Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in December 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

No relevant randomised controlled trials (RCTs) were identified that assessed clopidogrel monotherapy in people who have had a transient ischaemic attack (TIA). In addition, no high quality observational data were identified on the efficacy of clopidogrel monotherapy in people with TIA. Limited RCT evidence was identified for the use of clopidogrel in combination with aspirin for TIA.

Regulatory status: off-label

This topic of transient ischaemic attack: clopidogrel was chosen for an evidence summary as there were a high volume of requests from the NHS for information on this topic and potential for variation in practice.

Effectiveness

  • No relevant evidence was identified on the use of clopidogrel monotherapy in TIA.

  • Two RCTs were identified that compare clopidogrel plus aspirin with aspirin alone, initiated within 24 hours of TIA or minor ischaemic stroke. Primary outcome of both studies was any new stroke event (ischaemic or haemorrhagic) at 90 days.

  • One of the 2 RCTs found a statistically significant reduction in risk of any new stroke event at 90 days with clopidogrel plus aspirin for 21 days followed by clopidogrel alone. However this trial was carried out in a Chinese population; it has limitations and the results may not be generalisable to the UK.

Safety

  • The summary of product characteristics for clopidogrel lists haematoma, epistaxis, gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia, bruising and bleeding at puncture sites as common adverse effects (occurring in between 1 in 10 and 1 in 100 people). No relevant safety data were identified that compared clopidogrel monotherapy with alternative treatment in a population with TIA.

Patient factors

  • Additional antiplatelet therapy may add to the burden of polypharmacy.

Resource implications

  • Cost of £1.71 for 28 days' supply of generic clopidogrel 75 mg daily.

  • Cost of £33.26 for 28 days' supply of branded clopidogrel (Plavix) 75 mg daily.

Key points

Clopidogrel is licensed for the prevention of atherothrombotic events in people who have had an ischaemic stroke (from 7 days until less than 6 months) but it is not licensed for use in people who have had a TIA. NICE has issued guidance on clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events which recommends that modified-release dipyridamole in combination with aspirin is an option to prevent occlusive vascular events for people who have had a TIA.

No RCTs were identified that assessed clopidogrel monotherapy in people with TIA for either the acute phase or long-term treatment. In addition, no high quality observational data were identified on the efficacy of clopidogrel monotherapy in people with TIA.

Two RCTs (CHANCE and FASTER) were identified that compared clopidogrel plus aspirin with aspirin alone for 90 days in people with acute TIA or minor ischaemic stroke (NIHSS score ≤3) in the past 24 hours.

The CHANCE trial compared clopidogrel plus aspirin for 21 days followed by clopidogrel alone for a total of 90 days with aspirin alone for 90 days. The CHANCE trial only included people with TIA at a higher risk of early stroke (ABCD2 score ≥4). The CHANCE trial (n=5170) found a statistically significant reduction in the primary outcome of risk of new stroke events (ischaemic or haemorrhagic) at 90 days with clopidogrel plus aspirin for 21 days followed by clopidogrel alone compared with aspirin alone (8.2% compared with 11.7%; hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.57 to 0.81; p<0.001). The CHANCE trial found no statistically significant reduction in all-cause mortality or death from cardiovascular causes with clopidogrel plus aspirin for 21 days followed by clopidogrel alone compared with aspirin alone.

The FASTER trial (n=392) compared clopidogrel plus aspirin with aspirin alone for 90 days. It found no statistically significant difference between clopidogrel plus aspirin and aspirin alone for the same primary outcome (7.1% compared with 10.8%; risk ratio [RR] 0.7; 95% CI 0.3 to 1.2; p=0.19). However, it may have been underpowered to detect an effect.

The CHANCE trial, which was conducted in China, has a number of substantial limitations. In particular, the results may not be generalisable to the UK population because of differences between the Chinese and western populations in aetiology of stroke and background use of preventive interventions to reduce cardiovascular risk. An ongoing trial in the USA and worldwide (the POINT trial) is assessing the effects of clopidogrel plus aspirin started within 12 hours of high-risk TIA or minor ischaemic stroke with follow-up for 90 days. The results from this trial may be more applicable to a western population.

The CHANCE trial found no statistically significant difference in moderate or severe bleeding events between clopidogrel plus aspirin for 21 days followed by clopidogrel alone and aspirin alone (0.3% in both groups, p=0.73). The FASTER trial found a statistically significant increase in symptomatic bleeding events (3.0% compared with 0%; risk difference [RD] 3.0%, 95% CI 0.6% to 5.4%; p=0.03) and asymptomatic bleeding events (30.8% compared with 13.9%; RD 16.9%, 95% CI 8.8% to 25.0%; p=0.0001) with clopidogrel plus aspirin compared with aspirin alone.

The CHANCE and FASTER trials both lasted for 90 days and results, particularly safety results, may not apply to longer-term treatment.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.