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

  • 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

“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
    • lower risk of recurrent ischemia is offset by an increased risk of bleeding (MATCH, FASTER)

Testing of resistance

ASA

The measurement of thromboxane levels

  • TXA2 rapidly hydrolyzes into the stable metabolite TXB2, which is then transformed to 11-dehydroTXB2 in the liver
  • commercial tests are available to measure serum TXB2  or urine 11-dehydro-TXB2
  • there is a potential bias from extra-renal sources of thromboxane resulting in artificially elevated levels

VerifyNow Aspirin Assay

  • result are available within 10 minutes,
  • bedside monitoring with easy handling, using whole blood
  • therapeutic range for platelet function: 350-549 ARU (Aspirin Reaction Units )
  • resistance:  ≥ 550 ARU  [Hughes, 2015]
thienopyridine

Genetic testing

  • CYP 2C19
    • CYP2C19*2, CYP2C19*2 a CYP2C19*17

      • *1/*1: wild-type, extensive metabolizer
      • *1/*2 or 1/3: intermediate metabolizer (~ 23%)
      • *2/*2 , 2/3 nebo 3/3 : poor metaboliser (~ 2%)
      • *1/*17: rapid metabolizer
      • *17/*17: ultrarapid metabolizer
  • CYP3A4
  • CYP2C9
  • CYP2B6

VerifyNow PRU test (P2Y12 Assay)

  • an automated system based on the LTA principle
  • results available within 10 minutes
  • easy handling, bedside monitoring, uses whole blood
    • results are influenced by hematocrit and platelet count
  • tests the level of P2Y12 receptor blockade in P2Y12 reaction units (PRU)
  •  <180 PRU – suggests P2Y12 inhibitor effect
  • resistance: ≥ 230-240 PRU  [Marcucci,2009] other sources suggest > 200 or even > 180 PRU  [Aradi, 2015]
Optic aggregometry (LTA-Light Transmission Aggregometry)

  • previously considered the gold standard – today, MULTIPLATE or VerifyNow are preferred
  • LTA is time-consuming and influenced by platelet concentration, the agonist type used (ADP, arachidonic acid, adrenaline), and its concentration;  normal fibrinogen concentration is required
  • results vary between laboratories due to method standardization issues
  • cut-off values are also not unified

PFA-100 and 200 test (Platelet Function Analyser-100,200)

  • a promising test for evaluating response to antiplatelet medication
  • the time to capillary closure due to platelet aggregation (closure time) is measured
  • there is a set for both ASA and P2Y12 receptor inhibitors
  • the antiplatelet effect is sufficient at a closure time > 106 s
MULTIPLATE (Multiple Platelet Function Analyzer)

  • a potentially suitable method to monitor antiplatelet therapy efficacy
  • based on the impedance principle
  • compared to LTA, no centrifugation is required; uses whole blood
  • results are reproducible and show a good correlation with PFA-100
  • resistance (high platelet reactivity – HPR) : > 46 units [Aradi, 2015]
  • optimal platelet reactivity (OPR) is defined as 14-46 units
Bleeding test

  • simple but imprecise; affected by various factors

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:

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 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)

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Resistance to antiplatelet drugs
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