Update on secondary stroke prevention

Edward H C Wong 王浩中, Vincent C T Mok 莫仲棠

HK Pract 2007;29:271-276

Summary

Stroke survivors have a much higher risk of having another stroke than the general population of the same age. A comprehensive treatment plan can help to reduce this risk. We discuss the latest evidence-based strategies in secondary prevention of ischaemic stroke. These include modification of vascular risk factors, anticoagulation for cardio-embolic stroke, antiplatelet therapy and revascularization of relevant vessels. As stroke is a heterogeneous condition, we emphasize on the importance of a tailor-made treatment plan for each patient based on one's underlying stroke mechanism. Potential treatment for some locally relevant conditions such as intracranial artery stenosis and post-radiation carotid artery stenosis are also discussed.

摘要

曾患中風的病人較一般同齡人仕有更高的再次中風機會。而一個綜合性治療計劃有助降低這風險。 本文討論在次階段預防缺血性中風的最新而具實証基礎的策略。當中包括改善血管方面的致病因素， 心因性栓塞腦中風的抗凝血劑治療，抗血小板劑療法和相關血管的再血管化療法。中風是一種多相性病症， 因此我們強調根據每位病人的病發機制來訂定治療方案的重要性。本文亦討論一些相關疾病， 如顱內動脈血管狹窄和放射治療後頸動脈血管狹窄的可能性療法。

Introduction

Stroke emerges to be the commonest vascular disease in the 21^st century.¹ The first year recurrence rate of stroke among Chinese ischaemic victims was recently reported to be 11%, which was higher than that reported in Caucasians.² Failure to control modifiable risk factors might partly explain this discrepancy. Overall, relative risk of recurrent stroke after transient ischaemic attack (TIA) or minor stroke is about 12 times that of stroke-free people of the same age and sex.³ Secondary prevention strategies are thus of paramount importance to decrease this risk. As stroke is a heterogeneous condition, these preventive strategies have to be tailor-made for each patient with the understanding of the underlying stroke mechanism. As more than 80% of all stroke were ischaemic rather than haemorrhagic, the following sections focus on the long-term secondary preventive strategies for ischaemic stroke as well as specific treatment for some of the more common stroke aetiology.

The major secondary preventive strategies of ischaemic stroke can be summarized as below:

1. Modification of vascular risk factors
2. Anticoagulation for cardio-embolic stroke
3. Antiplatelet therapy for non-cardioembolic ischaemic stroke
4. Revascularization of relevant stenotic vessels

Modification of vascular risk factors

Hypertension

There is well-established evidence of a continuous relationship between hypertension and stroke risk.⁴ Meta-analysis has shown that lowering of systolic blood pressure (BP) of 10 mmHg is associated with one-third less risk of stroke.⁵ The association is continuous down to levels of at least 115/75 mm Hg and is consistent across both sexes, regions, and stroke subtypes and for fatal and nonfatal events. Although there is inconclusive evidence in terms of which class of hypertensive drugs is the most effective, the combination of perindopril, an angiotensin converting enzyme inhibitor (ACEI) and indapamide appears to be an effective strategy based on the PROGRESS study.⁶ Patients who were treated with combination of perindopril and indapamide achieved the biggest average reduction of BP of 12/5mmHg and 43% reduction in recurrent stroke, compared with patients on placebo treatment. There was no significant benefit when perindopril was given alone that may be due to the lack of effect from insufficient blood pressure lowering. Beta-blocker and ACEI, when used alone, have not been shown to significantly reduce the risk of recurrent stroke.⁷ It should be noted that these recommendation of BP lowering only applies to patients who are beyond the acute period (i.e. first 1-2 week post-stroke). During the acute period after ischaemic stroke, most consensus guidelines recommend that BP should not be treated unless hypertension is extreme (BP >220/120) or the patient has active ischaemic heart disease, heart failure, or aortic dissection.⁸ After the stabilization period anti-hypertensive treatment may then be introduced with monitoring of hypotensive side-effect. The long term treatment target of BP should be less than 140/90, and for patients with diabetes and chronic kidney disease the target should be less than 130/80.⁹

The management of hypertension in ischaemic stroke patients with pre-existing haemodynamically significant multiple extracranial or intracranial stenosis is more problematic. The lowering of BP may exacerbate cerebral hypoperfusion and cause more ischaemic events. In this group of patients, BP treatment should therefore be individualized as some patients may not tolerate even a minor degree of BP reduction. Elderly patients (more than 80 years old) have a similar problem as they are more prone to various adverse effects of the BP-lowering drugs. A gradual and cautious lowering of BP over several months is recommended and the BP goal may not need to be as low as the fore-mentioned level.

Diabetes

While tight glycaemic control has been shown to reduce mainly microvascular complications, such as nephropathy, retinopathy, and peripheral neuropathy, data on its efficacy in preventing macrovascular complication such as stroke is less robust. A comprehensive treatment approach to glycaemic control, hyperlipidaemia, hypertension, and microalbuminuria was shown to be effective in reducing the risk of cardiovascular events in diabetic patients.¹⁰

Hyperlipidaemia

Although effectiveness of statin in reducing stroke among patients with coronary heart disease has long been established, its effect among stroke patients without coronary heart disease has been controversial.¹¹ It is only in the most recent SPARCL study that statin has been convincingly shown to prevent recurrent ischaemic stroke among stroke patients who had no coronary heart disease.¹² It randomized more than 4700 patients with stroke or TIA within 1 to 6 months of the initial event and LDL level of between 2.6 and 4.9 mmol/L to atorvastatin 80mg daily versus placebo. The risk of stroke was reduced by 16% over 5 years. Even patients with "average" lipid level benefited from statin therapy as the mean baseline LDL and total cholesterol were 3.4 and 5.5mmol/L respectively in this study. Much of its effect in secondary prevention of ischaemic stroke has been attributed to not only lowering cholesterol level, but also to its role in plaque stabilization, reducing inflammation, improving endothelial function and slowing of atherosclerosis.¹³

Others lifestyle modification

Quitting cigarette smoking is very important for secondary stroke prevention as it is a major independent risk factor for ischaemic stroke by doubling its risk. Patients will need a combination of counselling, social support, and nicotine replacement therapy to achieve a high success rate of quitting. Heavy alcohol consumption (more than 5 standard drinks per day) is associated with increased stroke risk and should be discouraged. Obese patients should be encouraged to lose weight as this would improve blood pressure, fasting glucose values, and lipids, which are all risk factors for stroke. By the same principle, increasing the level of physical activity would help to improve the above parameters and lower recurrent stroke risk.

Anticoagulation for cardio-embolic stroke

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the elderly. Chronic or paroxysmal AF, is one of the most important risk factors for ischaemic stroke. In patients with non-valvular AF the stroke risk is related to age and the presence of other vascular risk factors such as hypertension, congestive heart failure, diabetes and history of ischaemic stroke or TIA. The risk of stroke is lowest at 1% per year for those below 65- years old with no vascular risk factors. It increases exponentially to more than 10% per year in patients older than 75-years old with one or more vascular risk factors or previous history of ischaemic stroke or TIA.¹⁴ The efficacy of warfarin in reducing stroke risk in patients with AF is phenomenal, with a relative risk reduction of 68%.¹⁵ Many patients are concerned by the potential risk of bleeding, especially with its narrow therapeutic window easily influenced by drug interaction and dietary intake. The use of warfarin is relatively safe with regular monitoring of INR. It increases the absolute risk of major bleeding per annum by approximately 1% compared to aspirin or placebo, provided due care has been taken to ensure an INR within the range of 2.0 to 3.0 with strict adherence of patients to follow-up, INR monitoring instructions, diet and drug compliance.¹⁶ Patients with paroxysmal AF carry the same cardio-embolic infarct risk as patients with chronic AF. Giving rhythm-controlled drugs such as amiodarone or sotalol to aim for maintenance of sinus rhythm does not reduce the risk of cardio-embolic stroke if the patients were not anticoagulated. This is because they could have asymptomatic episodes of breakthrough AF and thrombi can still be generated during these periods.¹⁷ Hence all patients with history of ischaemic stroke plus AF (paroxysmal or chronic) should be considered for warfarin therapy unless there is contraindication such as recent trauma or surgery, underlying bleeding tendency, uncontrolled hypertension and patient's non-compliance. Other relative contraindication includes previous history of symptomatic intracranial haemorrhage, presence of unruptured intracranial aneurysm, poor premorbid status, high fall-risk, presence of multiple asymptomatic cerebral microbleeds on MRI brain suggestive of underlying cerebral amyloid angiopathy, all of which the suitability of anticoagulation needs to be considered on a case-by-case basis or with specialist advice.

Warfarin is also indicated for patients with ischaemic stroke or TIA who have rheumatic mitral valve disease regardless of the presence of AF or not. Patients with mechanical heart valve require a more intense level of anticoagulation with target INR 2.5 to 3.5.¹¹

Because of the inherent inconvenience with chronic warfarin usage, other forms of treatment to prevent recurrent cardio-embolic stroke have been explored. Aspirin is an alternative but it is less effective in preventing ischaemic stroke in patients with AF. It reduces the risk by 22% versus 62% with dose-adjusted warfarin.¹⁸ A compromised regimen of fixed-dose, low-intensity warfarin plus aspirin was also ineffective.¹⁹ The use of double antiplatelet agents of aspirin plus clopidogrel versus warfarin was studied in the recent ACTIVE trial. The study was terminated early because patients in the double-antiplatelet arm had significantly more ischaemic event than the warfarin arm as well as having increased risk of haemorrhage.²⁰ Ximelagatran is a direct thrombin inhibitor which does not require coagulation monitoring and has much less food and drug interaction. It was shown to be not inferior to warfarin²¹ but unfortunately the drug has since been withdrawn from the market because of concerns of hepatotoxicity.

Antiplatelet therapy for non-cardioembolic ischaemic stroke

Aspirin

Aspirin is the most widely used antiplatelet agent. It inhibits the enzyme cyclooxygenase and reduces the production of thromboxane A2 to interfere with thrombi formation. Its use is validated in a meta-analysis in which the non-fatal stroke and fatal stroke risk was reduced by 28% and 16% respectively in patients with previous stroke or TIA.²² Low dose aspirin (e.g. 50-80mg) offers similar degree of efficacy compared to high dose aspirin (e.g. 1200mg)²³ but with less risk of gastrointestinal haemorrhage.

Clopidogrel

Another choice of antiplatelet agent is clopidogrel that inhibits ADP-dependent platelet aggregation. In the CAPRIE trial, the relative risk reduction of ischaemic stroke, myocardial infarction, or vascular death combined was 8.7% for clopidogrel over aspirin.²⁴ Subgroup analyses among the 6431 stroke patients demonstrated a non-significant reduction from 7.71% to 7.15% in outcome events; however the number of fatal strokes was reduced from 322 to 298. It, however, has a more favourable side-effect profile with less frequent gastrointestinal bleeding.²⁵

Aspirin plus dipyridamole

The stroke risk reduction offered by aspirin or clopidogrel, while statistically significant, was relatively modest. Hence combination therapy of antiplatelet agents was studied. The ESPS-2 trial comparing placebo, aspirin, dipyridamole, or aspirin plus dipyridamole showed either aspirin or dipyridamole alone offered similar degree of risk reduction by 18% and 16% respectively compared to placebo. In the combination group of aspirin plus 400mg per day of extended-release dipyridamole the risk reduction was significantly better at 37%.²⁶ The recently published ESPRIT trial compared aspirin plus dipyridamole (the majority was extended-release format) versus aspirin alone. The risk of the combined endpoints of non-haemorrhagic vascular death, non-fatal myocardial infarction, and non-fatal ischaemic stroke was reduced by 19% in the combination therapy group but the risk reduction of 16% for the secondary endpoint of ischaemic stroke risk was not statistically significant.²⁷ The most common side effect of dipyridamole was headache that can occur in up to 50% of patients. It is usually self-limiting but around 10% of patients in the combination treatment group of the ESPRIT trial withdrew because of headache. Of special note is that no excess in bleeding complications were noted in the combination group.

Aspirin plus clopidogrel

The results of two large trials MATCH and CHARISMA^28,29 published recently, found no significant benefit by using combination of aspirin plus clopidogrel compared to clopidogrel or aspirin alone respectively. Double antiplatelet therapy resulted in significantly more life-threatening bleeding in the MATCH study. It is not clear if certain subtype of stroke (e.g. intracranial large arterial stenosis) would benefit more from double-antiplatelet therapy but in the mean time it should not be used routinely for long-term secondary ischaemic stroke prevention unless there is a clear indication such as post-angioplasty and stenting.

Cilostazol

Cilostazol is another antiplatelet agent that is being investigated. It is a phosphodiesterase III inhibitor and antiplatelet agent with vasodilating effect. It has been shown in a Japanese study to be more effective (relative risk reduction of 41.7%) than placebo in secondary stroke prevention.³⁰ When used together with aspirin in patients with symptomatic middle cerebral artery stenosis it has been shown in one study to slow the progression of intracranial arterial stenosis.³¹ Further study is required to see if that will translate into better clinical outcome by reducing recurrent ischaemic stroke. The side effects profile is similar to that of dipyridamole. Overall the choice of antiplatelet agent depends on patient's tolerability and affordability. Assuming an annual recurrent stroke/TIA risk of 7%, the number of patients needed to be treated (NNT) to avoid one stroke/TIA with aspirin, clopidogrel and aspirin plus dypyridamole were 100, 62 and 53 respectively.³² Based on current evidence, aspirin plus extended-release dipyridamole offers the best risk reduction but at approximately 100 times the cost of standard aspirin alone.

Revascularization of relevant stenotic vessels

Carotid endarterectomy

If significant large-artery stenosis is found relevant to the site of ischaemic stroke, revascularization to restore blood flow to areas of the brain at risk is an important secondary prevention strategy. This is best studied in the case of carotid stenosis. In patients with symptomatic severe carotid stenosis (defined as 70-99% reduction in diameter), carotid endarterectomy (CEA) resulted in more than 60% reduction in ipsilateral ischaemic stroke risk compared to best medical therapy.³³ The benefit of surgery becomes less impressive for patients with moderate stenosis (50-69%). The 5-year risk of ipsilateral ischaemic stroke was 22% in the surgery group versus 15% in the medically treated group. Surgery offers no benefit for patient with less than 50% stenosis. CEA carries significant surgical and anaesthetic risk. The consideration of CEA has to take into account of the patient's general medical condition, co-morbidities, and the track record of one particular centre and the surgeon. It is generally recommended that CEA should only be performed by a surgeon with perioperative morbidity and mortality of less than 6%.¹¹ The surgery is most beneficial if done within 2 weeks of a mild stroke or TIA as the risk of recurrence is at its highest in this period.³⁴ These patients who have undergone CEA still need intensive medical therapy including antiplatelet agent, statin, and hypertensive treatment to reduce recurrent stroke risk. For patients with total occlusion of carotid artery, extracranial-intracranial bypass surgery is no longer recommended as it failed to show any benefit.³⁵

Carotid angioplasty and stenting

Carotid artery balloon angioplasty and stenting (CAS) is another revascularization option, especially for those patients with stenosis that is too caudal for surgical access, co-morbidities that increases the surgical and anaesthetic risk or "hostile" neck with radiation-induced stenosis that is not uncommon in this locality because of the high incidence of nasopharyngeal carcinoma treated with neck radiotherapy. Large, well-standardized, randomized studies comparing CAS and CEA head-to-head are still lacking. There were limited data that showed carotid angioplasty, with or without stenting, was not inferior to CEA.^36,37 The recently published EVA-3S study randomized more than 500 patients with symptomatic carotid stenosis of 60% or more to CAS or CEA, comparing the stroke and death rate at 30 days.³⁸ The study was terminated early because of significantly higher number of perioperative stroke and death in the CAS group (9.6% versus 3.9% in CEA). It has been criticized for the heterogeneity in terms of stenting device used, the lack of double antiplatelet drugs prior to the procedure in 17% of the stenting group, and the learning-curve effect of the operators.³⁹ A current ongoing large scale study with standardized use of stent, training and credential requirement will hopefully address this issue.⁴⁰

Intracranial angioplasty and stenting

Intracranial arterial stenosis is more prevalent among Chinese compared to the Caucasian population. It is found in more than one-third of all ischaemic stroke patients in Hong Kong.⁴¹ They have higher rate of recurrent ischaemic stroke despite antiplatelet therapy,⁴² and anticoagulation offers no additional benefit neither.⁴³ Improvement in catheter and stent-design in recent years have made intracranial angioplasty and stenting technically feasible. Individual case series have shown good technical results, low re-stenotic rate, but generally higher perioperative complication rate than CEA and CAS.^44,45 The efficacy of intracranial angioplasty compared to best medical therapy is not known. Intracranial angioplasty and stenting is considered to be investigational and reserved for patients with haemodynamically significant stenosis with ischaemic symptoms despite maximal medical therapy with antithrombotics, statins and risk-factor modification.¹¹

Conclusion

Stroke is a heterogeneous condition. There are now many effective treatments to lessen the risk of recurrent stroke according to the stroke subtype. A comprehensive assessment of the patients is required to understand stroke mechanism so that the most effective preventive strategies, likely to be a combination of treatment modalities, can be devised to achieve the best possible outcome for each individual patient.

Key messages

1. Stroke survivors are at higher risk of another stroke. Tailor-made strategies based on underlying stroke mechanisms are able to reduce this risk.
2. Secondary prevention of ischaemic stroke includes 4 modalities: (1) modification of vascular risk factors; (2) anticoagulation for cardioembolic stroke; (3) antiplatelet therapy; and (4) revascularization of stenosed symptomatic vessels.
3. Control of BP, hyperlipidemia and lifestyle modification (e.g. smoking cessation) are all important in reducing ischaemic stroke.
4. Cautious anticoagulation (INR 2-3) in elderly patients with chronic or paroxysmal AF is highly effective in preventing cardio-embolic stroke.
5. Aspirin, clopidogrel, aspirin plus dypyridamole and cilostazol are all effective in stroke prevention in non-cardioembolic ischaemic stroke.
6. Carotid endarterctomy is indicated in symptomatic severe carotid artery stenosis (70-99% diameter reduction) provided that patient is medically fit and perioperative morbidity and mortality is less than 6%.
7. Carotid and intracranial large artery angioplasty and stenting, although technically feasible, its efficacy and safety relative to that of standard therapy are still under investigation.