MEDICATION / ANTIPLATELET THERAPY

Created 01/12/2021, last revision 07/12/2023

• the term ‘”resistance to antiplatelet drugs” should be reserved for situations where specific laboratory tests have documented the drug’s failure to impact its pharmacological target
  
• identification of patients with high residual platelet reactivity (HRPR) may be useful in predicting their risk of atherothrombotic events
• the ideal laboratory test for this purpose is yet to be established; clinical utility and cost-effectiveness remain uncertain ⇒ monitoring of antiplatelet therapy should be considered investigational and is not currently recommended in stroke prevention guidelines

• stroke recurrence despite the use of antiplatelet agents and confirmed patient compliance
• laboratory tests may confirm the appropriate block of platelet function corresponding to the antiplatelet agent used
  
• in such cases, it is crucial to reconsider the possibility of alternative 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 (moyamoya, carotid artery web, etc.)
    

• laboratory resistance can be defined as the failure of antiplatelet agents to specifically inhibit platelet function
  • CLP – failure to effectively block P2Y12 receptors
  • ASA – failure to inhibit platelet function in a TXA2-dependent manner
• instead of “resistance”, the terms HPR (High on-treatment Platelet Reactivity) or HRPR (high residual platelet reactivity) are preferred  [Garabedian, 2013] [Cattaneo, 2013]
• meta-analyses indicate that resistance occurs in up to 30% of cases; these patients exhibit an increased risk of recurrent stroke/TIA

• there are no clear recommendations for managing patients with laboratory-detected resistance to antiplatelet therapy, or for those with recurrent stroke or TIA already on antiplatelet medication
  
• exclude:
  • patient’s noncompliance
  • significant drug interactions (e.g., PPIs with thienopyridines)
  • other stroke mechanisms (e.g., cardioembolism, vasculitis)
    
• there is no evidence to support increasing the dose or switching to a different agent in patients with stroke on aspirin
  
• routine laboratory testing of treatment efficacy, including CYP2C19 genetics, is not recommended in guidelines (due to insufficient evidence supporting its clinical efficacy)
  • aggregometry methods show low correlation and often poor reproducibility (the degree of inhibition varies with the same dose, even when the same method is used)
  • it is not clear whether a single or repeated measurement are necessary when testing platelet functions
    
  • it is not clear whether treatment should be adjusted based on results (increasing the dose may improve a laboratory parameter, but the clinical relevance and risk-benefit ratio remain uncertain)
  • the trial GIANT suggests that patients with the loss-of-function gene (CLP) may benefit from switching to prasugrel or doubling CLP dose (up to a 5-fold reduction in risk of MI, death, and stent thrombosis with medication adjustment was reported)
• clopidogrel is not recommended for CYP2C19*2 and 3 homozygotes; in heterozygotes (1/2, 1/3), CLP should be used preferably as part of dual therapy
  
• long-term combined antiplatelet therapy (DAPT) is generally not recommended
  • lower risk of recurrent ischemia is offset by an increased risk of bleeding (MATCH, FASTER)