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Prescribing after a stroke

New evidence on dipyridamole, clopidogrel and aspirin is changing practice for the secondary prevention of stroke. Stroke physicians Dr Anthony Rudd and Dr Nigel Smyth review the data

New evidence on dipyridamole, clopidogrel and aspirin is changing practice for the secondary prevention of stroke. Stroke physicians Dr Anthony Rudd and Dr Nigel Smyth review the data

41208001It's been a busy couple of years in terms of research on the secondary prevention of stroke. Dipyridamole and aspirin have been used for years by GPs but recently published trials – most notably ESPRIT and EXPRESS – have given new information on dosing and timing of each. Dipyridamole is usually seen as being a poor choice for secondary prevention as monotherapy but ESPRIT has shown it to have proven efficacy in combination with aspirin.

But even with a traditional drug such as aspirin, new results have come out suggesting aspirin resistance might be a problem for some of our patients. And even though clopidogrel's use after a coronary event is well established, there has been confusion over its efficacy in secondary prevention of stroke. On top of all this, new antiplatelet drugs are in development.

This review will look at the three main pharmacological choices for secondary prevention of stroke and summarise the latest data from the past two years or so.

Antiplatelets in primary versus secondary prevention

The use of antiplatelet agents is well established in the prevention of cerebrovascular events. A meta-analysis of 21 randomised controlled trials showed relative risk reductions of 28% and 16% in non-fatal and fatal strokes respectively when patients received an antithrombotic1. It must be remembered, though, that the absolute risk reduction is modest – 1-2% at most – and stroke prevention includes modification of many other risk factors.

There is little evidence for use of the drugs in primary stroke prevention. But the American Heart Association (AHA) suggests aspirin (75-160mg daily) for primary prevention of CVD and stroke in those with a higher risk of CHD, equating to a 10-year risk of CHD of more than 10%.

Aspirin is also included in the AHA and NICE guidelines for prevention of cardioembolic stroke in those with atrial fibrillation. Although not as effective as anticoagulation with warfarin – especially in the elderly – trials of aspirin show a modest reduction in stroke risk.

What dose to use is unclear but the general consensus is to use a more moderate dose than that for secondary prevention. In our patients with atrial fibrillation whom we feel are not suitable for anticoagulation, we treat with aspirin 300mg once a day.

In the secondary prevention of stroke, three agents are commonly used in the UK – aspirin, dipyridamole and clopidogrel.

They should be started immediately after a TIA – even before a scan – and as soon as an intracerebral bleed has been excluded in ischaemic stroke.

The EXPRESS trial showed that urgent treatment with antihypertensives, antiplatelets and cholesterol-lowering drugs for TIA or minor stroke reduced the early risk of progression to a major stroke by 80%2.

All patients after ischaemic stroke or TIA should ideally be on some form of antithrombotic therapy. Which drug or combination of drugs to use should be decided individually for each patient, and GPs must weigh up the benefits and potential side-effects.

Aspirin

Aspirin is the most established therapy with numerous trials proving reduction of all cardiovascular mortality as well as secondary prevention of stroke or TIA. Doses ranging from 50mg to 1,300mg daily have all been trialled and shown to be effective, reducing relative risk by 15%. There is no dose-responsive effect and so it is best to use a low dose to minimise potential side-effects.

In our work, in those presenting with acute stroke or TIA, we load with 300mg once a day for a period of two weeks and then decrease to a maintenance dose of 75mg once a day.

GI side-effects are uncommon but aspirin intolerance can be minimised by the additional use of a PPI where necessary for gastric protection.

Only in true cases of aspirin intolerance should other therapy, such as clopidogrel, be considered. Concomitant use of other NSAIDs may increase the GI bleeding risk as well as inhibiting aspirin's antiplatelet activity.

There has been some renewed interest of late in the possibility of a cohort of patients who are aspirin-resistant and continue to have cardiovascular events despite appropriate doses. Unfortunately there is no clearly defined test to assess this and few trials showing that alternative antiplatelet therapies benefit these patients. More work is being done but for now we should continue with our current prescribing practice.

Dipyridamole

By itself dipyridamole is not as efficacious as aspirin for secondary prevention. Its more frequent dosing, greater expense and more frequent side-effects – especially headache and diarrhoea – make it a poor choice for monotherapy.

However, two recent trials – ESPS23 and ESPRIT4 – have confirmed that a combination of low-dose aspirin and a 200mg twice-daily dose of modified-release dipyridamole is more effective than aspirin alone. ESPRIT showed the combination reduced relative risk by 20% – its primary outcome being death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication – compared with aspirin alone.

Despite this new data, a NICE technology appraisal has recommended the combination only be used for two years, after which aspirin should be used alone.

During the recent trials a significant number of patients dropped out of the combination arm because of side-effects.

This was mostly related to dipyridamole-triggered headache. Headache usually settles down after a few days treatment and can be minimised by simple analgesia and starting dipyridamole therapy as a single dose at night for one week before increasing to a twice-daily regimen.

Clopidogrel

Although widely used for treatment of coronary artery disease, clopidogrel's role in the secondary prevention of stroke is less clear.

The CAPRIE trial randomised patients with stroke, MI or peripheral vascular disease to either aspirin (325mg/day) or clopidogrel (75mg/day). The primary end point included further MI, stroke or death from any vascular cause. This occurred in 8.7% fewer patients treated with clopidogrel than with aspirin5. But a subgroup analysis of those with previous stroke showed the reduction seen with clopidogrel was smaller and statistically insignificant. Therefore as monotherapy clopidogrel may have only a slight benefit over aspirin alone and this would come at a significant financial cost – £35 for clopidogrel compared with £1.50 for a 28-day supply of aspirin. It is therefore not a first-line therapy unless there is true aspirin allergy or clopidogrel is required for another reason, such as coronary or carotid stenting.

Clopidogrel may also be of more benefit in those with evidence of widespread vascular disease.

Clopidogrel and aspirin in combination has been assessed specifically in the MATCH trial. High-risk patients after a recent TIA or stroke were randomised to either clopidogrel alone or clopidogrel plus aspirin. There was no significant difference in either primary or secondary outcomes and a significant increase in haemorrhage in the combination group6.

The recently released PRoFESS data compared the use of clopidogrel alone versus aspirin-dipyridamole combination in those post non-cardioembolic stroke. It has shown that the risk of a further stroke or vascular event was the same in both groups7.

Other agents

Other antiplatelet drugs are currently being evaluated. The PERFORM trial is currently under way following up patients post-cerebrovascular event for an average of three years. It is comparing the use of aspirin 100mg daily with terutroban, a new drug showing antiplatelet and antithrombotic activity.

It will be a number of years before the study is complete.

Recurrent cerebrovascular events on antiplatelet therapy

It is often frustrating and disappointing for both patients and their doctors when recurrent strokes or TIAs occur despite appropriate antiplatelet therapy. Unfortunately there is no evidence to suggest a change of antiplatelet therapy after the recurrence will prevent further events.

Those with recurring events should have their other risk factors (blood pressure, cholesterol, smoking and so on) reviewed and aggressively treated if necessary. Thought should be given to a possible cardioembolic source and paroxysmal atrial fibrillation should be considered.

New guidelines for stroke and TIA management have been published.

The NICE guidance covers the acute management of stroke and TIA at www.nice.org.uk/guidance. The Royal College of Physicians Guidance will cover the rest of the pathway including secondary prevention – see www.rcplondon.ac.uk.


Dr Anthony Rudd is stroke physician at Guy's and St Thomas' Hospital London, chair of the NICE acute stroke and TIA guidelines development group and chair of the Intercollegiate Stroke Working Party at the Royal College of Physicians

Competing interests: none declared

Dr Nigel Smyth is specialist registrar at Guy's and St Thomas' Hospital London

Competing interests: none declared

GP imps The role of antiplatelet prescribing for primary stroke prevention is unclear The role of antiplatelet prescribing for primary stroke prevention is unclear

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