James
69, Male

Risk Factor Management in answer to the questions

Hypertension: The major risk factor for stroke is hypertension and current trial data, although limited, suggest that lowering blood pressure by 5-6 mmHg diastolic and 10-12 mmHg systolic for 2-3 years should reduce annual risk of stroke from 7% to 4.8% with a number needed to treat (NNT) of 45 to avoid one stroke per year. The PROGRESS trial suggests that treatment with both perindopril and indapamide, producing a mean reduction in systolic blood pressure of 12 mmHg, reduces the risk of recurrence by 43% in both hypertensive and normotensive patients.

Smoking: Smoking increases the risk of stroke by around 50% and reduction by nicotine replacement patches, behavioural modification, combined with advice and social skills training and encouragement and brief advice given by well trained GPs or other health professionals during routine consultations are all effective. The NNT for smoking cessation is 43 to avoid one stroke per year.

Cholesterol reduction: The Heart Protection Study suggests that stroke can be reduced in high risk patients, such as those with previous stroke or TIA by reducing cholesterol even in patients with ‘normal’ cholesterol concentrations. The National Clinical Guidelines therefore recommend treating all patients with a total cholesterol of over 3.5mmol/L with a statin as well as giving dietary advice. NB, that hypothyroidism should be excluded as a cause of hypercholesterolaemia by measuring serum TSH concentration before starting statin treatment.

Antiplatelet drugs: A large body of evidence exists for three different anti-platelet agents with varying mechanisms of action (aspirin, dipyridamole and clopidogrel) in stroke secondary prevention. Large RCTs involving tens of thousands of patients worldwide have demonstrated the beneficial effect of aspirin treatment in the secondary prevention of ischaemic stroke. Giving aspirin to patients who have had an ischaemic stroke in doses above 75 mg daily reduces the risk of stroke by about 13% and the stroke risk per year from 7% to 6%. This equates to 1 stroke being prevented for every 100 patients who are prescribed aspirin.

Whilst aspirin has been shown to be more effective than dipyridamole for stroke prevention, a meta-analysis of individual patient data from RCTs has shown that the combination of aspirin with dipyridamole reduces the risk of subsequent TIA and stroke by 18% compared with aspirin alone. In patients with previous ischaemic stroke, myocardial infarction or symptomatic atherosclerotic peripheral arterial disease, the CAPRIE trial showed clopidogrel to reduce significantly the annual risk of ischaemic stroke, myocardial infarction or vascular death to 5.32% compared with 5.83% with aspirin (p=0.04). Although this study was not designed specifically to address secondary prevention of stroke, post-hoc analyses showed that the benefit of clopidogrel was amplified in diabetic patients and those receiving lipid-lowering therapy. More recently, the PROFESS trial showed there to be similar rates of recurrent stroke in patients randomised to the combination of aspirin plus extended-release dipyridamole versus clopidogrel. Two RCTs have also studied the effectiveness of clopidrogel in combination with aspirin for secondary prevention of stroke. Whilst the CARESS study in patients with significant carotid artery disease demonstrated a reduction in the number of embolisations from unstable atheromatous plaques, the MATCH study showed that adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or TIA was associated with a non-significant difference in reducing major vascular events but an increased risk of major bleeding. There is no evidence as yet to support triple antiplatelet therapy (with aspirin, dipyridamole and clopidogrel) and studies are ongoing to investigate this further and also to investigate newer antiplatelet agents such as prasugrel and ticragelor.

Given the high early risk of recurrent stroke, strategies of early antiplatelet therapy have been investigated. The Chinese Acute Stroke Trial demonstrated a 24% relative risk reduction of recurrent stroke when aspirin was provided within 48 hours of ictus and the CHANCE trial, testing a combination of aspirin and clopidogrel versus aspirin for 21 days, followed by monotherapy for up to 3 months, demonstrated a 32% reduction in recurrent stroke in those randomised to dual antiplatelet therapy.

In view of the aforementioned body of evidence, the most recent national guidelines recommend:
Aspirin 300mg daily for 2 weeks post-stroke, then to be substituted for long-term clopidogrel 75mg thereafter. If the patient cannot tolerate clopidogrel then the combination of aspirin 75mg and dipyridamole MR 200mg bd can be used as an alternative.

Anticoagulation: With the ageing of the population, the prevalence of atrial fibrillation is set to increase dramatically and management with aspirin or warfarin is effective at reducing recurrence. Warfarin is more effective (NNT12) and should be the first line treatment, although management is often difficult. Non-vitamin K antagonist oral anticoagulants (NOACs) compared to warfarin are, in randomised controlled trials (RCTs), demonstrated to be at least as effective for stroke prevention, with equal or lower risk for major bleedings (intracranial haemorrhage) in patients with atrial fibrillation - e.g. for rivaroaxaban [ROCKET AF trial], for apixaban [ARISTOTLE trial].

Carotid endarterectomy: The trial evidence would suggest an NNT of 26 for severe stenosis. It should be considered for patients with 70-99% symptomatic carotid stenosis after a TIA or non-disabling stroke. Recent evidence has shown that in women there is no benefit for surgery performed more than two weeks after the symptomatic event and 12 weeks in men. It is therefore essential that diagnosis is made rapidly and that surgeons are able to operate without delay.

Other behavioural risk factors: Being overweight, leading a sedentary lifestyle, excessive alcohol intake and having a poor diet all contribute to cardiovascular risk. Generally the evidence base for interventions here is poor however epidemiological data would suggest that persuading patients to modify lifestyle should be attempted in all patients.