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Modelling the Long Term Cost Effectiveness of Clopidogrel for the Secondary Prevention of Occlusive Vascular Events in the UK

Posted on: Thursday, 17 March 2005, 03:00 CST

Key words: Aspirin * Clopidogrel * Cost effectiveness * Markov model * QALY * Secondary prevention, occlusive vascular event (OVE) - UK

ABSTRACT

Objective: To assess the long term cost effectiveness of clopidogrel monotherapy compared with acetylsalicylic acid (aspirin; ASA) monotherapy in patients at risk of secondary occlusive vascular events (OVEs) in the UK.

Design: Cost utility analysis based on clinical data from CARRIE (a multicentre randomised controlled trial, involving 19185 patients); long-term effects were extrapolated beyond the trial period using a Markov model populated with data from UK observational studies. Health economic evaluation carried out from the perspective of the UK National Health Service.

Participants: A representative cohort of 1000 UK patients aged 60 years (approximate mean age of the CARRIE population), with the qualifying diagnoses of myocardial infarction, ischaemic stroke and peripheral arterial disease, who are at risk of secondary OVEs (non- fatal myocardial infarction, non-fatal stroke or vascular death).

Interventions: Patients were assumed to receive treatment with either clopidogrel (75 mg/day) for 2 years followed by ASA (325 mg/ day, average) for their remaining lifetime, or ASA alone (325 mg/ day, average) for life.

Main outcome measures: Incremental cost per life year gained and incremental cost per quality-adjusted life year (QALY) gained.

Results: In the base case, the incremental cost effectiveness of clopidogrel versus ASA in this population is estimated at 18888 per life year gained and 21489 per QALY gained. Multiple deterministic and probabilistic sensitivity analyses suggest the model is robust to variations in a wide range of input parameters.

Conclusion: Two years of treatment with clopidogrel can be considered a cost effective intervention in patients at risk of secondary OVEs in the UK.

Introduction

Atherosclerosis is a major disease of the large and medium sized arteries, caused by the deposition of lipids and platelets and accumulation of inflammatory cells, such as monocytes and macrophages, in the arterial wall. This results in the formation of atherosclerotic plaques, which cause narrowing of the lumen and restriction of blood flow, primarily in the coronary, cerebral and peripheral vessels1. Atherosclerosis is a systemic disease that is the underlying pathological mechanism responsible for coronary heart disease (CHD), cerebral vascular disease and peripheral arterial disease (PAD)1"3. The formation of atherosclerotic plaques may result in atherothrombosis, which is the formation of thrombi superimposed on existing plaques that have ruptured, eroded or fissured.

Historically, CHD, cerebral vascular disease and PAD have been regarded as discrete diseases. However, the same underlying mechanism means that the three conditions should be considered as manifestations of the same disease. Symptomatic disease in one vascular bed is often indicative of disseminated disease, and patients suffering from one of these manifestations are also at risk of the others4. Hence, many patients will suffer with more than one manifestation of the disease, sometimes at the same time, but more likely at different times over a number of years1-3. Both thrombi and the resulting emboli can precipitate life-threatening occlusive vascular events (OVEs) such as myocardial infarction (MI), ischaemic stroke and vascular death. The nature of atherothrombotic disease also means that the risk of suffering further OVEs remains high if untreated, and increases with time and advancing age.

Vascular diseases were the leading cause of death in the UK in 2000 and, although the UK death rate due to vascular disease has been falling for several years it is still among the highest in the world. UK data suggest that in 2002 there were approximately 274000 MIs in the UK5, equating to around 237 000 annually in England and Wales (456 per 100000 based on a population of 52 million). National studies of stroke incidence are limited, but stroke is thought to be less common than CHD, with current estimates of 110000 first strokes reported in England and Wales each year (207 per 100 000) and 30 000 cases of recurrent stroke6 (a total of 140000). Of these, 80% are due to ischaemia7, a manifestation of atherothrombotic disease, indicating that there are approximately 112 000 cases of incident ischaemic stroke per year (140000 0.8 = 112000)6,7. The prevalence of intermittent claudication, a common manifestation of PAD, increases dramatically with age8, however, not all of those affected present with symptoms9,10. PAD is, therefore, a common condition that is under diagnosed and under treated in the UK. Unpublished estimates indicate that there are 102000 incident cases of PAD in England and Wales per year (FGR Fowkes, personal communication).

In total, the current annual incidence of patients who are at risk of further (secondary) OVEs is around 451000. Approximately 52% of these are attributable to MF, 25% to stroke6,7 and 23% to PAD.

The high prevalence of vascular diseases has major economic consequences for the UK. In 1999, CHD cost the UK 1.7 billion in direct costs and 5.3 billion in indirect costs". Bosanquet and Franks estimated that caring for stroke patients accounted for 2.3 billion in 1995-1996, the equivalent of 5.8% of total National Health Service (NHS) and social services expenditure12. No comprehensive analyses of the UK costs of PAD have been published; however, median costs of surgical procedures to treat PAD vary from approximately 5300 for a bypass graft to 8000 for an amputation13.

Evidence-based treatment guidelines (European Guidelines on Cardiovascular Prevention in Clinical Practice 2003)14, recommend antiplatelet therapy for the prevention of OVEs in patients at risk; that is, patients with a previous history of MI or stroke or with a diagnosis of PAD. Antiplatelet therapy is a cornerstone of vascular event reduction15. The aims of therapy are (i) to prevent the occurrence of OVEs throughout the vascular system, through inhibition of thrombus formation, and (ii) to protect distal tissues through inhibition of micro-embolism. The efficacy of acetylsalicylic acid (aspirin; ASA) in preventing vascular death, stroke and MI is well established, and numerous trials and three meta-analyses carried out by the Antiplatelet Trialists Collaboration and Antithrombotic Trialists Collaboration demonstrate this15-17. They have shown that low dose ASA significantly reduces the risk of a serious vascular event by between 26%-32% compared with placebo (p < 0.0001)15. Furthermore, evidence of a correlation between outcome events indicates that comparable benefits could be seen with antiplatelet therapy in the prevention of MI, stroke and vascular death16. Currently, it is recommended that patients at risk of secondary OVEs receive 7 5-150 mg/ day ASA indefinitely15.

Clopidogrel is an adenosine diphosphate receptor antagonist that selectively inhibits the binding of adenosine diphosphate to its platelet receptor and the subsequent adenosine diphosphate mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This has been shown to provide early and long-term protection from vascular events in patients with a history of OVEs or PAD. CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events)18 was a multicentre randomised controlled trial, in which 19185 patients were randomised to receive either 325mg/day ASA (average) or 75mg/day clopidogrel. Mean duration of follow-up was 1.91 years. The primary outcome measure was the composite endpoint of nonfatal MI, non-fatal stroke or vascular death. This trial demonstrated that clopidogrel was more effective than ASA in reducing the risk of vascular events in this patient population (relative risk [RR] reduction of 8.7 [95% confidence interval (CI): 0.3-16.5; p < 0.05]), with equivalent safety and tolerability. To date, this is the only antiplatelet to demonstrate such a benefit15.

A review of the published economic evaluations19-27 of clopidogrel reveals that no analyses have been undertaken from a UK NHS perspective. Three studies have assessed the cost effectiveness of clopidogrel in the stroke population23-25, while Gaspoz et al.21 used the Coronary Heart Disease Policy model to estimate the cost effectiveness of clopidogrel versus ASA in a USA CHD population. A further three studies have assessed the cost effectiveness of clopidogrel in the broader atherothrombotic patient population19,22,26,27, all of which used data from the CAPRIE trial19,22,27. Clopidogrel has been shown to be cost effective in numerous countries, in several populations and under a variety of modelling conditions; however, limitations of modelling simplicity23, inappropriate patient populations21 or nonUK specific resource use data19'21"27 mean that the available economic studies are of limited value for decision making in the UK NHS.

Health economics is increasingly being used as a means of guiding health policy decisions and, in the UK, the National Institute for Clinical Excellence (NICE) uses an assessment of cost effectiveness when determining whether the NHS should use an intervention or not. This model was developed in support of the NICE technolo\gy appraisal of clopidogrel in patients at risk of secondary OVEs. In this paper an economic evaluation is described that has been designed to assess the long term cost effectiveness of clopidogrel monotherapy compared with ASA monotherapy in patients at risk of secondary OVEs in the UK.

Figure 1. Patient pathways in the Markov model

Methods

The health economic model was developed to calculate the incremental cost per quality-adjusted life year (QALY) gained of treatment with clopidogrel for 2 years followed by ASA indefinitely, compared with lifetime use of ASA alone over a maximum time horizon of 40 years. ASA is the only other antiplatelet drug proven to reduce a range of vascular events when compared with placebo15; it is, therefore, used as the comparator in this cost effectiveness analysis. Patients were assumed to receive treatment with either clopidogrel for 2 years followed by ASA for their remaining lifetime, or ASA alone for life.

The care pathways from a qualifying MI, stroke, or a diagnosis of PAD (atherothrombotic disease) to a death state, involving the transition of patients through a series of discrete health states is described using a Markov model (Figure 1 and the Appendix). Data from UK observational studies are used to inform vascular event rates, while trial-based measures of effectiveness are used to differentiate the alternative interventions. Costs ( Sterling, 2002) and utilities are applied to health states in order to estimate cost effectiveness from a UK NHS perspective. The long term costs and benefits are extrapolated beyond the initial period assessed in the CAPRIE trial. All input parameters are described as probability distributions to enable probabilistic analysis of the results.

Event rates

In CAPRIE, one-third of trial recruits had suffered MI, one- third stroke and one-third had a diagnosis of PAD18. However, UK- based sources suggest that 52% of the qualifying population would have had an MI event5, with stroke events and PAD diagnoses making up 25% and 23% of the remaining cases, respectively (FGR Fowkes, personal communication)6,7. These UK-specific ratios are used for the model's central estimate to ensure event rates in the first year are representative of the likely distribution in the UK.

Three main data sources have been used to quantify representative event rates, rather than applying those directly reported by the CAPRIE study. For patients with a qualifying condition of MI, UK data describing the occurrence of further MIs, strokes and vascular deaths are taken from a cohort of 695 patients in the Nottingham Heart Attack Register who were diagnosed with MI in 199228. It is recognised that the NHAR data are now around 10 years old , however, no significant differences were found in the survivor functions for the 1992 and 1998 cohorts of patients diagnosed with ACS used by Palmer et al.31. This finding provides increased confidence in the relevance of the NHAR dataset, although sensitivity analyses based on reduced event rates are presented. For patients with a qualifying condition of stroke, UK data describing the occurrence of further strokes and vascular deaths, but not MIs, are taken from a cohort of 1492 patients on the South London Stroke Register29. These data describe events in stroke patients diagnosed between 1997 and 2002, with follow-up to the end of 2002. For patients with a qualifying condition of PAD, UK data describing the occurrence of MIs, strokes and vascular deaths over a 6-year follow-up period are taken from a cohort of 607 patients diagnosed in 1989-1990 from the Edinburgh Claudication Study30. These sources are not able to differentiate between the risk of suffering the secondary event and the risk of suffering a third or fourth event. Third and fourth event rates in the model are assumed to be the same as those for secondary event rates. Vascular event rates used in the model are shown in Table 1 (see the Appendix for calculations).

Table 1. Examples of vascular event rates used in the model for patients aged 60 years and 90 years receiving ASA

To estimate the non-vascular mortality rate, interim life tables (1999-2000) published by the Government Actuary Department were adjusted for the proportion of deaths due to vascular causes based on national mortality statistics for England and Wales.

Clopidogrel effectiveness parameters

The CAPRIE trial was designed to assess the RR of a composite endpoint (non-fatal MI, non-fatal stroke or vascular death) between the treatment arms of clopidogrel monotherapy and ASA monotherapy18. From a health economic perspective, however, the three outcome events are very different, as the costs and consequences of a vascular death are not the same as those for a stroke, for example. Therefore, separate RRs for each endpoint were calculated based on the primary events experienced by CAPRIE patients during the trial period. Sensitivity analyses were carried out to explore the impact of changes in the RRs.

Cost input parameters

The cost of drugs and costs associated with the various health states used in the model were obtained from a variety of UK sources31-33 ( Sterling, 2002) and are presented in Table 2. Medications were costed annually, assuming 300mg/day ASA (the average) and 75mg/day clopidogrel, using prices listed in the British National Formulary33. In the base case analysis, cost estimates for treatment assume 100% compliance because the RRs in the CAPRIE trial were estimated on an intention-to-treat basis; the final observed compliance is assessed in a sensitivity analysis18,31,33.

Table 2. Relative risks, utilities and costs used in the model

Costs for each of the six health states were derived from a variety of UK specific sources31,32. The costs of MI, both for new MI and post new MI states, are taken from the GP IIb/IIIa analysis by Palmer et al.31. The costs of stroke are taken from Chambers et al.32 and assume 35% of patients will suffer a disabling stroke and require a high level of care, whereas 65% will retain at least some independence and have lower care costs. Costs associated with PAD are assumed (FGR Fowkes, personal communication), as no suitable UK data are available. Costs associated with vascular death were excluded from the model because it was not possible to estimate the relative costs of patients receiving care before they died, compared with those who died before care could be administered. The model estimates costs from a UK NHS perspective, so only direct costs are included. Costs are discounted at the rate of 6%34.

Utility input parameters

The model assesses cost effectiveness in terms of incremental cost per QALY gained (that is, the additional cost of achieving an additional number of years of life, weighted by an estimate of the quality of that extra life). Utility values used in the model are presented in Table 2. Utility values for the stroke states in the model are taken from a quality of life meta-analysis35. Three values for stroke are presented, one each for independent and dependent stroke and one that is a weighted value, combining dependent and independent stroke, on the assumption that 35% of strokes cause disablement leading to dependency on care.

Data for the remaining utility values are taken from the Harvard utilities database32,36,42. The various studies used to inform the individual utility values provide central estimates or values to define the possible range of variation. Values in the middle of the range are used as the central estimate, and values from papers at extremes of the range are used to inform a triangular distribution. From this distribution, 95% CIs are estimated. QALYs are discounted at the rate of 1.5%34.

Analyses

A base case analysis is presented and deterministic and probabilistic sensitivity analyses have been used to explore whether the base case model is robust to the assumptions employed. In the deterministic analyses, key parameters are varied separately or in combination either by using specific alternative values or the upper and lower 95% CIs. These variables include: health state costs; compliance and effectiveness; utility estimates; relative risks for the individual outcomes. In the probabilistic sensitivity analyses, each key parameter is varied randomly at the same time within a defined sample distribution, using Monte Carlo simulation. Simulations are performed 1000 times to produce a cost effectiveness acceptability curve. The curve shows the probability that clopidogrel will be cost effective for a range of cost per QALY thresholds that could theoretically be applied by the NHS.

Table 3. Clinical outcomes and costs for a cohort of 1000 patients at risk of secondary OVEs treated with clopidogrel for 2 years

Results

Base case estimate

The clinical and cost outcomes for a cohort of 1000 patients at risk of secondary OVEs are presented in Table 3. For a population of 1000 patients, during the first 2 years of treatment, clopidogrel results in the avoidance of approximately 23 vascular events compared with ASA, comprising 18 MIs, 2 strokes and 3 vascular deaths (Table 3). Treatment with clopidogrel results in an estimated total of 43 life years saved and 38 QALYs gained over the full term of the model (Table 3).

Table 3 also summarises the costs incurred by both treatment groups. The total cost of clopidogrel treatment is considerably higher than ASA treatment as a result of the higher drug costs in the clopidogrel arm. However, clopidogrel is associated with reduced health state costs over the first 2 years (a difference of 38 000) due to the avoidance of MIs and strokes. The results demonstrate an estimated incremental difference in lifetime costs of approximately 819 000. Overall, the incremental cost effectiveness of the clopidogrel versus ASA in this population is estimated at 18 888 per life year gained and 21 489 per QALY gained.

Deterministic sensitivity analyses

The resultsof the deterministic sensitivity analyses are presented in Table 4. One- and two-way sensitivity analyses were undertaken to investigate the stability of the base case estimates. The model is robust to variations in a wide range of input parameters.

The sensitivity analyses on the following parameters do not substantially affect the results for health benefits, costs or cost effectiveness ratios for clopidogrel monotherapy versus ASA monotherapy: health state costs (analyses 1-3), compliance (analyses 4-5), utilities (analyses 6-7), costs and utilities (analysis 8), RRs, including MI and stroke (analyses 9-13), age (analyses 19-20), discount rates (analysis 21) and event rates (analyses 22-23).

Table 4. Results of deterministic sensitivity analyses (lifetime results for a cohort of 1000 patients)

The key drivers of cost effectiveness in the model are the RRs that are applied, in particular the RR for vascular death (analyses 14-15). If the upper 95% CI for the vascular death rate is used, ASA dominates clopidogrel. A higher cost per QALY (32 894) is estimated using the upper 95% CI for the stroke endpoint (analysis 12), though a lesser effect is noted for the MI endpoint CI. The use of the composite outcome RR in place of the individual RRs leads to improved cost-effectiveness of clopidogrel (analysis 9). The importance of the RR for vascular death is also apparent from the results of the sensitivity analyses for the effect of using the upper or lower 95% CI for all the outcomes assessed (analyses 16- 17).

An additional analysis that has some effect on cost effectiveness is the inclusion of a statistically non-significant observed increase in the non-vascular death rate of clopidogrel. Inclusion of a RR for non-vascular death of 1.087 during the 2-year treatment period increases the cost per QALY gained to 34 349.

The base case model uses a mean annual risk of vascular events in the UK population of 10.46% over the first 2 years post diagnosis. Analyses 22-23 investigate the relationship between risk levels and cost effectiveness. Doubling the mean annual risk of vascular events (analysis 22) increases QALYs gained to 65, resulting in an incremental cost effectiveness of 12 245 per QALY gained. Reducing the mean annual risk of vascular events by half (analysis 23) reduces QALYs gained to 20, resulting in an incremental cost effectiveness of 41 486 per QALY gained.

Probabilistic sensitivity analyses

The results of the probabilistic sensitivity analyses are presented in the form of a cost effectiveness acceptability curve (Figure 2). All uncertain model parameters were allowed to vary at the same time using Monte Carlo simulation. Figure 2 shows that for a threshold of 30 000 per QALY decision threshold, clopidogrel is cost effective in approximately 60% of randomly sampled analyses.

Discussion

Compared with ASA, treatment with clopidogrel in patients at risk of secondary OVEs leads to significant health benefits, in terms of greater protection against MI, stroke and vascular death. Two years of treatment with clopidogrel can be considered a cost effective intervention compared with ASA (at 21 489/QALY).

Recent economic evaluations comparing alternative interventions for the prevention of vascular events include GPIIb/IIIa antagonists31, agents for thrombolysis43 and implantable cardioverter defibrillators (ICDs) for the prevention of sudden cardiac deaths44. Palmer and colleagues31 found that GPIIb/IIIa antagonists were only cost effective as part of initial medical management for patients with non-ST elevation acute coronary syndrome, with an estimated cost per QALY gained of 4605-10 343. Boland and colleagues43 present baseline cost effectiveness estimates for the newer thrombolytic agents (alteplase, tenecteplase and reteplase) compared with the standard therapy, streptokinase, of 11 000-17 000 per QALY gained. The estimated cost per QALY gained for ICDs ranged from 21 300 to 108 000(44).

Figure 2. Cost effectiveness acceptability curve for clopidogrel treatment

Exploration of the model's robustness in terms of the uncertainty around the input parameters reveals little impact on the results when most input parameters are varied using their upper and lower 95% CIs, with one exception - the RR for vascular death - which, in isolation, or in combination with other modified parameters, greatly affects the results and, in the extreme worst case, results in the dominance of clopidogrel by ASA. However, the extreme worst case is unlikely to be supported, given current clinical experience with clopidogrel.

The model's robustness to variations in the disaggregated RRs is explored in sensitivity analyses [10-17]. Sensitivity analyses (10- 15) examine changes to each RR in turn, in order to determine the extent to which the estimation of each RR can affect the model as a whole. Conceptually, however, the idea that an antiplatelet drug has a mechanism and a physiological effect that reduces the rate of an event such as MI, while at the same time causing more vascular deaths than its comparator, seems somewhat implausible. The likely explanation is that greater survival on clopidogrel increases the likelihood of dying later from vascular disease. Therefore, while not specifically representing alternative realities, these sensitivity analyses do provide evidence that the outcome of vascular death appears to affect the results more than either MI or stroke, both of which have significant associated costs.

Moreover, the 95% confidence limits for the RR of vascular death appear to drive the model when all disaggregated RRs are modified in unison (sensitivity analyses 16-17); while these latter sensitivity analyses more logically represent potential alternative realities, since the effect of clopidogrel is greater or smaller in relation to ASA across all endpoints in the same direction and at the same time. This leads us to the conclusion that we must be assured of the accuracy of these RRs, particularly that of vascular death.

One explanation for the considerable effect of varying the RRs by their 95% CIs is that the CAPRIE trial was not powered to show a significant difference in the individual outcomes. Individual outcomes were included in the model as, from a health economic perspective, the examination of each outcome is important because it allows the assessment of the health benefits and cost consequences of potentially very different endpoints (that is, stoke versus death). However, the low power of these estimations may lead to wider CIs for each outcome than would be apparent if the study was specifically powered for disaggregated endpoints.

The cost effectiveness of clopidogrel compared with ASA also depends on the risk of vascular events in the general population. However, sensitivity analyses show that the mean annual aggregate event rate over the first 2 years of clopidogrel treatment must be very low before clopidogrel is deemed not to be cost effective; even if the event rate is halved, the cost per QALY gained is still under the 30 000 threshold. When all parameters are varied randomly, clopidogrel remains cost effective in approximately 60% of the model estimations. Moreover, a recent paper by Ringleb and colleagues45, determined from the CAPRIE database that patients with a history of OVEs were at higher risk of subsequent OVEs and that the effect of clopidogrel on these patients appeared to be amplified. Thus, clopidogrel is more likely to be cost effective in higher risk patients.

Subdividing the secondary prevention population into their constituent qualifying conditions might expose advantages of clopidogrel treatment for one group over another, or indeed determine whether any qualifying condition predisposes a patient to any single or complex of secondary events. We considered post-hoc analyses of the use of clopidogrel in specific qualifying subgroup types but the nine RRs produced (three populations with three endpoint RRs) had wide confidence intervals and we felt it was inappropriate to introduce this level of uncertainty into the evaluation, particularly as the risk of any one endpoint is likely to be correlated with the risk of another endpoint. To explore the possible correlation of cross-risk within the qualifying populations we investigated a Bayesian statistical process to estimate the impact of correlations between the subgroups. This process, however, would require expert-based assumptions of the level of correlation, again the result of which would be to introduce further uncertainty which we felt could not be estimated or adequately described.

Uncertainties and restrictions of certain data sources are often a concern in economic evaluations, and no less so in this analysis. The CAPRIE trial, for example, was not prospectively designed with this analysis in mind, so issues of statistical power, patient predisposition, and previous disease history could detract from the generalisability of the results. The data used are the best currently available in the UK, and the analysis has attempted to use these data as comprehensively as possible; however, in some cases the data did not have sufficient resolution because of limitations in the way they were collected. For example, the UK baseline events data for MI, stroke and PAD populations were analysed to provide rates of secondary events, but the analysis fell short of providing specific rates of events subsequent to the secondary events. As a result of this the model had to assume that subsequent events occur with the same likelihood as the secondary event itself. Clearly, it might be expected that the type of secondary event and the period of time between that event and subsequent events could be connected, but no supposition of patients' predisposition to an event, or indeed the impact of this on the cost effectiveness analysis could be explored. Obtaining data from different sources (Nott\ingham Heart Attack Register versus South London Stroke Register versus ECS) may also add a layer of complexity to the results that is not easily explained, but in the absence of a complete dataset, exploration through sensitivity analyses is the only option. Until more encompassing data become available this analysis represents the most comprehensive UK assessment of the cost effectiveness of clopidogrel in patients at risk of secondary occlusive vascular events.

The analysis presented in this paper was based on the treatment duration in the CAPRIE trial. An assessment of the cost effectiveness of clopidogrel treatment maintained beyond this 2- year period is not possible at this time, as clinical effectiveness beyond this period is not proven. In order to assess cost effectiveness beyond 2 years, the risk of vascular events in patients previously treated with clopidogrel must be assessed. If a moderate to high risk remains after treatment, the benefits of continued clopidogrel use will remain, but if the risk is greatly reduced by previous treatment, the benefits of continued treatment with clopidogrel are less certain, particularly if it is replaced by ASA. Further research into the pathophysiology of atherothrombotic disease is needed to determine how antiplatelet therapy, and in particular, clopidogrel therapy, influences the vascular system and disease activity and progression, and whether the disease process is temporarily inhibited by clopidogrel, only to recommence shortly after cessation of clopidogrel treatment.

In conclusion, clopidogrel has been demonstrated to be a cost effective treatment in patients at risk of secondary OVEs, is clinically superior to ASA and has great potential for reducing the morbidity and mortality caused by these diseases.

Funding

This study was supported by Sanofi-Synthlabo and Bristol-Myers Squibb.

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2800_4, Accepted for publication: 02 December 2004

Published Online: 23 December 2004

doi: 10.1185/030079904X18036

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Jon Karnon(a), Alan Brennan(a), Abdullah Pandor(a), Gerry Fowkes(b), Amanda Lee(b), David Gray(c), Catherine Coshall(d), Charles Nicholls(e) and Ron Akehurst(a)

a School of Health and Related Research (ScHARR), University of Sheffield, UK

b Unit for Prevention of Peripheral Vascular Diseases, Public Health Sciences, University of Edinburgh, UK

c Division of Cardiovascular Medicine, University Hospital, Queen's Medical Centre, Nottingham, UK

d Department of Public Health Sciences, Guy's, King's and St Thomas' School of Medicine, King's College London, UK

e Evidence Research Unit, CMC Ltd, Macclesfield, UK

Address for correspondence: Jon Karnon, Senior Operational Research Analyst, School of Health and Related Research (ScHARR), University of Sheffield, Regent Court, 30 Regent Street, Sheffield, Sl 4DA, UK. Tel: +44 114 222 0736; Fax: +44 114 222 0785; email: j.karnon@sheffield.ac.uk

Appendix

Appendix

Copyright Librapharm Jan 2005

Source: Current Medical Research and Opinion

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