Intended for healthcare professionals

Rapid response to:

Primary Care

Coronary heart disease prevention: insights from modelling incremental cost effectiveness

BMJ 2003; 327 doi: (Published 27 November 2003) Cite this as: BMJ 2003;327:1264

Rapid Response:

Further commentary on the long-term efficacy of clopidogrel in preventing adverse cardiac events

In a recent rapid response letter [1], I challenged the author's
contention that clopidogrel is significantly efficacious in the long-term
primary preventive treatment of CAD by referring to the CURE trial's
results. After re-reading the author's article, I noticed that the author
stated the following:- "Compared with aspirin, the relative risk of a
coronary event while taking clopidogrel is 0.88 (0.76 to 1.01). {11}. I
looked up reference {11}, which was the Cochrane review by Hankey G J et
al. I could only find one comment in the Cochrane review that would allow
the authors to deduce that the relative risk of a coronary event while
taking clopidogrel is 0.88 compared to aspirin.

First, consider the Cochrane reviewers overall impression of the
value of thienopyridines.

"This review summarises the available data from the four published
randomised trials of a thienopyridine versus aspirin in patients at high
risk of vascular events. Although data were incomplete for some of the
outcome events, they were available for all outcomes of interest from the
largest trial, contributing 85% of the patients randomised (CAPRIE) and
for almost all of these outcomes for the second largest trial,
contributing 14% of the patients randomised (TASS).

Although there have only been four trials, these included a large
number of patients (over 20,000), and serious vascular
outcome events (over 2500). Most of the data reflect the results of the
CAPRIE and TASS studies.

Pooling the data from trials of clopidogrel and ticlopidine into one
group (the thienopyridines) increases the sample size and therefore the
accuracy of the estimates. Similarly, combining the vascular outcome
events into a composite outcome of stroke, MI or vascular death also
increases the statistical power and it is this analysis which provides the
most reliable (i.e. statistically robust) estimate of the effect of
thienopyridines in high risk patients. This analysis reveals that the
thienopyridines are statistically significantly more effective than
aspirin in preventing serious vascular events among high vascular risk
patients, but the magnitude of the additional benefit appears to be modest
and somewhat uncertain. The proportional odds (and risk) reduction is
about 9%, but may be as low as 2% or as high as 16% (the 95% confidence
limits). If the average absolute annual risk of a serious vascular event
with aspirin therapy is about 6% per year (CAPRIE), our best
estimate would be that substituting aspirin with a thienopyridine may
reduce this rate to about 5.5% (91% of 6%), but could reduce it to
anywhere between 5.9% (98% of 6%) and 5.0% (84% of 6%). This corresponds
to an absolute risk reduction (ARR) of about 0.5%, ranging between 0.1%
and 1.0%, and means that treating 1000 patients with thienopyridines may
prevent between 1 and 10 extra events each year compared with aspirin. The
number of high vascular risk patients who would need to be treated with a
thienopyridine to prevent one event per year, compared with aspirin, may
therefore vary from 100 to 1000."

Note that the above comments refer to clopidogrel and ticlopidine,
and it also refers to all CV events including stroke.

With respect to cardiac events alone, the Cochrane reviewers state
the following with respect to high vascular risk patients.

"Myocardial infarction: The thienopyridines were associated with a
non-significant reduction in MI (380/11159 [3.4%] vs
431/11157 [3.9%]; OR 0.88, 95% CI: 0.76 to 1.01)."

I presume that this is where the authors got the OR figure of 0.88.
However, that figure applies to all those studies, which includes
ticlodipine. If one examines the CAPRIE study alone, then one notes the
following results for patients with a previous MI [2] -- The RRR of
clopidogrel therapy to prevent a subsequent MI (fatal or not fatal) in
recent MI patients in the CAPRIE trial was 5.37%, the ARR was 0.16% and
the yearly NNT figure is 625.

In other words, if there is no substantial evidence that clopidogrel
is effective in preventing future MIs in high risk coronary patients (who
had a previous MI), the why should we expect it to have benefit when used
as primary preventive therapy in low risk coronary patients (7.5-15% five
year risk of an adverse cardiac event)?

Jeff Mann.


1. Mann J. Rapid response letter to the bmj. Long-term efficacy of
clopidogrel therapy. December 3rd 2003.

Available at

2. Mann J. The cost-effectiveness of clopidogrel therapy in the
secondary prevention of heart attacks and ischemic stroke: Weighing the
evidence from the CAPRIE trial.

Available at

Also available in the soapbox section of my website -- listed as the
title "Cost-effectiveness of clopidogrel in the prevention of heart
attacks and ischemic stroke" -- at

Competing interests:
None declared

Competing interests: No competing interests

04 December 2003
Jeffrey Mann
Retired physician
Salt Lake City, UT 84103.