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 cardiovascular (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 in this population

The population at increased cardiovascular risk
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Antiplatelet therapy in the secondary stroke prevention

Beyond specific situations requiring anticoagulation, the cornerstone of secondary prevention is antiplatelet therapy.
→ antiplatelet therapy in acute stroke
Single antiplatelet therapy (SAPT)
  • long-term stroke prevention or early stroke recurrence prevention (if DAPT is contraindicated)
    • aspirin (ASA) 75-325 mg once daily (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)
    • clopidogrel (CLP) 75mg once dialy  (AHA/ASA 2014 IIa/B)
      • annual ARR of clopidogrel versus ASA is 0.5% (NNT 200) – CAPRIE  trial
    • ticlopidine 250 mg twice daily
      • annual ARR of ticlopidine versus ASA is 0.9% (NNT 90) – TASS trial
      • use only when other agents are contraindicated
    • novel antiplatelet agents (prasugrel, ticagrelor, etc.) are not yet approved for long-term stroke prevention
  • ASA+dipyridamole (Aggrenox), ticlopidine and clopidogrel are more effective than ASA alone (annual ARR < 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 test results
  • antiplatelet therapy is also indicated in patients with aortic arch plaques (AAPs) (AHA/ASA 2014 I/A)
Dual antiplatelet therapy (DAPT)
  • short-term (usually 3-4 weeks) dual antiplatelet therapy appears to be beneficial and safe for TIA/minor stroke ( SAMMPRIS, CLAIR, CHANCE, POINT, THALES trials)
    • DAPT should be initiated within 24 hours of onset and continued for 3-4 weeks (AHA/ASA 2018 IIa/B-R))
    • beyond the acute period, the risk of hemorrhage outweighs the benefit of ischemic stroke reduction.

→ Antiplatelet therapy in acute stroke or TIA

  • long-term dual therapy (ASA+CLP or ASA+ ticagrelor) is not recommended in patients with either clinically evident cardiovascular disease or multiple risk factors, due to an increased risk of bleeding  (as shown in SPS3, MATCH, and CHARISMA trials)


  • published in 2006
  • included asymptomatic patients with multiple risk factors or those with documented CAD, stroke, or peripheral ischemic involvement (symptomatic) 
  • compared ASA+clopidogrel versus ASA alone
  • no significant efficacy in reducing myocardial infarction, stroke, or cardiovascular death with dual therapy (6.8% vs. 7.3%) was found


  • the trial tested ASA versus ASA+CLP in patients with lacunar infarction
  • the median follow-up time was 3.4 years
  • incidence of the primary endpoint (recurrent ischemic stroke or ICH) was 2.5% vs. 2.7%, but dual therapy was associated with doubled risk of GI bleeding


  • focused on high-risk patients post-stroke or TIA
  • nonsignificant reduction in stroke, myocardial infarction, or vascular death with dual therapy (15.7% vs. 16.7%) was demonstrated
  • this positive trend of dual therapy was offset by an increased risk of life-threatening bleeding
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


  • 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
      • strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin  (Sharma, 2019)
    • 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 daily is the 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 prolonged antiplatelet therapy:  [Biller, 2014]
    • residual stenosis or persistent occlusion (although evidence of benefit is lacking)
    • connective tissue disease and recurrent dissections

→ Arterial dissection

  • begin with aspirin 300mg daily + clopidogrel 75 mg twice daily, starting 3 days before the procedure
    • if clopidogrel is not applicable, ticlopidine 250 mg twice daily can be used as an alternative
  • in acute carotid stenting, administer 600 mg aspirin + 300-450mg of clopidogrel (4-6 tablets) as soon as possible
  • after the procedure, continue dual antiplatelet therapy (aspirin 100 mg + clopidogrel 75 mg daily) for 3 months

    • guidelines provide inconsistent advice from  at least 30 days(AHA) to 3 months (European Society of Vascular Surgery)
    • life-long aspirin therapy is recommended after discontinuing clopidogrel
    • prolonged DAPT (> 180 days) after CAS is associated with lower rates of stroke and increased risk of hemorrhagic complications. The potential benefit of prolonging DAPT must be balanced against the increased risk of hemorrhagic complications    (Sussman, 2021)
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  • in patients with AFib, the preventive effect of antiplatelet therapy 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 compared to warfarin (e.g., GI bleeding 1.9 vs. 0.8%) and also experienced more cardiovascular events (3.7 vs. 1.4%)   Bleeding risk of ASA and apixaban according to AVERROES trial   [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]
    • the RE-SPECT ESUS trial showed comparable bleeding risk with aspirin and dabigatran, with major bleeding rates of 1.7% vs. 1.4% (including 3 fatal bleeds)
  • use of 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 anticoagulant+antiplatelet therapy is not indicated due to excessive bleeding risk
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Antiplatelet therapy in stroke prevention