What is the role of antiplatelets (antiplatelet agents) with thrombolytics (tissue plasminogen activators, tPA) in patients with acute ischemic stroke or myocardial infarction (heart attack)?

From the Guidelines

Antiplatelet agents should be used alongside thrombolytics in acute ischemic stroke and myocardial infarction to enhance treatment efficacy and prevent reocclusion, with the most recent evidence suggesting that dual antiplatelet therapy may be beneficial for secondary stroke prevention 1. For acute ischemic stroke, aspirin (325mg initially, then 81-325mg daily) should be started 24 hours after tPA administration, not concurrently, as immediate combination increases bleeding risk. In myocardial infarction, dual antiplatelet therapy with aspirin (325mg loading dose, then 81mg daily) plus a P2Y12 inhibitor like clopidogrel (300-600mg loading dose, then 75mg daily), ticagrelor (180mg loading dose, then 90mg twice daily), or prasugrel (60mg loading dose, then 10mg daily) is typically started immediately with thrombolytics. This combination works by preventing platelet aggregation while the thrombolytic dissolves the existing clot. Thrombolytics like alteplase convert plasminogen to plasmin, which breaks down fibrin in clots, while antiplatelets prevent new clot formation by inhibiting different aspects of platelet activation. Some key points to consider when using antiplatelet agents with thrombolytics include:

• The benefits and risks of dual versus single antiplatelet therapy for secondary stroke prevention, with dual antiplatelet therapy potentially reducing recurrent stroke but also increasing severe bleeding compared with single antiplatelet therapy 1.
• The importance of careful monitoring for bleeding complications, especially intracranial hemorrhage, with dose adjustments needed for elderly patients or those with renal impairment.
• The use of antiplatelet agents in the setting of acute stroke, with limited experience with the use of clopidogrel or dipyridamole, but some studies suggesting that these agents may be safe and effective in this setting 1. The most recent and highest quality study on this topic is a systematic review and meta-analysis of the benefits and risks of dual antiplatelet therapy compared with single antiplatelet therapy for secondary ischemic stroke prevention, which was published in 2021 1.

From the FDA Drug Label

Ticagrelor tablets are a P2Y12 platelet inhibitor indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. Use ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg. Clopidogrel is a P2Y12 platelet inhibitor indicated for: Acute coronary syndrome –For patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), clopidogrel has been shown to reduce the rate of myocardial infarction (MI) and stroke.

The role of antiplatelets with thrombolytics in patients with acute ischemic stroke or myocardial infarction is to reduce the risk of cardiovascular events.

• Ticagrelor and clopidogrel are P2Y12 platelet inhibitors that can be used in these patients.
• Aspirin is often used in combination with these medications.
• The use of thrombolytics, such as tissue plasminogen activators (tPA), is not directly addressed in the provided drug labels, but antiplatelets are used to prevent further thrombotic events 2, 3.

From the Research

Role of Antiplatelets with Thrombolytics

The use of antiplatelets in combination with thrombolytics, such as tissue plasminogen activators (tPA), in patients with acute ischemic stroke or myocardial infarction is a complex issue. Key points to consider include:

• The safety and efficacy of this combination therapy
• The risk of symptomatic intracerebral hemorrhage (ICH)
• The impact on functional outcome and mortality

Safety and Efficacy

Studies have shown that antiplatelet therapy may increase the risk of symptomatic ICH following intravenous thrombolysis after ischemic stroke 4. However, the absolute excess of SICH is small compared to the benefit of thrombolysis seen in randomized trials. The combination of ASA and clopidogrel was associated with an increased risk for SICH, but no significant increase in the risk for mortality or poor functional outcome was found 4.

Risk of Symptomatic Intracerebral Hemorrhage

Pretreatment with aspirin monotherapy increases the bleeding risk of alteplase in both observational and randomized trials with no effect on clinical outcome 5. The risk of intracerebral hemorrhage is increased with the combination of aspirin and clopidogrel. Antiplatelet drugs should not be given in the first 24 hours after alteplase treatment 5.

Impact on Functional Outcome and Mortality

Early administration of intravenous aspirin in patients with acute ischemic stroke treated with alteplase does not improve outcome at 3 months and increases the risk of SICH 6. However, antiplatelet therapy with aspirin 160 to 300 mg daily, given orally and started within 48 hours of onset of presumed ischemic stroke, reduces the risk of early recurrent ischemic stroke without a major risk of early hemorrhagic complications and improves long-term outcome 7.

Mechanical Clot Disruption and Low-Dose Thrombolytic Agent

A prospective study evaluated the safety and effectiveness of aggressive mechanical disruption of clot in conjunction with intra-arterial administration of a low-dose third-generation thrombolytic agent (reteplase) to treat ischemic stroke 8. The results showed a high rate of recanalization and clinical improvement with no vessel rupture, dissection, or symptomatic intracerebral hemorrhages observed.

Some key points to consider when using antiplatelets with thrombolytics include:

• The risk of symptomatic ICH is increased with the combination of ASA and clopidogrel
• Antiplatelet drugs should not be given in the first 24 hours after alteplase treatment
• Early administration of intravenous aspirin in patients with acute ischemic stroke treated with alteplase does not improve outcome at 3 months and increases the risk of SICH
• Antiplatelet therapy with aspirin 160 to 300 mg daily, given orally and started within 48 hours of onset of presumed ischemic stroke, reduces the risk of early recurrent ischemic stroke and improves long-term outcome
• Mechanical clot disruption and low-dose thrombolytic agent may be a safe and effective treatment option for ischemic stroke.