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The

n e w e ng l a n d j o u r na l

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m e dic i n e

c or r e sp ondence

Mediterranean Diet for Primary Prevention


of Cardiovascular Disease
To the Editor: The interventional nutritional
study by Estruch et al. (April 4 issue)1 is limited
by low primary composite cardiovascular outcome rates (3.8% and 3.4% in the intervention
groups vs. 4.4% in the control group) with minor
absolute risk differences (range, 0.6 to 1%). Given these small margins of risk, there were at
least four statistically significant differences in
baseline characteristics between the groups,
which could contribute substantially to these minor absolute differences in risk. There were significantly higher percentages of men (+5.7%),
obese persons (+4.7%), diuretic use (+3.5%), and
oral hypoglycemic use (+3.2%) in the control
group than in the intervention group assigned to
a Mediterranean diet supplemented with nuts.
The implication of these baseline discrepancies may be reflected in the KaplanMeier survival curves for the primary composite cardiovascular outcome. The initial differences in risk
this weeks letters

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Mediterranean Diet for Primary Prevention


of Cardiovascular Disease

677

Surgery versus Physical Therapy for Meniscal


Tear and Osteoarthritis

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Sofosbuvir for Previously Untreated Chronic


Hepatitis C Infection

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Current and Future Therapies for Hepatitis C


Virus Infection

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Sugary Drinks and Obesity

681

Bilateral Toxoplasmosis Retinitis Associated


with Ruxolitinib

between the intervention and control groups,


starting at time zero, when no apparent difference in risk would be expected, particularly for
a dietary intervention,2 may have contributed substantially to the overall minor cumulative absolute differences in risk.
Eran Kopel, M.D., M.P.H.
Yechezkel Sidi, M.D.
Shaye Kivity, M.D.
Chaim Sheba Medical Center
Tel Hashomer, Israel
eran.kopel@mail.huji.ac.il
No potential conflict of interest relevant to this letter was reported.
1. Estruch R, Ros E, Salas-Salvad J, et al. Primary prevention

of cardiovascular disease with a Mediterranean diet. N Engl J


Med 2013;368:1279-90.
2. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of
dietary sodium reduction on cardiovascular disease outcomes:
observational follow-up of the Trials of Hypertension Prevention
(TOHP). BMJ 2007;334:885-8.
DOI: 10.1056/NEJMc1306659

To the Editor: In the PREDIMED trial (Prevencin con Dieta Mediterrnea), a modified Mediterranean diet supplemented with extra-virgin
olive oil or nuts was reported to have major cardiovascular benefits. There was a specific benefit
on the primary end point in the subgroup with
dyslipidemia and the subgroup with hypertension. Therefore, the reduction in levels of lowdensity lipoprotein (LDL) cholesterol and in blood
pressure could help to explain the outcome benefits. Extra-virgin olive oil, even in much smaller
amounts (30 ml per day) than that used in the
study (1 liter per week), delays gastric emptying
and decreases postprandial hyperglycemia.1 Extravirgin olive oil is high in monounsaturated fatty
acids, which reduce blood pressure and, in persons with type 2 diabetes, reduce glycated hemo-

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correspondence

globin levels.2 Eating tree nuts, such as almonds,


reduces LDL cholesterol levels by 3 to 19%.3 Mechanistically, it is therefore highly relevant to know
the initial and final LDL cholesterol and bloodpressure levels in the two treatment groups. Alternatively, the apparent benefits of the modified
Mediterranean diets, which were high in olive oil
or nuts, could reflect the adverse qualities of the
control diet, which was low in these beneficial
foods. Is this interpretation not possible?
Lionel H. Opie, M.D., D.Phil.
Hatter Institute for Cardiovascular Research in Africa
Cape Town, South Africa
lionel.opie@uct.ac.za
No potential conflict of interest relevant to this letter was reported.
1. Gentilcore D, Chaikomin R, Jones KL, et al. Effects of fat on

gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes. J Clin Endocrinol Metab 2006;91:2062-7.
2. Schwingshackl L, Hoffmann G. Monounsaturated fatty acids
and risk of cardiovascular disease: synopsis of the evidence
available from systematic reviews and meta-analyses. Nutrients
2012;4:1989-2007.
3. Berryman CE, Preston AG, Karmally W, Deckelbaum RJ,
Kris-Etherton PM. Effects of almond consumption on the reduc-

tion of LDL-cholesterol: a discussion of potential mechanisms


and future research directions. Nutr Rev 2011;69:171-85.
DOI: 10.1056/NEJMc1306659

To the Editor: The PREDIMED trial reported


that a Mediterranean diet supplemented with
extra-virgin olive oil or nuts reduced cardiovascular risk. Since the study was conducted in
Spain, many participants were already following
Mediterranean-type diets, which means that the
achieved dietary changes were modest. Are the
results too good to be true?
The Global Burden of Diseases, Nutrition, and
Chronic Diseases Expert (NUTRICODE) Group
systematically reviewed evidence for causal effects of dietary factors on chronic diseases and
obtained estimates of quantitative effects, largely based on observational cohorts.1-3 The reductions in risk achieved in PREDIMED, a study of
dietary patterns, are consistent with the predicted benefits calculated from observational
data on individual dietary components reported
by the NUTRICODE Group (Table 1).
Fewer cardiovascular events were apparent

Table 1. Observed and Predicted Effects in the Mediterranean-Diet Groups of Supplementation with Extra-Virgin Olive Oil or Nuts
on Myocardial Infarction.
Dietary Factor

PREDIMED
Change
Achieved with
Mediterranean
Diet with EVOO

NUTRICODE

Change
Achieved with
Mediterranean
Diet with Nuts

Estimated
Effect on
MI (RR)*

(g/day)

Predicted Predicted
Predicted
Effect on
Effect on
Effect on
Serving MI with
MI with
MI for Groups
Size EVVO (RR) Nuts (RR) Combined (RR)
(g/day)

Nuts

3.3

21.0

0.89

28.35

0.987

0.917

0.951

Vegetables

1.8

10.0

0.93

100

0.999

0.993

0.996

Legumes

2.4

2.4

0.93

100

0.998

0.998

0.998

Fruits

6.3

12.5

0.91

100

0.994

0.988

0.991

Marine n3 fatty acids

0.11

0.12

0.94

0.100

0.934

0.928

0.931

EVOO (% energy)

5.0

1.1

0.9

5.00

0.891

0.975

0.932

Predicted overall effect by NUTRICODE

0.814

0.813

0.814

Observed effect in PREDIMED

0.80

0.74

0.77

* In reviewing the reported dietary changes in the PREDIMED (Prevencin con Dieta Mediterrnea) trial, the NUTRICODE (Global Burden
of Diseases, Nutrition, and Chronic Diseases [GBDNG] Expert) Group13 found evidence of causal effects on myocardial infarction (MI)
with the consumption of fruits, vegetables, nuts, and marine n3 fatty acids. For most factors, the magnitudes of effect were quantified
with meta-analyses of multivariable-adjusted observational cohorts. Our analyses did not identify sufficient studies to confirm additional
effects of legumes or extra-virgin olive oil (EVOO), key dietary changes in PREDIMED. To enable comparison, the potential effects of legumes were imputed from those of vegetables and the potential effects of EVOO from those of polyunsaturated vegetable fats. Given the
smaller numbers of available prospective studies, the effects of key dietary factors (e.g., nuts) on stroke could not be quantified, making it
difficult to estimate the observed effects as compared with the predicted effects on stroke in PREDIMED. RR denotes relative risk.
In calculating the estimated effect of dietary n3 fatty acids on MI, we assumed that half of MIs were fatal, since the NUTRICODE estimated risk reduction for marine n3 fatty acids was specific for fatal MI, not nonfatal MI.

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The

n e w e ng l a n d j o u r na l

within 1 year, which is consistent with rapid


changes in risk factors when dietary quality is
altered in controlled feeding studies and in
populations when nutrition trends shift.4 These
benefits in the PREDIMED trial, long-term
observational cohorts, and short-term feeding
interventions are largely independent of
changes in adiposity (i.e., they are primarily due
to dietary composition). The consistency of the
results of the PREDIMED trial with prior evidence confirms the crucial importance of dietary quality focused on healthful foods and
dietary patterns rather than single nutrients
for cardiovascular disease.
Dariush Mozaffarian, M.D., Dr.P.H.
Brigham and Womens Hospital
Boston, MA
dmozaffa@hsph.harvard.edu
Dr. Mozaffarian reports receiving research grants from
GlaxoSmithKline, Sigma Tau Pharmaceuticals, and Pronova
Biopharma; travel reimbursement or honoraria from Bunge, the
Pollock Institute, Quaker Oats, and the Life Sciences Research
Organization; consulting fees from Foodminds and Nutrition
Impact; and royalties from UpToDate; and reports being a
member of the Unilever North America Scientific Advisory
Board. No other potential conflict of interest relevant to this
letter was reported.

of

m e dic i n e

than a chance increase in the rate of stroke


among controls, the protective mechanisms need
to be explained. A possible lack of adherence after initial compliance was addressed and ruled
out. In contrast with the findings by Estruch et al.,
a large secondary prevention trial has shown that
the protection conferred by a Mediterranean diet
was maintained for up to 4 years.1 It would be
shortsighted not to recognize the potential public health benefits of a Mediterranean diet; unfortunately, the current studys apparent limitations do not provide further support for the case.
Rudolf Hoermann, M.D., Ph.D.
Mathis Grossmann, M.D., Ph.D.
University of Melbourne
Heidelberg, VIC, Australia
rudolf.hoermann@gmail.com
No potential conflict of interest relevant to this letter was reported.
1. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mam-

elle N. Mediterranean diet, traditional risk factors, and the rate


of cardiovascular complications after myocardial infarction:
final report of the Lyon Diet Heart Study. Circulation 1999;99:77985.

DOI: 10.1056/NEJMc1306659

1. Micha R, Kalantarian S, Wirojratana P, et al. Estimating the

global and regional burden of suboptimal nutrition on chronic


disease: methods and inputs to the analysis. Eur J Clin Nutr
2012;66:119-29.
2. Khatibzadeh S, Micha R, Afshin A, Rao M, Yakoob MY,
Mozaffarian D. Major dietary risk factors for chronic diseases:
a systematic review of the current evidence for causal effects and
effect sizes. Circulation 2012;125:Suppl:AP060. abstract.
3. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet
2012;380:2224-60. [Erratum, Lancet 2013;381:1276.]
4. Mozaffarian D, Appel LJ, Van Horn L. Components of a cardioprotective diet: new insights. Circulation 2011;123:2870-91.
DOI: 10.1056/NEJMc1306659

To the Editor: Estruch et al. conclude that a


Mediterranean diet reduced the incidence of major cardiovascular events. However, this reduction was attributable only to a single event class
stroke and the difference in event rates was
apparent only early in follow-up. When events occurring in the first year were excluded in a supplementary sensitivity analysis, this difference
was no longer significant. Remarkably, the trial
was terminated after a median follow-up of just
4.8 years. Assuming that this early difference
was due to a protective effect of the diet, rather

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To the Editor: Estruch et al. report that the


2425 participants with type 2 diabetes in the two
groups assigned to the Mediterranean diet had
the same rate of reduction in cardiovascular
events as the nondiabetic population. In September 2012, the last patient in our own interventional trial,1 which compared the effects of a
Mediterranean diet (108 participants) with those
of a low-fat diet (107 participants) in a population
with newly diagnosed type 2 diabetes, reached
the primary end point (the need for an antihyperglycemic drug), with a follow-up of 8 years. The
mean (SD) values for the macronutrient composition of the Mediterranean diet (43.76.1% carbohydrate, 18.52.7% protein, and 37.85.1%
total fat) were similar to those in the study by
Estruch et al. The rate of regression in the intima
media thickness of the carotid artery2 was higher
and the rate of progression lower in the Mediterranean-diet group as compared with the low-fat
diet group; moreover, adiponectin levels were
higher and the homeostasis model assessment
of insulin resistance was lower (indicating
higher insulin sensitivity) in the Mediterraneandiet group (Fig. 1). In addition to reducing the

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correspondence

B Progression of IntimaMedia Thickness

100

100

75

75
P=0.03

Percent

Percent

A Regression of IntimaMedia Thickness

50

25

P=0.009
50

25

Mediterranean Diet

C Adiponectin
12

Low-Fat Diet

Mediterranean Diet

Low-Fat Diet

D HOMA Assessment of Insulin Resistance


8

P<0.001

P=0.01
6

HOMA

g/ml

Mediterranean Diet

Low-Fat Diet

Mediterranean Diet

Low-Fat Diet

Figure 1. Effects of a Mediterranean Diet and a Low-Fat Diet on Carotid IntimaMedia Thickness, Adiponectin Levels,
and Insulin Resistance.
The rates of regression (Panel A) and progression (Panel B) for carotid intimamedia thickness, the adiponectin levels
(Panel C), and the extent of insulin resistance (determined according to homeostasis model assessment [HOMA])
(Panel D) are compared for study participants assigned to a Mediterranean diet and those assigned to a low-fat
diet.2 In Panel D, the level of HOMA was calculated according to this formula: fasting plasma glucose in millimoles
per liter (fasting serum insulin in units per milliliter 25).

need for a first diabetes drug,1 a Mediterranean


diet improves long-term cardiovascular outlook
and insulin sensitivity in type 2 diabetes.
Katherine Esposito, M.D., Ph.D.
Dario Giugliano, M.D., Ph.D.
Second University of Naples
Naples, Italy
dario.giugliano@unina2.it
No potential conflict of interest relevant to this letter was reported.
1. Esposito K, Maiorino MI, Ciotola M, et al. Effects of Medi-

terranean-style diet on the need for antihyperglycemic drug


therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306-14 Medline. [Erratum, Ann Intern Med 2009;151:591.]
2. Esposito K, Giugliano D, Nappo F, Marfella R. Regression of
carotid atherosclerosis by control of postprandial hyperglycemia
in type 2 diabetes mellitus. Circulation 2004;110:214-9.
DOI: 10.1056/NEJMc1306659

To the Editor: The PREDIMED study is highly


flawed. The control group did not follow a lowfat diet. This is not surprising, since researchers
gave the control group little support in following
this diet during much of the study. In the lowfat control group, total fat consumption decreased insignificantly from 39 to 37% (Table S7
in the Supplementary Appendix, available with
the full text of the article by Estruch et al. at
NEJM.org). This level of consumption is much
higher than the level recommended in American
Heart Association guidelines for a low-fat diet
(<30% fat) or a diet that can reverse coronary
heart disease (<10% fat).1-5 There was no significant reduction in the rates of heart attack, death
from cardiovascular causes, or death from any
cause. The only significant reduction was in the

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The

n e w e ng l a n d j o u r na l

rate of death from stroke (see Table 3 of the


article).
The conclusion of the study should be, We
found a significant reduction in the rate of
stroke among those consuming a Mediterranean
diet as compared with those who were not
making any substantial changes in their diet. A
Mediterranean diet is better than what most
people are consuming; even better is a diet based
on whole foods and plants that is low in fat
(especially saturated and trans fat) and in refined carbohydrates while allowing for sufficient
consumption of n3 fatty acids.
Dean Ornish, M.D.
Preventive Medicine Research Institute
Sausalito, CA
dean.ornish@pmri.org
Dr. Ornish reports receiving royalties and honoraria for books
and lectures on health. No other potential conflict of interest
relevant to this letter was reported.
1. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle

changes for reversal of coronary heart disease. JAMA 1998;280:


2001-7 Medline. [Erratum, JAMA 1999;281:1380.]
2. Gould KL, Ornish D, Scherwitz L, et al. Changes in myocardial perfusion abnormalities by positron emission tomography
after long-term, intense risk factor modification. JAMA 1995;
274:894-901.
3. Ornish DM, Brown SE, Scherwitz LW, et al. Can lifestyle
changes reverse coronary heart disease? The Lifestyle Heart
Trial. Lancet 1990;336:129-33.
4. Ornish DM, Scherwitz LW, Doody RS, et al. Effects of stress
management training and dietary changes in treating ischemic
heart disease. JAMA 1983;249:54-9.
5. Silberman A, Banthia R, Estay IS, et al. The effectiveness and
efficacy of an intensive cardiac rehabilitation program in 24 sites.
Am J Health Promot 2010;24:260-6.
DOI: 10.1056/NEJMc1306659

The Authors Reply: Kopel et al. point out that


some imbalances in the baseline characteristics
of the three PREDIMED trial groups might explain in part the differences observed among the
groups in the incidence of cardiovascular events.
However, when we adjusted our statistical analyses for these variables to account for their potential confounding effect, the results remained unchanged. Kopel et al. also wondered about what
they believe to be an implausible early protective
effect of the two PREDIMED Mediterranean diets. In our previously published pilot study,1 we
found that the two Mediterranean diets conferred a substantial benefit with regard to classical and emergent cardiovascular risk factors
after only 3 months. In addition, the assumption

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of a long induction period for an association


between dietary factors and vascular events is
not supported by current concepts and evidence.2-4 We thank Mozaffarian for pointing
out that the extent of cardiovascular risk reduction in PREDIMED is in line with predictions
derived from observational studies and for underscoring the point that rapid changes in risk
factors are observed when the quality of diet is
changed.
Opie suggests that part of the protective effect of Mediterranean diets might be explained
by reductions in blood-pressure and LDL cholesterol levels. In our pilot study, we reported that
the PREDIMED diets had significant effects on
blood-pressure and LDL cholesterol levels as well
as other cardiovascular risk factors.1
Hoermann and Grossmann state that the
Mediterranean diet in our trial showed cardiovascular benefit only with regard to stroke, given
that stroke was the sole component of the primary end point that reached statistical significance when the trial was stopped. However, the
criteria for stopping the trial were defined a
priori and were calculated, as is customary in
cardiovascular prevention trials, for an aggregate of cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Thus,
strictly speaking, the PREDIMED trial has shown
that a Mediterranean-type diet has a protective
effect with regard to the primary outcome of
cardiovascular disease. Esposito and Giugliano
note that the results of their study of the Mediterranean diet and diabetes control are in line
with both the cardiovascular benefit observed in
participants with diabetes in PREDIMED and
prior data obtained in participants without diabetes.1,5
Ornish points to the fact, acknowledged and
discussed in our report, that the participants in
PREDIMED who were assigned to the low-fat
diet ended up consuming a relatively high-fat
diet. This finding does not detract from the view
that a diet that is very low in fat has cardiovascular benefits, as shown in his studies. In fact,
high-fat Mediterranean diets and low-fat vegetarian diets share a great number of food components, but major problems with a diet that is
very low in fat are its poor palatability and the
marginal long-term compliance.

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correspondence

Ramon Estruch, M.D., Ph.D.


Emilio Ros, M.D., Ph.D.

2. Libby P. Mechanisms of acute coronary syndromes and their

Hospital Clinic
Barcelona, Spain

cardioprotective diet: new insights. Circulation 2011;123:287091.


4. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ.
Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors.
BMJ 1999;319:1523-8.
5. Salas-Salvad J, Bull M, Babio N, et al. Reduction in the
incidence of type 2 diabetes with the Mediterranean diet: results
of the PREDIMED-Reus nutrition intervention randomized trial.
Diabetes Care 2011;34:14-9.

implications for therapy. N Engl J Med 2013;368:2004-13.

3. Mozaffarian D, Appel LJ, Van Horn L. Components of a

Miguel Angel Martnez-Gonzlez, M.D., Ph.D.


University of Navarra
Pamplona, Spain
Since publication of their article, the authors report no further potential conflict of interest.
1. Estruch R, Martnez-Gonzlez MA, Corella D, et al. Effects

of a Mediterranean-style diet on cardiovascular risk factors:


a randomized trial. Ann Intern Med 2006;145:1-11 Medline.

DOI: 10.1056/NEJMc1306659

Surgery versus Physical Therapy for Meniscal Tear


and Osteoarthritis
To the Editor: Katz et al. (May 2 issue)1 assessed functional outcomes of meniscectomy
versus physical therapy in patients with a meniscal tear and osteoarthritis. The primary outcome
was the change in the Western Ontario and
McMaster Universities Osteoarthritis Index
(WOMAC) physical-function score, and a secondary outcome was pain. But in efforts to assess the
benefits of an intervention aimed at restoring
meniscal function, more specific tools for meniscectomy, such as the Lysholm score2 or the International Knee Documentation Committee
(IKDC) score,3 would appear to have been more
appropriate.
Second, osteoarthritis was defined according
to the radiography-based criteria of Kellgren and
Lawrence.4 It is possible that some patients had
severe cartilage damage not detected by plain
radiography (but detectable by magnetic resonance imaging [MRI] or arthroscopy) and that
this reduced the apparent effectiveness of meniscectomy.
Lukas A. Holzer, M.D.
Andreas Leithner, M.D.
Medical University of Graz
Graz, Austria
lukas.holzer@medunigraz.at

Gerold Holzer, M.D.


Medical University of Vienna
Vienna, Austria
No potential conflict of interest relevant to this letter was reported.

1. Katz JN, Brophy RH, Chaisson CE, et al. Surgery versus phys-

ical therapy for a meniscal tear and osteoarthritis N Engl J Med


2013;368:1675-84.
2. Rodriguez-Merchan EC. Knee instruments and rating scales
designed to measure outcomes. J Orthop Traumatol 2012;13:1-6.
3. Crawford K, Briggs KK, Rodkey WG, Steadman JR. Reliability, validity, and responsiveness of the IKDC score for meniscus
injuries of the knee. Arthroscopy 2007;23:839-44.
4. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis 1957;16:494-502.
DOI: 10.1056/NEJMc1307177

The Authors Reply: Holzer et al. suggest that


we should have used an outcome measure more
specific for meniscectomy. Many sports-oriented
measures (such as the Lysholm and IKDC scores
suggested by these writers1,2) contain sportsrelated items that are typically not relevant for
the middle-aged and older population with a
meniscal tear and osteoarthritis. We included the
pain score on the Knee Injury and Osteoarthritis
Outcome Scale (KOOS),3 which was developed
for patients with injury as well as those with osteoarthritis and which contains items such as
pain with twisting and pivoting. The results for
the KOOS pain score paralleled those for the primary outcome, the WOMAC physical-function
score. These writers were also concerned that
participants found eligible on the basis of radiographic findings might nonetheless have severe
cartilage damage on MRI or arthroscopy. Because
of randomization, any underestimation of the severity of osteoarthritis would be balanced across
groups. Furthermore, data from our stratified

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