Secondary stroke prevention

Jorge Moncayo-Gaete MD (Dr. Moncayo-Gaete of the International University of Ecuador has no relevant financial relationships to disclose.)
Julien Bogousslavsky MD (Dr. Bogousslavsky of the Swiss Medical Network has no relevant financial relationships to disclose.)
Steven R Levine MD, editor. (Dr. Levine of the SUNY Health Science Center at Brooklyn has received honorariums from Genentech for service on a scientific advisory committee and a research grant from Genentech as a principal investigator.)
Originally released March 14, 2012; last updated June 14, 2016; expires June 14, 2019


Worldwide stroke epidemiology is changing. Over the period from 1990 to 2013, a significant global increase in the absolute number of ischemic and hemorrhagic stroke events and deaths occurred (Feigin et al 2015). According to the Global Burden of Disease Study 2013, stroke is the second leading cause of death and the leading cause of long-term disability worldwide, as well as the fifth-ranked cause of death in the United States (Feigin et al 2015; Writing Group Members et al 2016). There are approximately 800,000 strokes per year in the United States, 23% of them recurrent. Moreover, nearly one fifth of ischemic strokes are preceded by a transient ischemic attack. Most recurrent strokes are of the same subtype as the index event, and 1-year stroke recurrence rates are higher for infarcts due to large artery disease than for other ischemic stroke subtypes (Writing Group Members et al 2016). Prevention of stroke and transient ischemic attack includes both conventional approaches to vascular risk factor management (blood pressure lowering, cholesterol reduction with statins, smoking cessation, and antiplatelet therapy) and more specific interventions, such as carotid revascularization or anticoagulation for atrial fibrillation. In this article, the authors discuss effective interventions for optimal secondary stroke prevention.

Antithrombotic therapy for prevention of stroke.

Antiplatelet agents. Because it was known to cause bleeding, aspirin was first suggested as an antithrombotic drug in 1953 by Lawrence Craven, a general practitioner working in Glendale, a suburb of Los Angeles, California (Craven 1953). The antiplatelet effects were not discovered until the late 1960s (Weiss and Aledort 1967) after which several trials were started (Fields et al 1977; Anonymous 1978). The benefit of aspirin was demonstrated in reducing the incidence of stroke in patients with prior symptomatic cerebrovascular disease; from this, aspirin has become the mainstay of secondary stroke prevention. Aspirin is also beneficial for acute stroke patients (Anonymous 1997a; Anonymous 1997b). Demonstrations of further benefit by other antiplatelet agents were evidenced by well-designed clinical trials. Ticlopidine, clopidogrel, and a combination of dipyridamole plus aspirin are available for patients requiring a drug other than aspirin (Hass et al 1989; Anonymous 1996; ESPRIT Study Group et al 2006).

Anticoagulants. What came to be called heparin was discovered in 1916 (McLean 1916) and used in patients from the 1930s whereas oral anticoagulants were discovered in the 1930s and introduced into clinical practice in the 1940s (Link 1959). After the clinical and autopsy studies linking nonvalvular atrial fibrillation to stroke, data from epidemiological studies demonstrated this condition to be the most powerful precursor of stroke, particularly in the elderly (Wolf et al 1987). The 5-fold increased incidence of stroke in patients with atrial fibrillation was significantly reduced in a remarkable series of randomized clinical trials on warfarin anticoagulation conducted in the late 1980s and early 1990s in primary and secondary prevention of stroke (Anonymous 1994). Anticoagulation with warfarin to achieve a well-defined level of anticoagulation (INR between 2 and 3) has been shown to be effective and generally safe in patients with atrial fibrillation. But for patients with sinus rhythm, the enthusiasts were wrong, and so far there has been no trial evidence indicating that warfarin is better than aspirin (Mohr et al 2001).

Carotid revascularization. Carotid endarterectomy is 1 of the most common vascular and neurosurgical operations. However, controversies regarding its indication and safety required several decades before general resolution, and its methodology is still being debated. After early failures in China (Chao et al 1938) and Argentina (Carrea and Murphy 1955), the first successful carotid endarterectomy was performed in the United States in 1953 by DeBakey in 1975 (DeBakey 1975). However, even 30 years after the first surgical treatment of carotid stenosis, physicians were questioning the utility of the procedure in light of the high rate of perioperative complications. In 1962, WS Fields started the first randomized trial of carotid endarterectomy (Fields et al 1993). This trial demonstrated the benefit of the procedure in stroke prevention, but a high rate of complications tarnished the results. In 1987, HJM Barnett designed a large-scale clinical trial to evaluate risks and benefits of carotid endarterectomy in symptomatic patients with transient ischemic ataxia or minor stroke: the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Results of this study reported in 1991 clearly demonstrated the benefit of the surgical procedure in patients with stenosis of the internal carotid artery greater than 70% (Anonymous 1991b). Also, a European trial, the European Carotid Study Trial, showed the same benefit from surgery in comparison to medical treatment for patients with symptomatic severe carotid stenosis (Anonymous 1991a). Since these results were published, the number of carotid endarterectomies performed for stroke prevention has gradually increased.

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