A contemporary viewpoint on ‘aspirin resistance’

Figures & data

Table I. Platelet function tests commonly used for measurement of antiplatelet effect of aspirin.

Laboratory method	Principle of the method	Remarks
Aggregometry
Turbidimetric light transmittance aggregometry (LTA)	Analysis of light transmission in anti-coagulated platelet-rich plasma after stimulation of platelets with agonists (AA, ADP, epinephrine, collagen)	Lack of standardization. Low reproducibility. Depending on the type and concentration of agonist used, the aggregation response only partially and variably modulated by TxA2, synthesized from AA in the platelet membrane, or ADP, released from platelet granules
Impedance aggregometry	Measurement of electrical impedance between two platinum electrodes immersed in a sample of whole blood after platelets form aggregates on them following addition of an agonist	Drawbacks listed for LTA are also applicable to this technique. Few studies using this assay have been performed in patients on aspirin therapy
Point-of-care assays
Platelet function analyzer (PFA-100)	Whole blood assay. Assessment of closure time—in-vitro cessation of high shear blood flow through a 150-µm aperture in a membrane coated with collagen plus ADP or collagen plus epinephrine by platelet plug	Assay is sensitive to many variables including platelet count, red blood cells, platelet reactivity to collagen, plasma vWF, the effects of which on platelet aggregate formation can easily outweigh the effects of mild inhibition of platelet function
Rapid platelet function assay (Ultegra RPFA-ASA, VerifyNow Aspirin)	Whole blood assay. Measurement of the agglutination of fibrinogen-coated beads by platelets stimulated by agonist (AA, propyl gallate, ADP, TRAP cartridges)	Diagnostic criterion for aspirin resistance is based on a cut-off established by comparison with optical platelet aggregation in response to epinephrine after a single 325-mg dose of aspirin. Although sensitive to antiplatelet effect of aspirin, epinephrine-induced platelet aggregation is not highly specific for the pharmacological effect of aspirin
Multiple platelet function analyzer (Multiplate®analyzer)	Whole blood assay. Measurement of electrical impedance between two pairs of silver-coated sensor wires incorporated in a test cell, after platelets stick on them following addition of an agonist (ADP, ADP + prostaglandin E1, AA, TRAP-6, collagen, ristocetin)	Majority of studies using this assay have been performed in patients on both aspirin and clopidogrel therapy and showed that this assay can be used for predicting early stent thrombosis in patients after PCI
Other assays
Thromboelastography (TEG)	Whole blood assay. Measurement of viscoelastic changes that occur during clot formation in whole blood	It is influenced by platelet function, coagulation factors, natural inhibitors of coagulation and fibrinolysis. Largely platelet-independent unless platelet agonists used. Needs to be validated in clinical settings

Figure 1. Potential mechanisms of aspirin resistance.

Table II. Studies evaluating the effect of modifying therapy based on platelet responsiveness to aspirin (113–122).

Study	Design	Treatment arms	Outcomes measure
BOCLAplan	Design: Treatment, open label, single group assignment, safety/efficacy study Condition: CAD-PCI (either ACS or stable CAD) Enrolment: 500	Aspirin, clopidogrel: If the treatment with aspirin and/or clopidogrel was insufficient (platelet function testing) the dose was increased (aspirin 300 mg, aspirin 500 mg, clopidogrel 150 mg) or the drug was changed (clopidogrel to ticlopidine 2 × 250 mg, or prasugrel 10 mg, prasugrel 20 mg)	Whole blood LTA 48 hours after PCI to evaluate responders and low-responders to antiplatelet therapy. In the latter case alternative antiplatelet therapy according to the study plan was administered (time-frame: 2 years)
ASCET	Design: Treatment, randomized, open label, active control, parallel assignment, safety/efficacy study Condition: CAD Enrolment: 1,001	Aspirin (active comparator): aspirin 160 mg Clopidogrel (active comparator): clopidogrel 75 mg Patients were randomized to either continued treatment with aspirin 160 mg/d or change to clopidogrel 75 mg/d after initial determination of their platelet reactivity while on aspirin treatment (PFA-100^®)	Primary: composite end-point of all-cause death, non-fatal MI, ischaemic stroke, and unstable angina (time-frame: 2 years) Secondary: in-stent restenosis and/or thrombosis detected by coronary angiography (time-frame: 2 years)
RESIST	Design: Treatment, randomized, open label, parallel assignment, efficacy study Condition: stable angina–PCI Enrolment: 36 patients resistant to aspirin (VerifyNow Aspirin)	Conventional strategy: patient receives 325 mg aspirin orally and loading does of 600 mg clopidogrel at time of procedure Aggressive strategy (active comparator): patient receives 325 mg aspirin orally and loading dose of 600 mg clopidogrel at time of procedure with addition of IV GP IIb/IIIa inhibitor bolus intra-procedurally	Primary: elevation of cardiac enzyme (time-frame: 24 hours) Secondary: MACE (time-frame: 30 days): death, MI, stent thrombosis, urgent revascularization, bleeding
Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting	Design: Prevention, randomized, open label, parallel assignment, safety/efficacy study Condition: CAD Enrolment: 200 patients resistant to aspirin (multiple electrode aggregometry)	Patients with inappropriate response to aspirin 300 mg therapy after CABG randomized to receive aspirin monotherapy (no intervention) or dual antiplatelet therapy (active comparator): clopidogrel 75 mg in addition to aspirin	Primary: MACE events (death, non-fatal MI, stroke, cardiac rehospitalization) (time-frame: 6 months)
ARCTIC	Design: Treatment, randomized, open label, parallel assignment, efficacy study Condition: CAD, elective PCI-DES Enrolment: 2,500	First randomization: Monitoring arm (experimental): dose adjustment of both aspirin and clopidogrel in suboptimal responders identified based on a point of care assay (VerifyNow). Conventional arm (active comparator): fixed dose regiment of both aspirin and clopidogrel in all patients following DES implantation according to international guidelines Second randomization after 1 year of follow-up: Pursuit arm (experimental): pursuit of a dual oral antiplatelet therapy (aspirin and clopidogrel) beyond 1 year Interruption arm (active comparator): interruption of clopidogrel therapy.	Primary: composite end-point of death, MI, stroke, urgent coronary revascularization, stent thrombosis assessed at 1 year for the first hypothesis and between 6 up to 18 months of follow-up for the second hypothesis (time-frame: during the study—1 year in both ‘monitoring’ and ‘conventional’ arms and during the period from 6 up to 18 months in the ‘interruption’ and ‘pursuit’ arms)
TEG-CABG	Design: Treatment, randomized, open label, parallel assignment, safety/efficacy study Condition: elective/subacute multivessel CABG Enrolment: 375 TEG and multiplate aggregometry are performed to assess platelet reactivity and resistance to aspirin and clopidogrel	Clopidogrel+aspirin, hypercoagulable (experimental) Aspirin, hypercoagulable control (active comparator) Aspirin, normocoagulable control (active comparator)	Primary: graft patency at 3 months and 1 year (time-frame: 3 months, 1 year) Secondary: - rate of other thromboembolic events (e.g. MI, stroke, pulmonary embolus, etc.) (time-frame: 3 months, 1 year) - assessing coagulation profile pre- and postoperatively, including aspirin and clopidogrel resistance (time-frame: 1 year)
The ITALIC Study	Design: Treatment, randomized, open label, parallel assignment, safety/efficacy study Condition: Patients after DES implantation, excluding primary PCI for acute MI and left main PCI Enrolment: 3,200	Aspirin-clopidogrel regimen versus mono-aspirin regimen after 6 months of dual antiplatelet therapy in good aspirin responder patients	Primary: composite end-point of death, MI, repeat urgent revascularization, stroke requiring a new hospitalization, major bleedings at 12 months Secondary: Incidence the same composite end-point at 24 and 36 months and incidence of minor bleeding complications at 12, 24, and 36 months