MEDICATION / ANTIPLATELET THERAPY
Resistance to antiplatelet therapy
David Goldemund M.D.
Updated on 11/03/2024, published on 01/12/2021
- 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
Clinical resistance
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stroke recurrence despite the use of antiplatelet agents and confirmed patient compliance
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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
- laboratory resistance can be defined as the failure of antiplatelet agents to specifically inhibit platelet function
- CLP, ticagrelor – 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), but may be beneficial
- 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
- in clopidogrel-resistant patients, switching to ticagrelor is reasonable (CHANCE 2 trial)
- long-term combined antiplatelet therapy (DAPT) is generally not recommended
Testing of resistance
ASA |
The measurement of thromboxane levels
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VerifyNow Aspirin Assay
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thienopyridine |
Genetic testing
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VerifyNow PRU test (P2Y12 Assay)
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Optic aggregometry (LTA-Light Transmission Aggregometry)
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PFA-100 and 200 test (Platelet Function Analyser-100,200)
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MULTIPLATE (Multiple Platelet Function Analyzer)
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Bleeding test
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Aspirin resistance
- laboratory resistance = the 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:
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Clinical
Cellular
Genetic
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- a meta-analysis of 20 trials (prospectively following 2,930 patients with CVD) showed a higher risk of cardiovascular events in patients with aspirin resistance, regardless of the detection 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 score) and a greater infarct size in acute stroke patients [Zheng, 2013]
Clopidogrel resistance
- the issue with resistance or variable sensitivity also applies to clopidogrel
- CLP resistance is characterized by the inability to block P2Y12 receptors effectively
- it often occurs in patients who have aspirin resistance as well
- according to meta-analysis, the prevalence of CLP resistance is 27-35%, and patients with resistance have a higher risk of recurrent stroke/TIA, even on DAPT (as indicated by subanalyses of SPS3, CHANCE, and other trials) [Wang, 2016] [Hernandez-Suarez, 2017]
- in clopidogrel-resistant patients, ticagrelor can be used (CHANCE 2 trial)
- patients with minor ischemic stroke/TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel
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Ticagrelor resistance
- ticagrelor has a lower risk of resistance compared to clopidogrel, but it is not rare (0-20%) (He, 2023)
- ticagrelor-resistant patients have more ischemic thrombotic events than ticagrelor responders
- mechanisms underlying ticagrelor resistance may include:
- genetic factors (polymorphisms in the CYP3A4/5 enzymes responsible for ticagrelor metabolism or the P2Y12 receptor itself)
- drug-drug interactions that reduce ticagrelor absorption or metabolism
- inadequate dosing
- patient-specific factors such as high platelet reactivity, which can be influenced by clinical conditions like diabetes mellitus or obesity
- assessment of ticagrelor resistance:
- light transmission aggregometry (LTA) is considered the gold standard
- VASP (vasodilator-stimulated phosphoprotein) phosphorylation assays, which evaluate the inhibitory effect of ticagrelor on platelet aggregation
- VerifyNow, PFA P2Y, and Multiplate are three instruments that are currently widely used as alternatives to LTA (He, 2023)
- ticagrelor-resistant: VerifyNow ≥208 PRU, Multiplate ≥468 AU, PFA P2Y CT* < 106 s
- instead of the “absolute value” definition, there are also a few studies that used the “relative ratio” definition, which focuses on the decreased rate of the platelet aggregation function before and after antiplatelet therapy – patients with a PRU value that decreased < 30% from the baseline were defined as having ticagrelor resistance or HTPR
- management:
- ensure adherence to medication
- switch to an alternative antiplatelet agent with a different mechanism of action (e.g., prasugrel or clopidogrel with genetic testing guidance), or adding an anticoagulant in selected cases
- other possible solutions for ticagrelor resistance are under investigation (adjusting the dose or changing the drug form)