MEDICATION / ANTIPLATELET THERAPY

Resistance to antiplatelet therapy

Created 01/12/2021, last revision 12/05/2022

  • the definition ‘resistance to antiplatelet drugs’ should be limited to situations in which the failure of the drug to hit its pharmacological target has been documented by specific laboratory tests
  • identification of patients with high residual platelet reactivity (HRPR) may be useful to predict their risk of atherothrombotic events
  • the ideal laboratory test needs to be identified and there is still unknown clinical utility and cost-effectiveness ⇒ monitoring of antiplatelet therapy should be considered for investigational purposes  and it is not recommended in stroke prevention guidelines

Clinical resistance

  • stroke recurrence despite the use of antiplatelet agents and good patient´s compliance
  • laboratory tests may confirm a block of platelet function corresponding to the antiplatelet agent
  • in such cases, always reconsider the possibility of different stroke etiology
    • e.g., cardioembolism in paroxysmal atrial fibrillation (⇒ order repeated ECG Holter or long-term ECG monitoring)
    • extensive atherosclerosis with embolization of calcified plaques
    • advanced arteriolopathy
    • vasculitis or non-inflammatory vasculopathy

“Laboratory” resistance

  • the inability of antiplatelet agents to inhibit platelet function in a specific manner
    • CLP – inability to effectively block P2Y12 receptors
    • ASA – inability to inhibit platelet function in a TXA2-dependent manner
  • instead of resistance, the term HPR (High on-treatment Platelet Reactivity) or HRPR (high residual platelet reactivity) is also used  [Garabedian, 2013] [Cattaneo, 2013]
  • according to meta-analyses, resistance is present in up to 30% of cases, these patients have a higher risk of recurrent stroke/TIA
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Testing of resistance

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Aspirin resistance

  • laboratory resistance = inability of aspirin to reduce TXA2 production (COX-1 dependent) and subsequently inhibit TXA2-dependent platelet function
Variable response to aspirin may be due to these factors:

Clinical

  • absorption failure
  • patient´s non-compliance
  • drug interactions (e.g. ibuprofen)

Cellular

  • insufficient COX-1 suppression
  • overexpression of COX2 mRNA
  • erythrocyte-mediated platelet activation
  • increased sensitivity of platelets to collagen and ADP)
Genetic
  • COX-1 a COX2 polymorphisms
  •  GP IIb/IIIa receptor polymorphism
  • VWF receptor polymorphism
  • a meta-analysis of 20 trials (prospectively followed 2930 patients with CVD) showed a higher risk of CV events in patients with aspirin resistance, regardless of the method used. Aspirin resistance was detected in 28% of patients. However, the meta-analysis did not demonstrate a clinical effect of add-on antiplatelet therapy in aspirin-resistant patients [Krasopoulos,  2008]
  • aspirin resistance seems to be associated with a more severe neurological deficit (higher NIHSS) and greater infarct size in acute stroke patients [Zheng, 2013]

Clopidogrel resistance

  • the problem with resistance or variable sensitivity also applies to clopidogrel
  • CLP resistance is defined as the inability to block P2Y12 receptors effectively
  • it often occurs in patients who have aspirin resistance as well
  • according to meta-analysis, the prevalence is 27-35%, and patients with resistance have a higher risk of recurrent stroke/TIA even on dual antiplatelet therapy (subanalyses of SPS3, CHANCE, and other trials)  [Wang, 2016] [Hernandez-Suarez, 2017]
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