An Update on Antiplatelet Therapy for Secondary Stroke Prevention

Use of antiplatelet therapy for the secondary prevention of ischemic stroke is now standard of care. Given that relatively recently published results from the PRoFESS trial suggest that clopidogrel and aspirin/extended-release dipyridamole (ASA/ER-DP) have similar efficacy, choice of a specific agent often depends on physician and patient preference. Practical considerations, such as once-daily dosing may make clopidogrel preferable. Twice-daily ASA/ER-DP is associated with a risk of headache. But if cost is a significant concern, data suggest some patients can obtain sufficient benefit from aspirin alone. Evidence now suggest the higher aspirin doses may actually be associated with improved benefits.¹

RECENT DEVELOPMENTS
To determine the effects of higher aspirin doses on all-cause mortality and bleeding, Herbert D. Aronow, MD, MPH of Michigan Heart, and colleagues investigated outcomes in patients with recent cerebrovascular or coronary ischemic events.¹ They found that aspirin doses of 162mg/day or more were associated with lower rates of all-cause mortality, although there was no influence on the composite endpoint of death, nonfatal myocardial infarction, or nonfatal stroke. Despite these findings, Dr. Aronow says, "I have been cautious to employ changes in aspirin dosing based upon my study, as it was observational rather than randomized. Randomized study of this question is underway."

Among his patients, Dr. Aranow says that for secondary prevention of noncardioembolic stroke, "I use either aspirin/dipyridamole or clopidogrel (usually with aspirin as well) depending on other patient comorbidities. As a cardiologist, most of my patients also have coronary disease, so clopidogrel ends up being the more commonly used agent for stroke secondary prevention."

One area of concern for physicians and patients may be the use of antiplatelets in the perioperative period. As Dr. Aranow points out, "There are circumstances where these agents should be discontinued, but it is very dependent upon the reason for which antiplatelet therapy was initiated, the duration of treatment to date, and the risk of bleeding associated with the surgery/medical procedure."

Despite the need for individualized decisions, some general suggestions have been made.² Typically, aspirin taken for secondary prevention does not need to be withdrawn before surgery, while aspirin taken for primary prevention may be discontinued about seven days before surgery with a higher bleeding risk. Clopidogrel may be withdrawn if the procedure in question is associated with high hemorrhagic risk or moderate to high risk of cerebrovascular sequelae. There is a risk of rebound thrombosis upon withdrawl of antiplatelets, and this risk may be greater than the risk of bleeding associated with many surgeries.

Finally, the question of adjunctive lipid management continues to garner attention, with recent AHA guidelines suggesting lipid-lowering through statin therapy for patients with atherosclerotic ischemic stroke or TIA and without known CHD.³

LOOMING QUESTIONS
As Dr. Aronow points out, data from randomized trials is essential to support clinical decision-making, and there is little to no dispute about the quality of data related to use of antiplatelet therapy for secondary stroke prevention.

However, a new analysis points out that the trial designs may overlook a significant proportion of "typical patients."⁴ The Netherlands Stroke Survey enrolled 972 patients with TIA or ischemic stroke based on enrollment criteria from seven large antiplatelet trials. But researchers found that only 25 to 67 percent of patients fit enrollment criteria. Of note, mortality rates were significantly higher among ineligible patients than among those meeting criteria: 27 to 41 percent for the former versus 16 to 20 percent for the latter.

"Patients with ischemic attack and stroke enrolled in randomized clinical trials are only partially representative of patients in clinical practice," the authors note, calling for less strict enrollment criteria to enhance the "generalizability" of study conclusions.

1. Aronow HD, Califf RM, Harrington RA, Vallee M, Graffagnino C, Shuaib A, Fitzgerald DJ, Easton JD, Van de Werf F, Diener HC, Ferguson J, Koudstaal PJ, Amarenco P, Theroux P, Davis S, Topol EJ. Relation between aspirin dose, all-cause mortality, and bleeding in patients with recent cerebrovascular or coronary ischemic events (from the BRAVO Trial). Am J Cardiol. 2008 Nov 15;102(10):1285-90
2. Chang, S. Perioperative Antiplatelet Therapy. Presented Sept. 24, 2007. National Taiwan University.
3. Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH; American Heart Association; American Stroke Association. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008 May;39(5):1647-52.
4. Maasland L, van Oostenbrugge RJ, Franke CF, Scholte Op Reimer WJ, Koudstaal PJ, Dippel DW; Netherlands Stroke Survey Investigators. Patients enrolled in large randomized clinical trials of antiplatelet treatment for prevention after transient ischemic attack or ischemic stroke are not representative of patients in clinical practice: the Netherlands stroke survey. Stroke. 2009 Aug;40(8):2662-8.