July 2002, Vol 24, No. 7
Update Articles

Update in prevention of ischaemic stroke

A C F Hui 許志輝, K S Wong 黃家星

HK Pract 2002;24:344-353

Summary

Stroke is a leading cause of death. For many years epidemiological data have identified a number of risk factors for ischaemic stroke. Only recently have clinical trials been conducted to assess the effect of intervention on reducing cerebrovascular disease. We review the current medical and surgical means of stroke prevention in light of the latest information from trials and guidelines.

摘要

中 風 是 一 種 主 要 的 致 命 病 症 。 多 年 來 ， 流 行 病 學 已 確 認 了 一 些 缺 血 性 中 風 的 風 險 因 素 ， 但 直 到 最 近 才 有 臨 床 研 究 去 評 價 各 種 降 低 腦 血 管 疾 病 發 病 措 施 的 成 效 。 我 們 從 最 新 的 臨 床 研 究 結 果 和 指 引 ， 檢 討 了 預 防 中 風 的 內 外 科 方 法 。

Stroke is the third commonest cause of mortality in Hong Kong, resulting in about four thousand deaths every year - over 10% of all deaths. In the United Kingdom one person suffers a cerebrovascular event every five minutes. Many survivors suffer from disability, depression and dementia. Reducing this immense burden on patients, families, friends and society at large is a crucial part of general practice. This article reviews the medical and surgical approaches to stroke prevention.

Lifestyle

Smoking

Active smoking is associated with promotion of thrombosis through different mechanisms: increased arterial wall stiffness, increased levels of fibrinogen, increased platelet aggregation and haematocrit. Exposure to environmental tobacco smoke may contribute to both coronary heart disease and stroke. Although no prospectively randomised study has assessed the effect of abstinence, the epidemiological evidence is overwhelming: a systematic review of 22 studies show that smokers are at a substantial risk of stroke compared with people who have never smoked.1 The increased risk drops to non-smoker levels within 2-5 years of cessation of smoking; stopping all forms of smoking - pipe and cigars included - is strongly recommended.

Obesity

Obesity, in particular abdominal obesity, is associated with raised lipids, insulin resistance and hypertension. Excessive body weight correlates with increased stroke risk so that weight reduction in theory should improve individual risk profile but this has not been tested in randomised controlled trials (RCTs).2

Exercise

Physical inactivity is related to a higher stroke rate and a number of guidelines recommend regular exercise to reduce the risk of stroke.3

Medical treatment

1.

Antiplatelet drugs

Aspirin

Aspirin inhibits the cyclo-oxygenase mediated breakdown of arachidonic acid to thromboxane A2, a platelet aggregator and vasoconstrictor. Three large trials have investigated the prophylactic use of aspirin in asymptomatic apparently healthy individuals. In these studies, aspirin did not have a significant benefit over placebo in decreasing ischaemic stroke.4-6 The incidence of haemorrhagic stroke may actually increase. In a US study, 22071 male physicians were randomised to aspirin 325mg every other day or placebo; 23 subjects in the aspirin group suffered a haemorrhagic stroke as compared to 12 in the placebo group but this did not reach statistical significance (p=0.06).4

In patients with hypertension but without previous stroke, the addition of aspirin also did not produce a beneficial effect. The Hypertensive Optimal Treatment Study randomly assigned 18790 patients with a diastolic blood pressure (DBP) of 100-115mmHg to one of three DBP target groups. They were also randomised to receiving 75mg aspirin per day or placebo. At 3.8 years there was no difference in stroke incidence between the two.7

The Antiplatelet Trialists Collaboration analysed information from 145 trials using aspirin for any vascular indication.8 This meta-analysis showed that aspirin at a dose of 75-1500mg daily was associated with an odds reduction of 22% in fatal stroke, non-fatal myocardial infarction (MI) or vascular death. As to the optimal dose there is no clear evidence that any regime is superior to medium dose aspirin (75mg - 325mg), which was the most commonly tested regime. The UK and Dutch transient ischaemic attack (TIA) trials compared the efficacy of daily aspirin, at doses of 300mg versus 1200mg and 30mg versus 283mg respectively. They failed to detect a difference in efficacy but higher dosages were associated with more gastrointestinal symptoms.9,10

Dipyridamole

Dipyridamole inhibits platelet aggregation by several mechanisms. The European Stroke Prevention Study (ESPS) demonstrated that 225mg dipyridamole and 990mg aspirin together reduced the relative risk of death or recurrent stroke by 33.5% compared to placebo.11 The second ESPS included an aspirin monotherapy and dipyridamole alone groups in addition to combination treatment. Taking the two drugs together, aspirin 50mg bd and persantin 200mg bd, resulted in a lower risk than either of the two drugs individually (37% reduction versus 18% for aspirin alone and 16% for dipyridamole alone).12 However when this trial is included in a systemic review along with previously negative studies, the results showed that dipyridamole on top of aspirin did not produce additional benefits.13

Clopidogrel and ticlopidine

Clopidogrel and Ticlopidine are thienopyridine derivatives. They inhibit adenosine diphosphate-induced fibrinogen binding to platelets. In the Canadian American Ticlopidine Study, ticlopidine 250mg twice daily, in patients who had sustained a stroke, reduced the combined risk of stroke or vascular death by 23% compared to placebo and in the Ticlopidine Aspirin Stroke Study, a similar dose reduced the 3 year risk of recurrent stroke by 21% compared to aspirin at 650mg twice daily.14,15 The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events trial compared clopidogrel 75mg daily to aspirin 325mg daily, recruiting 19,185 patients with recent stroke, MI or peripheral arterial disease.16 The relative risk reduction was 8.7% with clopidogrel. Clopidogrel may not be substantially superior to aspirin but at least it can be used as a substitute for patients intolerant of aspirin.

The incidence of skin rash and diarrhoea was increased with both drugs but ticlopidine is associated with haematological adverse effects: neutropenia (0.9-0.8%), and thrombocytopenic thrombotic purpura (with a mortality rate of 33%), which have reduced the enthusiasm for this agent. The experience from coronary heart disease patients is that clopidogrel is safer and better tolerated than ticlopidine.17

 
2.

Anticoagulation

Long term anticoagulation is the standard therapy for patients with rheumatic heart disease and valvular atrial fibrillation (AF). Although there are no rigorous RCTs for this situation, the risk of stroke is 17 times higher for this group of individuals. In one retrospective study, the embolic event rate was 0.7% in anti-coagulated patients, as opposed to 5.46% in patients without anticoagulants.18

The Framingham Heart Study had shown that stroke associated with AF rises with increasing age. Patients in their 50s had stroke incidences of 1.5% while the figure rises to 23.5% for those in their 80s.19 The value of warfarin in non-valvular AF was the focus of five RCTs on the primary prevention of stroke and one on secondary prevention.20-25 Anticoagulation significantly decreased the risk of stroke. Risk reduction was 66% with warfarin and 19% with aspirin. Aspirin is an alternative for those in whom warfarin is contraindicated. The participants in these studies were carefully selected and their International Normalised Ratios (INRs) were carefully regulated; whether the low rate of haemorrhage applies to a specific individual requires clinical judgement.

Patients with lone AF under the age of 60 (without hypertension, diabetes mellitus, ischaemic heart disease or stroke) had annual stroke incidences of 0%. These data indicate that patients with lone non-valvular AF under 60 years old do not require anticoagulation; aspirin should be given.26,27

There is no evidence to support anticoagulation in non-cardioembolic strokes. The Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke study tested the hypothesis that warfarin may be superior to aspirin in secondary stroke prevention in cases without AF.28 However it did not demonstrate any significant differences in stroke recurrence between patients in the aspirin arm and subjects on warfarin (INR maintained at 1.4-2.8, mean 2). An earlier trial had used a higher intensity of anticoagulation (INR of 3-4.5) and was terminated because of excessive haemorrhagic complications.29

 
3.

Antihypertensive therapy

Despite the fact that elevated systolic and diastolic blood pressures contribute directly to the incidence of cerebrovascular disease, hypertension is under-diagnosed and under-treated.30 Both beta-blockers and diuretics are effective in preventing strokes by a third in hypertensive individuals mostly without a history of cerebrovascular disease. This effect is also seen in another trial using a calcium antagonist.31,32 These primary prevention trials involved over 50,000 people. The benefit extends to the elderly as demonstrated by the 36% reduction in stroke from the Systolic Hypertension in the Elderly Program study.33

Good hypertensive control is particularly important in diabetic patients as diabetes mellitus is an independent risk predictor for ischaemic stroke, up to six times the risk of normal individuals. The UK Prospective Diabetes Study demonstrated a 44% relative risk reduction of stroke in diabetics with tight blood pressure control as opposed to those with suboptimal control.34 There remained uncertainty on the role of anti-hypertensive agents in cases with a history of cerebrovascular disease.35 Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was specifically designed to investigate this. 6105 hypertensive and normotensive patients with a previous history of stroke or TIA were given perindopril with or without indapamide or placebo.36 Ten percent of those on active treatment suffered a stroke compared to 14% of those on placebo. Patients on perindopril or indapamide alone had a more modest reduction in blood pressure and did not produce a significant reduction in stroke risk, but those on combination treatment had an average blood pressure reduction of 12/5mmHg and a 43% drop in risk.32 The Heart Outcomes Prevention Evaluation Study (HOPE) recruited 9297 patients with coronary arterial disease of whom half had hypertension. It showed that an angiotensin-coverting enzyme inhibitor (ACEI), ramipril, led to a reduction in MI by 25% and stroke by 33% as compared to placebo, even in patients without hypertension.7 The investigators concluded that ACEI lowers stroke rate independently of blood pressure reduction. One possible mechanism is the effect of ACEIs on endothelial dysfunction, which contributes to atherosclerosis. Adverse effects include electrolyte disturbance and cough, which is particularly troublesome side effects in Chinese. Further trials comparing different classes of anti-hypertensive agents are in progress.

Regular screening for hypertension in asymptomatic people every two years is recommended by the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of high Blood Pressure.37

 
4.

Statins

Elevated low density lipoprotein (LDL) cholesterol is an independent predictor for ischaemic stroke but until the introduction of statins there had been no consistent evidence that lipid lowering drugs reduces this risk. The Cholesterol and Recurrent Events and the Scandinavian Simvastatin Survival Study reported the effects of simvastatin and pravastatin respectively in patients with a recent history of MI and elevated LDL-cholesterol.38,39 The combined incidence of stroke was reduced by one third in the trials. Several other trials and meta-analyses have also supported the benefits of statins in stroke prevention in patients with coronary heart disease (CHD).40,41 This effect may be mediated through mechanisms other that lipid lowering. Statins promotes release of tissue plasminogen activator, block platelet activation, reduce cerebral inflammatory response and improve endothelial function. Ultrasound demonstration of intima media thickening (IMT) has become an outcome measure in some trials as IMT is a preclinical predictor for atherosclerotic vascular disease. Efficacy of statin in retarding the progression of atherosclerosis as measured by IMT reduction has also been demonstrated.42 These clinical trials have excluded elderly patients and studied mainly cases with a history of CHD; the recently presented Heart Protection Study suggested that stroke should be regarded as a CHD risk equivalent.43 It also confirmed the benefit of statins for stroke prevention in patients without CHD and regardless of initial cholesterol levels. Current guidelines emphasise aggressive lipid-lowering of LDL-cholesterol in people with CHD and in CHD risk equivalent conditions (includes symptomatic carotid artery stenosis, peripheral arterial disease and diabetes mellitus), in recognition of the fact that patients with these related disorders have a high risk of developing vascular events. Treatment target of LDL-C is set at <100mg/dL (2.6mmol/L) in patients with CHD or CHD risk factor; HDL-C levels at >40mg/dL (1.03 mmol/L)is recommended.44

Statins are generally well tolerated but side-effects include myopathy and deranged liver enzymes. In 2001, Bayer withdrew cerivastatin (Lipobay/Baycol) after the deaths of 31 patients from rhabdomyolysis.

Surgical treatment

1.

Carotid endarterectomy

The atherosclerotic plaque in the internal carotid artery is removed in this procedure. Carotid endarterectomy (CEA) was first performed in 1954 and grew in popularity as it was a rational method of treating structural obstruction until it was revealed that the average stroke and death rate was 10%.45 Three RCTs subsequently compared CEA with medical treatment in prevention of strokes in symptomatic patients with carotid artery disease. Two of these demonstrated that CEA was superior; the third study was stopped when the results from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) were released.46-48 In NASCET, 662 patients with a TIA or minor stroke with ipsilateral carotid artery stenosis received aspirin up to 1300mg per day or CEA. At 2 years, the cumulative rate of ipsilateral stroke was reduced from 26% in the aspirin group to 9% in the CEA group in patients with severe carotid artery disease (>70% stenosis of the cross sectional diameter of the artery). It should be noted that the initial incidence of stroke and mortality within 30 days of surgery was higher than the medical group.47 Perioperative major stroke or death was 2.1%. Patients above 80 years of age or with AF, valvular heart disease were not included. The European Carotid Surgery Trial (ECST) demonstrate that patients with mild stenosis (0% to 29%) did not benefit from endarterectomy. Both NASCET and ECST continue to recruit patients with moderate stenosis (30-69%) to study the effect of CEA.

Three studies have studied the effect of prophylactic CEA in asymptomatic patients. The Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin (CASANOVA) trial did not show any benefit from surgery but the Veterans Affairs Cooperative Study (VA) and Asymptomatic Carotid Atherosclerosis Study (ACAS) trials demonstrated that CEA was superior to medical therapy.49-51 ACAS was a RCT that assigned 1662 patients with asymptomatic high grade (>60%) carotid artery disease to either CEA or Aspirin 325mg/day. The risk of ipsilateral stroke or death was 5.1% with CEA and 11% with Aspirin.51 Major peri-operative complication rate (stroke or death) was 3.5% (1.2% after angiography and 2.3% after CEA); subgroup analysis revealed that the relative reduction was only 16% in women, as compared with 69% for men. This was ascribed to a higher complication rate in women during this study. This is a reminder that the benefit of surgery in asymptomatic patients depends on surgery units having a low risk of complications and should be performed only in centres with a mortality and morbidity rate of <3%.

 
2.

Extracranial/intracranial arterial bypass

In this operation an anastomosis is created between the superficial temporal artery to the distal ipsilateral middle cerebral artery in order to bypass an intracranial arterial stenosis or occlusion. Extracranial/intracranial bypass was performed in 652 patients in one study but primary and subgroup analyses did not suggest benefit of this procedure over the non-surgical group.52

 
3.

Carotid angioplasty

Cerebral angioplasty with or without stenting is emerging as a promising method of extracranial arterial revascularisation. It avoids the need for cervical dissection, general anaesethesia and is applicable to surgically inaccessible lesions. The role of angioplasty was assessed in carotid and vertebral artery transluminal angioplasty study (CAVATAS) but the sample size was too small to provide reliable figures on efficacy.53 Further trials are underway.

 
4.

Distal embolic protection device

Embolic strokes may occur in patients undergoing stenting of a stenotic segment of the carotid artery. This is thought to be due to release of atheromatous plaque material induced by the stenting procedure. Distal-balloon protection systems have been developed to reduce migration of this plaque material into the cerebral circulation.54 The use of such devices reduces the number of microembolic signals on transcranial ultrasound in patients by over a half as compared to those who underwent conventional angioplasty.55

Conclusion

Prevention of stroke begins with the identification and modification of risk factors. At present, these risk modification treatment such as anticoagulants, anti-hypertensive and lipid-lowering drugs are underutilised. For patients who have had a stroke or TIA, investigations to determine the underlying vascular pathology would allow the most appropriate form of therapy to be offered. This strategy of targeting individuals at high risk of developing ischaemic stroke is sensible and is supported by the results of RCTs. It should be noted, however, that most strokes occur in those without atrial fibrillation or carotid stenosis, so that concentrating preventative treatment only at those with high risk will have limited success. An alternative mass strategy of reducing the average level of risk factors in the general population would have a greater impact.

Twenty years ago, there was little evidence-based treatment for reducing the incidence of cerebrovascular disease (Table 1). Effective interventions are now established but many uncertainties remain, such as the role of carotid angioplasty, the optimal combination of anti-platelet drugs and the effect of lowering homocysteine levels. Chinese patients were enrolled in the PROGRESS and Post-stroke Antihypertensive Treatment Study but many important studies were performed in predominantly white or black populations. Given that there are ethnic differences, such as the vascular distribution of atherosclerotic disease and the different pharmacokinetic responses to drugs such as warfarin and ACEI between Chinese and Caucasians, careful judgement is required before applying overseas trial data to local patients.

Table 1: Interventions with established efficacy for stroke prevention

Primary Intervention
Hypertension Anti-hypertensives
Hyperlipidaemia with CHD Statins
Atrial fibrillation Anticoagulants
Carotid stenosis Carotid endarterectomy
Cigarette smoking Cessation of smoking
Diabetes mellitus Tight control
   
Secondary Intervention
Prior TIA/stroke Antiplatelet agents
Hypertension Anti-hypertensives
Hyperlipidaemia Statins
Atrial fibrillation Anticoagulants
Carotid stenosis Carotid endarterectomy
Cigarette smoking Cessation of smoking
Diabetes mellitus Tight control

Acknowledgement

We would like to thank Ms Caran Chan and Ms Dora Sun for assistance on the manuscript.

Key messages

  1. Treat hypertensive individuals to 140/80mmHg or below. In patients with prior transient ischaemic attacks (TIA) or cerebral infarct consider using angiotensin-converting enzyme inhibitor based anti-hypertensive therapy.
  2. Prescribe statins to lower low density lipoprotein - cholesterol to below 2.6mmol/L in patients with coronary heart disease or risk equivalent conditions.
  3. Consider anticoagulation in those individuals with non-rheumatic atrial fibrillation.
  4. Use aspirin or clopidogrel as anti-platelet therapy in patients with TIA or ischaemic stroke for secondary prevention.
  5. Screen for carotid stenosis in cases with TIA or ischaemic stroke as they may be eligible for carotid endarterectomy.

A C F Hui, MRCP, FHKAM
Senior Medical Officer,

K S Wong, MD, FRCP
Associate Professor,
Department of Medicine and Therapeutics, Prince of Wales Hospital.

Correspondence to : Dr A C F Hui, of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.

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