Health Technology Assessment 2009; Vol. 13: No. 31
Health Technology Assessment
NIHR HTA programme
The effect of different treatment
durations of clopidogrel in patients
with non-ST-segment elevation acute
coronary syndromes: a systematic
review and value of information analysis
W Rogowski,1 J Burch,2* S Palmer,3
C Craigs,2 S Golder2 and N Woolacott2
1Helmholtz Zentrum München, German Research Center for
Environmental Health, Institute of Health Economics and Health Care
2Centre for Reviews and Dissemination, University of York
3Health Economics Centre for Health Economics, University of York
The effect of different treatment durations of
clopidogrel in patients with NSTE-ACS
Executive summary: The effect of different treatment durations of clopidogrel in patients with NSTE-ACS
Acute coronary syndrome (ACS) is a fissuring
or rupturing of atheromatous plaques leading
to occlusive thrombi in the arteries. Non-ST-
elevation-ACS (NSTE-ACS) can be classified as
unstable angina with undetectable markers but with
electrocardiogram changes, or non-ST-elevation
myocardial infarction (NSTEMI) where there is
evidence of myocardial necrosis. Sixteen-year
survival rates for men aged 50–59 years are 34%
with a history of myocardial infarction (MI) and
53% with a history of angina, compared with 72%
of those with no history of coronary disease. For
patients with confirmed NSTE-ACS, UK guidelines
recommend early treatment with antiplatelets,
which are effective in preventing ischaemic vascular
events in patients at increased risk. Guidance by
the National Institute for Health and Clinical
Excellence (NICE) in 2004 was based in part on
a Technology Assessment Report undertaken
by the Centre for Reviews and Dissemination
(CRD) and the Centre for Health Economics
(CHE), and published as a Health Technology
Assessment (HTA) report (Main et al., 2004).
The report presented the results of a systematic
review assessing the clinical effectiveness and
cost-effectiveness of clopidogrel in combination
with aspirin for people with NSTE-ACS. Only one
relevant trial was identified for inclusion in the
systematic review [the Clopidogrel in Unstable
angina to prevent Recurrent Events (CURE) trial].
For patients with NSTE-ACS at moderate to high
risk of ischaemic events treated with clopidogrel,
the NICE guidance recommended that it be given
in combination with aspirin.
The objective of this research project was to
update the previous model, and formally assess
the potential value and feasibility of further
research to address the optimal duration of
clopidogrel treatment using value of information
(VOI) analysis and a Bayesian decision theoretic
approach. In line with this we aimed to update the
previous systematic review of the use of clopidogrel
in combination with aspirin for patients with
NSTE-ACS, investigating the optimal duration of
treatment and effects of withdrawal from treatment.
We conducted a systematic review of the clinical
effectiveness and cost-effectiveness literature. Ten
electronic databases and internet resources were
searched from 2003 to February 2007, including
MEDLINE, MEDLINE In-Process, EMBASE,
BIOSIS, CENTRAL and CINAHL. Randomised
controlled trials (RCTs) of clopidogrel plus aspirin
compared with aspirin alone were used to evaluate
clinical effectiveness and safety. Inclusion criteria
were broadened to include any comparator trial
for duration of treatment studies, and any study
design conducted in patients with NSTE-ACS,
percutaneous coronary intervention (PCI), stroke,
peripheral artery disease (PAD) or ST-elevation
myocardial infarction (STEMI) for evidence
of rebound (a reactivation of the condition or
concentration of adverse events) on withdrawal
of treatment. The primary outcomes for the
evaluation of efficacy, safety and the duration
of treatment were non-fatal MI, ischaemic heart
disease (IHD) without MI, death and bleeding
The systematic reviews were used to assist in
updating the existing model in order to provide
a more robust approach to evaluating the cost-
effectiveness of alternative durations of clopidogrel.
The previous work was also extended to include
a formal assessment of the potential value of
further research using VOI approaches. These
approaches were applied to estimate the expected
costs of decision uncertainty predicted by the
model and the maximum value that can be placed
on additional research aimed at reducing this
uncertainty. The costs of decision uncertainty were
quantified using the expected value of perfect
information (EVPI). These were used to help
identify the potential design and value of further
research which could be undertaken in this area.
Consideration was also given to the potential
impact that the introduction of a generic version of
clopidogrel may have on the VOI results.
Two RCTs were included for the review of
clinical effectiveness and safety. The only RCTs
identified that evaluated different durations of
Health Technology Assessment 2009; Vol. 13: No. 31 (Executive summary)
clopidogrel treatments were conducted in patients
with stroke, PAD, STEMI or PCI. Two small
RCTs and one uncontrolled retrospective cohort
study were identified for the review of rebound
after thienopyridine withdrawal in patients with
medically-treated NSTE-ACS. When the criteria
were broadened, five RCTs, two observational
cohorts, nine case series and 33 case reports were
identified in patients post-PCI, and two case series
and two case reports were identified in patients
with stroke, PAD or STEMI.
The CURE trial reported that the proportion of
patients experiencing cardiovascular death, MI or
stroke was lower in the clopidogrel group at 30 days
[relative risk (RR) 0.79; 95% confidence interval
(CI) 0.67–0.92) and from 30 days to 12 months
(RR 0.82; 95% CI 0.70–0.95). Overall, clopidogrel
seems to be effective in reducing adverse
cardiovascular events in patients with NSTE-ACS
at intermediate (RR 0.86; 95% CI 0.75–0.98) and
high (RR 0.77; 95% CI 0.64–0.93) risk of ischaemic
events, and there is evidence that clopidogrel
increases the risk of bleeding when compared
with aspirin in patients with intermediate risk of
ischaemic events (RR 1.44; 95% CI 1.12–1.86).
A post hoc analysis indicated that the treatment
effect in the first 3 months may be greater than
in later periods; however, this analysis comprised
non-randomised comparisons. There were no
direct comparisons of the effectiveness of different
durations of clopidogrel treatment in patients
with NSTE-ACS. The evidence available relating
to the potential rebound effect on withdrawal of
clopidogrel therapy in patients with NSTE-ACS was
limited and provided no conclusive evidence of its
presence or absence.
In terms of the cost-effectiveness of alternative
durations of clopidogrel, the updated model
reinforced the conclusions from the earlier analysis.
That is, a policy of 12 months of clopidogrel
for patients with NSTE-ACS appears to be cost-
effective both in ‘average’ patients (i.e. based on
the average across all patient risks considered) and
in the subgroup of higher-risk patients (presence
of any of the following: age > 70, presence of ST
depression or diabetes), compared with shorter-
term durations. The incremental cost-effectiveness
ratio (ICER) of 12 months’ duration ranged
from £13,380 to £20,661 per additional quality-
adjusted life-year (QALY) across the different
scenarios considered. However, for lower-risk
patients (absence of any of the risk factors)
treatment with clopidogrel beyond 3 months does
not appear to be cost-effective. The ICER of 12
months’ treatment with clopidogrel varied between
£49,436 and £58,691 per QALY. These conclusions
appeared robust to alternative assumptions related
to whether the relative effect of clopidogrel was
assumed to remain constant over time or where the
treatment effect in the first 3 months was assumed
to be greater than in later periods.
Estimates of EVPI were markedly higher for the
combined analysis of all patients (representing an
average of the risks) and for analysis of high-risk
patients alone, compared with those for lower-
risk patients (ranging between £48.69 million
and £108.4 million at a threshold of £30,000
per QALY). It was also acknowledged that more
recent changes in routine clinical practice in the
UK has shifted to the extent that the CURE trial
itself (or the model presented here) may no longer
considered to be representative of current practice
for groups at high risk, and as such the EVPI
results for this group of patients may be overstated.
At a threshold of £20,000–£30,000 per QALY, total
EVPI ranged between £3.27 million and £20.38
million in the lower-risk group. Given that a trial
is unlikely to be able to report until after the entry
of generic clopidogrel, equivalent EVPI estimates
for this scenario ranged between £10.8 million and
£11.9 million. The expected value of partial perfect
information (EVPPI) calculations demonstrated
that approximately 40–45% of this value was
related to the treatment effectiveness parameters
for clopidogrel (i.e. those for which an RCT would
Limitations and uncertainties
Our review was limited by the lack of available data.
Although one additional trial was identified that
provided information on the clinical effectiveness
of clopidogrel in patients with NSTE-ACS, this trial
was likely to be underpowered and reported limited
results. Thus the CURE trial remains the primary
source of data.
No studies directly compared different durations
of clopidogrel treatment, and insufficient evidence
was identified to adequately assess the clinical
significance of any rebound effect after withdrawal
of clopidogrel in these patients. Therefore, there is
still a large degree of uncertainty surrounding both
the optimal duration of clopidogrel treatment and
the impact of withdrawal of clopidogrel treatment,
which can only be addressed by further research.
The cost-effectiveness and VOI analyses are subject
to a number of potential limitations. These relate
not only to the limitations noted above pertaining
Executive summary: The effect of different treatment durations of clopidogrel in patients with NSTE-ACS
to the clinical effectiveness data, representing
important assumptions and parameters of the
model, but also to the uncertainty surrounding
a range of other factors. Firstly, the issue of risk
stratification is clearly an important consideration.
However, it should be noted that the pragmatic
approach to risk stratification applied in the
decision model (due to limited patient numbers
and information available from the epidemiological
data used) dichotomised the population into two
separate risk categories (higher- and lower-risk
patients). This meant that consideration could not
be given to a wider categorisation (i.e. including a
third group to represent patients at intermediate
risk). Similarly, these definitions are not directly
comparable with other risk stratification
approaches that have been applied elsewhere.
Indeed, it should be recognised that the sample
of patients included in the epidemiological data
set were all hospitalised for NSTE-ACS and hence
are likely to be more representative of patients
at intermediate to high risk using conventional
classifications. Thus, the interpretation of the
results in low- and high-risk groups should be
seen in this context. Secondly, changes in routine
clinical practice (particularly for the high-risk
group) may mean that the results presented here
are more reliable for the lower-risk group. Finally,
the results of the VOI demonstrate considerable
variation in the potential value of further research.
More importantly, the EVPI results present an
upper bound to further research and hence do not
provide both a necessary and a sufficient condition,
even if the cost of trial fell below this amount. This
is because a trial will resolve only a proportion
of the uncertainty and, as such, the amount of
uncertainty that is likely to be resolved would
have to be assessed against the cost of the trial to
ensure that any further research was considered an
efficient use of resources.
•?Clopidogrel combined with aspirin reduces
adverse cardiovascular events in comparison
with aspirin alone in patients with NSTE-ACS,
but may increase the risk of bleeding.
The optimal duration of clopidogrel treatment
in patients with NSTE-ACS is uncertain and
requires further research.
There is some evidence that a rebound
effect occurs following the withdrawal of
thienopyridine treatment, but its clinical
significance is uncertain.
The results of the updated decision model
suggest that durations of clopidogrel treatment
beyond 3 months do not appear to be cost-
effective in patients at lower risk. However,
for an average-risk patient (and in higher-
risk patients), 12 months of treatment with
clopidogrel appear to be cost-effective.
These conclusions appeared robust to
alternative assumptions related to whether
the treatment effect remained constant over
a 12-month period or was assumed to decline
after 3 months.
There is considerable variation in the costs
of uncertainty surrounding the different
scenarios and populations considered. The
validity of these may also be less reliable in the
higher-risk groups owing to changes in clinical
practice. The results in the lower-risk group
suggested that the upper bound of the value
of a future trial was between £10.8 million and
£11.9 million (and of this total, approximately
40–45% related to parameters for which a
randomised design would be essential).
An adequately powered, well-conducted RCT
that directly compares different durations of
clopidogrel treatment in patients with NSTE-ACS
would ideally be required to provide more robust
evidence in relation to the impact of clopidogrel
withdrawal. The use of an RCT would minimise
possible biases associated with establishing causality
with any potential rebound effect and providing
robust estimates of the relative effect of alternative
durations of treatment, However, the design and
cost of this trial need to be evaluated carefully in
relation to the VOI estimates reported here and
against other uses of NHS resources. In lower-risk
groups, for which shorter durations of clopidogrel
appear more cost-effective, it would seem unlikely
that an adequately powered RCT would be
considered to provide value for money owing to the
significant cost that would be required to undertake
such a study and the cost of the uncertainty that
such a trial might resolve.
Rogowski W, Burch J, Palmer S, Craigs C, Golder
S, Woolacott N. The effect of different treatment
durations of clopidogrel in patients with non-ST-
segment elevation acute coronary syndromes: a
systematic review and value of information analysis.
Health Technol Assess 2009;13(31).
Health Technology Assessment 2009; Vol. 13: No. 31 (Executive summary)
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