MEDICATION / ANTIPLATELET THERAPY

Resistance to antiplatelet therapy

David Goldemund M.D.
Updated on 07/05/2024, published on 01/12/2021

  • stroke may occur despite antiplatelet therapy; the broader term clinical resistance should be used in this scenario if the exact cause of stroke has not yet been identified
  • 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 (indicated by high residual platelet reactivity – HRPR)
    • the ideal laboratory test 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

  • clinical resistance can be defined as the inability of the antiplatelet drug to protect the patient from an ischemic vascular event
  • it may have 2 main causes:
    • resistance to a specific antiplatelet agent (indicated by high residual platelet activity)
      • noncompliance
      • drug interactions decreasing the effect of antiplatelet medication
      • increased production of platelets by the bone marrow in response to stress, introducing into the bloodstream newly formed platelets unexposed to aspirin during the 24-hour dose interval
      • genetic polymorphisms involving platelet receptors, factor XIII, antiplatelet drug metabolism (clopidogrel), etc.
    • factors beyond the effect of antiplatelet medication – if laboratory tests confirm the drug-appropriate inhibition of platelet function, it is crucial to exclude alternative (non-atherothrombotic) causes of stroke
      • 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.)
      • alternative pathways of platelet activation (e.g., red cell-induced platelet activation, stimulation of epinephrine and thrombin receptors on platelets, 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 strong evidence which would support increasing the dose or switching to a different drug
  • 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 single or repeated measurements 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 the 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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Clopidogrel CYP2C19 genotypes
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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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