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Update on Secondary Stroke Prevention
By Andreas Schoeck, M.D., Division of Neurology/Vascular Neurology
Relatively little has changed in recent years to lessen the role of stroke as the third leading cause of death behind heart disease and cancer. In the U.S., one stroke occurs every 45 seconds and kills one person every 3-4 minutes. The direct and indirect cost of stroke in 2007 amounted to $63 billion. Of the 700,000 strokes that occur each year, 200,000 are recurrent. Secondary stroke prevention can have an enormous socioeconomic impact.
The patient with stroke or transient ischemic attack has to have an individually tailored treatment approach, taking into account the pathomechanism of the ischemic event, the patient’s age, gender, comorbidities, life-expectancy, and factors such as information on periprocedural complication rate of a physician performing a carotid endarterectomy (CEA) or stenting procedure.
Antiplatelets
Aspirin (ASA), used in low and medium doses (81-325 mg/d), still
plays the role of the first-line antiplatelet in secondary stroke prophylaxis, Clopidogrel is an alternative in patients with ASA-intolerance or allergy, and it shows its greatest benefit in patients with TIA/stoke with coexistent peripheral arterial disease (PAD). Its combination with ASA has not been shown to be superior to either ASA or Clopidogrel alone, with an excess in bleeding complications (MATCH and CHARISMA trials) for the combination. ASA coupled with extended release Dipyridamol (Aggrenox®) prevented twice as many strokes as ASA when compared to placebo in the ESPS-2 trial (European Stroke Prevention Study). Aggrenox® can currently be considered the “strongest” antiplatelet-agent in secondary stroke prevention.
Anticoagulation Warfarin is the established treatment in cardioembolic strokes due to valvular or non-valvular atrial fibrillation, although young (<65 years) patients with lone atrial fibrillation and no additional risk factors can be treated with ASA in primary stroke prevention. Ximelagatran®, a direct Thrombin-inhibitor, was promising in the treatment of atrial fibrillation due to lack of need for INR monitoring as well as an equal benefit-and-risk profile when compared to Warfarin. However, this drug was not FDA-approved due to hepatic side effects. The WASID trial (Warfarin vs. Aspirin in Symptomatic Intracranial Disease) showed no benefit of anticoagulation in intracranial stenosis when compared to ASA. In patients with non-cardioembolic cryptogenic stroke, the formerly often used “we-have–to-do-something” approach of anticoagulating the patient who already was on an antiplatelet was shown to be without scientific basis in the WARSS trial (Warfarin-Aspirin Recurrent Stroke Study). Warfarin is commonly used in the treatment of cervical artery dissection (after initial treatment with I.V. heparin), although studies have shown a comparable benefit of ASA and Warfarin in this stroke subgroup.
Patent Foramen Ovale (PFO)
In one well-designed French study, the stroke recurrence risk with patent foramen ovale (PFO) in combination with an atrial septal (AS-) aneurysm was shown to significantly increase to ~15% in four years compared to 0-4% with isolated PFO, AS-aneurysm or neither defect in stroke or TIA patients treated with ASA only. PFO in isolation has not been shown to be a definite independent risk factor for stroke recurrence in other studies as well, although high-risk PFO-patients with established DVT or hypercoagulable state may benefit from anticoagulation.
Carotid Disease
Carotid endarterectomy is a well-established (NASCET-trial) treatment for patients with high-grade (70-99%) stenosis of the internal carotid artery (ICA), especially when performed within the first two weeks. The benefit is considerably less but statistically significant in patients with symptomatic moderate ICA-stenosis of 50-69%. The benefit is even less impressive in patients with asymptomatic ICA-stenosis >60% (ACAS and ACST trials). This is especially true in women, older patients, in situations where the surgeon’s periprocedural complication rate exceeds 3%, and when severe and debilitating strokes are considered.
Conservative management of patients with asymptomatic ICA-stenosis, known from the stroke-trial literature as “best medical treatment” (BMT), has significantly evolved since the ACAS (Asymptomatic Carotid Atherosclerosis Study) and ACST (Asymptomatic Carotid Surgery Trial) trials in the early to mid 1990s. New and more aggressive guidelines regarding treatment of hypertension, hyperlipidemia, and diabetes, and life-style modification have been developed since and were not implemented in the “asymptomatic CEA trials.” Carotid stenting is a promising treatment and has shown non-inferiority to CEA in one trial (SAPPHIRE). Appropriate patient selection for this treatment is critical. Patients need to be enrolled in ongoing trials (CREST, ACT I) to further test this method. The same is true for transcatheter closure of PFO, which remains an experimental treatment.
Summary
While stroke remains a significant cause of mortality and disability in the United States, the development of treatment plans tailored to the individual patient can have a considerable impact in the prevention of recurrent or secondary stroke.
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