MEDICATION / ANTIPLATELET THERAPY

Resistance to antiplatelet therapy

Created 01/12/2021, last revision 01/10/2022

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; clinical utility and cost-effectiveness are still unknown ⇒ monitoring of antiplatelet therapy should be considered for investigational purposes, it is not recommended in stroke prevention guidelines

Clinical resistance

stroke recurrence despite the use of antiplatelet agents and good patient 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

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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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 noncompliance 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]

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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