DRUGS / ANTIPLATELET THERAPY
Antiplatelet therapy in stroke prevention
Created 28/11/2021, last revision 05/11/2023
Antiplatelet therapy in the primary stroke prevention
General population
- aspirin in primary prevention in the general population leads to only a modest or no reduction in CV risk while increasing the risk of bleeding [Zheng, 2019] [Abdelaziz, 2019]
- in the START trial, the addition of aspirin to standard blood pressure treatment did not reduce the risk of cardiovascular events
- ASPREE trial showed that low-dose aspirin as a primary prevention strategy in older adults (> 70 years of age) resulted in a significantly higher risk of major hemorrhage and did not significantly reduce the risk of cardiovascular disease
- negative ASCEND and ARRIVE trials
- data on antiplatelet agents other than ASA in primary prevention are not available
⇒ antiplatelet therapy is not indicated
The population at increased cardiovascular risk
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Antiplatelet therapy in the secondary prevention
Beyond specific situations requiring anticoagulation, the cornerstone of secondary prevention is antiplatelet therapy.
→ antiplatelet therapy in acute stroke
→ antiplatelet therapy in acute stroke
Single antiplatelet therapy (SAPT)
- long-term stroke prevention or early stroke recurrence prevention (if DAPT is contraindicated)
- aspirin (ASA) at a dose of 75-325 mg/d (AHA/ASA 2014 I/A)
- annual ARR of aspirin versus placebo is 1% (NNT 100) – SALT trial
- there is no significant difference in efficacy and safety of dose 81 mg vs. 325 mg (Jones, 2021)
- annual ARR of aspirin versus placebo is 1% (NNT 100) – SALT trial
- clopidogrel (CLP) 75mg 1x d (AHA/ASA 2014 IIa/B)
- annual ARR of clopidogrel versus ASA is 0.5% (NNT 200) CAPRIE trial
- annual ARR of clopidogrel versus ASA is 0.5% (NNT 200) CAPRIE trial
- ticlopidine 250 mg 2x
- annual ARR of ticlopidine versus ASA is 0.9% (NNT 90) – TASS trial
- use only when other agents are contraindicated
- annual ARR of ticlopidine versus ASA is 0.9% (NNT 90) – TASS trial
- novel antiplatelet agents (prasugrel, ticagrelor, etc.) are not yet approved for long-term stroke prevention
- aspirin (ASA) at a dose of 75-325 mg/d (AHA/ASA 2014 I/A)
- ASA+dipyridamole (Aggrenox), ticlopidine and clopidogrel are more effective than ASA (ARR/year < 2%)
- the PROFESS trial showed comparable efficacy of Aggrenox and clopidogrel
- it is unclear whether patients with acute stroke/TIA while on antiplatelet therapy benefit from switching to another antiplatelet agent or from increasing the dose (AHA/ASA 2018 IIb/B-R)
- in clinical practice, switching from aspirin to clopidogrel (or vice versa) is common – a meta-analysis suggests that it may be associated with a reduced risk of recurrent stroke (Lee, 2017)
- consider temporary dual antiplatelet therapy (see below)
- the efficacy of antiplatelet therapy can be verified by aggregometry, but there are no robust data on the clinical benefit of testing and adjusting therapy according to the results of these tests
- in clinical practice, switching from aspirin to clopidogrel (or vice versa) is common – a meta-analysis suggests that it may be associated with a reduced risk of recurrent stroke (Lee, 2017)
- antiplatelet therapy is also indicated in patients with aortic arch plaques (AAPs) (AHA/ASA 2014 I/A)
Dual antiplatelet therapy (DAPT)
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Triple antiplatelet therapy
- TARDIS trial, testing triple therapy (ASA+CLP+dipyridamole) vs. monotherapy, showed no benefit of triple therapy (higher incidence of bleeding negated the positive trend in ischemia reduction with triple therapy)
Combination of aspirin + low-dose DOAC
ASPIRIN + RIVAROXABAN
- positive results of the COMPASS trial
- rivaroxaban 2 x 2.5 mg + ASA 100 mg
- patients with stable cardiovascular disease
- age ≥ 65 years: CAD or PAD
- age < 65 years – atherosclerosis involving at least two vascular territories (CAD+PAD /significant carotid stenosis) or CAD + at least 2 additional risk factors (diabetes, current smoking, GFR < 60 mL/min, heart failure, history of non-lacunar stroke ≥ 1 month)
- those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone
- rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events
Specific situations in antiplatelet therapy
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- aspirin 75-100 mg /d is standard secondary prevention for dissection-related stroke
- consider short-term DAPT (ASA + CLP) for extracranial dissection
- duration of therapy
- DAPT for ≤ 3 months
- SAPT 3-6 months, it is not clear whether to continue with long-term SAPT in patients without connective tissue disease ( studies are not available)
- likely indications for long-term antiplatelet therapy: [Biller, 2014]
- in patients with residual stenosis or persistent occlusion (but evidence of benefit is lacking)
- in patients with a connective tissue disease and recurrent dissections
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- in patients with AF, the preventive effect is small, and the risk of bleeding is not negligible ⇒ antiplatelet therapy cannot be considered a safe and effective alternative to anticoagulant therapy [Själander, 2014] [Hart, 2007]
- according to a large meta-analysis, warfarin is more effective than ASA (risk reduction 64% vs. 19%) with a relatively small increase in the risk of major bleeding < 0.3%/year [Hart, 2007]
- patients after RF ablation had a higher risk of bleeding with aspirin than with warfarin (e.g., GI bleeding 1.9 vs. 0.8%) and also more cardiovascular events (3.7 vs. 1.4%)
[Jacobs, 2017] - according to the AVERROES trial, the annual risk of bleeding with ASA is 3.8% vs. 4.5% with apixaban, while the incidence of cardiovascular events was 3.4% vs. 1.4% [Flaker, 2012]
- comparable bleeding risk with ASA and dabigatran was in the RE-SPECT ESUS trial – major bleeding 1.7% vs 1.4% (3 fatal bleeds)
- ASA + warfarin/DOAC is recommended only temporarily in high-risk patients (recent stent placement, acute coronary syndrome, etc.) (AHA/ASA 2014 IIb/C)
- long-term warfarin+antiplatelet therapy is not indicated due to excessive bleeding risk
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