Antiplatelet therapy in the primary stroke prevention

General population
  • aspirin in primary prevention in the general population leads only to a modest or no reduction in CV risk while increasing the risk of bleeding   [Zheng, 2019] [Abdelaziz, 2019]
    • in the START trial, adding aspirin to standard management for blood pressure 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 lower the risk of cardiovascular disease than
    • negative ASCEND and ARRIVE trials
  • data on antiplatelet agents other than ASA are not available in primary prevention

⇒  antiplatelet therapy is not indicated

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 the 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 effectivity and safety of dose 81 mg vs 325 mg (Jones, 2021)
    • clopidogrel (CLP) 75mg 1xd  (AHA/ASA 2014 IIa/B)
      • annual ARR of clopidogrel versus ASA is 0.5% (NNT 200) CAPRIE  trial
    • ticlopidine 250 mg 2xd
      • annual ARR of ticlopidine against 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 in long-term stroke prevention
  • 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, aspirin is often switched to clopidogrel (or vice versa) – 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)
    • efficacy of antiplatelet therapy can be verified by aggregometry, but there are no robust data about the clinical benefit of testing and adjustment of therapy according to the results of these tests
  • antiplatelet therapy is indicated even 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  [expand title=”  “]
    • rivaroxaban 2 x 2.5 mg + ASA 100 mg
    • patients with stable cardiovascular disease
      • age ≥ 65 years: CAD or PAD
      • age < 65 years – documentation of atherosclerosis involving at least two vascular bed or at least 2 additional risk factors (DM, 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 [/expand]

Specific situations in antiplatelet therapy

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  • aspirin  75-100 mg /d  is standard secondary prevention in dissection-related stroke
  • consider short-term DAPT (ASA + CLP) in 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 disorder ( 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

→ more about dissection here

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  • in AF patients, 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 on aspirin than on warfarin (e.g., GI bleeding 1.9 vs 0.8%) and also 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 on ASA is 3.8% vs 4.5% on apixaban, while the incidence of cardiovascular events was 3.4% vs 1.4% [Flaker, 2012]
    • comparable bleeding risk on 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, 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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