Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 50, Num. s1, 2002, pp. S70-S77

Neurology India, Vol. 50, (Suppl. 1), Dec, 2002, pp. S70-S77

Pharmacotherapy for Secondary Prevention of Stroke

J. Mani, S. Sitajayalakshmi, R. Borgohain, S. Mohandas, M.V.R. Reddy

Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, India.
Correspondence to : Dr. J. Mani, Department of Neurology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad - 500 082, India.

Code Number: ni02166

Summary

Stroke is a leading cause of mortality worldwide. It has well modifiable risk factors, which makes prevention an effective strategy. Antithrombotics and anticoagulants have been the main pharmacological options in secondary prevention. A number of new antiplatelet drugs have been introduced over the past decade. The more recent concepts in the understanding of stroke and atherosclerosis have paved the way for a number of newer pharmacological interventions like angiotensin enzyme inhibitors, statins and vitamins. The pharmacological armamentarium to treat stroke is expanding.

Key words : Stroke prevention, Pharmacotherapy.

Introduction

Stroke is the second leading cause of mortality worldwide.¹ About 2/3 or more of the deaths due to stroke occur in the developing world.² Stroke is well suited for prevention since it has a high prevalence and well modifiable risk factors.³ Atherosclerosis and atherothrombosis are the main processes that precipitate strokes, coronary artery disease and peripheral arterial disease.^4,5 Thrombosis by convention refers to thrombus formation in an already partially occluded vessel. The underlying occlusive process is usually atherosclerosis. When a sub-intimal atherosclerotic plaque ruptures, it damages the intima and exposes the subendothelial matrix and collagen.⁶ The contact of the blood products especially platelets to the subendothelial collagen underlying the plaque triggers parallel activation of platelets and blood coagulation. This in turn, leads to platelet aggregation and fibrin deposition resulting in thrombus formation. The physiologic goal of secondary prevention is the long-term inhibition of thrombus formation. It can be accomplished, by inhibition of platelet aggregation and by anticoagulation. Hence antithrombotic drugs have been the most widely used drugs in the prevention of stroke. The realization that atherosclerosis is an inflammatory process has led to new stroke risk factors and treatments.⁴

Role of platelets in thrombogenesis

Platelets have assumed a central role in the development of focal cerebral ischemia by virtue of their participation in the formation of thromboemboli that initiate stroke symptoms. When the vascular endothelium is damaged, platelet activation occurs at the injury site. Activated platelets start a cascade of platelet-mediated events which results in the formation of a platelet rich thrombus at the site of the injury. The platelet plug provides scaffolding for coagulation activation. The formation of the platelet thrombus happens through three stages of platelet adhesion, activation, and aggregation.⁷

Platelet adhesion : Circulating platelets encounter components of the exposed vascular subendothelium like collagen and von Willebrand factor, in an area of vascular injury. The surface integrin and glycoprotein (GP) receptors mediate the adhesion of platelets to the collagen to form a platelet monolayer.

Platelet activation : The adhered platelets interact with the various subendothelial matrix proteins and become activated. Platelet activation is stimulated by a number of activators like epinephrine, ADP thromboxane A2 and Thrombin. Platelet activation is associated with a number of events that includes change in the shape of the platelet (Pseudopod formation), change in the conformation of the integrin surface receptor GP IIb IIIa, degranulation of the platelets with release of vasoactive amines and expression of receptors for coagulation factors like Va and Xa. The degranulation of platelets releases ADP which in turn activates more platelets. All these events also set the stage for the next and final step in platelet thrombus formation i.e. platelet aggregation.

Platelet aggregation : Integrin receptors GP IIb IIIa are in abundance over the surface of the platelet (80,000 per platelet). Platelet activation causes a conformational change in the structure of these receptors. Circulating fibrinogen molecules crosslink neighbouring platelets via the activated integrin receptors resulting in platelet aggregation.

Antiplatelet drugs

Acetyl Salicylic Acid (Aspirin)

Platelets can be activated by different agonists that are released at the site of thrombosis. These include ADP, thrombin and thromboxane A2. Acetylsalicylic acid (aspirin) inhibits the formation of thromboxane A2 from its precursor arachidonic acid by blocking the cyclo-oxygenase COX 1 enzyme. In low concentrations agonists like ADP and thrombin require the presence of thromboxane A2 to exert their effects on platelets. As aspirin inhibits the formation of thromboxane A2 from platelets, it prevents the activity of a range of agonists, giving it a broad spectrum of activity. Aspirin is the most widely used antiplatelet agent for management of thrombotic vascular events.

Role of Aspirin in secondary prevention of stroke : More than 10 randomised clinical trials have compared aspirin and placebo for stroke prevention. Only 3 of these trials ^8-10 were large enough to have the power to answer the question of the efficacy of aspirin in secondary stroke prevention. In summary aspirin reduced the relative risk of the combined end point of stroke, myocardial infarction (MI) and death from vascular causes by 13%. Meta analyses indicate an overall 22% reduction in nonfatal stroke and a 25% reduction on the constellation of nonfatal stroke, MI or vascular death.¹¹ The appropriate dose of aspirin for secondary prevention of transient ischemic attack (TIA) or stroke has been hotly debated for many years. Americans favour high doses (over 900 mg),^12,13 whereas most Europeans use lower doses.¹⁴ In a meta- analysis by Algra et al^15,16 there was no correlation between the dose of aspirin and risk reduction of ischemic stroke. The American food and drug administration recently ruled that the recommended daily dose of aspirin for secondary prevention of stroke is 50 to 325 mg.¹⁷ The efficacy of aspirin, as an antiplatelet agent for stroke prevention in atrial fibrillation (AF) is not clear. Aspirin was significantly less effective than anticoagulation in two of the three clinical trials. It has some degree of efficacy in preventing AF associated stroke but is less effective than anticoagulation. Pending further clinical studies, low risk AF, (age<75 years) may be treated with 325mg/day of aspirin to prevent stroke.¹⁸

Risks of aspirin : he major risk of aspirin therapy is bleeding. The risk of bleeding is not found to be dose dependent. In the Dutch TIA trial,¹⁹ the incidence of major bleeding complications was 3.4% v/s 2.6% in the high and low dose groups respectively, which was not significant. A comparison of the various large aspirin trials, using different doses, showed no significant difference in the bleeding complications. However, there is a relationship between the aspirin dose and gastrointestinal (GI) side effects. In the UK TIA trial the incidence of upper GI symptoms were 41.5% in the 1200mg group, 31.4% in the 300mg aspirin group and 25.7% in the placebo group.⁸ A similar trend was also noted in other trials.

Aspirin and gender : Contrary to the earlier reports, recent trials have established that aspirin is beneficial for preventing stroke in both men and women^11,20,21

Aspirin and stroke subtype : Since lacunar infarcts occur by the process of lipohyalinosis, it is reasonable to ask about the efficacy of aspirin in preventing these. The efficacy of aspirin in preventing lacunar infarcts has not been extensively assessed but there is a suggestion from a few clinical studies that aspirin may be beneficial in this stroke subtype. In the Ticlopidine Aspirin Stroke Study only 8% of recurrent strokes in aspirin treated patients were lacunar.²² In the randomized AICLA trial,²³ subgroup analysis showed a 10% incidence of recurrent strokes in patients with lacunar infarcts on aspirin compared to 26% with placebo (62% risk reduction). Aspirin was more effective in preventing non cardioembolic strokes than strokes presumed to be cardioembolic in patients with atrial fibrillation.²¹ Hence there is increasing evidence that the efficacy of aspirin may vary with the etiologic subtype of stroke.

Summarising, aspirin leads to a moderate but significant reduction in the incidence of recurrent stroke, MI and death from vascular causes in the patients with TIA and ischemic stroke. There is no gender bias in the effects but there may be some variation according to stroke subtype. The efficacy and the major bleeding complications are not dose dependent, but the gastrointestintal symptoms may be dose related.

Ticlopidine

The need for better drugs for prevention of ischemic events led to the discovery of Ticlopidine. Both, Ticlopidine and Clopidogrel are ADP antagonists. This class of drugs prevents the activation of GP IIb/IIIa receptor byADP, in turn decreasing fibrinogen binding during platelet aggregation.²⁴ The Canadian American Ticlopidine Study has shown ticlopidine to be superior to placebo for preventing recurrent stroke, MI and death, and in particular in reducing the incidence of stroke by 33.5%.²⁵A randomized clinical trial comparing ticlopidine and aspirin in patients with TIA or minor stroke the event rates diverged favoring ticlopidine in the first year, but at the end of 3 years the difference was no longer statistically significant. The overall incidence of adverse events with ticlopidine was 62.3% versus 53.2% for aspirin. The commonest side effect with ticlopidine was diarrhea, reported in 20% of patients. Severe neutropenia occurred with ticlopidine in 0.9% of patients.²⁵ More recently several cases of thrombotic thrombocytopenic purpura have been reported in patients on ticlopidine.^26,27

Ticlopidine is effective in secondary prevention of stroke. It is superior to aspirin for certain endpoints. Due to its unfavorable side effect profile its use is reserved for patients who cannot tolerate other antiplatelet drugs.

Clopidogrel

This agent is chemically related to ticlopidine. It acts by selectively and irreversibly inhibiting the binding of ADP to its platelet receptor P2Y1. This in turn affects the ADP dependent activation of the GpIIb-IIIa complex, which is the major receptor for available fibrinogen. The final effect is to inhibit ADP induced platelet aggregation. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study²⁸ compared the efficacy and safety of clopidogrel versus aspirin in preventing a variety of vascular end points following stroke and found a significant relative risk reduction (p=0.043) of 8.7% in favor of clopidogrel versus aspirin. In a subgroup analysis the maximum benefit was observed in the subgroup of peripheral vascular disease rather than MI or stroke. The safety profile of aspirin and clopidogrel were similar. Neutropenia occurred only in 0.1% of clopidogrel treated patients. However in the CAPRIE trial the frequency of severe rash was higher in the clopidogrel compared to the aspirin group.

Hence, Clopidogrel is a second-line treatment in patients intolerant to aspirin and first line treatment for patients with stroke and peripheral vascular disease.

Dipyridamole

Dipyridamole inhibits cyclic nucleotide phosphodiesterase resulting in elevated levels of cAMP and cGMP that block Ca⁺² mediated platelet activation. It also stimulates vascular prostacyclin synthesis and blocks the uptake of vasodilator adenosine by the vascular endothelium.²⁹ Early clinical trials comparing acetylsalicylic acid with the ASA + dipyridamole combination showed no additional benefits of the combination over those for ASA alone.^15,16 However these studies comprised relatively small patient numbers, limiting their statistical power. Even the meta analyses of these studies by Tijssen did not show the differences to be satisfactory in view of the wide 95% confidence intervals.³⁰ The more recently completed ESPS-2 trial is a large trial, which randomised 6602 patients of stroke or TIA to Placebo or Aspirin +Dipyridamole or Dipyridamole (250 mg bd extended release) or Aspirin (25mg bd) alone. The trial confirmed the additive effects of Aspirin and Dipyridamole with a risk reduction of 37% for the combination, 18% for aspirin and 16% for dipyridamole compared to placebo. The combination of aspirin and dipyridamole is thus superior to aspirin alone. Headache was the commonest cause for discontinuation in the dipyridamole and in the combination group.¹⁰

Aspirin Failure : A frequent problem encountered in practice is, when a patient who is already on aspirin for coronary artery disease or previous cerebral ischemic event suffers a first or recurrent TIA or stroke. No clinical trial has addressed this issue as yet. Possible strategies are to continue aspirin, add dipyridamole to the therapeutic regimen or switch to ticlopidine or clopidogrel or to anticoagulation with an INR of 2.0 to3.0. Ticlopidine is superior to aspirin for certain end points, but has already been replaced by clopidogrel in view of the better safety profile of the latter.

Current recommendations for use of antiplatelet drugs stroke prevention after atherothrombotic stroke or TIA

According to The American College of Chest Physicians (ACCP), antiplatelet drugs form the mainstay of pharmacological prevention of atherothrombotic stroke or TIA.^29,31 On the basis of the results from various trials the ACCP recommends the use of an antiplatelet drug in this setting provided there are no contraindications (Grade A level I). Any of the four agents are acceptable as first line therapy (Grade A level I). The choice of antiplatelet drugs would be based on direct trials comparing efficacy and safety. As aspirin is the longest and most widely used drug, the newer drugs have been compared with it in different trials. However these comparisons are indirect and there were differences in study design and patient profile. Hence it may not be appropriate to draw conclusions on their comparative efficacy. In the current ACCP guidelines aspirin is recommended in the daily dose of 50-325 mg /day as the least expensive initial therapy unless the patient is allergic to aspirin. Clopidogrel is recommended over ticlopidine because of its more favorable side effect profile.³¹ The combination of Aspirin plus extended release Dipyridamole may be the drug for the near future because it is more effective than clopidogrel and has a similarly favorable side effect profile.

The Future of antiplatelet therapy

Other inhibitors of platelet function are also being explored in acute ischemic stroke. Thrombin inhibitors eg hirudin, blockers of platelet integrin receptors and of platelet collagen binding are potential therapeutic agents. All these drugs have considerable differences in their risk profiles and therefore need appropriate animal studies before trials in human subjects. All anti-thrombotic agents carry the potential risk for inducing symptomatic intracerebral hemorrhage in ischemic stroke. The future of antiplatelet agents in the acute setting will be determined by the agents with increased benefit to risk ratios.

Anticoagulants

Warfarin is a highly protein bound inhibitor of Vitamin K that is necessary for biosynthesis of coagulation factors II, VII, IX, X, protein C and S. Warfarin therefore inhibits the intrinsic and the extrinsic coagulation cascade. Various trials demonstrate the effectiveness of warfarin in the prevention of stroke due to different etiologies. The dose and duration of anticoagulation varies with the etiology. The specific indication for the use of anticoagulants is atrial fibrillation. All major trials have demonstrated a dramatic benefit of anticoagulation over aspirin in nonvalvular AF (>50% risk reduction compared to aspirin) with minimal risks of hemorrhage.^32-36 A recent study failed to demonstrate the superiority of warfarin over aspirin for non cardioembolic stroke.³⁷ The current ACCP guidelines recommend the use of warfarin (INR between 2-3) in preference to aspirin for all patients with atrial fibrillation and previous stroke (Level A1). There have been no controlled trials for the use of warfarin in other cardiac lesions and the evidence is anecdotal and based on the thrombogenic nature of these diseases. These conditions include sick sinus syndrome, dilated cardiomyopathy with ejection fraction less than 25%, rheumatic valve disease with or without AF, akinetic cardiac segments, left ventricular thrombus after MI and prosthetic valves (Level C1).³⁸A preliminary retrospective study on the role of warfarin in the prevention of strokes in patients with significant intracranial stenosis showed beneficial results with warfarin.³⁹ Larger prospective trials are under way to address the role of anticoagulation in intracranial artery stenosis.

Stroke prevention : beyond antithrombotics

Destabilization of the atherosclerotic plaque is the forerunner of ischemic stroke and myocardial infarction. The vulnerable atherosclerotic plaque has become the main focus for new directions in the prevention and treatment of stroke and coronary artery atherosclerosis. Medical therapy beyond traditional antithrombotic agents, for plaque stabilization promises to reduce the risk of thrombosis associated with ahterosclerosis. These include statins, angiotensin converting enzyme inhibitors and vitamins.

Statins

The link between serum cholesterol level and stroke has never been fully established. Meta analyses of all cholesterol lowering trials before the statin era failed to demonstrate a significant reduction in stroke.⁴⁰ However the new data on the reduction of the incidence of stroke in three statin trials and in one fibrate trial conducted in patients with MI argue for the repappraisal of the link between cholesterol and stroke risk.^41-43

3 hydroxy-3 methylglutaryl coenzyme A (3 HMGCoA) reductase inhibitors are generically classified as 'statins'. These drugs are similar to HMGCoA, the precursor of cholesterol and competitively inhibit HMG-CoA reductase, the last regulated reaction in the synthesis of cholesterol. These drugs act by upregulating LDL receptor activity and preventing the entry of LDL into the circulation. The statins are divided to natural (lovastatin, pravastatin and simvastatin) and synthetic statins (atorvastatin, cerivastatin and fluvastatin).⁴⁵ They differ in their potency and their lipophilicity. Apart from their lipid lowering effects statins may attenuate inflammatory responses associated with cerebral ischemia and possess anti oxidant properties that ameliorate oxidative stress in the brain. The precise mechanism of the beneficial effect of statins remains controversial and may include a combination of lipid lowering and pleiotropic effects. A meta analyses of the statin trials shows that stroke risk is reduced by statin agents, especially for non fatal stroke. The apparent lack of association between cholesterol and stroke in earlier studies could be due to methodological issues.^46,47 These results have led the US FDA to approve pravastatin and simvastatin for stroke prevention in patients with coronary artery disease.³ It is not clear however, whether the reduction in stroke risk is due to the secondary effect of reduction in coronary artery disease and subsequent cardioembolic stroke or some other mechanism. In the stroke subtype analysis of the LIPID trial, it was worth noting that the risk reduction was greater in the cardioembolic group and the group with lipohyalinotic arteriopathy than in the atherothrombotic group.⁴³ Statins are generally well tolerated.⁴⁸ Common adverse events include gastrointestinal upsets, muscle aches and hepatitis. Rare problems include myopathy, rash, peripheral neuropathy and insomnia. In summary the current recommendations for patients with a stroke and a previous MI is to add simvastatin or pravastatin even when serum cholesterol level is in the 'normal range'. Patients with low HDL and LDL may be considered for gemfibrozil therapy. For the remaining patients with ischemic stroke without IHD (80% of all strokes) the approach is less clear. Many randomized controlled trials are underway. The recommendations of the of the Third Report of the National Cholesterol Education Program (CEP) Expert Panel on the Detection Evaluation and Treatment of High Blood Cholesterol in Adults may be followed.⁴⁹

Angiotensin converting enzyme inhibitors

Hypertension may predispose to stroke by potentiating atherosclerosis of the aorta and the large cerebral arteries, causing lipohyalinosis and arteriosclerosis of the small penetrating arteries, and promoting heart disease.⁵⁰ The Renin Angiotensin System (RAS) has been implicated in hypertension as well as in a number of genetic, humoral and cellular mechanisms that may be involved in atherogenesis or related phenomena in hypertensives. The RAS is involved in vascular remodeling modulation of left ventricular hypertrophy generation of oxidative stress. It is also involved in the inflammation as a part of the atherosclerotic process by effects on adhesion molecules, growth factors and chemoattractant molecules that modulate inflammation in the subendothelial compartment.⁵¹ The ACE I/D genotype has been associated with ischemic stroke in hypertensives and the D/D genotype with lacunar stroke. LowACE levels and the D allele are associated with increased risk for early death from acute cerebral infarction.⁵²

The ACE inhibitors were first introduced in the 1970s for treatment of hypertension. These agents block the conversion of Angiotensin I to II by inhibiting the Angiotensin converting enzyme. Angiotensin II is a potent vasoconstrictor and has a negative influence on renin secretion. The ACE inhibitors are particularly effective in patients with high renin hypertension. ACE inhibitors have been shown to increase vascular compliance⁵³ with normalization of the resistance artery structure.

The Heart Outcomes and Prevention Evaluation (HOPE) study evaluated the effects of ACE inhibitor ramipril and vitamin E in patients with vascular disease or diabetes mellitus and one another cardiovascular risk factor in the absence of heart failure on the incidence of myocardial infarction stroke or death from cardiovascular cause over 5 years. There was a significant reduction in the primary composite end point though the change in the blood pressure was marginal. This suggested a beneficial effect of the ACE inhibitor independent of its antihypertensive or anti-failure effect. There was predominant benefit in the prevention of recurrent MI and first stroke in subgroup analysis.⁵⁴ In the Perindopril Protection against Recurrent Stroke (PROGRESS) trial patients with first stroke were randomized to placebo or a combination of perindopril (ACE inhibitor) and indapamide (diuretic). Patients with any stroke other than subarachnoid hemorrhage were eligible; irrespective of their hypertensive status.⁵⁵ There was a significant reduction in the incidence of the primary outcome of total recurrent stroke, irrespective of age gender diabetic or hypertensive status. The most impressive benefits were seen among Asians and those on combination therapy.

The findings of the PROGRESS and HOPE study complement each other in the incidence of recurrent stroke and first stroke respectively. They emphasise the role of ACE inhibitors in the prevention of stroke beyond the antihypertensive effect. In both the studies, non-hypertensives benefited from the ACE-I therapy.

Vitamins

Homocysteine is a sulfur containing amino acid, which is converted to cysteine or methionine by vitamin B6 or B12 dependent enzymes respectively. Accordingly deficiencies in these vitamins can lead to high levels of homocysteine. High levels of homocysteine have been associated with cardiovascular disease and stroke. The mechanisms proposed is predominantly related to interference in endothelial function and a thrombotic tendency related to coagulation factors and platelet dysfunction.⁵⁶ The evidence for the association between high homocysteine levels and stroke are based on a few epidemiological studies,^57,58 but have not been demonstrated in prospective studies.^59-61 Well designed randomized studies are required to determine whether reduction of homocysteine levels with vitamin therapy is of clinical benefit.

Summary

Secondary preventive measures have been the mainstay of stroke management. Apart from modifying risk factors a number of pharmacological tools are now available which mainly interrupt the process of thrombosis. Recent concepts in the understanding of atherosclerosis have widened the spectrum of pharmacological interventions to include not only newer anti thrombotic drugs but also statins, ACE inhibitors and vitamins. Promoting awareness of stroke risk factors and a wide spread use of available medical strategies are the need of the hour if we are serious in our mission to bridge the stroke prevention gap in the developing world.

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