American Heart Association Prevention Conference IV: Prevention and Rehabilitation of Stroke

Ischemic Stroke Mechanism

Embolism to the brain. Embolism to the brain may be arterial or cardiac in origin. Commonly recognized cardiac sources include atrial fibrillation (AF), sinoatrial disorder, recent acute myocardial infarction (AMI), marantic or subacute bacterial endocarditis, cardiac tumors, and valvular disorders, both native and artificial.

Myocardial infarction. Stroke is an important complication in patients with AMI, occurring in 1% to 3% of all infarctions and in 2% to 6% of patients with anterior wall infarctions.

Atrial fibrillation. Pooling of blood in the dysfunctional atrium leads to clots and emboli. AF increases risk of thromboembolism up to 18 times. Risk of stroke in patients with AF can be reduced by up to 70% using oral anticoagulant therapy. Compared with placebo, aspirin reduces risk by 20% to 30%.

Valvular disease. Rheumatic mitral stenosis is the most common valve disorder associated with thromboembolism.

Mitral valve prolapse. Patients with mitral valve prolapse (MVP) who have suffered ischemic brain events should be given prophylactic anticoagulant medication. If they are asymptomatic, MVP patients do not need medication; if they have stroke symptoms, they should receive anticoagulation therapy.

Prosthetic heart valves. Tissue prosthetic valves are believed to be associated with a smaller risk of thromboembolism than mechanical valves.

Repaired cardiac valves. Surgical repair of the mitral valve for mitral insufficiency is lasting and has lower morbidity and mortality and a lower incidence of thromboembolism than valvular replacement. Percutaneous balloon mitral valvuloplasty is associated with significant risk of embolization.

Embolism of aortic arch origin. A causal link between brain infarcts and complicated plaques with highly mobile thrombi in the lumen of the aortic arch is likely. Plaques without mobile components might merely be markers for diffuse atherosclerosis.

Patent foramen ovale. The diagnosis of patent foramen ovale may be suspected in any stroke patient. When the patent foramen ovale is large, surgical closure may be an option.

Cerebral ischemia due to perfusion failure and arterial source for embolism. Stroke due to perfusion failure occurs with severe stenosis of the carotid and basilar artery and when there is microstenosis of the small deep arteries.

Large artery atherosclerotic plaque. Factors that lead these lesions to become symptomatic are not well understood, but stenoses >70% are linearly associated with increased risk of distal brain infarct.

Vasculitis. Inflammatory conditions can involve the cerebral vasculature. Their causes are poorly understood, and the bedside diagnosis is problematic for lack of an accurate noninvasive test and the relatively nonspecific nature of clinical manifestations.

Surgical management of large artery occlusive disease. The North American Symptomatic Carotid Endartectomy Trial (NASCET) demonstrated the benefit of surgery for patients with recent stroke or TIA with extracranial internal carotid artery stenosis ranging from 70% to 99%. The beneficial results in stroke prevention were largely dependent on the skill of the surgeons, who attained an acceptably low rate (5.8%) of perioperative stroke and death. In a European study, medical therapy was clearly superior to surgery at <30% stenosis. Results are awaited for the moderate phase of NASCET, for stenosis ranging from 30% to 69%.

The Asymptomatic Carotid Atherosclerosis Study (ACAS) demonstrated a benefit for surgery for stenosis >60% with low rates of perioperative complications. However, this conclusion is not universally accepted by the stroke community. Some believe the rate of surgical and angiographic complications do not warrant the 1% annual reduction in absolute risk of stroke.

Small artery occlusion. Small, deep cavitary (lacunar) infarcts are mainly due to small arterial occlusions, a fundamental principle in the pathogenesis of small deep infarcts.

Intrinsic small artery disease. Microatheroma may be the most frequent pathology underlying symptomatic lacunar infarcts.

Other causes of small vessel occlusion. Potential causes are (1) cardiogenic embolism; (2) rheumatic heart disease; (3) artery-to-artery embolism; (4) complications of aortic arch plaque; and (5) carotid stenosis and asymptomatic small deep infarcts.

Prothrombotic states. Primary prothrombotic states include abnormalities of certain hemostatic regulatory proteins, including the antithrombins, heparin cofactor II, proteins C and S, and fibrinolytic system derangements. Definitive studies of hemostatic disorders of large populations of subjects with stroke are lacking.

Recommendations

• Patients with MI who are at high risk for systemic embolization should receive oral anticoagulation at a target international normalized ratio (INR) range of 2.5 to 3.5 for 6 months or more.

• Patients with cardiac valvular disorders, prosthetic heart valves, and repaired valves have a variable risk of stroke. Their need for antiplatelet or anticoagulant therapy should be evaluated.

• In the absence of a mobile thrombus, the presence of aortic arch plaque >4 mm should be viewed as a marker of high risk of recurrent stroke, MI, peripheral embolism, and vascular death. The natural history of mobile aortic arch plaques, development of new noninvasive techniques to define plaque composition, and initiation of therapeutic trials may be topics for research in the future.

• When faced with lacunar infarction or syndrome, the possibility of underlying large-vessel, especially intracranial, cardiac source embolism and hypercoagulable state should be considered, as should small-vessel disease.

• Carotid endarterectomy is beneficial for patients with recent cerebral ischemia and ipsilateral carotid artery stenosis of 70% to 99%. It is not beneficial for patients with 0% to 29% stenosis, and it is still uncertain if it is beneficial for those with 30% to 69% stenosis.

• Much work is needed to define the spectrum and role of hypercoagulable states, including that of antiphospholipid antibodies, in stroke.

• The etiology (hemorrhage, ischemia versus non–stroke-related potential causes) of transient cerebral symptoms should be diagnosed in every patient who experiences them. For those for whom the cause is likely to be ischemic and who do not require warfarin, the best dose of aspirin for stroke prophylaxis is debated. Ticlopidine is more effective than aspirin, but the cost and risk of adverse effects are higher.

Public Health Burden of Stroke

The distribution of the burden of stroke morbidity and mortality is heterogeneous in the US population and is changing dramatically with time. Stroke mortality remains the third leading cause of death in the United States, accounting for 1 in every 15 deaths during 1992. Despite this burden, US stroke mortality rates are among the lowest in the world. The estimated US stroke mortality rate for women was 36.7 per 100 000; for men it was 46.6 per 100 000. There has been a striking 60% decline in US stroke mortality between 1960 and 1990. Despite this decline, nearly 150 000 Americans died of a stroke during 1995, which corresponds to 1 death every 3.5 minutes.

• The burden of stroke is heterogeneous and is greater among the elderly, men, and African-Americans. In the southeastern United States, stroke risk is approximately 1.4 times that of other regions.

• Stroke incidence rates have been level since the mid 1980s, but the decline in stroke mortality has continued at least through 1992.

• Besides mortality, morbidity in 3 890 000 surviving stroke victims is also substantial, making stroke the leading cause of serious disability in the United States. Among long-term (>6 months) stroke survivors, 48% have hemiparesis, 22% cannot walk, 24% to 53% report complete or partial dependence on activity of daily living (ADL) scales, 12% to 18% are aphasic, and 32% are clinically depressed.

• Although stroke incidence appears stable and stroke mortality is slowly declining, the absolute magnitude of stroke is likely to grow over the next 30 years. With the aging of the population and an increased proportion of African-Americans, the number of stroke victims is likely to increase substantially.

Risk Factors for Ischemic Stroke

Multiple Risk Factors

The realization that the probability of stroke is increased severalfold by the presence of multiple risk factors may help both patient and physician to more fully appreciate the need for serious risk factor management.

Intracerebral and subarachnoid hemorrhage. Subarachnoid (SAH) and intracerebral hemorrhage (ICH), which account for only 15% to 25% of total strokes, result in significant morbidity, mortality, and cost. Aneurysms and arteriovenous malformations are the most commonly identified causes of SAH, while hypertensive arteriolar disease, amyloid deposition, intrainfarct hemorrhage, and arteriovenous malformations are the bases of most ICHs. ICH is twice as common as SAH in studies with CT documentation.

Recommendations

New and Emerging Treatments for Acute Ischemic Stroke

The acute care of patients with stroke aims to control and prevent medical and neurological complications as well as reverse the neurological effects of the stroke itself. The most important advance is the hyperacute administration of r-TPA. A review of thrombolytic drugs and updated guidelines for their use has recently been prepared.

Recent trials of intravenous thrombolysis. The results of five recent clinical trials of intravenous thrombolytic therapy for acute ischemic stroke are conflicting. The National Institute of Neurological Disorders and Stroke (NINDS) study showed that intravenous r-TPA significantly improved stroke outcomes at 3 months in carefully selected patients when administered within 3 hours of onset, following protocol requirements.

Recent studies of intra-arterial thrombolysis. Available evidence suggests that recanalization after intra-arterial delivery is in the range of 60% to 70%, which is superior to the rate for intravenous delivery, which is 30% to 40%. Although these data encourage further testing of intra-arterial thrombolysis, the procedure should still be considered investigational.

Antithrombotic and antiplatelet aggregating drugs. Conclusive data are lacking about the ability of heparin to prevent early recurrent embolism among persons with presumed cardioembolic stroke. Low-molecular-weight heparins and heparinoids have selective antithrombotic actions that may improve safety and reduce the risk of severe symptomatic autoimmune thrombocytopenia. The immediate effects of 325 mg of aspirin on platelet aggregation suggest its usefulness in acute stroke as it has been shown to be in treating acute myocardial ischemia. Drugs such as anti-ICAM-1, which produces effects at the microvasculature level, are being tested.

Neuroprotective drugs. There is no convincing evidence that any current neuroprotective drug is effective in either reducing size of infarction or improving overall outcome.

Calcium entry antagonists. A meta-analysis of nimodipine trials suggests a potential benefit if the drug is given within 12 hours of stroke onset. Additional studies of nimodipine given within 6 hours of onset are under way.

Glutamate antagonists. A major problem with the use of NMDA receptor antagonists in humans is the high rate of neuropsychiatric and hypotensive side effects.

Sodium channel antagonists and glycine antagonists. Inhibition of presynaptic glutamate release by antagonists of presynaptic sodium channels may be useful in stroke.

Opioid antagonists. Nalmafene, an exomethylene derivative of naltrexone, has been tested for safety in patients with acute stroke; a small placebo-controlled, dose-ranging study is nearing completion.

Antioxidants/free radical scavengers. Trials in Europe and North America were halted prematurely after interim analyses suggested a lack of efficacy. Further studies are testing higher doses.

Angioplasty and stenting. Percutaneous transluminal angioplasty and intravascular stenting of the supra-aortic vessels are being examined for safety, feasibility, and long-term durability as an alternative to carotid endarterectomy and other revascularization procedures of the extracranial cerebral vessels.

Intracranial angioplasty. While angioplasty is technically feasible, procedure-related stroke and death rates have been substantially higher in patients having percutaneous transluminal angioplasty of intracranial vessels than for those undergoing extracranial procedures.

Neither angioplasty nor stenting of the extracranial or intracranial vasculature has been evaluated in clinical trials. Their use is considered investigational.

Healthcare system issues of dissemination and implementation of information. State-of-the-art acute stroke care delivery systems are relatively primitive compared with emergency trauma or cardiac care.

Patient factors. The same factors that lead patients to delay seeking medical assistance for AMI also cause them to delay seeking medical help for stroke. Attempts to influence such behavior have had limited success.

Medical System Factors

Prehospital care. Aggressive stroke protocols and educational programs keyed to emergency medical services can markedly reduce the time from stroke onset to initiation of treatment.

Hospital care. It is expedient to treat patients with intravenous thrombolytic agents in the emergency department (ED) before admission to the hospital.

Administrative and triage issues. With high-risk therapies such as thrombolysis, many patients with acute stroke must be treated in an intensive-care setting. The optimal structure and cost-effectiveness of such stroke units have not been well studied.

Diagnostic issues. Early signs of infarction and other CT diagnoses (eg, hemorrhagic infarction versus parenchymal hematoma) are easily missed, even by experienced investigators. Tele-medicine links could provide services for interpreting neuroimaging studies in outlying EDs.

Physician issues. The emergency physician can make the decision to administer thrombolytic therapy, but special training should be required for ED personnel, along with standardization of treatment and diagnostic protocols in conjunction with neurologists. Neurologists and radiologists must also be available to the ED.

Drug administration issues. Stocking the thrombolytic drug in the ED instead of a central pharmacy significantly decreases delay to therapy.

Acute stroke trials with rapidly changing available therapies. Past stroke trials recruited patients for comparison of a therapeutic agent with placebo. A potential therapy must be compared with the best available therapy as defined by recent clinical trials.

Multiple competing studies. An attempt should be made to allow concurrent patient enrollment in multiple studies with a low likelihood of interfering with the primary outcome measure.

Single site with multiple concurrent overlapping studies. Investigators should look for complementary protocols so that most acute stroke patients arriving at their centers will be eligible for some study.

Outcome measures. Functional scales (eg, Barthel and Modified Rankin Scale) are essential for establishing a meaningful benefit to stroke patients and for procuring Food and Drug Administration approval of a new agent.

Evolution of monotherapy to multiple concurrent or sequential therapies. Therapies targeted at only one facet of the complicated process of stroke are likely to be of only limited benefit.

Healthcare system problems and reimbursement issues. In some countries there is a strong tendency to charge all medical costs for treating a patient in a prospective clinical trial to the trial sponsor, even costs that are considered standard treatment and care. If this practice continues, the cost of performing any prospective trial will be prohibitive.

Recommendations

Scientific Basis for Stroke Rehabilitation

Rehabilitation is effective. At present, however, we cannot easily differentiate between the influence of specific interventions and the natural recovery process. The state of the science in stroke rehabilitation was summarized in the 1995 AHCPR Post-Stroke Rehabilitation Practice Guideline.

Current Issues in Stroke Rehabilitation

Access to and cost-effectiveness of rehabilitation. The effective delivery of post-stroke rehabilitation requires development of an integrated care system that spans acute care, acute rehabilitation, subacute rehabilitation, outpatient services, home care, and community support services.

Recommendations

The rehabilitation panel prepared the following recommendations for clinical practice, public policy, education, and research activities.