid use disorder and overdose. Clinicians should carefully reassess individual ben-efits and risks when increasing a dose to 50 MME or more per day. Doses of 90 MME or more should be avoided, or the decision to ti-trate above this level should be carefully considered and justified. When prescribing opioids, the rule of thumb is to “start low and go slow.”

Third, clinicians should exer-cise caution when prescribing opioids and should monitor all patients closely. Prescribers should mitigate risk by, for example, avoiding concurrent use of ben-zodiazepines if possible, review-ing data from a prescription-drug monitoring program when deciding whether to start or con-

tinue opioid therapy, offering naloxone at least to patients who are at greater risk for overdose, having a clear “off-ramp” plan to taper and discontinue therapy, reevaluating the dosage and ne-cessity of opioid treatment regu-larly, and obtaining urine toxi-cology screening at the initiation of treatment and, for some pa-tients, periodically thereafter. For patients who become addicted to opioids, treatment with metha-done, buprenorphine, or naltrex-one improves outcomes.

Initiation of treatment with opioids is a momentous decision and should be undertaken only with full understanding by both the physician and the patient of the substantial risks involved. Clinicians need to recognize the risk associated with any treat-ment with opioids and should prescribe only the shortest course needed. Although the guideline addresses chronic pain, many pa-tients become addicted to opioids after being treated for acute pain. Three days of treatment or less will often be sufficient; more than 7 days will rarely be re-quired. Some trauma and surgery may require longer courses; treat-ment of postsurgical pain is be-yond the scope of this guideline. Furthermore, it is important to discuss storage of opioids in a secure location to prevent diver-sion, as well as to counsel pa-tients regarding the overdose risk posed to household members and other persons.

Management of chronic pain is an art and a science. The sci-ence of opioids for chronic pain is clear: for the vast majority of patients, the known, serious, and too-often-fatal risks far outweigh the unproven and transient ben-efits.

An audio interview with Dr. Houry is

available at NEJM.org

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From the Centers for Disease Control and Prevention, Atlanta.

This article was published on March 15, 2016, at NEJM.org.

1. Van Zee A. The promotion and market-ing of oxycontin: commercial triumph, pub-

lic health tragedy. Am J Public Health 2009; 99: 221-7.2. CDC guideline for prescribing opioids for chronic pain — United States, 2016. MMWR Recomm Rep 2016; 65(RR-1): 1-49.3. Braden JB, Young A, Sullivan MD, Walitt B, Lacroix AZ, Martin L. Predictors of change in pain and physical functioning among post-menopausal women with recurrent pain conditions in the Women’s Health Initiative observational cohort. J Pain 2012; 13: 64-72.4. Hina N, Fletcher D, Poindessous-Jazat F,

Martinez V. Hyperalgesia induced by low-dose opioid treatment before orthopaedic surgery: an observational case-control study. Eur J Anaesthesiol 2015; 32: 255-61.5. Kaplovitch E, Gomes T, Camacho X, Dhalla IA, Mamdani MM, Juurlink DN. Sex differences in dose escalation and overdose death during chronic opioid therapy: a pop-ulation-based cohort study. PLoS One 2015; 10(8): e0134550.DOI: 10.1056/NEJMp1515917Copyright © 2016 Massachusetts Medical Society.

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Perspective


September 15, 2016


The adult population of the United States will soon have

a different primary care experi-ence than we’ve been used to. In the primary care practice of the future, the physician’s role will increasingly be played by nurse practitioners (NPs). In addition, the 150 million adults with one or more chronic conditions will receive some of their care from registered nurses (RNs) function-ing as care managers.

Workforce experts agree on the growing gap between the popula-tion’s demand for primary care and the number of primary care physicians available to meet that demand. About 8000 primary care physicians (including doctors of osteopathy and international med-ical graduates) entered the work-force in 2015, up only slightly from 7500 in 2005. And in fact, the number of yearly entrants is expected to plateau at around 8000. But the number of primary care physicians who retire each year is projected to reach 8500 in

2020 — in other words, the num-ber of retirees may exceed that of new entrants. And the size of the primary care physician workforce will be declining even as the U.S. population grows, ages, and be-comes more adequately insured.1

In contrast, the number of NPs entering the workforce each year has mushroomed from 6600 in 2003 to 18,000 in 2014. The number of primary care NPs is projected to increase by 84% be-tween 2010 and 2025. The num-ber of physician assistants (PAs) entering the workforce is also growing, though not as rapidly. If these trends continue, the pro-portion of primary care practi-tioners who are physicians will drop from 71% in 2010 to 60% in 2025 and will continue to de-cline thereafter. The proportion of practitioners who are NPs will jump from 19% to 29% during those years and will continue to rise.2 In rural communities, this trend is even more pronounced, since NPs are considerably more

likely than physicians to settle in rural America.

Clearly, more and more pa-tients will see an NP or a PA as their primary care practitioner. Physicians will probably focus on diagnostic conundrums and lead teams caring for patients with complex health care needs. A large and growing body of research demonstrates that care delivered by NPs is at least as high quality as that delivered by physicians. In addition, patient-satisfaction scores are similar for NPs and physicians.3 Moreover, care may cost less when it’s provided by NPs rather than physicians: Medi-care beneficiaries assigned to an NP had primary care costs that were 29% lower and office-visit and inpatient costs that were 11 to 18% lower than those of benefi-ciaries assigned to a primary care physician.

Even with the increased num-bers of NP and PA graduates, the ratio of primary care practitioners to population will decline, because

Rethinking the Primary Care Workforce — An Expanded Role for NursesThomas Bodenheimer, M.D., and Laurie Bauer, R.N., M.S.P.H.

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the 20th anniversary of the hospitalist


only 50% of NPs and 32% of PAs choose primary care careers. Thus, other professionals will be needed to care for the growing number of U.S. adults with chronic condi-tions and geriatric syndromes. Enter the enhanced role of the RN.

While the NP role begins to approximate that of the physician, RNs are assuming three impor-tant emerging primary care func-tions: managing the care of pa-tients with chronic disease by helping them with behavior change and adjusting their medications (e.g., for hypertension and diabe-tes) according to physician-written protocols; leading complex care management teams to help im-prove care and reduce the cost of care for patients with multiple diagnoses who are high users of health care services; and coordi-nating care between the primary care home and providers of other health care services — in par-ticular, assisting with transitions among hospital, primary care settings, and home.4

RNs are well on their way to filling the gap. In 2015, a total of 43% of U.S. physi-

cians worked with nurse care managers for patients with chronic conditions. The 3.1 mil-lion RNs in the United States rep-resent the country’s largest health profession, and its numbers are projected to grow by an aston-ishing 33% between 2012 and 2025. Government data show that the number of RN graduates per year has increased from 69,000 in 2001 to 155,000 in 2013 (see graph); a separate analysis put the number of RN graduates at 200,000 in 2014. Thus, primary care practices are likely to bene-fit from a pool of RNs who could be hired to serve as chronic care managers.

Several studies indicate that

RNs are qualified to perform these enhanced roles. For exam-ple, in a randomized, controlled trial, patients with diabetes and elevated blood pressure who re-ceived care from RN care man-agers (including initiation of medi-cations and titration of doses) were more likely to reach their blood-pressure goals than patients whose care was managed by phy-sicians alone.5 Some state boards of registered nursing have created a mechanism by which RNs can change medication doses using standardized procedures author-ized by their physician leader-ship.4 Using these procedures, RNs who’ve been trained as health coaches could provide most of the care for patients with uncompli-cated diabetes, hypertension, and hyperlipidemia, thereby adding considerable primary care capac-ity. And RN coordination of tran-sitions from hospital to home has resulted in improved patient self-management and reduced hospi-tal readmissions.

Although NPs and RNs are in-creasingly central to primary care, there are still obstacles to their performing these roles that need to be overcome. Physicians report that new NP graduates are not

initially comfortable taking re-sponsibility for a panel of pa-tients. To address this problem, intensive 1-year primary care NP residencies are springing up. Thus far, 37 such programs exist. Doc-tor of Nursing Practice degree programs were designed to sup-plant master’s level NP programs, but they are growing more slowly than expected.

As for an enhanced role for RNs, one barrier is that public and private insurers rarely pay for RN services, but that barrier is beginning to crumble. Even under the fee-for-service payment model, practices can receive pay-ment for Medicare wellness visits and chronic care management encounters, both of which can be conducted entirely by RNs. As alternative payment models grad-ually expand, primary care pay-ment will become less visit-based, which will allow practices to re-allocate more and more responsi-bilities to RNs and other team members.

The inadequacy of primary care training in nursing schools pre-sents another obstacle to RNs’ be-coming chronic care managers. The focus of nursing education on inpatient care skills has left

Numbers of Nursing Graduates, 2001–2013.

Data are from the U.S. Bureau of Health Workforce.N

o. o

f Nur

sing

Gra

duat

es

160,000

100,000

110,000

70,000

60,000

120,000

80,000

90,000

0

130,000

140,000

150,000

2001 2003 2005 2013201120092007

69,00077,000

99,000

120,000

135,000

145,000

155,000

An audio interview with Dr. Bodenheimer

is available at NEJM.org

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Rethinking the Primary Care Workforce


some primary care RNs unpre-pared for the care manager role. The American Academy of Am-bulatory Care Nursing and nurs-ing leaders are addressing this problem with new curricula and training programs.

Finally, although RNs may be attracted to primary care’s regu-lar work hours, its focus on pre-vention, and long-term relation-ships with patients, the fact that salaries are lower in primary care than in hospitals could also be a barrier.

Despite these challenges, the shortage of primary care physi-cians and the increasing preva-

lence of chronic diseases are powerful forces pushing primary care toward stronger NP and RN participation. It’s fortunate that the growth in the supply of NPs and RNs enables us to rethink who does what in primary care.

Disclosure forms provided by the authors are available at NEJM.org.

From the Center for Excellence in Primary Care (T.B.) and the School of Nursing (L.B.), University of California, San Francis-co, San Francisco.

1. Petterson SM, Liaw WR, Tran C, Baze-more AW. Estimating the residency expan-sion required to avoid projected primary care physician shortages by 2035. Ann Fam Med 2015; 13: 107-14.

2. Auerbach DI, Chen PG, Friedberg MW, et al. Nurse-managed health centers and patient-centered medical homes could miti-gate expected primary care physician short-age. Health Aff (Millwood) 2013; 32: 1933-41.3. Stanik-Hutt J, Newhouse RP, White KM, et al. The quality and effectiveness of care provided by nurse practitioners. J Nurse Pract 2013; 9: 492-500.4. Bodenheimer T, Bauer L, Olayiwola JN, Syer S. RN role reimagined: how empower-ing registered nurses can improve primary care. California Health Care Foundation, 2015 (http://www .chcf .org/ publications/ 2015/ 08/ rn-role-reimagined).5. Denver EA, Barnard M, Woolfson RG, Earle KA. Management of uncontrolled hy-pertension in a nurse-led clinic compared with conventional care for patients with type 2 diabetes. Diabetes Care 2003; 26: 2256-60.

DOI: 10.1056/NEJMp1606869

Copyright © 2016 Massachusetts Medical Society.Rethinking the Primary Care Workforce

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