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The n e w e ng l a n d j o u r na l of m e dic i n e

original article

Clopidogrel and Aspirin versus Aspirin Alone

for the Prevention of Atherothrombotic Events
Deepak L. Bhatt, M.D., Keith A.A. Fox, M.B., Ch.B., Werner Hacke, M.D.,
Peter B. Berger, M.D., Henry R. Black, M.D., William E. Boden, M.D.,
Patrice Cacoub, M.D., Eric A. Cohen, M.D., Mark A. Creager, M.D.,
J. Donald Easton, M.D., Marcus D. Flather, M.D., Steven M. Haffner, M.D.,
Christian W. Hamm, M.D., Graeme J. Hankey, M.D., S. Claiborne Johnston, M.D.,
Koon-Hou Mak, M.D., Jean-Louis Mas, M.D., Gilles Montalescot, M.D., Ph.D.,
Thomas A. Pearson, M.D., P. Gabriel Steg, M.D., Steven R. Steinhubl, M.D.,
 Christian W. Hamm, M.D., Graeme J. Hankey, M.D., S. Claiborne Johnston, M.D.,
Koon-Hou Mak, M.D., Jean-Louis Mas, M.D., Gilles Montalescot, M.D., Ph.D.,
Thomas A. Pearson, M.D., P. Gabriel Steg, M.D., Steven R. Steinhubl, M.D.,
Michael A. Weber, M.D., Danielle M. Brennan, M.S., Liz Fabry-Ribaudo, M.S.N., R.N.,
Were subjects randomly assigned to the
Joan Booth, R.N., and Eric J. Topol, M.D., for the CHARISMA Investigators*

d (D.L.B.,
and Roy- treatment group? A BS T R AC T
Edinburgh
berg, Hei- • It ensures that each subject has the same probability of being
Background
University,
edical Col-
selected for active treatment protocols rather than for a control
Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been stud-
Hospital, treatment or placebo
pital Pitié-
ied in a broad population of patients at high risk for atherothrombotic events.
Hospital
gie–CHU Methods
opital Bi-
brook and
We randomly assigned 15,603 patients with either clinically evident cardiovascular
ce Centre, disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose
Women’s aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them
l School,
d Hospital
for a median of 28 months. The primary efficacy end point was a composite of
e (J.D.E.); myocardial infarction, stroke, or death from cardiovascular causes.
n (M.D.F.);
e Center at
Results
H.); Kerck-
Germany The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspi-
nd School rin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence
University
H.); Univer-
interval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacy
 ion, stroke (of any er at the two-sided 0.05 significance level in this
scular causes (in- event-driven trial, assuming an annual event rate
cipal secondary ef- of 3.1 percent in the control group and 18 to 42
ccurrence of myo- months of follow-up. The primary efficacy out-
Were all the subjects accounted for and
rom cardiovascular come was monitored with use of a Peto–Haybittle
attributed at the end of the study?
unstable angina, a type of stopping rule based on the P value of the
revascularization log-rank test. Two preplanned interim analyses
• All Oth-
r peripheral). study were
participants should
conducted be analyzed
by a statistician in the groups
associated with to which they
d death fromwere originally
any assigned.data
the independent Thisand
principle is called “intention-to-treat
safety monitoring board.
cular causes as well A two-sided type I error of 0.001 was used at each
hemic stroke, any analysis. A type I error of 0.049 was preserved for
r unstable angina, the final analysis.
ascularization, con- Data were analyzed on an intention-to-treat
basis, with the inclusion of all patients according
t was severe bleed- to their randomly assigned treatment group and
tilization of Strep- the inclusion of outcomes occurring from random-
ogen Activator for ization to a common study end date (August 29,
USTO) definition, 2005). The time to the first occurrence of any
and intracranial event in the composite cluster was used for analy-
caused hemody- sis. Data on patients who did not reach the pri-
blood or fluid re- mary end point by the study end date were cen-
r surgical interven- sored on the date of the patients’ last assessment
 the adenosine diphosphate P2Y12 receptor unaf- for auditing at individual study
fected. Dual antiplatelet therapy with clopidogrel tive committee bears complete
(Plavix, Sanofi-Aventis), a P2Y12-receptor antago- the analysis of the results, the v
nist, plus aspirin has been shown to reduce is- pleteness of the reporting, and t
chemic events in patients with unstable angina, manuscript; the sponsors did h
myocardial infarction without ST-segment eleva- nity to review the manuscript.
Was the study “blinded”?
tion, or myocardial infarction with ST-segment
elevation, as well as those undergoing angioplasty Patients
and stenting.6-9 Patients were eligible to enroll i
Accordingly, we tested the hypothesis that long- were 45 years of age or older an
• Participants who are
termaware
treatmentofwith
their group assignments
a combination of clopidogrel may biasconditions:
following study multiple a
results by behavingplus
and/or responding
aspirin may differently.
provide greater protection against risk factors, documented corona
cardiovascular events than aspirin alone in a broad mented cerebrovascular disease
• Clinicians who are population
aware ofofsubject
patients atassignments
high risk. may treat individuals
symptomatic peripheral arterial
in the intervention group differently than those in the control group,
clusion criteria for those with m
unconsciously (or consciously) manipulating
Me thods the study design
tors and or
for those with establis
ease are shown in Table 1.
analysis. Trial Design Patients were excluded from
The Clopidogrel for High Atherothrombotic Risk were taking oral antithromboti
and Ischemic Stabilization, Management, and nonsteroidal antiinflammatory
Avoidance (CHARISMA) trial was a prospective, term basis (although cyclooxyge
multicenter, randomized, double-blind, placebo- were permitted). Patients were
controlled study of the efficacy and safety of in the judgment of the investiga
clopidogrel plus aspirin as compared with aspi- tablished indications for clopidog
rin alone in patients at high risk for a cardiovas- as a recent acute coronary syndro
cular event. The details of the trial design have were scheduled to undergo a r
been published previously.10 The trial was approved were not allowed to enroll unt
by the institutional ethics committee of each par- had been completed; such patien
ticipating institution as well as the appropriate if they were considered to requi
 The n e w e ng l a n d j o u r na l of m e dic i n e

Were the study groups Table 1. Inclusion Criteria for Patients with Multiple Atherothrombotic Risk Factors and for Those with Established
Cardiovascular Disease.

similar at the start of the

Clopidogrel Placebo
Patients and Criteria plus Aspirin plus Aspirin
no. of patients (%)

investigation?
Patients with multiple atherothrombotic risk factors* 1659 1625
Major risk factors 1535 (92.5) 1490 (91.7)
Type 1 or 2 diabetes (with drug therapy) 1360 (82.0) 1295 (79.7)
Diabetic nephropathy 716 (43.2) 687 (42.3)
Ankle–brachial index <0.9 94 (5.7) 92 (5.7)
Asymptomatic carotid stenosis ≥70% of luminal diameter 123 (7.4) 132 (8.1)
≥1 Carotid plaque, as evidenced by intima–media thickness 198 (11.9) 213 (13.1)

• There are always some Minor risk factors

Systolic blood pressure ≥150 mm Hg, despite therapy for at least 3 mo
1474 (88.8 )
809 (48.8)
1454 (89.5)
744 (45.8)

established risk factors that may Primary hypercholesterolemia

Current smoking >15 cigarettes/day
993 (59.9)
284 (17.1)
1030 (63.4)
271 (16.7)

affect the study outcome. Male sex and age ≥65 yr or female sex and age ≥70 yr
Patients with established cardiovascular disease†
841 (50.7)
6062
853 (52.5)
6091

• Therefore, it is important to Documented coronary disease

Angina with documented multivessel coronary disease
2892 (47.7)
888 (14.6)
2943 (48.3)
885 (14.5)

determine whether these factors History of multivessel percutaneous coronary intervention

History of multivessel coronary-artery bypass grafting
398 (6.6)
736 (12.1)
434 (7.1)
733 (12.0)

are equally balanced between Myocardial infarction

Documented cerebrovascular disease
1903 (31.4)
2157 (35.6)
1943 (31.9)
2163 (35.5)

the intervention and control Transient ischemic attack during previous 5 yr

Ischemic stroke during previous 5 yr
617 (10.2)
1634 (27.0)
616 (10.1)
1611 (26.4)

groups. Documented symptomatic peripheral arterial disease

Current intermittent claudication and ankle–brachial index ≤0.85
1418 (23.4)
885 (14.6)
1420 (23.3)
892 (14.6)
History of intermittent claudication and previous intervention 835 (13.8) 801 (13.2)
(e.g., amputation, peripheral bypass, or angioplasty)

* Data on the other 166 patients enrolled but not categorized were not adequately differentiated on the basis of medical
records. To meet the criterion for enrollment on the basis of multiple risk factors, patients were required to have two
major or three minor or one major and two minor atherothrombotic risk factors.
† To meet the criterion for enrollment on the basis of established cardiovascular disease, patients were required to have
one of the listed conditions.

162 mg per day) or to placebo plus low-dose aspi- month, three months, and six months and every
rin. Study-drug assignment was performed central- six months thereafter until the end of the trial. At
ly by an interactive voice-response system on the these visits, patients’ compliance was assessed,
 Ischemic stroke during previous 5 yr 1634 (27.0)
Documented symptomatic peripheral arterial disease 1418 (23.4)
Current intermittent claudication and ankle–brachial index ≤0.85 885 (14.6)
History of intermittent claudication and previous intervention 835 (13.8)
(e.g., amputation, peripheral bypass, or angioplasty)

Were the study groups treated equally?

* Data on the other 166 patients enrolled but not categorized were not adequately differentiated on the b
records. To meet the criterion for enrollment on the basis of multiple risk factors, patients were require
major or three minor or one major and two minor atherothrombotic risk factors.
† To meet the criterion for enrollment on the basis of established cardiovascular disease, patients were re
• As one might imagine, if subjects in the intervention and control
one of the listed conditions.
groups were treated differently, maintaining blinding protocols would
be difficult. 162 mg per day) or to placebo plus low-dose aspi- month, three months, and six mon
rin. Study-drug assignment was performed central- six months thereafter until the end o
ly by an interactive voice-response system on the these visits, patients’ compliance w
basis of a preestablished randomization scheme, standard medication was adjusted a
stratified according to site. All patients also re- and all interventions, outcome event
ceived standard therapy as appropriate (e.g., statins events were recorded. According to t
or beta-blockers) at the discretion of the investi- culations described below and the
gator and other responsible clinicians. The use of design of the trial, all patients were
appropriate background therapy was emphasized til a common study end date base
to the investigators, who were provided with in- specified target of 1040 primary
ternational guidelines. points was reached.
Follow-up evaluations were performed at one

1708 n engl j med 354;16 www.nejm.org april 20, 2006

 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 4. Composite and Individual Primary and Secondary End Points.

Result End Point

Clopidogrel
plus Aspirin
(N = 7802)
Placebo
plus Aspirin
(N = 7801)
Relative Risk
(95% CI)* P Value
no. (%)
Efficacy end points
Primary efficacy end point 534 (6.8) 573 (7.3) 0.93 (0.83–1.05) 0.22
Death from any cause 371 (4.8) 374 (4.8) 0.99 (0.86–1.14) 0.90
Death from cardiovascular causes 238 (3.1) 229 (2.9) 1.04 (0.87–1.25) 0.68
Myocardial infarction (nonfatal) 146 (1.9) 155 (2.0) 0.94 (0.75–1.18) 0.59
Ischemic stroke (nonfatal) 132 (1.7) 163 (2.1) 0.81 (0.64–1.02) 0.07
Stroke (nonfatal) 150 (1.9) 189 (2.4) 0.79 (0.64–0.98) 0.03
Secondary efficacy end point† 1301 (16.7) 1395 (17.9) 0.92 (0.86–0.995) 0.04
Hospitalization for unstable angina, transient 866 (11.1) 957 (12.3) 0.90 (0.82–0.98) 0.02
ischemic attack, or revascularization
Safety end points
Severe bleeding 130 (1.7) 104 (1.3) 1.25 (0.97–1.61) 0.09
Fatal bleeding 26 (0.3) 17 (0.2) 1.53 (0.83–2.82) 0.17
Primary intracranial hemorrhage 26 (0.3) 27 (0.3) 0.96 (0.56–1.65) 0.89
Moderate bleeding 164 (2.1) 101 (1.3) 1.62 (1.27–2.08) <0.001

* CI denotes confidence interval.

† The secondary efficacy end point was the first occurrence of myocardial infarction, stroke, death from cardiovascular
causes, or hospitalization for unstable angina, a transient ischemic attack, or a revascularization procedure (coronary,
cerebral, or peripheral).