n engl j med 369;14 nejm.

org october 3, 2013

1375
correspondence
The new engl and journal o f medicine
Clopidogrel with Aspirin in Minor Stroke or Transient
Ischemic Attack
To the Editor: Wang et al. (July 4 issue)
1
report
the results of the Clopidogrel in High-Risk Pa-
tients with Acute Nondisabling Cerebrovascular
Events (CHANCE) trial, which showed that in pa-
tients with transient ischemic attack (TIA) or mi-
nor stroke who can be treated within 24 hours
after the onset of symptoms, the combination of
clopidogrel and aspirin was superior to aspirin
alone for reducing the risk of stroke in the first
90 days, with no apparent increase in the risk of
hemorrhage. Recent evidence favors early carotid
endarterectomy in patients with severe carotid
stenosis who have neurologic symptoms similar
to those listed as inclusion criteria in this trial.
2
We wonder whether carotid atherosclerosis was
identified in patients in the CHANCE trial and, if
so, how it was managed in the two study groups.
We also wonder about the results of a subgroup
analysis stratified according to this characteristic.
We suspect that patients with carotid stenosis
might have had a more pronounced clinical bene-
fit because of the unstable plaque behavior, which
could not only explain at least part of the benefit
for patients in this trial, but also help readers to
comprehend in depth the results of the trial.
Stavros K. Kakkos, M.D., Ph.D.
Ioannis A. Tsolakis, M.D., Ph.D.
University of Patras Medical School
Patras, Greece
kakkos@upatras.gr
No potential conflict of interest relevant to this letter was re-
ported.
1. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in
acute minor stroke or transient ischemic attack. N Engl J Med
2013;369:11-9.
2. Salem MK, Sayers RD, Bown MJ, Eveson DJ, Robinson TG,
Naylor AR. Rapid access carotid endarterectomy can be per-
formed in the hyperacute period without a significant increase
in procedural risks. Eur J Vasc Endovasc Surg 2011;41:222-8.
DOI: 10.1056/NEJMc1309713
To the Editor: Dual antiplatelet therapy is high-
ly effective in acute coronary syndromes,
1
but the
same cannot be said about acute ischemic
strokes. Results of the rigorous CHANCE trial
need to be interpreted with caution. In addition
to the questionable generalizability of the study,
it should be noted that the dual antiplatelet ther-
apy was continued in the clopidogrelaspirin group
only for the first 21 days. Perhaps the authors
could describe the benefits in the subgroups 0 to 21
days and 22 to 90 days after the start of treatment.
Similar benefits were shown in the Stenting
and Aggressive Medical Management for Pre-
venting Recurrent Stroke in Intracranial Stenosis
(SAMMPRIS) trial
2
and in a subgroup of symp-
tomatic patients in the Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization,
Management, and Avoidance (CHARISMA) trial.
3

However, the Secondary Prevention of Small
Subcortical Strokes (SPS3) trial,
4
which was con-
ducted in a more diverse population with respect
to race and ethnic group, did not establish any
such benefit in lacunar strokes confirmed on
magnetic resonance imaging. Therefore, since the
controversy continues, we should wait for the
results of the Platelet-Oriented Inhibition in New
this weeks letters
1375 Clopidogrel with Aspirin in Minor Stroke
or Transient Ischemic Attack
1377 Eculizumab in Atypical HemolyticUremic
Syndrome
1380 Mental Health and the Global Agenda
1381 Primaquine Failure and Cytochrome P-450 2D6
in Plasmodium vivax Malaria
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The new engl and journal o f medicine
n engl j med 369;14 nejm.org october 3, 2013
1376
TIA and Minor Ischemic Stroke (POINT) trial
(ClinicalTrials.gov number, NCT00991029) (www
.pointtrial.org) before we reach a consensus on
this issue. Finally, the Triple Antiplatelets for
Reducing Dependency After Ischemic Stroke
(TARDIS) trial (NCT01661322) (www.tardistrial
.org) is under way to determine whether it is the
number of antiplatelet agents or the agents them-
selves that matter.
Mohit Sharma, M.B., B.S.
Priyank Khandelwal, M.B., B.S.
State University of New YorkDownstate Medical Center
Brooklyn, NY
mohitsharma.dr@gmail.com
No potential conflict of interest relevant to this letter was re-
ported.
1. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clo-
pidogrel to aspirin and fibrinolytic therapy for myocardial infarc-
tion with ST-segment elevation. N Engl J Med 2005;352:1179-89.
2. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus
aggressive medical therapy for intracranial arterial stenosis.
N Engl J Med 2011;365:993-1003.
3. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin
versus aspirin alone for the prevention of atherothrombotic
events. N Engl J Med 2006;354:1706-17.
4. The SPS3 Investigators. Effects of clopidogrel added to aspi-
rin in patients with recent lacunar stroke. N Engl J Med 2012;
367:817-25.
DOI: 10.1056/NEJMc1309713
To the Editor: The benefit of intensified plate-
let-oriented inhibition has been proved in pre-
venting early recurrent atherothrombosis in pa-
tients who have had a stroke and who have a low
risk of hemorrhagic transformation, just as it
has been proved in patients who have received
stents for coronary artery disease. However, the
unique characteristics of the East Asian patients
enrolled in this study hamper the generalizabil-
ity of the observed finding. As compared with
Westerners, East Asians have a lower risk of
thrombotic disease with a higher risk of serious
bleeding during the same regimen or level of anti-
thrombotic treatment
1,2
; this may be related to
different hypercoagulability factors. Because of a
different prevalence of carriage of the CYP2C19
loss-of-function allele among East Asians as
compared with Westerners (approximately 65%
vs. approximately 25%),
3
the inhibitory level of
platelet P2Y12 receptor is much lower in East
Asians during clopidogrel therapy.
4
Further-
more, a considerable proportion of East Asians
(and approximately 24% of patients in the
CHANCE study) frequently use traditional med-
ical herbs that have antithrombotic potential.
Because platelet activation and hypercoagulabil-
ity after ischemic stroke may change over time,
the therapeutic level of platelet inhibition can
be different across patients. Future clinical tri-
als must evaluate separately the clinical efficacy
and safety of an antiplatelet strategy according
to the race and ethnic group of the patients as
well as the disease entity and activity.
Young-Hoon Jeong, M.D., Ph.D.
Gyeongsang National University School of Medicine
Jinju, South Korea
goodoctor@naver.com
Dr. Jeong reports receiving honoraria for lectures from Sanofi-
Aventis, Daiichi SankyoLilly, Nanosphere, Haemonetics, and
Otsuka, and research grants or support from Hanmi Pharma-
ceuticals, Boehringer Ingelheim, Otsuka, Accumetrics, and
Haemonetics. No other potential conflict of interest relevant to
this letter was reported.
1. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/
ethnic differences in the risk of intracranial hemorrhage among
patients with atrial fibrillation. J Am Coll Cardiol 2007;50:309-
15.
2. Mak KH, Bhatt DL, Shao M, et al. Ethnic variation in adverse
cardiovascular outcomes and bleeding complications in the Clo-
pidogrel for High Atherothrombotic Risk and Ischemic Stabili-
zation, Management, and Avoidance (CHARISMA) study. Am
Heart J 2009;157:658-65.
3. Man M, Farmen M, Dumaual C, et al. Genetic variation in
metabolizing enzyme and transporter genes: comprehensive as-
sessment in 3 major East Asian subpopulations with comparison
to Caucasians and Africans. J Clin Pharmacol 2010;50:929-40.
4. Kim IS, Jeong YH, Tantry US, et al. Relation between the
vasodilator-stimulated phosphoprotein phosphorylation assay
and light transmittance aggregometry in East Asian patients af-
ter high-dose clopidogrel loading. Am Heart J 2013;166:95-103.
DOI: 10.1056/NEJMc1309713
The Authors Reply: We concur with Kakkos
and Tsolakis that patients with carotid stenosis
might have had greater clinical benefit with the
combination of clopidogrel and aspirin because
of the instability of atherosclerosis plaque. We
assessed extracranial atherosclerosis in a sub-
study, and data are not yet available.
Sharma and Khandelwal appropriately point
out that there is some inconsistency in the re-
sults of trials evaluating combined antiplatelet
therapy. As mentioned in the article, we believe
that early treatment during a period of par-
ticularly high risk of ischemic events explains
the large benefit seen in our trial but not in
other trials that allowed enrollment days to
weeks after a stroke or TIA. Regarding the risk
of stroke during different phases of the follow-
up period, the hazard ratio for stroke in the
clopidogrelaspirin group, as compared with the
aspirin group, was 0.69 (95% confidence interval
The New England Journal of Medicine
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Copyright 2013 Massachusetts Medical Society. All rights reserved.
correspondence
n engl j med 369;14 nejm.org october 3, 2013
1377
[CI], 0.57 to 0.83) for the first 21 days, 1.00
(95% CI, 0.57 to 1.76) for 22 to 60 days, and 0.38
(95% CI, 0.18 to 0.82) for 61 to 90 days. We also
await results of trials such as POINT and
TARDIS for confirmation of these results in
non-Chinese populations.
We agree with Jeong that there may be impor-
tant differences according to the patients eth-
nicity and environment that limit the generaliz-
ability of our results, and we await the results of
future clinical trials.
Yilong Wang, M.D., Ph.D.
Beijing Tiantan Hospital
Beijing, China
S. Claiborne Johnston, M.D., Ph.D.
University of California, San Francisco
San Francisco, CA
Yongjun Wang, M.D.
Beijing Tiantan Hospital
Beijing, China
Since publication of their article, the authors report no further
potential conflict of interest.
DOI: 10.1056/NEJMc1309713
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0 20 40 60 80 100
Delay in Administration of Eculizumab (days)
Figure 1. Scatter Plot of the Change in Creatinine Level
in Relation to the Delay before the Administration
of Eculizumab.
The change in the creatinine level from baseline to
64 weeks (see section 4 in the Supplementary Appendix,
available with the full text of the article by Legendre
et al. at NEJM.org) and the delay before the adminis-
tration of eculizumab (section 2 in the Supplementary
Appendix of the article) are shown. For all included pa-
tients (two patients with data that were measured only
at baseline and one patient who received continuous
hemodialysis were excluded), the correlation coefficient
was 0.51 (P=0.06). Exclusion of the outlier at the ex-
treme right side of the figure yields a correlation coeffi-
cient of 0.20 (P=0.50). Each dot represents one patient.
Eculizumab in Atypical HemolyticUremic Syndrome
To the Editor: With regard to the article by
Legendre et al. (June 6 issue)
1
: assessment of the
37 patients with atypical hemolyticuremic syn-
drome is difficult, since the process of selection
seems opaque, particularly for the 20 patients in
trial 2. It would have been beneficial to have
these patients undergo randomization, given the
fluctuating, relapsing nature of the underlying
disease. In trial 1, a shorter delay before admin-
istration of the first dose of eculizumab was re-
ported to result in a better recovery of renal func-
tion. My colleagues and I evaluated these data
with consideration of the delay before adminis-
tration of eculizumab and of the change in creat-
inine values; our findings provided a different
answer (Fig. 1). Omitting an outlier with a delay
of 96 days, we found a correlation coefficient of
0.20 (P = 0.50).
The article states, atypical hemolyticuremic
syndrome is a genetic, life-threatening, chronic
disease of complement-mediated thrombotic
microangiopathy, yet 24 to 30% of the study
patients had no proven genetic disease, and proof
of ongoing complement activation was lacking,
except for the alleged effect of eculizumab.
Methods to detect ongoing complement activa-
tion in patients with this rare condition are be-
ing developed
2
; 20% of these patients are report-
ed to be hematologically normal at presentation.
3

Not all patients with atypical hemolyticuremic
syndrome have a straightforward response to
eculizumab, and explanations other than com-
plement activation may be relevant.
4,5
Troels Ring, M.D.
Aalborg University Hospital
Aalborg, Denmark
tring@gvdnet.dk
No potential conflict of interest relevant to this letter was re-
ported.
1. Legendre CM, Licht C, Muus P, et al. Terminal complement
inhibitor eculizumab in atypical hemolyticuremic syndrome.
N Engl J Med 2013;368:2169-81.
2. Thurman JM, Rohrer B. Noninvasive detection of comple-
ment activation through radiological imaging. Adv Exp Med Biol
2013;735:271-82.
3. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frmeaux-
Bacchi V. Use of eculizumab for atypical haemolytic uraemic syn-
drome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643-57.
4. Lemaire M, Frmeaux-Bacchi V, Schaefer F, et al. Recessive
mutations in DGKE cause atypical hemolytic-uremic syndrome.
Nat Genet 2013;45:531-6.
5. Modde F, Agustian PA, Wittig J, et al. Comprehensive analy-
sis of glomerular mRNA expression of pro- and antithrombotic
The New England Journal of Medicine
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