Antiplatelet Therapies After Ischemic Stroke

Stroke is a leading cause of death and disability worldwide.¹ Ischemic stroke, which represents approximately 87% of all strokes globally,² is a result of permanent brain tissue injury caused by prolonged hypoperfusion.³ Stroke management depends on the underlying cause, and because most ischemic strokes are thrombotic in origin, antithrombotic medications are a mainstay of stroke prevention.^4,5

At sites of blood vessel injury (eg, a ruptured atherosclerotic plaque), platelet aggregate—stabilized by fibrin—rapidly forming hemostatic plugs. These plugs, or thrombi, cause the thromboembolic complications of atherosclerosis, including heart attacks, strokes, and peripheral vascular disease.⁶ Currently, antiplatelet therapies are recommended as the main antithrombotic agent for most individuals who experience ischemic stroke or a transient ischemic attack (TIA).^3,7

Antiplatelet Therapy Mechanisms of Action

The mechanisms of action of most commonly used antiplatelet therapies are illustrated in the Figure. Aspirin (acetylsalicylic acid, ASA) is the most widely used antiplatelet agent and irreversibly inhibits the enzyme cyclooxygenase-1 (COX-1) in platelets, reducing production of thromboxane A2 (TXA2).⁸ COX-1-dependent TXA2 inhibition prevents platelet aggregation interfering with thrombus formation.⁹ Aspirin reaches serum peak value in approximately 1 hour and has a half-life of approximately 2 to 3 hours at standard doses. Because of irreversible inhibition, platelet activity recovers by approximately 10% per day from release of new platelets.¹⁰ Clopidogrel is a thienopyridine derivative prodrug that requires hepatic activation through the CYP2C19 enzyme. Clopidogrel activity is dependent on the P2Y¹² receptor and reaches its maximum antiplatelet activity within 4 to 5 days by blocking the adenosine diphosphate (ADP) pathway of platelet aggregation.^11,12 Resistance can occur, and individuals lacking the CYP2C19 enzyme will not have a typical response to clopidogrel. Ticagrelor also blocks the ADP P2Y¹² receptor on platelets, similar to the thienopyridines, reducing platelet aggregation by preventing ADP-mediated activation of the GPIIb/IIIa receptor complex.¹³ In contrast to clopidogrel, ticagrelor reaches peak concentration after 1.5 hours and does not require hepatic activation, reducing the impact of CYP2C19 genetic polymorphisms.^14,15 Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells, and erythrocytes to increase local adenosine concentration and inhibit platelet aggregation.¹⁶ Cilostazol is a phosphodiesterase 3 inhibitor that increases cyclic adenosine monophosphate (cAMP) leading to reversible inhibition of platelet aggregation and arterial vasodilation.

Clinical Trials of Antiplatelet Monotherapy

Major antiplatelet monotherapy trials are summarized in Table 1. The decision to start antiplatelet therapy should be made after considering eligibility for thrombolytic therapy and mechanical thrombectomy, as well as stroke etiology (eg, cardioembolic, intracranial atherosclerosis, small vessel disease, embolic stroke of undetermined source [ESUS], or other).

In 2 large randomized controlled trials, initiation of aspirin within 48 hours of stroke onset was beneficial for prevention of acute ischemic stroke (AIS) recurrence with a dose of aspirin 300 or 160 mg/day.^5,17 Pooled analysis showed aspirin therapy after AIS reduced nonfatal strokes or deaths by 11 per 1,000 people in the first few weeks but caused approximately 2 hemorrhagic strokes per 1,000 people.¹⁸ In an analysis of pooled individual patient data from these 2 trials, aspirin reduced the risk of recurrent ischemic stroke for those with mild-to-moderate, but not severe, stroke-related neurologic deficits; for those with mild-to-moderate deficits, risk reduction was maximal by the third day after starting aspirin (hazard ratio [HR] 0.37, 95% CI 0.25-0.57).¹⁹ A 2014 systematic review of antiplatelet therapy for acute stroke included 6 additional trials and showed that administration of aspirin (160 to 300 mg daily) within 48 hours of stroke onset reduced the risk of early recurrent ischemic stroke (odds ratio [OR] 0.77, 95% CI 0.69 to 0.87; P<.00001), with a small but definite increased risk of bleeding (OR 1.23, 95% CI 1.00 to 1.50; P=.04).²⁰

Few randomized trials have tested aspirin directly against other antiplatelet agents for the prevention of ischemic stroke or TIA in the acute period. In a large trial, monotherapy with ticagrelor or aspirin within 24 hours of symptom onset did not show significantly different rates of the 90-day composite endpoint of stroke, myocardial infarction, or death (HR, 0.89; 95% CI, 0.78 to 1.01; P=.07).²¹ In a prespecified exploratory analysis, however, ticagrelor was superior to aspirin in the subgroup of participants with stroke of possible atherosclerotic origin, defined by presence of ipsilateral atherosclerotic stenosis of an extracranial or intracranial artery.²² Cilostazol has been studied extensively in Asia and is considered a reasonable option for persons of Asian descent or those with allergies to other antiplatelet agents.²³ Cilostazol requires twice-daily dosing and has lower tolerability and higher cost compared with aspirin. Clopidogrel has not been well studied as monotherapy in trials that start treatment in the first 24 to 48 hours of AIS. Clopidogrel is, however, shown to be effective with aspirin as dual antiplatelet therapy for short-term use in secondary prevention of ischemic stroke.^24,25

Clinical Trials of Dual Antiplatelet Therapy

Major dual antiplatelet trials are summarized in Table 2.

Short Term—Within 90 Days

Because aspirin has been established as the primary antiplatelet agent for stroke prevention, further studies have explored the use of dual antiplatelet therapy (DAPT). In a large trial in China, participants with high-risk TIA (ABCD² score≥4) or minor strokes (National Institute of Health Stroke Scale [NIHSS] score≤3) were treated with clopidogrel (loading dose 300 mg, maintenance dose 75 mg) and aspirin vs placebo and aspirin within 24 hours of symptom onset for 21 days followed by aspirin monotherapy.²⁵ DAPT with clopidogrel and aspirin decreased the rate of recurrent stroke (HR 0.68; 95% CI, 0.57 to 0.81; P<.001) with no significant increase in intracranial hemorrhage (0.3%) or severe bleeding (0.3%), but an increase in minor bleeding. In an international trial, participants with minor stroke (NIHSS score≤3) or high-risk TIA (ABCD² score≥4) treated with aspirin and clopidogrel (loading dose 600 mg, maintenance dose 75 mg) for 90 days vs aspirin alone had lower risk of recurrent ischemic stroke at 90 days (adjusted HR, 0.70; 95% CI, 0.61-0.81; P<.001), but a higher rate of major bleeding (adjusted HR, 1.59 [95% CI, 0.88-2.86]; P=.12), with a significant increase after the first 30 days.²⁶ Thus it has been recommended to use DAPT for 21 to 30 days.²⁷

Ticagrelor is also a P2Y¹² receptor antagonist, but unlike clopidogrel, it does not require metabolic activation through the hepatic enzyme CYP2C19, and so is particularly useful for the population of CYP2C19-negative individuals who are nonresponders to clopidogrel. In a clinical trial in participants with high-risk TIA (ABCD² score≥6) or minor stroke (NIHSS score≤5), DAPT with ticagrelor and aspirin for 30 days reduced recurrent stroke compared with aspirin alone (HR, 0.83; 95% CI, 0.71 to 0.96; P=.02).²⁸ A recent multicenter randomized controlled trial in China compared the efficacy of aspirin and ticagrelor vs aspirin and clopidogrel in CYP2C19-negative participants with TIA (ABCD² score≥4) or minor ischemic stroke (NIHSS score≤3). Recurrent stroke risk at 90 days was significantly lower with ticagrelor and aspirin compared with clopidogrel and aspirin (HR 0.77; 95% CI 0.64 to 0.94; P=.008). Although the risk of severe or moderate bleeding did not differ between the 2 treatments, ticagrelor was associated with a higher number of total bleeding events.²⁹

DAPT is also used for secondary stroke prevention in people with symptomatic intracranial atherosclerosis (70%-99% stenosis). A randomized trial compared aggressive medical management (including DAPT for 90 days with clopidogrel and aspirin, an blood pressure, diabetes, and lipid management) alone vs combined with the intervention of percutaneous transluminal angioplasty and stenting (PTAS).³⁰ Recurrent stroke and death within 30 days were higher in those who had DAPT with stenting compared with medical therapy and aggressive lifestyle changes (14.7% vs 5.8%, P=.002), and the observed event rate was significantly lower in medically treated patients than seen in prior trials.³¹

Studies suggest that 23% to 41% of patients with lacunar stroke exhibit neurologic deterioration after symptom onset.³² For those with stuttering lacunar stroke, there may be a role for early DAPT with aspirin and clopidogrel.³² In a small trial, stuttering symptoms were present in 77% of those who received aspirin monotherapy vs 21% of those who received DAPT.³⁴ Specifically, in patients with lacunar stroke and evidence of branch atheromatous disease, a multicenter observational study showed that aspirin plus cilostazol within 12 hours from onset was associated lower likelihood of clinical progression compared with aspirin alone.³⁵ This study, however, was open-label and nonrandomized, and results should be interpreted with caution given the potential for bias.

Long Term—Beyond 90 Days

Long-term use of DAPT is associated with a higher bleeding risk, with a clinical trial showing that 18 months of treatment with aspirin plus clopidogrel did not reduce the risk of major vascular events (relative risk [RR] -6.4%; 95% CI -4.6 to 16.3%) and there was a 1.3% increase in risk of life-threatening hemorrhage (95% CI 0.6 to 1.9).³⁶ Another study compared long-term DAPT with clopidogrel and aspirin to aspirin alone in people who had lacunar strokes and showed no significant reduction in recurrent stroke. In this trial, however, DAPT doubled risk of major hemorrhage compared with aspirin alone (HR 1.97; 95% CI 1.41 to 2.71) and all-cause mortality (HR 1.52; 95% CI 1.14 to 2.04).³⁷

Dipyridamole and aspirin combination has also been studied in comparison to aspirin for stroke reduction and reduced stroke and death rates compared with aspirin alone.³⁸ In another trial, however, dipyridamole and aspirin treatment vs clopidogrel monotherapy resulted in similar stroke reduction rates (HR 1.01; 95% CI 0.92 to 1.11), but an increased rate of hemorrhagic strokes (0.9% vs 0.5%).³⁹

Antiplatelet Therapy Caveats

Antiplatelet treatments are an integral part of secondary stroke prevention. It is therefore important to consider caveats of utilization, specifically medication resistance that hinders the antiplatelet efficacy and side effects that contribute to nonadherence.

Clopidogrel Resistance

As discussed, genetic polymorphisms in the CYP2C19 enzyme, found in 60% of people identified as Asian and 25% of people identified as white,⁴⁰ can confer nonresponse to clopidogrel. Platelet reactivity testing is not routinely needed, however, unless there is clinical concern for treatment failure, such as a thrombotic event despite use of clopidogrel.⁴¹ There are numerous options for evaluating antiplatelet response; the P2Y¹² receptor inhibition assay is commonly used. If clopidogrel resistance is discovered, an alternate antiplatelet therapy such as ticagrelor can be pursued.⁴² Omeprazole, a potent inhibitor of CYP2C19, may also decrease the active metabolite level of clopidogrel, decreasing its antiplatelet activity, when administered together.⁴³

Aspirin Resistance

Aspirin irreversibly inhibits COX-1 inhibition, decreasing thromboxane A2 levels,⁸ which if hindered may allow thrombotic events to occur despite aspirin treatment.⁴⁴ Potential contributors to decreased aspirin efficacy include genetic variability of COX-1, COX-2, or thromboxane A2; medication nonadherence, enteric-coated formulation, drug interactions, absorption limitations, stress, and infection. Platelet evaluation is not routinely performed unless treatment failure warrants laboratory testing to evaluate aspirin effects. Various laboratory tests that can be considered for evaluation of aspirin response, without a clear consensus about appropriate choice of test or normal values for findings.⁴⁵

Sustained Release Aspirin-Dipyridamole Side Effects and Administration

The sustained-release combination of aspirin and dipyridamole for DAPT has several side effects to consider, including bleeding risk, as with all antiplatelet therapies. In addition, dipyridamole can cause headaches that may affect adherence to treatment. Because headaches caused by dipyridamole are mild-to-moderate in severity, self-limited, and improve with continued use of dipyridamole, patients should be counseled about the mild and self-limited nature of these headaches and that, if they occur, they can be expected to improve with time on treatment.⁴⁶ Some studies have also shown that a decreased initial dose can be effective in minimizing headache during treatment initiation.⁴⁷ Other side effects of dipyridamole include gastrointestinal symptoms such as diarrhea, nausea, and abdominal pain. Twice-daily dosing is also a limiting factor for use of this formulation.

Ticagrelor

Although ticagrelor has the advantage of not being affected by CYP2C19 polymorphisms, it currently has a much higher cost compared with other agents. Ticagrelor twice-daily dosing is also a limiting factor for its use.

Summary and Recommendations

The decision to initiate antiplatelet therapy during the postacute period of ischemic stroke has to be customized to the individual. For those with high-risk TIA (ABCD² score≥4) or minor stroke (NIHSS score≤5) without cardioembolic source, we recommend using DAPT for 21 days (eg, aspirin and clopidogrel or aspirin and ticagrelor). Ticagrelor may be the initial therapy, together with aspirin, provided CYP2C19 gene point-of-care testing is available showing the patient is expected to be a nonresponder to clopidogrel.

For those with large artery intracranial atherosclerosis, DAPT for 90 days followed by aspirin monotherapy is warranted. Short-term use of DAPT has been shown to be beneficial in those with neurologically deteriorating lacunar stroke, although more high-quality studies are needed. Use of DAPT for more than 90 days is not routinely recommended because of the higher risk of bleeding complications. Future research is still needed to understand the optimal antiplatelet therapy for each individual patient.