Correspondence
lieve that asking about the sex of a persons part-
ner is a less accurate and more judgmental as-
sessment of risk than a questionnaire that asks
about, for example, frequency of partner ex-
change, condom use, and prior screening for hu-
man immunodeficiency virus (HIV). In their guid-
ance for industry, the FDA reports that, as of
2013, men who have sex with men accounted for
2.6% of male blood donors, despite the existing
ban.1 Thus, a blanket deferral policy, while widely
seen as discriminatory, is also ineffective at ex-
cluding this population. Too often this issue is
framed as a false choice between maintaining a
safe blood supply and ending a policy that per-
petuates stigma. With modern HIV testing and
individual risk-based assessments, both can be
achieved. We acknowledge the complexity of the
issue, including the possible financial implica-
tions for the global market,2 and support the ef-
Ticagrelor versus Clopidogrel in Peripheral Artery Disease
To the Editor: In reporting on the landmark
Examining Use of Ticagrelor in Peripheral Artery
Disease (EUCLID) trial, Hiatt et al. (Jan. 5 issue)1
observe the nonsuperiority of ticagrelor over
clopidogrel in preventing cardiovascular sequelae
in patients with peripheral vascular disease. The
equally groundbreaking Study of Platelet Inhibi-
tion and Patient Outcomes (PLATO) showed that
ticagrelor was superior to clopidogrel.2
In November 2009, the manufacturer of clop-
idogrel cautioned that clopidogrel should not be
administered with omeprazole. This warning was
strongly reaffirmed by the Food and Drug Ad-
ministration (FDA).3 Omeprazole inhibits cyto-
chrome P-450 2C19, preventing clopidogrel acti-
vation.
Recruitment in PLATO began in October 2006.
The proportion of participants who received
proton-pump inhibitors (PPIs) was equivalent in
both the clopidogrel and ticagrelor cohorts in
PLATO. However, omeprazole adversely affects
the efficacy of clopidogrel but not the efficacy of
ticagrelor. PLATO may thus have been affected
by the differential effects of omeprazole on the
two antiplatelet agents.
Recruitment in the EUCLID trial began in
December 2012. The authors provided no infor-
mation on the extent of concomitant PPI use. It
n engl j med 376;15nejm.org April 13, 2017
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
fort to reassess this policy, as guided by the best
scientific evidence.
ChanaA. Sacks, M.D.
RobertH. Goldstein, M.D., Ph.D.
RochelleP. Walensky, M.D., M.P.H.
Massachusetts General Hospital
Boston, MA
csacks@partners.org
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Food and Drug Administration. Guidance for industry:re-
vised recommendations for reducing the risk of human immu-
nodeficiency virus transmission by blood and blood products.
December 2015 (https://w ww.fda.gov/downloads/BiologicsBlood
Vaccines/GuidanceComplianceRegulatoryInformation/Guidances/
Blood/UCM446580.pdf).
2. BCC Research healthcare report:the global blood industry.
Wellesley, MA:BCC Research, March 2015 (http://www.bccresearch
.com/market-research/healthcare/g lobal-blood-industry-report
-hlc008j.html).
DOI: 10.1056/NEJMc1701828
may be necessary to report this information.
However, adherence to the FDA guidance in this
trial would have negated any potentially con-
founding omeprazole effect, thus revealing the
true potency of clopidogrel. Hence, in the com-
parison of ticagrelor with clopidogrel, the extent
to which patients also receive omeprazole is an
important factor.
FeliciaA. Uzoigwe, B.Sc.
8 Harcourt Crescent
Sheffield, United Kingdom
c.uzoigwe@nhs.net
No potential conflict of interest relevant to this letter was re-
ported.
1. Hiatt WR, Fowkes FGR, Heizer G, et al. Ticagrelor versus
clopidogrel in symptomatic peripheral artery disease. N Engl J
Med 2017;376:32-40.
2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus
clopidogrel in patients with acute coronary syndromes. N Engl J
Med 2009;361:1045-57.
3. Food and Drug Administration. FDA reminder to avoid con-
comitant use of Plavix (clopidogrel) and omeprazole (http://www
.fda.gov/Drugs/DrugSafety/ucm231161.htm).
DOI: 10.1056/NEJMc1701197
To the Editor: During antiplatelet treatment,
Asians have a greater bleeding tendency with a
different therapeutic window of platelet reactivity
than white populations.1 In Asian patients, as com-
pared with white patients, clopidogrel responsive-
1487
 The n e w e ng l a n d j o u r na l
ness is decreased because of a higher prevalence
of CYP2C19 loss-of-function alleles, whereas tica
grelor responsiveness is increased (the pharmaco-
kinetic profile is 20 to 40% higher in Asian pa-
tients than in white patients). These findings
need to be considered in evaluating the clinical
efficacy and safety of antiplatelet regimens in
Asians.
In the EUCLID trial, which involved patients
with symptomatic peripheral artery disease, the
risk of major bleeding was not different between
the ticagrelor group and the clopidogrel group
in the total cohort (1.6% vs. 1.6%, P=0.49); how-
ever, the Asian population had a different trend
(3.8% vs. 1.6%; hazard ratio, 2.30; 95% confi-
dence interval, 1.09 to 4.85). Overall, adjunctive
use of ticagrelor with aspirin in the Asian popu-
lation did not achieve favorable net clinical bene-
fits (i.e., these patients had a higher bleeding
risk than patients who received other antiplatelet
regimens).2,3 Ticagrelor monotherapy in patients
with stroke may reduce the risk of an ischemic
event with a bleeding risk that is similar to that
of aspirin monotherapy.4
JongHwa Ahn, M.D., Ph.D.
Gyeongsang National University School of Medicine
Changwon, South Korea
PaulA. Gurbel, M.D.
Inova Heart and Vascular Institute
Fairfax, VA
YoungHoon Jeong, M.D., Ph.D.
Gyeongsang National University School of Medicine
Changwon, South Korea
goodoctor@naver.com
Dr. Gurbel reports receiving consulting fees and honoraria
from Daiichi Sankyo, Bayer, AstraZeneca, Merck, Boehringer
Ingelheim, New Haven Pharmaceuticals, Janssen, and CSL Beh-
ring and grants from Daiichi Sankyo, CSL Behring, AstraZeneca,
Harvard Clinical Research Institute, Haemonetics, New Haven
Pharmaceuticals, Duke Clinical Research Institute, Sinnowa
Medical Science and Technology, and Coramed Technologies,
and holding patents in the field of platelet function testing; and
Dr. Jeong, receiving lecture fees from AstraZeneca, Sanofi-
Aventis, Daiichi Sankyo and Lilly, Haemonetics, Otsuka and
Yuhan Pharmaceuticals and research grants or support from
AstraZeneca, the Korean Society of Interventional Cardiology,
Hanmi Pharmaceuticals, and Haemonetics. No other potential
conflict of interest relevant to this letter was reported.
1. Levine GN, Jeong YH, Goto S, et al. Expert consensus docu-
ment: World Heart Federation expert consensus statement on
antiplatelet therapy in East Asian patients with ACS or undergo-
ing PCI. Nat Rev Cardiol 2014;11:597-606.
2. Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Tica
grelor vs. clopidogrel in Japanese, Korean and Taiwanese pa-
tients with acute coronary syndrome randomized, double-
blind, phase III PHILO study. Circ J 2015;79:2452-60.
3. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of tica
1488 n engl j med 376;15nejm.org April 13, 2017
The New England Journal of Medicine
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
grelor in patients with prior myocardial infarction. N Engl J Med
2015;372:1791-800.
4. Wang Y, Minematsu K, Wong KS, et al. Ticagrelor in acute
stroke or transient ischemic attack in Asian patients: from the
SOCRATES Trial (Acute Stroke or Transient Ischemic Attack
Treated With Aspirin or Ticagrelor and Patient Outcomes).
Stroke 2017;48:167-73.
DOI: 10.1056/NEJMc1701197
The authors reply: We appreciate Uzoigwes
concern regarding the concomitant use of PPIs,
CYP2C19 status, and outcomes in the EUCLID
trial. As stated in the trial protocol, the use of
omeprazole was prohibited after randomization
because of theoretical concerns about outcomes
related to interaction with the cytochrome P-450
2C19 pathway and clopidogrel metabolism. There
was no interaction between PPI use and the pri-
mary outcome, as shown in the Figure S1 in the
Supplementary Appendix, available with the full
text of our article at NEJM.org. The findings
from the EUCLID trial are applicable only to pa-
tients with stable peripheral artery disease who
received the monotherapies prescribed by the
protocol. We therefore do not think that any re-
sults from our trial can be extrapolated to pa-
tients with an acute coronary syndrome. Further-
more, patients in PLATO received dual antiplatelet
therapy, which was not the design of the EUCLID
trial, and an analysis of PPI use in PLATO does
not provide support for an interaction.1
Regarding the question from Ahn et al. about
outcomes in patients from Asia who were en-
rolled in our trial: patients with CYP2C19 homo-
zygous loss-of-function alleles were excluded
from the trial, as was aspirin therapy at baseline.
As noted, Asian patients appear to have higher
bleeding rates with ticagrelor, although the P val-
ue for interaction is not significant without a
similar finding for efficacy. Finally, ours was
arandomized trial of ticagrelor monotherapy ver-
sus clopidogrel, so conclusions about the use of
aspirin and ticagrelor together cannot be made.
ManeshR. Patel, M.D.
Duke University School of Medicine
Durham, NC
manesh.patel@duke.edu
F.GerryR. Fowkes, M.D.
University of Edinburgh
Edinburgh, United Kingdom
WilliamR. Hiatt, M.D.
University of Colorado School of Medicine
and CPC Clinical Research
Aurora, CO
 Correspondence

Since publication of their article, the authors report no fur- ton pump inhibitor use on cardiovascular outcomes with clopi-
ther potential conflict of interest. dogrel and ticagrelor: insights from the Platelet Inhibition and
Patient Outcomes trial. Circulation 2012;125:978-86.
1. Goodman SG, Clare R, Pieper KS, et al. Association of pro- DOI: 10.1056/NEJMc1701197

Arrhythmogenic Right Ventricular Cardiomyopathy

To the Editor: With regard to the review article
by Corrado et al. (Jan. 5 issue)1: we write to discuss
the role of a missense mutation, p.S358L, with-
in the transmembrane protein 43 gene (TMEM43)
that is associated with arrhythmogenic right ven-
tricular cardiomyopathy (ARVC) type 5. Initially
described in families from Newfoundland and
probably inherited from common European an-
cestors,2 this gene codes for a nondesmosomal
nuclear envelope protein3 and has been shown
to cause a fully penetrant and high-risk form of
ARVC.2 The phenotype is modified according to
sex; the median age at death is 40 years in un-
treated men and 67 years in untreated women.4
As stated in the review article, genotyping is
mainly used to identify disease-causing muta-
tions among family members. However, this mu-
tation may also be useful for risk stratification.
It has been suggested that in patients with the
genetic subtype of ARVC caused by the mutation
in TMEM43 (p.S358L), the use of an implantable
cardioverterdefibrillator (ICD) on the basis of
genotype alone may provide a significant sur-
vival advantage and therefore may be considered
even if the patient does not meet international
task force criteria.5
Sarju Ganatra, M.D.
Ajay Sharma, M.D.
Lahey Hospital and Medical Center
Burlington, MA
sarju.ganatra@lahey.org Although the families in whom this TMEM43
No potential conflict of interest relevant to this letter was re-
ported.
1. Corrado D, Link MS, Calkins H. Arrhythmogenic right ven-
tricular cardiomyopathy. N Engl J Med 2017;376:61-72.
2. Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmo-
genic right ventricular cardiomyopathy type 5 is a fully pene-
trant, lethal arrhythmic disorder caused by a missense mutation
in the TMEM43 gene. Am J Hum Genet 2008;82:809-21.
3. Milting H, Klauke B, Christensen AH, et al. The TMEM43
Newfoundland mutation p.S358L causing ARVC-5 was imported
from Europe and increases the stiffness of the cell nucleus. Eur
Heart J 2015;36:872-81.
4. Hodgkinson KA, Connors SP, Merner N, et al. The natural
history of a genetic subtype of arrhythmogenic right ventricular
cardiomyopathy caused by a p.S358L mutation in TMEM43. Clin
Genet 2013;83:321-31.
5. Hodgkinson KA, Howes AJ, Boland P, et al. Long-term clini-
cal outcome of arrhythmogenic right ventricular cardiomyopa-
thy in individuals with a p.S358L mutation in TMEM43 following
implantable cardioverter defibrillator therapy. Circ Arrhythm
Electrophysiol 2016;9(9):e003589.
DOI: 10.1056/NEJMc1701400
The authors reply: In our review article, we fo-
cused on the most common desmosomal gene
related ARVC and, because of space limitations,
we did not address rare nondesmosomal disease
variants. Only a few specific defects in desmo-
somal genes may be considered to be risk factors
for sudden cardiac death; these include com-
pound heterozygous mutations and single trun-
cating mutations in the desmoplakin gene DSP.1
However, ICD therapy is never recommended
on the basis of a genetic test result in isolation
because of the low penetrance and highly vari-
able phenotypic expression of desmosomal gene
related ARVC.2 As Ganatra and Sharma indicate,
Hodgkinson et al. suggest that the nondesmo-
somal TMEM43 p.S358L missense mutation, which
has been shown to be fully penetrant and highly
lethal, may be an exception to this general rec-
ommendation.3 Nevertheless, this founder muta-
tion is extremely rare; it is almost exclusively
identified in Newfoundland and has been report-
ed in only a few families from other countries.
founder mutation has been identified are of
English ancestry, the p.S358L mutation was not
identified among 143 ARVC probands from the
United Kingdom who underwent full TMEM43
sequencing.4
Domenico Corrado, M.D., Ph.D.
University of Padua Medical School
Padua, Italy
domenico.corrado@unipd.it
MarkS. Link, M.D.
University of Texas Southwestern Medical Center
Dallas, TX

n engl j med 376;15nejm.org April 13, 2017 1489

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