Individualised Antiplatelet Therapy
Data from a recent study suggest that pharmacodynamic and genetic information may have clinical relevance in overcoming clopidogrel resistance and avoiding ischaemic and bleeding events among high-risk patients.83
However, no such increase in bleeding was observed among subsets of patients with diabetes81 (STEMI).82
or ST-segment-elevation myocardial infarction However, this study is limited by its very
small size (n=7) and the specific characteristics in the selected patients: all patients had STEMI and exhibited clinical resistance (stent thrombosis on clopidogrel treatment) and biological resistance (high platelet aggregation). Additionally, four of the seven patients had a history of MI, and six patients were CYP2C19*2 carriers.
The novel non-thienopyridine P2Y12 ADP receptor antagonist ticagrelor (AZD 6140) has recently demonstrated its clinical potency. This agent
acts directly on the P2Y12 receptor. Data from the A Study of Platelet Inhibition and Patient Outcomes (PLATO) study demonstrate significant
reductions in the rate of cardiac death, MI or stroke with ticagrelor over clopidogrel among patients with an ACS.84
Recent data from
phase II studies also show that ticagrelor elicits a more rapid onset and offset of platelet inhibition compared with clopidogrel in patients with stable coronary artery disease (CAD) receiving concomitant aspirin therapy.85,86
The ability to rapidly and reversibly inhibit platelet reactivity
makes ticagrelor an attractive new candidate in platelet inhibition therapy. However, the twice-daily dosing schedule of ticagrelor has raised concerns regarding patient compliance.
Genetic Testing to Predict Responsiveness
As previously mentioned, genetic factors have been proposed to influence patient responsiveness to antiplatelet therapies.28,29 Importantly, some genetic polymorphisms have been associated with cardiovascular complications and increased rates of major
cardiovascular events.21,34,52–54
In particular, findings on CYP2C19 have
been of the most interest, with the greatest consistency in the literature with regard to clopidogrel response. Moreover, there are strong prognostic implications for carriers of the allele receiving clopidogrel
therapy.52–54,87
Carriage of the CYP2C19*2 allele is associated with
significant excess mortality owing to increased risk of stent thrombosis among patients treated with clopidogrel following stent implantation.87,88 The presence of this polymorphism can therefore be interpreted as an independent predictor of recurrent events, especially in patients with ACS who have undergone stent PCI and are exposed to clopidogrel.88 While specific genetic polymorphisms are therefore known to affect clopidogrel response, there is ongoing debate as to whether these polymorphisms have a direct clinical impact or not, particularly among stable patients without stenting. This underscores that there is indeed merit in the use of genetic testing; the findings concerning CYP2C19*2 have prompted many to suggest genetic testing for this polymorphism to predict clopidogrel response.
Genetic information about drug metabolism can be used to assist in subsequent clinical decisions regarding drug therapy, but this practice is not recommended as there is currently insufficient evidence to support the use of genetic testing in this way. This highlights the need for additional investigation and prospective studies to establish how to best treat patients based on their genotypes.
Principles and Challenges of Platelet Function Assays
The rationale behind platelet function testing is to acquire clinically useful information regarding the degree of platelet inhibition to identify
EUROPEAN CARDIOLOGY
patients with poor response to antiplatelet therapy. Doing so may allow cardiologists to determine the potential for recurrence of atherothrombotic events. Recently developed alternatives to platelet function assays involve the assessment of clinical variables in correlation with the response to antiplatelet therapy. One such method is the Patient Refined Expectations for Deciding Invasive Cardiac Treatments (PREDICT) score, a simple scoring system that uses data from the clinical history of patients receiving clopidogrel to identify those who are at increased risk of residual platelet reactivity.89
The
clinical variables used include well-known risk factors for stent thrombosis, such as age >65 years, ACS, diabetes, renal failure and reduced left ventricular function; the resulting score has been shown to correlate to the risk of developing high on-treatment platelet reactivity.
Historically, turbidometric light transmittance aggregometry (LTA) was the ‘gold standard’ of platelet function assays as the most widely used technique to monitor the effects of antiplatelets on platelet aggregation in plasma. Multiple widely available studies using LTA have drawn correlations between impaired platelet inhibition and adverse outcomes, despite arbitrary definitions of response and non-
response.6–10,12,39
However, LTA is not standardised and is subject to
many methodological variables; moreover, it is very time-consuming and labour-intensive, precluding the use of this technique in daily practice. Other platelet function assays employ flow cytometry, either to determine activation-dependent changes on platelet surface membrane receptors, such as P-selectin, glycoprotein (GP) IIb/IIIa and leukocyte–platelet aggregates, or by vasodilator-stimulated phosphoprotein (VASP) to measure intracellular signalling that reflect
the levels of inhibition or activation of P2Y12. While these assays are advantageous in that they can use whole blood to determine the degree of platelet inhibition, they are also limited by various technique complexities (see Table 1).
The development of bedside or ‘point-of-care’ platelet function assays has allowed for simpler and more rapid assessments of platelet function using whole-blood samples, presenting the potential for widespread clinical use of these tests to identify patients who are at risk of recurring cardiac events. The recent introduction of the VerifyNow® instrument, formerly the Rapid-Platelet Function Analyzer (RPFA, Accumetrics Inc.), provides a method of obtaining rapid reproducible evaluations of platelet function in whole blood, whether patients are treated with aspirin, clopidogrel or GPIIb/IIIa receptor antagonists. Each of these three tests, using their respective disposable cartridges and platelet agonists, has shown good correlation to LTA.90–94
Multiple-electrode platelet aggregometry, as in
Multiplate® (Dynabyte), is another novel method of measuring platelet aggregation in whole blood, recording the adherence of activated platelets to sensor wires. This system is sensitive for aspirin, clopidogrel and GPIIb/IIIa antagonists, with demonstrated correlation to LTA95
and predictivity for thrombotic events.17,18,96 Similarly,
Plateletworks® (Helena Laboratories) measures platelet aggregation. The Platelet Function Analyzer (PFA-100®, Dade Behring) assesses platelet adhesion and aggregation under high shear conditions in
vitro.97–99
This semi-automated assay uses whole blood in disposable
cartridges, and has shown good reproducibility between laboratories. The Thromboelastography® (TEG) Platelet Mapping System measures platelet activation based on blood coagulation and clot strength. Various haematological parameters, including platelets, plasma factors, erythrocytes and leukocytes, are obtained by constantly rotating whole blood with a platelet agonist in a cylindrical cup.19,100
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