© Springer International Publishing Switzerland 2016
Bruce Ovbiagele (ed.)Ischemic Stroke Therapeutics10.1007/978-3-319-17750-2_1010. Heterogeneous Causes of Stroke: Antithrombotics
(1)
Division of Neurocritical Care, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
(2)
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
Keywords
StrokeTransient ischemic attackTIAAntiplateletAspirinClopidogrelAspirin-dipyridamoleCase Presentation
A 65-year-old male with multiple risk factors for cerebrovascular disease presents to the hospital with several days of dizziness, vertigo, and headache. He is admitted to the hospital and a thorough work-up reveals multifocal strokes in the territory of the right posterior-inferior cerebellar artery, the basilar artery perforators, and right posterior-cerebral artery. The left vertebral artery is calcified and completely occluded. The right vertebral artery is >50 % occluded in its intracranial portion on CT angiogram. The basilar artery has a near complete occlusion in the mid-section with evidence of acute perforator strokes in the pons. The patient is admitted to the neurological intensive care unit for close monitoring. Physical examination reveals an awake and oriented patient with weakness in the left upper and lower extremities, left visual field deficit, and a skew deviation. The patient also has moderate dysphagia and dysarthria. The cause of stroke is determined to be secondary to an artery-to-artery stroke and after a prolonged and complicated hospitalization, the patient undergoes tracheostomy and feeding tube placement and is discharged on a combination of aspirin and clopidogrel for secondary prevention against stroke.
Indications
Anti-platelet agents can be used for the recurrence of ischemic stroke in patients who do not suffer from atrial-fibrillation [1–3]. The most recent American Heart Association (AHA)/American Stroke Association (ASA) guidelines for secondary prevention of stroke recommend the following treatment in patients with heterogeneous causes of stroke [4]:
1.
Acute non-cardioembolic ischemic stroke or TIA (Class I; Level A recommendation): Aspirin (50–325 mg/day) monotherapy (Class I; Level of Evidence A) or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level of Evidence B) is recommended as initial secondary prophylaxis. Clopidogrel (75 mg) monotherapy is a reasonable alternative (Class IIa; Level of Evidence B), especially for patients who are allergic to aspirin. A combination of aspirin and clopidogrel can also be initiated within 1 day of a minor ischemic stroke or TIA and continued for 90 days (Class IIb; Level of Evidence B).
2.
In the presence of a low-risk situation in which antiplatelet therapy would be the treatment recommendation outside of pregnancy, low-dose aspirin (50–150 mg/day) is reasonable after the first trimester of pregnancy (Class IIa; Level of Evidence B).
Antiplatelet Agents Used in the Secondary Prevention of Stroke/Transient Ischemic Attacks (TIA)
Aspirin
Aspirin is the antiplatelet agent that has been most extensively studied in stroke and TIA prophylaxis. Several studies have reported that aspirin prevents recurrent ischemic events. Lower doses of aspirin have been shown to be as effective as higher doses, especially between 75 and 1,500 mg [1, 5, 6]. Although efficacy data is limited for doses less than 75 mg, higher doses do tend to have higher toxicity risks [1, 7–10]. Doses as low as 30 mg of aspirin per day have been shown to be effective in preventing strokes and TIA, as shown in the Dutch TIA trial [10]. The UK-TIA study also reported favorable results in 2,435 patients taking aspirin (300 mg or 1,200 mg) compared to placebo, after from suffering a minor stroke [9]. In this randomized placebo-controlled study, participants were followed for a maximum of 6 years. The odds of suffering a vascular event, including a major stroke, were 15 % less in both of the aspirin groups compared to the placebo group [9]. Similarly, a meta-regression analysis of 11 randomized, placebo- controlled trials that included 5,228 patients treated with aspirin also concluded that aspirin doses from 50 to 1,500 mg/day uniformly decreased the risk of stroke by about 15 % (risk ratio, 0.85; 95 % CI, 0.77–0.94) [5].
Aspirin is recommended for secondary prophylaxis beginning immediately after an acute stroke. A Cochrane review of 12 trials involving 43,041 participants [mostly from the International Stroke Trial (IST) [11] and Chinese Acute Stroke Trial (CAST) [12] concluded that with aspirin treatment there was a significant decrease in death or dependency at the end of maximum follow-up of 6 months (odds ratio, 0.95; 95 % confidence interval, 0.91–0.99) [13]. This review placed the number needed to treat to reduce the risk of early recurrent ischemic stroke and improve long-term outcome at 79 despite there being a small increase in hemorrhagic complications [13]. Recent guidelines strongly recommend aspirin administration (325 mg) in the first 24–48 h after an acute stroke [14, 15]. At the present time, the AHA/ASA guideline for the early management of patients with acute ischemic stroke does not recommend clopidogrel, tirofiban, eptifibatide, or glycoprotein IIb/IIIa receptor inhibitors as substitute for aspirin early after stroke.
In the Canadian cooperative study, 585 patients were treated with an antiplatelet agent and observed for approximately 26 months for subsequent ischemic events. The patients taking aspirin had a 19 % reduction in the risk of continuing ischemic attacks, stroke, or death compared to patients taking oral placebo or sulfinpyrazone (P < 0.05) [16]. In the Warfarin–Aspirin Recurrent Stroke Study (WARS), the effect of warfarin (dose adjusted to achieve INR of 1.4–2.8) was compared to that of aspirin (325 mg/day) in 2,206 patients randomized equally between the two groups. The primary end point of death or recurrent ischemic stroke at 2 years was observed in 17.8 % in the warfarin group and 16.0 % in the aspirin group (P = 0.25), with the hazard ratio being 1.13 (95 % CI, 0.92–1.38) [17].
To assess the efficacy of antiplatelet agents in preventing recurrent strokes in the African American population, the investigators of the African American Antiplatelet Stroke Prevention Study (AAASPS) randomized 1,809 patients to receive either Aspirin or Ticlopidine. Although no difference was found in the primary outcomes of a vascular event (including strokes) between the two groups, the Kaplan-Meier curves for time to the secondary outcome of fatal or nonfatal stroke approached a statistically significant reduction favoring aspirin (P = 0.08). The investigators concluded that aspirin was better than ticlopidine for the prevention of vascular events in the studied population [18].
A Cochrane review of antiplatelet therapy for acute ischemic stroke (12 trials, N = 43,041) recommended the use of aspirin within 48 h versus no aspirin at all. This analysis demonstrated a relative risk ratio (RRR) of 12 % (95 % CI, 3–21), adjusted risk ratio (ARR) of 0.5 %, and NNT of 200 (over 2–4 weeks) [13, 19]. In terms of annual protection against stroke, myocardial infarction, or vascular death with aspirin (versus no aspirin), the RRR, ARR, and NNT are 13 % (95 % CI, 6–19), 0.9 %, and 111 per year respectively.
Clopidogrel
This platelet ADP receptor antagonist has been studied as a single agent, and in comparison to aspirin and a combination of aspirin plus dipyridamole. Limited data is available in the setting of an acute stroke and hence clopidogrel may not be recommended in this setting [14]. The reader should also be cautioned that clopidogrel takes 3–7 days to provide effective platelet inhibition when given at standard doses (75 mg/day) and therefore will not provide immediate recurrent stroke prevention unless a bolus dose (300 mg) is given [20].
A double-blind, active and placebo-controlled study known as the prevention regimen for effectively avoiding second strokes (PRoFESS) trial investigated the preventive effects of antiplatelets and the angiotensin II receptor antagonist telmisartan. Patients with an ischemic stroke were randomly assigned to receive either 25 mg aspirin plus 200 mg extended-release dipyridamole twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. Median follow-up duration was 2.4 years for 20,332 patients with a mean age of 66 years. Nine percent of patients in each group had a recurrent stroke and modified Rankin scores (mRS) were not statistically different in patients with recurrent stroke who were treated with aspirin plus dipyridamole group versus clopidogrel (p = 0.38) [21].
In the MATCH (management of athero-thrombosis with clopidogrel in high-risk patients) study, 7,599 high-risk patients with recent ischemic stroke or TIA and at least one additional vascular risk factor were randomized to receive clopidogrel 75 mg plus either aspirin (75 mg/day) or placebo [22]. At the end of the follow-up period of 18 months, the composite end point (which included recurrent stroke) in the aspirin plus clopidogrel group showed a relative risk reduction of 6.4 % (95 % CI, −4.6 to 16.3] and an absolute risk reduction of 1 % (95 % CI, −0.6 to 2.7) compared to clopidogrel alone. The risk of major bleeding was higher in the combination antiplatelet group (absolute risk increase 1.36, 95 % CI 0.86–1.86; p < 0.0001) but there was no change in mortality. Life-threatening bleeding was higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (absolute risk increase 1.3 %, 95 % CI 0.6–1.0; p < 0.0001). As a result of MATCH study, the AHA/ASA Guideline for the prevention of stroke in patients with stroke or transient ischemic attack was updated to include caution regarding the routine long-term use of dual antiplatelet therapy for stroke and TIA prevention.
The CHANCE trial (clopidogrel in high-risk patients with acute nondisabling cerebrovascular events) randomized 5,170 patients within 24 h after the onset of minor ischemic stroke or high-risk TIA to clopidogrel (300 mg initially followed by 75 mg daily for 90 days) and aspirin (75 mg/day for the first 21 days) or to placebo plus aspirin (75 mg/day for 90 days) [23]. Each patient received open-label aspirin at a clinician-determined dose of 75–300 mg on day 1 after the event. At 90 day follow-up, recurrent stroke occurred in 8.2 % of patients in the clopidogrel–aspirin group, as compared with 11.7 % of those in the aspirin group (hazard ratio, 0.68; 95 % CI, 0.57–0.81; P < 0.001). Moderate to severe hemorrhage rates in both groups were similar. This study however only included Chinese participants. The ongoing POINT trial (Platelet-oriented inhibition in new TIA and minor ischemic stroke) will test the efficacy of clopidogrel plus aspirin versus aspirin taken <12 h after TIA or minor ischemic stroke symptom onset in preventing major ischemic vascular events at 90 days in the high-risk western population [24].
CAPRIE (clopidogrel versus aspirin in patients at risk of ischemic events) was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome of ischemic stroke, myocardial infarction, or vascular death [25]. A total of 19,185 patients were followed for 1–3 years. Patients treated with clopidogrel had a 5.32 % risk of ischemic stroke, myocardial infarction, or vascular death compared with 5.83 % with aspirin (p = 0.043) with a relative risk reduction of 8.7 % in favor of clopidogrel (95 % CI, 0.3–16.5). The overall safety profile of clopidogrel was found to be at least as good as that of aspirin. The annual RRR, ARR, and NNT for clopidogrel are 7 % (95 % CI, −6 to 19), 0.6 %, and 167, when compared to aspirin alone [19, 25, 26].
For early recurrence of stroke (~3 months), a combination of clopidogrel and aspirin has an RRR, ARR, and NNT of 30 % (95 % CI, 18–41), 3.3 %, and 30 respectively, when compared with aspirin alone [20, 23, 27]. Versus clopidogrel, the RRR, ARR, and NNT over 18 months are 17 % (95 % CI, −93 to 64), 0.8 %, and 125 respectively [19, 27]. A recent review by Hankey summarizes effective strategies to prevent recurrent stroke [19].
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