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Letters to the Editor
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Cardiovascular disease (CVD)
Report on CHARISMA study is misleading
From Mrs A. G. Riley, MRPharmS, and Mrs A. Evans, MRPharmS
The news report on the CHARISMA (clopidogrel for high atherothrombotic
risk and ischaemic stabilisation management and avoidance) study is misleading
(PJ, 18 March, p312). The article puts undue emphasis on a secondary
endpoint and fails to mention the significant increase in bleeding observed
in the clopidogrel arm of the trial.
To recap, in the CHARISMA trial1, 15,603 patients were randomised to
receive either clopidogrel, 75mg plus low dose aspirin (75–162
mg/day), or placebo plus low dose aspirin. Trial participants were aged
45 years or over and had either multiple atherothrombotic risk or documented
cardiovascular or cerebrovascular disease.
The results showed no difference in the primary efficacy end point of
myocardial infarction, stroke or death from cardiovascular causes.
However, a statistically significant, but small, reduction was seen in
the principal secondary endpoint (a composite of MI, stroke, death from
CV causes, admission to hospital for unstable angina, transient ischaemic
attack or vasculisation procedure) for the clopidogrel group (16.7 per
cent versus 17.9 per cent [relative risk 0.92, P=0.04]).
There was also a non-significant increase in the primary safety end point
of severe bleeding (1.7 per cent in the clopidogrel group versus 1.3
per cent in the placebo group [RR 1.25, P=0.09]).
Importantly, there was a significant increase in the rate of moderate
bleeding — defined as needing a blood transfusion (2.1 per cent
versus 1.3 per cent, respectively, P<0.001).
A total of 94 ischaemic (secondary) end points were prevented with clopidogrel
at a cost of 93 moderate or severe bleeding events.
Symptomatic versus asymptomatic patients were then separated into two
groups for the purpose of a prospectively planned subgroup analysis.
The authors of an accompanying editorial,2 criticise the use of “symptomatic” and “asymptomatic” groups
in the subgroup analysis, arguing that the characteristics used to differentiate
between the subgroups were not significantly distinct. Some of the patients
termed asymptomatic had previously had major cardiovascular events and
a large number of the symptomatic group probably also had multiple risk
factors.
In this subgroup analysis, the asymptomatic clopidogrel group had a significant
increase in the rate of death from all causes (5.4 per cent versus 3.8
per cent, P=0.04) and death from CV causes (3.9 per cent versus 2.2 per
cent, P=0.01).
Among the 12,153 symptomatic patients, there was a significant reduction
in the primary end point with clopidogrel (6.9 per cent versus 7.9 per
cent [RR 0.88, P=0.046]).
The trial authors do point out that this observation should be treated
with caution, as the reduction was only marginally significant and this
subgroup analysis was only one of several performed.
Based on the data on mortality, the CHARISMA researchers recommend that
dual antiplatelet therapy should be avoided in patients without established
vascular disease. They state that there was a potential benefit in patients
with established vascular disease, but this finding requires further
study.
The editorial2 discusses the results of CHARISMA in the context of previous
trials. The evidence demonstrates benefits of short-term dual therapy
with aspirin and clopidogrel in acute vascular injury. CHARISMA is unlike
previous trials in that it examined the benefits and risks of long-term
dual antiplatelet therapy in patients with vascular disease.
The results showed no significant lowering of risk of adding clopidogrel
to aspirin in this patient population and there was an increased risk
of at least moderate bleeding.
This effectively argues against the use of dual antiplatelet therapy
in this patient population on a risk versus benefit basis.
Genine Riley
Head of Medicines Management
Amanda Evans
Deputy Head of Medicines Management
Burntwood, Lichfield and Tamworth Primary Care Trust
References
1. Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, et al.
Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. New England Journal of Medicine 2006;354.
2. Pfeffer MA, Jarch JA. The charisma of subgroups and the subgroups
of CHARISMA. New England Journal of Medicine 2006;354.
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The news item addressed here (PJ, 18 March, p312) was not misleading.
It quite clearly set out the different findings in the different subgroups,
showing no benefit in asymptomatic patients. Bleeding side effects were
not mentioned due to the word count limit and it was assumed that readers
would assume that two antiplatelets would cause more bleeding than one.
In response to reports of the CHARISMA trial, the European Society of
Cardiology has stated: “While the CHARISMA trial results have shown no benefit overall
of the combination of clopidogrel and aspirin in the long term in stable vascular
patients and some indication of harm in patients in primary prevention, the ESC
would like to remind patients that dual antiplatelet therapy is an essential,
approved and recommended therapy for one year in patients post acute coronary
syndrome without ST-segment elevation, and for at least six months post stenting.”
— EDITOR
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The
Pharmaceutical Journal