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
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.
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.
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 al15,16 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, (age50% 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.
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.
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.
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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