European Heart Journal (2009) 30, 192–201 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehn534 Peripheral arterial disease

Patients with peripheral arterial disease

in the CHARISMA trial
Patrice P. Cacoub 1,2*, Deepak L. Bhatt 3, P. Gabriel Steg 4, Eric J. Topol 5, and
Mark A. Creager 6 for the CHARISMA Investigators
1
Department of Internal Medicine, La Pitié-Salpêtrière Hospital, AP HP, 47-83 Boulevard de l’Hôpital, F-75651 Paris Cedex 13, France; 2UMR CNRS 7087, Université Pierre et Marie
Curie-Paris 6, Paris, France; 3VA Boston Healthcare System and Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Cardiology, Bichat Hospital, AP HP and INSERM
U-698 Université Paris 7, Paris, France; 5Scripps Translational Science Institute, Scripps Clinic, and Scripps Health, La Jolla, CA 92037, USA; and 6Division of Cardiovascular Medicine,
Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Received 31 March 2008; revised 3 November 2008; accepted 18 November 2008

See page 131 for the editorial comment on this article (doi:10.1093/eurheartj/ehn565)

Aims The aim of this study was to determine whether clopidogrel plus aspirin provides greater protection against major
cardiovascular events than aspirin alone in patients with peripheral arterial disease (PAD).
.....................................................................................................................................................................................
Methods This is a post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHAR-
and results ISMA trial. The rate of cardiovascular death, myocardial infarction (MI), or stroke (primary endpoint) was higher in
patients with PAD than in those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25; 95% CI 1.08, 1.44; P ¼ 0.002].
Among the patients with PAD, the primary endpoint occurred in 7.6% in the clopidogrel plus aspirin group and 8.9%
in the placebo plus aspirin group (HR, 0.85; 95% CI, 0.66– 1.08; P ¼ 0.18). In these patients, the rate of MI was lower
in the dual antiplatelet arm than the aspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42– 0.96; P ¼ 0.029), as was
the rate of hospitalization for ischaemic events: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68–0.95; P ¼ 0.011). The rates
of severe, fatal, or moderate bleeding did not differ between the groups, whereas minor bleeding was increased with
clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99; 95% CI, 1.69–2.34; P , 0.001).
.....................................................................................................................................................................................
Conclusion Dual therapy provided some benefit over aspirin alone in PAD patients for the rate of MI and the rate of hospital-
ization for ischaemic events, at the cost of an increase in minor bleeding.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Peripheral vascular disease † Aspirin † Clopidogrel † Prognosis

Collaboration meta-analysis of 42 trials including 9717 patients

Introduction
Peripheral arterial disease (PAD) is a common manifestation of
atherosclerosis, affecting an estimated 27million people in Europe
and North America.1 PAD is associated with an increased risk
for cardiovascular events due to coexistence of coronary artery
disease (CAD) and cerebrovascular disease (CVD), such events
being more frequent than ischaemic limb events.2,3 There is a
20 –60% increased risk for myocardial infarction (MI), a two- to
six-fold increased risk of cardiovascular death, and a 40% increased
risk of stroke in patients with PAD.4 These adverse consequences
of PAD occur, in part, because many affected patients are not diag-
nosed, and those with known PAD often are undertreated.5,6
Antiplatelet therapy reduces the risk of MI, stroke, and
vascular death in patients with PAD. The Antithrombotic Trialists’
with PAD found a 22% odds reduction for adverse cardiovascular
events (MI, stroke, or vascular death) in patients with PAD treated
with antiplatelet therapy compared with those who were not
treated.7 Both aspirin and clopidogrel are recommended for
patients with PAD.4
Among the 6452 patients with PAD in the CAPRIE trial, clopido-
grel reduced the risk of MI, stroke, or vascular death by 23.8%
more than aspirin.8 The combination of aspirin and clopidogrel is
more effective in preventing adverse cardiovascular events than
aspirin alone in high-risk groups including patients undergoing per-
cutaneous coronary intervention,9,10 patients with acute coronary
syndromes without ST-segment elevation,11 and patients with
ST-elevation MI.12 It is not known, however, whether dual antipla-
telet therapy with aspirin plus clopidogrel is more effective than a

* Corresponding author. Tel: þ33 142 17 80 27, Fax: þ33 142 17 80 33, Email: patrice.cacoub@psl.aphp.fr
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
Patients with PAD in CHARISMA
single antiplatelet agent in patients with PAD. Analyses derived
from the CAPRIE and CURE studies suggested that the absolute
benefit of clopidogrel over aspirin was amplified in certain high-risk
subgroups of patients.13,14
The combination of aspirin plus clopidogrel was most recently
evaluated in the CHARISMA trial, which enrolled patients with
either established atherothrombotic disease or multiple risk
factors for atherothrombotic events.15 In CHARISMA, dual antipla-
telet therapy vs. aspirin alone was associated with a non-significant
7.1% relative risk reduction in MI, stroke, or cardiovascular death
over a median of 28 months.16 In a post hoc subgroup analysis of
the CHARISMA population, patients with documented prior MI,
ischaemic stroke, or symptomatic PAD appeared to derive signifi-
cant benefit from dual antiplatelet therapy.17
In this context, we hypothesized and pre-specified that long-
term treatment with a combination of clopidogrel plus aspirin
may provide greater protection against cardiovascular events
than aspirin alone in the very high-risk subgroup of patients with
either symptomatic or asymptomatic PAD from the CHARISMA
trial.
Methods
The CHARISMA trial was a prospective, multicentre, randomized,
double-blind, placebo-controlled study. It was approved by the Insti-
tutional Review Committee of each participating institution as well
as by appropriate National Ethics Committees. All patients gave
written informed consent. The details of the trial design have been
published previously.18 Briefly, patients with documented CAD, docu-
mented CVD, documented symptomatic PAD, or multiple athero-
thrombotic risk factors were randomly assigned to receive
clopidogrel (75 mg per day) plus low-dose aspirin (75 – 162 mg per
day) or placebo plus low-dose aspirin and followed for a median of
28 months.
This study includes the 3096 patients with PAD who were identified
in the CHARISMA study. Of these, 2838 (91.7%) were symptomatic
and 258 (8.4%) were asymptomatic. To fulfil the symptomatic PAD
inclusion criterion, patients had to have either current intermittent
claudication together with an ankle-brachial index (ABI) 0.85, or a
history of intermittent claudication together with a previous related
intervention (amputation, surgical or catheter-based peripheral revas-
cularization). Asymptomatic patients with an ABI , 0.90 were ident-
ified among those with multiple risk factors.
Endpoints
The primary efficacy endpoint was the first occurrence of MI, stroke
(of any cause), or death from cardiovascular causes (including haemor-
rhage). The principal secondary efficacy endpoints were the first
occurrence of MI, stroke, death from cardiovascular causes, hospitaliz-
ation for unstable angina, a transient ischaemic attack, or a revascular-
ization procedure (coronary, cerebral, or peripheral). The primary
safety endpoint was severe bleeding according to the GUSTO defi-
nition,19 which includes fatal bleeding and intracranial haemorrhage,
or bleeding that caused haemodynamic compromise requiring blood
or fluid replacement, inotropic support, or surgical intervention.
Moderate bleeding according to the GUSTO criteria,19 which includes
bleeding that led to transfusion but did not meet the criteria for severe
bleeding, and other bleeding events, which were qualified as minor,
were also examined. The study clinical events committee, whose
193
members were unaware of treatment assignments, adjudicated all
primary endpoints.
Statistical analysis
Data were analysed on an intention-to-treat basis, as described pre-
viously for the entire CHARISMA cohort.15 All randomized subjects
were included in the analysis. Subjects with no events were counted
in the analysis and censored at the last known follow-up time (or
time of death). Demographic and baseline characteristics were
described using frequencies. Group comparisons were performed
using the Pearson x 2 test. Cardiovascular endpoint rates were com-
pared using hazard ratios (HRs) and 95% confidence intervals (CIs)
generated from a Cox proportional hazard model and tested using
the log-rank test. Odds ratios (ORs) and 95% CIs were generated
for the bleeding endpoints. Statistical significance was accepted at
the two-sided 0.05 level. Analyses were carried out using SASw 8.02
(SAS Institute Inc., Cary, NC, USA). The proportional hazards assump-
tion was examined by plotting the log(2log(survival)) vs. the log of
survival time. The proportionality test in the SAS procedure for
PROC PHREG was also implemented. Although there were some
slight deviations from the normality assumption, the estimates pro-
vided should only be interpreted as the average effect over time.
The authors had full access to the data and take responsibility for its
integrity. All authors have read and agree to the manuscript as written.
Results
In the CHARISMA study, there were 15 603 participants, including
12 153 patients with established cardiovascular disease. Of these,
2838 patients had documented symptomatic PAD (Figure 1). In
addition, there were 3284 patients with multiple atherothrombotic
risk factors only. Of these, 258 patients had an ABI , 0.90 and
were classified as patients with asymptomatic PAD. Hence, the
current study includes the subset of 3096 patients with sympto-
matic or asymptomatic PAD.
Profile of patients with peripheral
arterial disease
Considering the entire CHARISMA cohort, patients with PAD
(symptomatic or not) were older than patients without PAD
(median age 66 vs. 64 years; P , 0.001, Table 1). A prior history
of MI, stroke, transient ischaemic attack, and percutaneous coron-
ary intervention was reported less often in patients with PAD than
in patients without PAD. Inclusion criteria of the present study
explain these seemingly contradictory results. The majority
(9315/12 341) of the patients without PAD had established CAD
or CVD by definition of the inclusion criteria, whereas 3026/
12 341 had multiple risk factors only. By comparison, PAD patients
only needed to have PAD to be included in this group. Carotid
endarterectomy and peripheral angioplasty or bypass surgery
was more frequent in the PAD group. Concerning the athero-
thrombotic risk factors, the group of patients with PAD had a
greater prevalence of smokers and a lesser prevalence of hyper-
cholesterolaemia, diabetes, and diabetic nephropathy than patients
without PAD (though this had to do with the inclusion criteria for
patients enrolled into the trial with multiple risk factors). Overall,
85.9% of the patients with PAD received cardiovascular drugs vs.
93.3% of the patients without PAD (P , 0.001), respectively,
194
Figure 1 Design of the study. PAD, peripheral arterial disease.
including 72.7% vs. 77.9% who received statins (P , 0.001), 12.2%
vs. 14.6% who received other lipid-lowering agents (P ¼ 0.001),
and 36.0% vs. 43.1% received antidiabetic medications (P ,
0.001). PAD patients tended to be on a lower dose of daily
aspirin: daily aspirin , 100 mg 48.6% vs. 45.2%; daily aspirin ¼
100 mg 31.9% vs. 31.8%; daily aspirin . 100 mg 19.4% vs. 23.0%
in PAD vs. no PAD, respectively (P , 0.001).
Among the patients with PAD, asymptomatic patients were
older than symptomatic patients by 2 years (median age 68 vs.
66 years; P ¼ 0.029) and included a larger proportion of women
(40.7% vs. 29.1%, P , 0.001) (Table 2). Asymptomatic patients
had more frequent history of stroke and transient ischaemic
attack, whereas prior MI and vascular interventions (apart from
peripheral angioplasty or bypass) were reported with similar
rates in the two groups. Atherothrombotic risk factors, other
than smoking, were also more frequent in asymptomatic than
symptomatic patients (though again, this was likely due to the
inclusion criteria of the trial).
Outcome of patients with peripheral
arterial disease
The overall rate of cardiovascular death, MI, or stroke was 8.2% in
patients with PAD and 6.8% in patients without PAD (HR, 1.25;
95% CI, 1.08–1.44; P ¼ 0.002, Table 3). Patients with PAD had
also higher rates of death from any cause (HR, 1.80; 95% CI,
1.54 –2.11; P , 0.001), death from cardiovascular causes (HR,
1.73; 95% CI, 1.42–2.12; P , 0.001), MI (HR, 1.33, 95% CI,
1.05 –1.68; P ¼ 0.017), and hospitalization for ischaemic events
(HR, 1.97; 95% CI, 1.78– 2.17; P , 0.001). Though the rate of
severe bleeding in patients with PAD (1.7%) was similar to that
observed in patients without PAD (1.5%, P ¼ 0.30), the rate of
P.P. Cacoub et al.
moderate bleeding was significantly higher in patients with PAD
(2.2% vs. 1.6%, P ¼ 0.032).
Outcome of patients with symptomatic PAD was similar to that
of asymptomatic PAD patients (data not shown), except for the
rate of hospitalization for ischaemic events, which was higher in
symptomatic patients (18.9% vs. 11.2%, P ¼ 0.002).
Effect of clopidogrel or dual antiplatelet
therapy in patients with peripheral
arterial disease
In the subset of 3096 patients with PAD, 1545 patients were ran-
domized to receive clopidogrel plus aspirin and 1551 patients were
randomized to receive placebo plus aspirin. The baseline charac-
teristics of these patients in the two randomized arms were well
matched (Table 4). The only difference was the prevalence of
patients with a history of hypertension, which was lower in the clo-
pidogrel group than in the placebo group (69.9% vs. 74.6%, P ¼
0.004). Use of concomitant medication was also similar in the
two treatment groups, except use of calcium antagonists, which
was lower in the clopidogrel arm than in the placebo arm
(38.5% vs. 43.1%, P ¼ 0.010).
After a median duration of follow-up in PAD patients of 26
months (28 months in the entire CHARISMA cohort), the
overall rate of cardiovascular death, MI, or stroke (primary efficacy
endpoint) was 7.6% in the clopidogrel group and 8.9% in the
placebo group (HR, 0.85; 95% CI, 0.66–1.08; P ¼ 0.18, Table 5).
A significant benefit was observed for the rate of MI, which was
2.3% in the clopidogrel group and 3.7% in the placebo group
(HR, 0.63; 95% CI, 0.42–0.96; P ¼ 0.029), and for the rate of hos-
pitalization for ischaemic events, which was 16.5% in the
Patients with PAD in CHARISMA 195

Table 1 Baseline characteristics and concomitant medications of patients with or without peripheral arterial disease in
the CHARISMA trial

Entire CHARISMA cohort P-value

..................................................................
PAD (n ¼ 3096) No PAD (n ¼ 12 341)
...............................................................................................................................................................................
Demographics
Age, median, years 66 (59, 73) 64 (56, 71) ,0.001
Female 930 (30.0) 3659 (29.6) 0.671
Race ,0.001
Caucasian 2660 (85.9) 9709 (78.7)
Hispanic 281 (9.1) 1318 (10.7)
Asian 30 (1.0) 739 (6.0)
Black 96 (3.1) 379 (3.1)
Other 29 (0.9) 196 (1.6)
...............................................................................................................................................................................
Selected clinical characteristics
Smoking status
Current 995 (32.1) 2129 (17.3) ,0.001
Former 1646 (53.2) 5894 (47.8) ,0.001
Hypertension 2237 (72.3) 9109 (73.8) 0.079
Hypercholesterolaemia 2160 (69.8) 9239 (74.9) ,0.001
Congestive heart failure 199 (6.4) 717 (5.8) 0.193
Prior myocardial infarction 772 (24.9) 4591 (37.2) ,0.001
Atrial fibrillation 124 (4.0) 452 (3.7) 0.369
Prior stroke 269 (8.7) 3538 (28.7) ,0.001
Transient ischaemic attack 217 (7.0) 1627 (13.2) ,0.001
Diabetes 1120 (36.2) 5368 (43.5) ,0.001
Percutaneous coronary intervention 462 (14.9) 3045 (24.7) ,0.001
Coronary artery bypass graft 574 (18.5) 2480 (20.1) 0.052
Carotid endarterectomy 290 (9.4) 533 (4.3) ,0.001
Peripheral angioplasty or bypass 1567 (50.6) 167 (1.4) ,0.001
Diabetic nephropathy 232 (7.5) 1768 (14.3) ,0.001
...............................................................................................................................................................................
a
Concomitant medications
Aspirin 3087 (99.7) 12 303 (99.7) 0.876
Diuretics 1495 (48.3) 5846 (47.4) 0.361
Nitrates 725 (23.4) 2923 (23.7) 0.754
Calcium antagonists 1263 (40.8) 4420 (35.8) ,0.001
Beta-blockers 1468 (47.4) 7075 (57.3) ,0.001
Angiotensin II-receptor blockers 734 (23.7) 3229 (26.2) 0.005
Ramipril 464 (15.0) 2312 (18.7) ,0.001
Other angiotensin-converting-enzyme inhibitors 1307 (42.2) 5853 (47.4) ,0.001
Other antihypertensive agents 445 (14.4) 1467 (11.9) ,0.001
Statins 2252 (72.7) 9618 (77.9) ,0.001
Atorvastatin 1070 (34.6) 4453 (36.1) 0.114
Simvastatin 1007 (32.5) 4310 (34.9) 0.012
Pravastatin 312 (10.1) 1593 (12.9) ,0.001
Fluvastatin 107 (3.5) 383 (3.1) 0.317
Lovastatin 102 (3.3) 450 (3.6) 0.346
Other statins 164 (5.3) 754 (6.1) 0.087
Other lipid-lowering agents 379 (12.2) 1801 (14.6) 0.001
Fibrates 222 (7.2) 1092 (8.8) 0.003
Binding resins 111 (3.6) 534 (4.3) 0.065
Nicotinic acid 91 (2.9) 441 (3.6) 0.084
Antidiabetic medications 1114 (36.0) 5323 (43.1) ,0.001

Continued
196 P.P. Cacoub et al.

Table 1 Continued

Entire CHARISMA cohort P-value

..................................................................
PAD (n ¼ 3096) No PAD (n ¼ 12 341)
...............................................................................................................................................................................
Insulin 544 (17.6) 2127 (17.2) 0.659
Thiazolidinediones 178 (5.7) 1053 (8.5) ,0.001
Other oral hypoglycaemic agents 837 (27.0) 4472 (36.2) ,0.001

PAD, peripheral arterial disease.

Data are presented as n (%) unless otherwise specified.
a
Values indicate the maximal frequency of use of each agent at any time during the trial (assessed at baseline and at every follow-up visit).

Table 2 Baseline characteristics of patients with symptomatic or asymptomatic peripheral arterial disease

Patients with PAD P-value

..............................................................................
Symptomatic (n ¼ 2838) Asymptomatic (n ¼ 258)
...............................................................................................................................................................................
Demographics
Age, median, years 66 (59, 73) 68 (61, 74) 0.029
Female 825 (29.1) 105 (40.7) ,0.001
Race ,0.001
Caucasian 2451 (86.4) 209 (81.0)
Hispanic 263 (9.3) 18 (7.0)
Asian 18 (0.6) 12 (4.7)
Black 80 (2.8) 16 (6.2)
Other 26 (0.9) 3 (1.2)
...............................................................................................................................................................................
Selected clinical characteristics
Smoking status
Current 938 (33.1) 57 (22.1) ,0.001
Former 1529 (53.9) 117 (45.3) 0.009
Hypertension 2029 (71.5) 208 (80.6) 0.002
Hypercholesterolaemia 1948 (68.6) 212 (82.2) ,0.001
Congestive heart failure 173 (6.1) 26 (10.1) 0.013
Prior myocardial infarction 716 (25.2) 56 (21.7) 0.210
Atrial fibrillation 112 (3.9) 12 (4.7) 0.580
Prior stroke 237 (8.4) 32 (12.4) 0.027
Transient ischaemic attack 190 (6.7) 27 (10.5) 0.023
Diabetes 980 (34.5) 140 (54.3) ,0.001
Percutaneous coronary intervention 426 (15.0) 36 (14.0) 0.648
Coronary artery bypass graft 520 (18.3) 54 (20.9) 0.302
Carotid endarterectomy 267 (9.4) 23 (8.9) 0.795
Peripheral angioplasty or bypass 1553 (54.7) 14 (5.4) ,0.001
Diabetic nephropathy 186 (6.6) 46 (17.8) ,0.001

PAD, peripheral arterial disease.

Data are presented as n (%) unless otherwise specified.

clopidogrel group and 20.1% in the placebo group (HR, 0.81; 95%
CI, 0.68 –0.95; P ¼ 0.011). The other efficacy outcomes were
reported with similar rates in the two groups.
The rate of the primary safety endpoint (severe bleeding) was
1.7% in each treatment group (P ¼ 0.90). The rate of minor bleed-
ing was 34.4% in the patients treated with clopidogrel, when com-
pared with 20.8% in the group treated with placebo (P , 0.001).
Though the difference was not statistically significant, the rate of
moderate bleeding was also higher in the clopidogrel group
(2.5% vs. 1.9%, P ¼ 0.26). Among patient requiring revasculariza-
tion procedures, there was a trend for a benefit of clopidogrel
plus aspirin combination in all subgroups (Table 6), although this
was statistically significant only in the coronary stent group (3.1%
vs. 4.4%; P ¼ 0.05).
Patients with PAD in CHARISMA 197

Table 3 Composite and individual primary endpoints in patients with or without peripheral arterial disease in the
CHARISMA trial

Entire CHARISMA cohort HR (95% CI)a P-value

......................................................
PAD (n ¼ 3096) No PAD (n ¼ 12 341)
...............................................................................................................................................................................
Efficacy endpoints
Cardiovascular death, MI, or stroke (primary endpoint) 255 (8.2) 843 (6.8) 1.25 (1.08–1.44) 0.002
Death from any cause 221 (7.1) 514 (4.2) 1.80 (1.54–2.11) ,0.001
Death from cardiovascular causes 136 (4.4) 327 (2.6) 1.73 (1.42–2.12) ,0.001
Myocardial infarctionb 93 (3.0) 290 (2.3) 1.33 (1.05–1.68) 0.017
Ischaemic strokeb 71 (2.3) 302 (2.4) 0.97 (0.75–1.25) 0.782
Strokeb 82 (2.6) 356 (2.9) 0.94 (0.74–1.20) 0.635
Hospitalizationc 566 (18.3) 1244 (10.1) 1.97 (1.78–2.17) ,0.001
...............................................................................................................................................................................
Safety endpoints
Severe bleeding 53 (1.7) 180 (1.5) 1.18 (0.86–1.60) 0.301
Fatal bleeding 13 (0.4) 30 (0.2) 1.73 (0.90–3.32) 0.095
Primary intracranial haemorrhage 9 (0.3) 44 (0.4) 0.81 (0.40–1.67) 0.576
Moderate bleeding 67 (2.2) 198 (1.6) 1.36 (1.03–1.79) 0.032
Minor bleeding 854 (27.6) 3,227 (26.1) 1.08 (0.98–1.17) 0.105

CI, confidence interval; HR, hazard ratio; PAD, peripheral arterial disease.
Data are presented as n (%).
a
For the safety endpoints, the ORs and 95% CI are calculated.
b
Fatal plus non-fatal events.
c
For unstable angina, transient ischaemic attack, or revascularization.

Discussion suggested previously.13,14,21 In a separate post hoc analysis of a

In this post hoc subgroup analysis of the CHARISMA trial, major car-
diovascular events occurred more frequently in patients with PAD,
either symptomatic or not, when compared with patients enrolled
with CAD or CVD or with multiple risk factors. The rate of cardi-
ovascular death, MI, or stroke (primary endpoint) was significantly
higher in patients with PAD than in those without PAD. These
results are consistent with those of the REACH registry, which
found an event rate of 5.4% at 1 year for the same composite end-
point in patients with established PAD.20 Taken together, these
observations underscore the fact that PAD has important prognos-
tic implications for cardiovascular ischaemic events.2,3
The primary efficacy and safety endpoints occurred with similar
frequency in PAD patients treated with the combination of clopi-
dogrel and aspirin and in those treated with aspirin alone.
Nonetheless, this analysis suggests that in patients with PAD,
dual antiplatelet therapy with clopidogrel plus aspirin may
provide some benefits compared with aspirin alone. The combi-
nation of clopidogrel with aspirin therapy reduced the rate of MI
and the rate of hospitalization for ischaemic events, but at the
cost of an increased rate of minor bleeding. MI, the endpoint for
which a benefit of dual therapy was found, was also the least fre-
quent among the endpoints, both in the PAD subgroup and in the
overall CHARISMA population. PAD patients, independent of the
treatment group, showed an increased rate of moderate bleeding
(2.2% vs. 1.6%; P ¼ 0.032). The use of dual antiplatelet therapy
to reduce cardiovascular events may be particularly relevant to
high-risk groups of patients with atherothrombosis, as has been
‘CAPRIE-like’ subgroup of patients with documented prior MI,
ischaemic stroke, or symptomatic PAD from the CHARISMA
trial, there was a significant 1.7% absolute risk reduction in the
composite of cardiovascular death, MI, or stroke in patients
treated with clopidogrel plus aspirin vs. aspirin alone.17 In that
analysis, the PAD group included only symptomatic patients. We
have extended the analyses to include all patients with PAD,
whether symptomatic or asymptomatic, and specifically examined
the efficacy of dual antiplatelet therapy in this population on the
major secondary efficacy and safety endpoints. Our findings are
consistent with observations made in the CAPRIE trial,8 which
showed reduced rate of cardiovascular events with clopidogrel
compared with aspirin in the PAD subgroup, though the number
of PAD patients in CHARISMA was considerably less than in
CAPRIE, thereby limiting statistical power. In CHARISMA, addition
of clopidogrel to aspirin appeared to confer benefits in terms of
reducing MI and hospitalizations among patients with PAD.
Given the well-known limitations and potential confounding of
post hoc subset analyses,22 – 24 our results should be viewed as
merely hypothesis generating and need confirmation with appro-
priately designed prospective studies. Nevertheless, the PAD sub-
group represented a large part (20%) of the entire CHARISMA
cohort and included more than 3000 patients.
In conclusion, in the CHARISMA trial, patients with symptomatic
or asymptomatic PAD showed a worse outcome than patients
without PAD, i.e. CAD or CVD patients or those with multiple
risk factors. Dual antiplatelet therapy with clopidogrel plus
aspirin provided some benefit over aspirin alone in patients with
198 P.P. Cacoub et al.

Table 4 Baseline characteristics and concomitant medications of patients with peripheral arterial disease in the two
treatment arms of the CHARISMA trial

Patients with PAD P-value

.......................................................................................
Clopidogrel plus aspirin (n ¼ 1545) Placebo plus aspirin (n ¼ 1551)
...............................................................................................................................................................................
Demographics
Age, median, years 66 (59, 73) 66 (59, 73) 0.734
Female 463 (30.0) 467 (30.1) 0.931
Race 0.478
Caucasian 1324 (85.7) 1336 (86.1)
Hispanic 144 (9.3) 137 (8.8)
Asian 14 (0.9) 16 (1.0)
Black 52 (3.4) 44 (2.8)
Other 11 (0.7) 18 (1.2)
...............................................................................................................................................................................
Selected clinical characteristics
Smoking status
Current 483 (31.3) 512 (33.0) 0.297
Former 827 (53.5) 819 (52.8) 0.687
Hypertension 1080 (69.9) 1157 (74.6) 0.004
Hypercholesterolaemia 1069 (69.2) 1091 (70.3) 0.486
Congestive heart failure 106 (6.9) 93 (6.0) 0.327
Prior myocardial infarction 386 (25.0) 386 (24.9) 0.950
Atrial fibrillation 70 (4.5) 54 (3.5) 0.137
Prior stroke 128 (8.3) 141 (9.1) 0.426
Transient ischaemic attack 119 (7.7) 98 (6.3) 0.132
Diabetes 555 (35.9) 565 (36.4) 0.770
Percutaneous coronary intervention 228 (14.8) 234 (15.1) 0.797
Coronary artery bypass graft 282 (18.3) 292 (18.8) 0.681
Carotid endarterectomy 152 (9.8) 138 (8.9) 0.369
Peripheral angioplasty or bypass 794 (51.4) 773 (49.8) 0.388
Diabetic nephropathy 108 (7.0) 124 (8.0) 0.288
...............................................................................................................................................................................
a
Concomitant medications
Aspirin 1539 (99.6) 1548 (99.8) 0.342
Diuretics 745 (48.2) 750 (48.4) 0.940
Nitrates 339 (21.9) 386 (24.9) 0.053
Calcium antagonists 595 (38.5) 668 (43.1) 0.010
Beta-blockers 716 (46.3) 752 (48.5) 0.233
Angiotensin II-receptor blockers 374 (24.2) 360 (23.2) 0.515
Ramipril 227 (14.7) 237 (15.3) 0.647
Other angiotensin-converting-enzyme inhibitors 627 (40.6) 680 (43.8) 0.066
Other antihypertensive agents 220 (14.2) 225 (14.5) 0.832
Statins 1132 (73.3) 1120 (72.2) 0.509
Atorvastatin 523 (33.9) 547 (35.3) 0.407
Simvastatin 504 (32.6) 503 (32.4) 0.910
Pravastatin 159 (10.3) 153 (9.9) 0.693
Fluvastatin 62 (4.0) 45 (2.9) 0.090
Lovastatin 54 (3.5) 48 (3.1) 0.533
Other statins 80 (5.2) 84 (5.4) 0.768
Other lipid-lowering agents 174 (11.3) 205 (13.2) 0.097
Fibrates 105 (6.8) 117 (7.5) 0.420
Binding resins 49 (3.2) 62 (4.0) 0.217
Nicotinic acid 41 (2.7) 50 (3.2) 0.348
Antidiabetic medications 554 (35.9) 560 (36.1) 0.886

Continued
Patients with PAD in CHARISMA 199

Table 4 Continued

Patients with PAD P-value

.......................................................................................
Clopidogrel plus aspirin (n ¼ 1545) Placebo plus aspirin (n ¼ 1551)
...............................................................................................................................................................................
Insulin 274 (17.7) 270 (17.4) 0.811
Thiazolidinediones 86 (5.6) 92 (5.9) 0.662
Other oral hypoglycaemic agents 416 (26.9) 421 (27.1) 0.891

PAD, peripheral arterial disease.

Data are presented as n (%) unless otherwise specified.
a
Values indicate the maximal frequency of use of each agent at any time during the trial (assessed at baseline and at every follow-up visit).

Table 5 Composite and individual primary endpoints in patients with peripheral arterial disease in the two treatment
arms of the CHARISMA trial

Patients with PAD HR (95% CI)a P-value

....................................................................................
Clopidogrel plus aspirin (n ¼ 1545) Placebo plus aspirin (n ¼ 1551)
...............................................................................................................................................................................
Efficacy endpoints
Primary endpoint 117 (7.6) 138 (8.9) 0.85 (0.66– 1.08) 0.183
Death from any cause 104 (6.7) 117 (7.5) 0.89 (0.68– 1.16) 0.387
Death from cardiovascular causes 65 (4.2) 71 (4.6) 0.92 (0.65– 1.28) 0.613
Myocardial infarctionb 36 (2.3) 57 (3.7) 0.63 (0.42– 0.96) 0.028
Ischaemic strokeb 32 (2.1) 39 (2.5) 0.82 (0.52– 1.32) 0.416
Strokeb 36 (2.3) 46 (3.0) 0.79 (0.51– 1.21) 0.275
Hospitalizationc 255 (16.5) 331 (20.1) 0.81 (0.68– 0.95) 0.011
...............................................................................................................................................................................
Safety endpoints
Severe bleeding 26 (1.7) 27 (1.7) 0.97 (0.56– 1.66) 0.901
Fatal bleeding 7 (0.5) 6 (0.4) 1.17 (0.39– 3.49) 0.776
Primary intracranial haemorrhage 3 (0.2) 6 (0.4) 0.50 (0.12– 2.01) 0.507
Moderate bleeding 38 (2.5) 29 (1.9) 1.32 (0.81– 2.16) 0.259
Minor bleeding 531 (34.4) 323 (20.8) 1.99 (1.69– 2.34) ,0.001

CI, confidence interval; HR, hazard ratio; PAD, peripheral arterial disease.
Data are presented as n (%).
a
For the safety endpoints, the ORs and 95% CI are calculated.
b
Fatal plus non-fatal events.
c
For unstable angina, transient ischaemic attack, or revascularization.

symptomatic or asymptomatic PAD. Benefit was observed for the
rate of MI and the rate of hospitalization for ischaemic events, at
the cost of an increase in minor, though not moderate or severe
bleeding. Such patients may benefit from antithrombotic therapy
intensification beyond aspirin alone, a concept that future PAD
trials will need to validate.
Conflict of interest: P.P.C has received research grants/honor-
aria/consultant fees from Astra Zeneca, Bristol–Myers Squibb,
Encysive, Gilead, Roche, Sanofi Aventis, Schering Plough, and
Servier. D.L.B. has received research grants/honoraria/consultant
fees from Arena, Astra Zeneca, Bayer, Bristol– Myers Squibb,
Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly,
Ethicon, Glaxo SmithKline, Heartscape, Johnson & Johnson,
McNeil, Medtronic, Millenium, Otsuka, Paringenix, PDL, Portola,
Sanofi Aventis, Schering Plough, Scios, The Medicines Company,
tns Healthcare, and Vertex; he also provided expert testimony
regarding anti-thrombotic therapy (the compensation was
donated to a non-profit organization; .2 years). P.G.S. has
received research grants/honoraria/consultant fees from Astra
Zeneca, Boehringer-Ingelheim, Bristol– Myers Squibb, Glaxo
SmithKline, Merck Sharp and Dohme-Chibret, Nycomed, Sanofi
Aventis, Servier, Takeda, The Medicines Company, and
ZLB-Behring. E.J.T. has received research grants from Bristol–
Myers Squibb and Sanofi Aventis. M.A.C. has received research
grants/honoraria/consultant fees from Bristol– Myers Squibb,
Genzyme, Sanofi Aventis, and Sigma Tau.
200 P.P. Cacoub et al.

Table 6 Vascular interventions during treatment in patients with peripheral arterial disease in the two treatment arms
of the CHARISMA trial

Intervention Patients with PAD P-value

...............................................................................................................
Clopidogrel plus aspirin (n ¼ 1545) Placebo plus aspirin (n ¼ 1551) Total (n ¼ 3096)
...............................................................................................................................................................................
Peripheral arterial bypass surgery 58 (3.8) 79 (5.1) 137 (4.4) 0.070
Coronary stent 48 (3.1) 69 (4.4) 117 (3.8) 0.050
Percutaneous coronary angioplasty 33 (2.1) 49 (3.2) 82 (2.6) 0.076
Coronary artery bypass graft 27 (1.7) 34 (2.2) 61 (2.0) 0.374
Carotid endarterectomy 16 (1.0) 26 (1.7) 42 (1.4) 0.123
Leg amputationa 12 (0.8) 17 (1.1) 29 (0.9) 0.356
Carotid percutaneous angioplastyb 11 (0.7) 7 (0.5) 18 (0.6) 0.340
Other intervention for PAD 142 (9.2) 151 (9.7) 293 (9.5) 0.605

PAD, peripheral arterial disease.

Data are presented as n (%).
a
For critical leg ischaemia.
b
With or without stent.

Funding
The CHARISMA trial was funded by Sanofi-Aventis and Bristol– Myers
Squibb.
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doi:10.1093/eurheartj/ehn410
CARDIOVASCULAR FLASHLIGHTS Online publish-ahead-of-print 9 September 2008
.............................................................................................................................................................................

Infradiaphragmatic interruption of the inferior vena cava mimicking

a double aorta
Lucy Hudsmith*, Benjamin Holloway, and Paul Clift
Department of Cardiology, The Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK
* Corresponding author. Tel: þ44 1865 741166, Fax: þ44 1865 221111, Email: lucyhudsmith@hotmail.com

A 17-year-old male with previous

subclavian flap repair of a coarcta-
tion was referred for cardiovas-
cular magnetic resonance (CMR)
imaging for the surveillance of his
surgical repair site. He was well
to follow-up with good blood
pressure control and no remark-
able clinical findings.
CMR (Symphony, Siemens, 1.5 T)
showed no evidence of recoarctation
or aneurysm formation. However,
cine images gave the impression of a
double aorta (Figure). This resulted
from a continuation of the hemiazy-
gos vein joining with a left-sided
superior vena cava draining into
the coronary sinus and infrahepatic
interruption of the inferior vena
cava (IVC). The hepatic veins empty
into the right atrium. There was no
evidence of atrial isomerism.
Infradiaphragmatic interruption
of the IVC is a rare anatomical
variant seen in 2 –3% of congenital
heart disease patients and can be misdiagnosed as an aortic dissection or partial rupture with echocardiography. It results from the
failure of the connection between the right subcardinal vein and the liver and the dilatation of the supracardinal vein which develops
into the azygos and hemiazygos veins. The hepatic veins drain directly into the right atrium.
The interruption of the infradiaphragmatic IVC may be associated with other cardiac malformations and polysplenia. Failure to
identify this anomaly may result in complications in interventional and surgical procedures.
Top: Sagittal (left) and transverse (right) CMR images demonstrating the continuation of the hemiazygos vein (HA) combined with
the left-sided superior vena cava posterior to the aorta (Ao).
Bottom: Coronal black blood images showing the hepatic veins draining into the right atrium (RA), and the left superior vena cava
(LSVC) draining into the coronary sinus (CS).

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.