FAQ
A review of the update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack
Introduction
The American Heart Association (AHA) and the American Stroke Association (ASA) recently updated their guidelines on the secondary prevention of stroke. The guidelines were last published in 2006, and this update takes into account recent trials that evaluated antiplatelet therapy in patients with noncardioembolic ischemic stroke or transient ischemic attack (TIA) and statin therapy in the prevention of recurrent cerebrovascular events.
The guidelines apply classification recommendations with Class I indicating evidence for and/or general agreement that the treatment or procedure is useful and effective; Class II indicating conflicting evidence and/or a divergence of opinion about the effectiveness/efficacy of a procedure or treatment. Class II has 2 subcategories with IIa indicating the weight of evidence or opinion is in favor of the procedure or treatment and Class IIb indicating the usefulness/efficacy is less well established by evidence or opinion. Finally, a Class III recommendation indicates evidence and/or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful. Classification designations are also accompanied by levels of evidence toward treatment effect; Level A indicating data are derived from multiple randomized controlled trials; Level B indicating data are derived from a single randomized trial or nonrandomized studies; and level C indicating recommendations are based on expert opinion or case studies.
Highlights from the 2008 updated guidelines regarding secondary prevention of ischemic stroke and TIA are summarized below. Clinicians are encouraged to review the full update at http://stroke.ahajournals.org/cgi/reprint/STROKEAHA.107.189063 or http://www.americanheart.org.
Antiplatelet therapy
Key trials since the publication of the 2006 guidelines include the Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothombotic Events (CHARISMA) and the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT). The CHARISMA trial was a double blind, randomized study that enrolled 15 603 patients with cardiovascular (CV) disease or multiple risk factors for CV disease. Patients received clopidogrel (75 mg/day) plus aspirin (75 to 162 mg/day) or placebo plus aspirin (75 to 162 mg/day) and were followed for a median of 28 months. There was not a significant difference in the primary endpoint (nonfatal ischemic strokes) between the combination group and the aspirin alone group (1.7% vs. 2.1%, respectively, p=0.07). The aspirin alone group did experience a higher incidence of nonfatal strokes compared to the combination group (2.4% vs. 1.9%, respectively, p=0.03). Although cerebral and severe or fatal bleeding rates were similar between groups, the combination group had a higher rate of moderate bleeding. This trial, coupled with the results of a similar trial, led to the recommendation that clopidogrel should not be combined with aspirin for the secondary prevention of ischemic stroke.
The ESPRIT study compared aspirin (30 to 325 mg/day) with or without dipyridamole 200 mg twice daily in patients with a TIA at least 6 months prior to enrollment. This randomized, open-label trial followed 2763 patients for an average of 3.5 years. Based on the intent-to-treat analysis, the combination group had a significantly lower incidence of death from all CV causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complications (primary endpoint) compared to aspirin alone (HR 0.80; 95% CI 0.66 to 0.98). Although there were noted limitations with study design, aspirin doses, dipyridamole formulations and a high adverse event rate, the results from this trial and those before it propelled the authors to strengthen the recommendation of using aspirin plus dipyridamole over aspirin alone to a Class I recommendation with grade B evidence to support it.
Table 1 lists the current recommendations regarding antiplatelet therapy for the secondary prevention of a stroke or a TIA. Changes from the last guidelines are bolded.
Table 1: Current recommendations for antiplatelet therapy
| Class I Recommendations |
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Class II Recommendations
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Class III Recommendations
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It should also be noted that the guidelines specifically state there is no evidence that increasing the aspirin dose in patients who experience an ischemic cerebrovascular event while taking aspirin is of any benefit. Additionally, there is little evidence on using any of the antiplatelets either alone or in combination with other antiplatelets in patients who have an ischemic cerebrovascular event while taking aspirin.
Statin therapy
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a randomized, double-blind, placebo controlled study that evaluated the effects of atorvastatin 80 mg/day compared to placebo in 4731 patients with no known coronary heart disease (CHD) who suffered a stroke or TIA within 6 months of enrollment. The primary endpoint was the incidence of fatal or nonfatal stroke. After a median follow up of 4.9 years, the primary endpoint was significantly reduced in the atorvastatin group (11.2% vs. 13.1%, 5-year absolute reduction in risk 2.2%; adjusted HR 0.84; 95% CI 0.69 to 0.92; p=0.03). Atorvastatin also significantly reduced secondary endpoints including stroke or TIA (p<0.001), major coronary events (p=0.003), acute coronary events (p=0.001), any coronary event (p<0.001), revascularization (p<0.001) and any cardiovascular event (p<0.001). There was no statistically significant difference in mortality rates. The atorvastatin group had more hemorrhagic strokes compared to placebo (55 vs. 33, respectively). As expected, atorvastatin significantly reduced low-density lipoprotein (LDL) cholesterol (133 mg/dL at baseline vs. 73 mg/dL during treatment) compared to placebo (134 mg/dL at baseline vs. 129 mg/dL during treatment). No significant differences in serious adverse events were noted. Based on the results of the SPARCL trial, intensive lipid lowering therapy with a statin is now recommended by the AHA/ASA for patients with atherosclerotic ischemic stroke or TIA and without known CHD. Table 2 summarizes the current recommendations for lipid lowering therapy to prevent recurrent strokes. The bolded entry is an update from the last published guidelines.
Table 2: Current recommendations for lipid therapy
| Class I Recommendations |
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| Class II Recommendations |
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References
Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;36:000-000 (published ahead of print).
Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717.
ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial. Lancet. 2006;367(9523):1665-1673.
Amarenco P, Bogousslavsky J, Callahan A, et al. Stroke prevention by aggressive reduction in cholesterol levels (SPARCL) investigators: high dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559.