The base trial for the current subgroup analysis is the CHARISMA^1^
trial which enrolled a stable population with either established
atherothrombotic disease or multiple risk factors for atherothrombotic
events. The primary end point for this trial showed a nonsignificant
7.1% relative risk reduction in cardiovascular death/MI or stroke over a
median of 28 months with the combination of clopidogrel and aspirin vs.
aspirin alone. Dual therapy conferred significantly higher risks for
all-cause and cardiovascular mortality in the multiple risk-factor
subgroup, but not in those with clinically evident disease. Overall,
severe bleeding was somewhat more common with dual therapy than with
aspirin alone (1.7% vs. 1.3%; *P*=0.09).

In a prespecified subgroup analysis^2^, the 12,153 patients with
documented cardiovascular, cerebrovascular, or peripheral arterial
disease (a secondary-prevention population, symptomatic) seemed to
derive a significant benefit from combination therapy, while the 3284
patients without documented disease but with multiple risk factors (a
primary-prevention population, asymptomatic) did not derive any benefit.

In a separate post-hoc subgroup analysis published by Bhatt et al;
explored a group of secondary-prevention patients\--those at the higher
end of the risk stratification. The CHARISMA investigators explain that
this high-risk group is similar to those patients enrolled in the
previous CAPRIE^3^ study, which showed a benefit of clopidogrel
monotherapy over aspirin monotherapy. They hypothesized that if the
CHARISMA trial had examined only a \"CAPRIE-like\" high-risk
secondary-prevention population instead of a broader and overall
lower-risk population, as was actually done, greater benefit of dual
antiplatelet therapy over aspirin might have been evident.

The results were analyzed for the 9478 patients who met the CAPRIE
criteria (with documented prior MI, ischemic stroke, or symptomatic
PAD). Results showed that in this group, the rate of cardiovascular
death, MI, or stroke was significantly lower in the
clopidogrel-plus-aspirin arm than in the placebo-plus-aspirin arm, as
was the rate of hospitalizations for ischemia.

**CHARISMA subgroup analysis in \"CAPRIE-type\" patients: Efficacy
results**

  -------------------- -------------------- ------------ -------------- ---------
  **End point**        **Clopidogrel plus   **Aspirin    **HR (95%      **p**
                       aspirin (%)**        alone (%)**  CI)**          

  **CV                 7.3                  8.8          0.83           \<0.01
  death/MI/stroke**                                      (0.72--0.96)   

  **Hospitalization    11.4                 13.2         0.86           \<0.008
  for ischemia**                                         (0.76--0.96)   
  -------------------- -------------------- ------------ -------------- ---------

**CHARISMA subgroup analysis in \"CAPRIE-type\" patients: Safety
results**

**NNH =500 sv, 143 mod**

  --------------- ---------------------- -------------- -------------- -------
  **End point**   **Clopidogrel plus     **Aspirin      **HR (95%      **p**
                  aspirin (%)**          alone (%)**    CI)**          

  **Severe        1.7                    1.5            1.12           0.50
  bleeding**                                            (0.81--1.53)   

  **Moderate      2.0                    1.3            1.60           0.004
  bleeding**                                            (1.16--2.20)   
  --------------- ---------------------- -------------- -------------- -------

The current post hoc subgroup analysis of patients with prior MI,
stroke, or symptomatic PAD from the CHARISMA trial suggests a
significant 1.5% absolute risk reduction in the composite of
cardiovascular death, MI, or stroke over a median of 27.6 months
(NNT=67), which compares with a 2% absolute risk reduction in the same
end point in the CURE trial in ACS patients over a median of nine months
(NNT=50).

The authors also report that the CURE^4^ and CREDO^5^ trials suggested
that dual antiplatelet therapy would prevent 20 to 30 ischemic events
per 1000 patients treated for about one year, while the CAPRIE-like
cohort from the CHARISMA trial shows a more modest degree of benefit,
with 14.4 episodes of cardiovascular death, MI, or stroke and 17.5
hospitalizations for ischemic events or revascularization averted over
the course of an average of 27.6 months per 1000 patients treated, at a
cost of 1.7 severe bleeds and 7.6 moderate bleeds.

Several patterns emerge from examination of this data set: the benefit
in preventing ischemic events is greatest early after treatment began
and in patients with a recent previous ischemic event, although coupled
with increased bleeding rates for patients receiving dual antiplatelet
therapy compared with aspirin alone in the first few months of therapy
and little difference afterward. This is not similar to results seen
with other long-term prospective randomized trials involving clopidogrel
and aspirin in combination (MATCH, ATIVE-W---the bleeding in these
trials were not "front loaded" as these are prospective trials).
Additionally,

Several problems exist with the overall data analysis in this subgroup
analysis as with the original CHARISMA trial.^6^ In this subgroup
analysis, publication data was not tested for heterogeneity nor were the
data corrected for multiple tests on the same data. These omissions
could have caused a treatment effect to appear when there may not be
one. Additionally, the confidence intervals in this figure are very wide
in regards to the populations of prior PAD and prior MI, with PAD
crossing 1 which would correlate to no benefit. Furthermore, in Table 4
of the subgroup analysis, all the confidence intervals cross 1 for rates
of CV death, MI or stroke across time periods from within 30 days to
more than 30 months.

The results of this subgroup analysis serve to identify a subpopulation
that may potentially benefit from dual antiplatelet therapy. Patients
who had the ischemic event within the prior month demonstrated the
largest absolute benefit than in those with events in the past 30 days
to \>30 months. Additionally, patients who have had a plaque rupture or
other thrombotic effect are most likely to benefit from dual therapy.

In an associated editorial on the original CHARISMA trial, Pfeffer and
Jarcho^6^ highlight the pertinent clinical implications of the subgroup
analysis; the data show no significant benefit with long term dual
antiplatelet therapy. Additionally, they discuss the large degree of
overlap between the symptomatic and asymptomatic populations. Further
trials should seek to define these populations in a manner that does not
overlap. Their recommendation is that dual antiplatelet therapy not be
used in patients with stable disease.

Wang, et al. has published an analysis of the mortality rates seen in
the primary prevention (asymptomatic) population of the CHARISMA
trial.^7^ These authors' analyzed data on the 3248 patients considered
asymptomatic in the CHARISMA trial. Of this population, 995 did have a
history of a cardiovascular (CV) event and were excluded from the
analysis of the CHARISMA defined asymptomatic population, creating a
primary prevention cohort. The analysis of the asymptomatic cohort
determined a highly significant increase in CV death, 2.2%in the aspirin
group, 3.9% in the dual therapy group (p=0.001). Within the primary
prevention cohort, a multi variate analysis showed a trend towards
excess CV death (p=0.054; CI 0.99-2.97). Independent predictors of death
included hypertension, history of heart failure, atrial fibrillation and
increasing age. They authors report they were unable to determine the
cause of increased death and suggest further investigation. In an
accompanying editorial,^8^ Serebrunay describes potential explanations
for ta higher mortality in the dual therapy population. The issue of
compliance is not addressed by any of the authors of the recent
subanalysis trials. However, non-compliance with antiplatelet therapy
may cause rebound platelet activation to occur which may lead to fatal
secondary vascular events. Additionally, chronic antiplatelet therapy
can lead to activation of other pathways which can lead to vascular
events. The use of prolonged dual antiplatelet therapy is not without
concern. Many factors need to be addressed to decrease the potentially
adverse consequences to a seemingly "safe" therapy.

In another attempt to define the role of clopidogrel in therapy,
Eshaghian, et al^9^; published an evidence evaluation of the key trials
with clopidogrel in an attempt to determine duration of therapy,
superiority of dual therapy and place in therapy across several disease
states. The trial employs a Bayesian analysis quantifying the posterior
probabilities of benefit and harm. This approach analyzes a desired
clinical benefit of \>0% to \>20% and the probability of that benefit
occurring. (Table 1) In comparing the landmark trials for clopidogrel;
to achieve benefit of \>10% only CURE and CLARITY^8^ exceed 95%. To
predict a \>20% probability of benefit, only CLARITY exceeds the 95%
level.

A critical appraisal of the literature on duration of dual antiplatelet
therapy and which populations may require longer therapy remains
undefined. To extrapolate a CAPRIE like cohort has not provided evidence
to support indefinite use of dual antiplatelet therapy. Given the
concerns with the initial CAPRIE analysis (results driven by a single
subgroup, confidence intervals which crossed 1, small effect size and
marginal statistical significance) to extend this subgroup definition to
the CHARISMA cohort should be questioned. At best, given current
evidence, dual antiplatelet therapy is beneficial in high risk patients
(unstable angina, NSTEMI, STEMI, use of DES), has no benefit in reducing
ischemic stroke rates, is associated with an increased bleeding risk and
appears to provide benefit in reducing nonfatal myocardial infarction
with little impact on death or stroke. Lastly, as stated by the authors
\"As a post hoc subgroup analysis, it can only be considered hypothesis
generating\" requiring further validation in studies".^3^

1.  CAPRIE Steering Committee. A randomized, blinded, trial of
    clopidogrel versus aspirin in patients at risk of ischemic events
    (CAPRIE). Lancet 1996;348:1329-1389.

2.  Bhatt DL, Topol EJ; Clopidogrel for High Atherothrombotic Risk and
    ischemic Stabilization, Management, and Avoidance Executive
    Committee. Clopidogrel added to aspirin versus aspirin alone in
    secondary prevention and high-risk primary prevention: rationale and
    design of the Clopidogrel for High Atherothrombotic Risk and
    Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.
    Am Heart J. 2004 Aug;148(2):263-8.

3.  Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial
    infarction, stroke, or symptomatic peripheral arterial disease in
    the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982-1988

4.  Fox KA, Mehta SR, Peters R, et al; Clopidogrel in Unstable angina to
    prevent Recurrent ischemic Events Trial. Benefits and risks of the
    combination of clopidogrel and aspirin in patients undergoing
    surgical revascularization for non-ST-elevation acute coronary
    syndrome: the Clopidogrel in Unstable angina to prevent Recurrent
    ischemic Events (CURE) Trial. Circulation. 2004 Sep 7;110(10):1202-8

5.  Steinhubl SR, Berger PB, Mann JT 3rd, et al;CREDO Investigators.
    Clopidogrel for the Reduction of Events During Observation. Early
    and sustained dual oral antiplatelet therapy following percutaneous
    coronary intervention: a randomized controlled trial. JAMA. 2002 Nov
    20;288(19):2411-20.

6.  Pfeffer MA, Jarcho JA. The CHARISMA of subgroups and the Subgroups
    of CAHRISMA. NEJM 2006; 354:1744

7.  Wang TH, Bhatt Dl, Fox KAA, et al. Analysis of mortality rates with
    dual-antiplatelet therapy in the primary prevention population of
    the CHARISMA trials. Eur Heart J 2007 Published online August 2,
    2007.

8.  Serebruany VL. Aggressive antiplatelet strategies: time to
    reconsider? Eur Heart J 2007 Published online August 2, 2007.

9.  Eshaghian S, Kaul S, Amin S, Shah PK, Diamond GA. Role of
    clopidogrel in managing atherothrombotic cardiovascular disease. Ann
    Intern Med. 2007 Mar 20;146(6):434-41.

10. CLARITY-TIMI 28 Investigators Addition of clopidogrel to aspirin and
    fibrinolytic therapy for myocardial infarction with ST-segment
    elevation. NEJM 2005 Mar 24;352(12):1179-89