Correspondence

groups with respect to mortality from cancer but increases harms among men with low-risk
was 1.1 percentage points when we used a higher- disease or those who are older than 65 years of
certainty cause-of-death definition. Results sug- age. We encourage physicians and guideline groups
gest modest reductions in all-cause mortality to recommend initial observation for these men.
among younger men and those with intermediate- For younger, healthy men with intermediate-risk
risk disease. or high-risk disease, treatment decisions should
In reply to Sharma and Karnes: adherence to include balancing benefits with harms.
radical treatment in PIVOT was similar to that in TimothyJ. Wilt, M.D., M.P.H.
other studies.2,3 Adherence to observation was Minneapolis Veterans Affairs Health Care System
superior to adherence to nonradical treatment in Minneapolis, MN
the Prostate Testing for Cancer and Treatment tim.wilt@va.gov
(ProtecT) trial.3 Although per-protocol analyses GeraldL. Andriole, M.D.
may slightly alter effect estimates, the results of Washington University School of Medicine
St. Louis, MO
previous nonrandomized trials led to the uncer-
tainty that gave rise to these randomized trials. MichaelK. Brawer, M.D.
Myriad Genetics Laboratories
Contemporary prostate-specific antigenSalt Lake City, UT
detected cancers have a better prognosis with Since publication of their article, the authors report no fur-
observation than the cancers in PIVOT.3 Refine- ther potential conflict of interest.
ments in surgery and radiation therapy cost more 1. Maurice MJ, Abouassaly R, Kim SP, Zhu H. Contemporary
and provide modest, if any, improvement in tu- nationwide patterns of active surveillance use for prostate cancer.
mor control or reduction in treatment harms JAMA Intern Med 2015;175:1569-71.
Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prosta-
than observation.4 In addition, new chemothera- 2. tectomy or watchful waiting in early prostate cancer. N Engl J
pies for disseminated prostate cancer yield larg- Med 2014;370:932-42.
er reductions in mortality than surgery for local- 3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes
ized disease, and these agents are associated with after monitoring, surgery, or radiotherapy for localized prostate
cancer. N Engl J Med 2016;375:1415-24.
acceptable harms. Therefore, men who currently 4. Wilt TJ, Dahm P. Value of prostate cancer care: new informa-
5

undergo surgery or receive radiation therapy tion on new therapies suggest less is more. Eur Urol 2017 May 29
probably have smaller mortality benefits than (Epub ahead of print).
5. James ND, de Bono JS, Spears MR, et al. Abiraterone for
those in our trial and probably have similar prostate cancer not previously treated with hormone therapy.
harms. Multiple randomized trials now show N Engl J Med 2017;377:338-51.
that early treatment does not decrease mortality DOI: 10.1056/NEJMc1710384

Changes in Diet Quality and Total and Cause-Specific Mortality

To the Editor: Sotos-Prieto et al. (July 13 issue)1
report that improvement in diet quality during
the 12-year study period was consistently associ-
ated with a reduced risk of death. Their report
may be easily interpreted as suggesting that bene-
ficial effects of specific foods or a type of diet
(e.g., the Alternate Mediterranean Diet and Di-
etary Approaches to Stop Hypertension [DASH]
diet, as evaluated in the study) contributed to the
reduction in the risk of death.
However, in nutritional research, associations
derived from observational studies may not be
reliable indicators of causal effects, even with
the most rigorous study designs achievable.2
Since changing ones diet is a difficult task, a shinsw@kumc.or.kr
highly motivated and physically and psychologi-
cally healthy person could succeed in changing
and maintaining his or her diet.3 The reduced
risk of death could be because of a persons ini-
tial physical and psychological health, not from
the beneficial effect of a changed diet. Thus, the
association that was found in this study could be
due to attribution bias. Accordingly, we think
that the exact cause of the reduced risk of death
remains speculative.
SongJ. Lee, Ph.D.
Chungnam University
Daejeon, South Korea
SangW. Shin, M.D., Ph.D.
Korea University
Seoul, South Korea
No potential conflict of interest relevant to this letter was re-
ported.

n engl j med 377;13nejm.org September 28, 2017 1303

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Copyright 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

1. Sotos-Prieto M, Bhupathiraju SN, Mattei J, et al. Association
of changes in diet quality with total and cause-specific mortality.
N Engl J Med 2017;377:143-53.
2. Ejima K, Li P, Smith DL Jr, et al. Observational research
rigour alone does not justify causal inference. Eur J Clin Invest
2016;46:985-93.
3. Shepherd R, Shepherd R. Resistance to changes in diet. Proc
Nutr Soc 2002;61:267-72.
DOI: 10.1056/NEJMc1710523
To the Editor: The approach of the study by
Sotos-Prieto et al. is informative; however, we
think that an approach that considered the tra-
jectories of diet quality over 12 years would have
added considerable value to this work. Our con-
cern is that the group with an improved diet
quality includes several distinct diet improve-
ment profiles, including those whose diet im-
proved progressively during the 12-year study
period and those who had poor diet (possibly
suboptimal with respect to guidelines) during
the first 9 years but an improved diet during the
last 3 years. Such heterogeneity may lead to an
underestimation of the effect of improving diet
quality during the 12-year period. Adjusting for
the initial diet-quality score may not be sufficient
to address this issue.
If diet changes at different time points were
considered, the trajectory approach1 would be
more suitable for capturing the association of
period was consistently associated with a de-
creased risk of death. We pooled data from our
own randomized, controlled trials1-4 that evalu-
ated the effect of the Mediterranean diet on sur-
rogate biomarkers of longevity5 among men and
women who were followed for up to 8 years and
had both baseline and final values available. The
102 participants who had a higher score with re-
spect to diet quality (a median or greater intake
of whole grain, fruit, olive oil, nuts, and legumes)
were compared with the 98 who had a lower
score (intake lower than median). Participants
who consumed a higher-quality diet had lower
levels of glucose and insulin, higher levels of
adiponectin (indicating higher insulin sensitiv-
ity), and lower plasma levels of total 8-iso-prosta-
glandin F2 (indicating decreased oxidative stress)
than those who consumed a lower-quality diet.
Thus, we would note that in controlled dietary
trials, the increased quality of a Mediterranean
diet was associated with more favorable biomark-
ers of longevity in men and women who were
obese or had newly diagnosed type 2 diabetes.
Katherine Esposito, M.D., Dr.P.H.
Dario Giugliano, M.D.
MariaI. Maiorino, M.D., Dr.P.H.
University of Campania Luigi Vanvitelli
Naples, Italy
dario.giugliano@unicampania.it

diet quality with risk of death. By classifying No potential conflict of interest relevant to this letter was re-
ported.
participants into distinct, exclusive trajectory
groups, such an approach would allow for close 1. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediter-
scrutiny of population heterogeneity in diet- ranean-style diet on endothelial dysfunction and markers of vas-
cular inflammation in the metabolic syndrome: a randomized
quality changes during the 12-year period and trial. JAMA 2004;292:1440-6.
would permit a direct comparison of outcomes 2. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle
across these groups. changes on erectile dysfunction in obese men: a randomized
controlled trial. JAMA 2004;291:2978-84.
Bamba Gaye, Ph.D. 3. Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss
Xavier Jouven, M.D., Ph.D. and lifestyle changes on vascular inflammatory markers in
obese women: a randomized trial. JAMA 2003;289:1799-804.
JeanP. Empana, M.D., Ph.D. 4. Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Med-
Paris Descartes University iterranean-style diet on the need for antihyperglycemic drug
Paris, France therapy in patients with newly diagnosed type 2 diabetes: a ran-
bamba.gaye@inserm.fr domized trial. Ann Intern Med 2009;151:306-14.
No potential conflict of interest relevant to this letter was re- 5. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month
ported. calorie restriction on biomarkers of longevity, metabolic adapta-
tion, and oxidative stress in overweight individuals: a random-
1. Song M, Hu FB, Wu K, et al. Trajectory of body shape in ized controlled trial. JAMA 2006;295:1539-48.
early and middle life and all cause and cause specific mortality: DOI: 10.1056/NEJMc1710523
results from two prospective US cohort studies. BMJ 2016;353:
i2195.
DOI: 10.1056/NEJMc1710523
The authors reply: We agree with Lee and Shin
that a causal relationship cannot be established
solely from observational studies. However, our
To the Editor: Sotos-Prieto and colleagues re- data are consistent with strong evidence from
port that improved diet quality during a 12-year many well-designed observational studies and

1304 n engl j med 377;13nejm.org September 28, 2017

The New England Journal of Medicine

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Copyright 2017 Massachusetts Medical Society. All rights reserved.
 Correspondence

randomized, controlled clinical trials that sup- Mercedes SotosPrieto, Ph.D.

port the health benefits of greater adherence to Ohio University
healthy dietary patterns and lower risk of all- Athens, OH
msotosp@hsph.harvard.edu
cause and cardiovascular disease mortality.1 Al-
though residual confounding cannot be complete- ShilpaN. Bhupathiraju, Ph.D.
ly ruled out in observational studies, we carefully Harvard Medical School
controlled for both baseline factors and lifestyle Boston, MA
changes and for the presence of coexisting ill- FrankB. Hu, M.D., Ph.D.
nesses. The consistency of our findings across Harvard T.H. Chan School of Public Health
various subgroups (according to baseline factors Boston, MA
and changes in health conditions) suggests that Since publication of their article, the authors report no fur-
the results are unlikely to be due to changes in ther potential conflict of interest.
physiologic health.
1. Scientific report of the 2015 Dietary Guidelines Advisory
Gaye et al. raise an interesting point. In our Committee. Washington, DC:Department of Health and Human
view, the approach to studying trajectories in diet Services, Department of Agriculture, February 2015 (https://
quality will add valuable information by classify- health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific
-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf).
ing people into different groups, depending on 2. Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Med-
their trajectory of diet-quality changes over time. iterranean-style diet on the need for antihyperglycemic drug
Esposito et al. describe the pooled results of therapy in patients with newly diagnosed type 2 diabetes: a ran-
domized trial. Ann Intern Med 2009;151:306-14.
randomized, controlled trials2,3 that showed the 3. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediter-
positive effects of a Mediterranean diet interven- ranean-style diet on endothelial dysfunction and markers of vas-
tion on surrogate biomarkers of longevity. We cular inflammation in the metabolic syndrome: a randomized
trial. JAMA 2004;292:1440-6.
believe that these findings provide further sup-
port for the biologic plausibility of our findings. DOI: 10.1056/NEJMc1710523

Beating, Fast and Slow

To the Editor: Jani et al. (July 6 issue)1 describe
a 52-year-old man who presented with a recent
history of exertional chest discomfort and dys-
pnea. Cardiac positron-emission tomographic per-
fusion scanning with intravenous dipyridamole
was performed as the initial diagnostic test, and
the findings showed a reversible myocardial per-
fusion defect in the inferior wall. The patient re-
ceived a prescription of atenolol, and severe brady-
ischemia a diagnosis that led to the inappro-
priate and near disastrous prescription of a beta-
blocker. This case underscores the point that in
the pursuit of the correct diagnosis, less can
indeed be more.
Peter Bogaty, M.D.
Quebec Heart and Lung Institute
Quebec, QC, Canada
peter.bogaty@fmed.ulaval.ca

arrhythmia developed after he took the first
dose. Subsequent investigation, including coro-
nary angiography, led to the diagnosis of giant-
cell myocarditis. Nuclear perfusion imaging with
No potential conflict of interest relevant to this letter was re-
ported.
1. Jani SM, Nallamothu BK, Cooper LT, Smith A, Fazel R. Beat-
ing, fast and slow. N Engl J Med 2017;377:72-8.

dipyridamole is a nonphysiological and relatively DOI: 10.1056/NEJMc1710015

expensive diagnostic approach, and it may not be
specific for the detection of myocardial ischemia,
as shown by the incorrect diagnosis in this case.
Neither the authors in their commentary nor the
expert clinician discussant mention that a simple
electrocardiographic treadmill exercise test would
have directly addressed the patients exertional
symptoms, would probably have identified chro-
notropic insufficiency as their cause, and would
not have suggested the presence of myocardial
The authors reply: We agree with Bogaty that
exercise stress testing with cardiac imaging would
have been the preferred approach and more ap-
propriate than vasodilator stress testing in our
patient.1 Exercise stress testing provides valuable
prognostic information that is based on exercise
duration, heart-rate recovery, ST-segment response,
exercise-induced hypotension, and chronotropic
incompetence. However, our patients pretest

n engl j med 377;13nejm.org September 28, 2017 1305

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Copyright 2017 Massachusetts Medical Society. All rights reserved.