Antiplatelet therapy is the standard of care for patients with acute coronary syndromes (ACS) and/or patients undergoing percutaneous coronary intervention (PCI) with stenting.1–3 Plaque rupture and/or iatrogenic vascular damage during PCI would normally result in the development of intravascular thrombus. Findings across multiple investigations consistently demonstrate the effectiveness of dual antiplatelet therapy with aspirin and clopidogrel in the reduction of atherothrombotic complications, in both the short and long term.4 However, several recent studies have demonstrated wide inter-individual differences in the magnitude of on-treatment platelet reactivity.5–18 The heterogeneous nature of the response to oral antiplatelet therapy results in the so-called ‘high on-treatment platelet reactivity’ state in a substantial subset of patients; even more importantly, this state has been linked to adverse outcomes. Consequently, much attention is now being focused on monitoring antiplatelet inhibition as an evaluation of an individual patient’s pharmacological response to antiplatelet therapy.19
Limitations of Antiplatelet Therapies
Antiplatelet agents are downregulators of haemostasis. Although long-term use of oral antiplatelet therapies in patients with atherothrombotic burden can in fact reduce the incidence of atherothrombotic events, it has also been previously associated with a risk of bleeding.20,21 A further limitation associated with antiplatelet therapies is occasional poor pharmacological response or persistent high on-treatment platelet reactivity.
Aspirin
The routine administration of aspirin during cardiovascular interventions is associated with decreased atherothrombotic events. Aspirin preferentially and irreversibly inhibits the constitutively expressed cyclo-oxygenase-1 (COX-1) enzyme, which has regulatory housekeeping cellular functions including vascular haemostasis, gastric mucosal integrity and renal blood flow. More importantly, the inhibition of COX-1 effectively prevents downstream platelet signalling events from occurring that would otherwise result in platelet activation and aggregation: metabolisation of arachidonic acid from COX-1 to prostaglandins G2 (PGG2) and H2 (PGH2); conversion of PGH2 to thromboxane A2 (TXA2); cell-membrane-mediated platelet activation; and irreversible platelet aggregation by TXA2.
True lack of response to aspirin is rare. Rather, the observed high on-treatment platelet reactivity can result from a number of factors. Several studies have attempted to estimate the incidence of poor response to aspirin; reports identify anywhere between 0.4 and 83.3% of patients with cardiovascular disease as being poor responders.22 This wide range has been attributed to a number of differences in study design, with variations in study populations, definitions of aspirin non-responsiveness, the specific platelet function assay used, dosing regimens and patient compliance to therapy.23,24 Platelet turnover is biologically dynamic such that 10% of the platelet pool is replenished on a daily basis. This, in combination with the fact that the half-life of aspirin is quite short at 15–20 minutes, means not only that repeat daily dosing of low-dose aspirin can fully inhibit platelet COX-1, but also that the magnitude of platelet function can greatly vary depending on the timing of the assay relative to when a patient takes his or her aspirin. Other studies have reported that the prevalence of poor response to aspirin is higher among women25,26 and also increases with age.26,27 Genetic factors may also play a role:28,29 several genetic polymorphisms have been implicated as having an influence on aspirin response and poor prognosis.30–37 However, the degree of corroborating evidence appears to vary substantially according to the polymorphism in question.
The clinical consequences of aspirin non-response are unclear, and any data linking this to clinical outcome are weak. Small studies have suggested that patients with poor response, as determined by platelet function tests, are at an increased risk of major atherothrombotic events.16,25,38–40 None of the platelet function assays used in these studies was specific for COX-1, which could lead to poor assessment of aspirin efficacy.41 Recent data from a prospective study suggest that poor clinical outcomes in patients receiving aspirin therapy can be attributed to multiple mechanisms, including but not confined to inadequate inhibition of COX-1.42 Using clinical outcomes information at a mean of 25 months after platelet function testing, COX-1-dependent and -independent assays of platelet function were found to correlate with the occurrence of subsequent cardiovascular events (cardiovascular death, myocardial infarction [MI], revascularisation-related hospitalisation or ACS). By contrast, no such correlation was found with indirect measures of platelet COX-1. Additionally, many of the aforementioned studies16,25,39,40 did not thoroughly address treatment compliance, which is proposed to be a major cause of poor pharmacological response to aspirin.43–46 Upper gastrointestinal side effects associated with aspirin therapy have been shown to negatively affect compliance, with 12% of patients adopting irregular use of aspirin owing to bothersome upper gastrointestinal symptoms.47 This may also account for the poor biological response observed. The inability to verify a patient’s adherence to aspirin therapy presents potential for the use of platelet function assays to determine platelet reactivity to aspirin.
Clopidogrel
The thienopyridine derivative clopidogrel, being a prodrug, requires transformation to an active metabolite through the hepatic cytochrome P450 (CYP) system, and then irreversibly inhibits the P2Y12 receptor and restricts platelet activation. The mechanisms leading to high on-clopidogrel platelet reactivity are not clear, but, similar to poor response to aspirin, are multifactorial. Carriers of polymorphisms in genes encoding for the two-step process oxidising clopidogrel from prodrug to active metabolite have demonstrated diminished responses to the drug’s antiplatelet effects.48–51
In particular, the loss of function due to the CYP2C19*2 polymorphism inactivates the enzyme and impairs metabolism of clopidogrel, ultimately leading to high on-clopidogrel platelet reactivity. This polymorphism is present in an estimated 30% of the general Caucasian population and is associated with increased rates of major cardiovascular events; for example, the rate of stent thrombosis is three to six times greater among carriers than non- carriers of the CYP2C19*2 variant.52–54 Perhaps more importantly, recent data from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management (CHARISMA) sub-study show that patients homozygous for CYP2C19*2 were at high risk of atherothrombotic events regardless of whether they were taking clopidogrel or placebo, although the risk was not statistically significant for the placebo group.55 This corresponds with previous studies in which certain genes have been linked to pre-existing variability in platelet function, independent of clopidogrel use.56 Such information has prompted much discussion concerning the role of this allele in drug metabolism and cardiovascular risk.
Intrinsic factors are also important determinants of clopidogrel responsiveness. Several studies have shown that patients with ACS, increased body mass index and/or diabetes are more prone to increased baseline platelet reactivity.57–60 Several studies have demonstrated that this variability in clopidogrel response among patients with ACS has serious clinical outcomes, including stent thrombosis, post-stenting ischaemic events and peri-procedural MI.7,9,10,61–64 Incomplete inhibition of the P2Y12 receptor and high on-clopidogrel platelet reactivity are proposed risk factors for sub-acute stent thrombosis.65 Clopidogrel response can also vary because of inter-individual differences in drug absorption, resulting in lower levels of the active metabolite.66 Medications such as statins and certain proton pump inhibitors (PPIs) have been proposed to affect the metabolisation of clopidogrel by the CYP isozyme 3A4, although data supporting this are controversial.6,67–72 Individuals with low baseline metabolic activity of the CYP3A4 enzyme have also been shown to have poor clopidogrel responsiveness.73
Overcoming Poor Response to Antiplatelet Therapies
Evidence as to whether modifications can improve clinical outcome in patients who are poorly responsive to antiplatelet therapy is currently limited. While observations from earlier studies have suggested that increased aspirin doses – some as high as 1,300mg/day – have the potential to enhance clinical benefits in patients with poor response to antiplatelets, large clinical trials have found no such benefits. They have also not shown any trend towards clinical benefits with high aspirin doses.74 However, it has been proposed that increasing the frequency of aspirin administration rather than the dose can provide safer and more effective control over platelet inhibition, as the effect of aspirin is variably detected by functional assays depending on the time delay from intake to platelet function measurement.75 Interestingly, a substantial number of patients with poor response to clopidogrel may also be poorly responsive to aspirin, such that these patients face an increased risk of atherothrombotic events.76,77 This underscores the existing need to address poor responses to antiplatelet therapies.
Prasugrel is an oral and irreversible third-generation thienopyridine that shows good potential as an alternative to clopidogrel therapy. Similar to clopidogrel, prasugrel is a prodrug requiring biotransformation to an active metabolite via the CYP system. However, a recent analysis of data from the phase III Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) study (NCT00097591) has shown that, unlike clopidogrel, the common functional genetic variants in CYP genes have no effect on active prasugrel metabolite levels, the resulting platelet reactivity or clinical cardiovascular event rates among patients receiving the drug.78 While prasugrel has been shown to induce more rapid and more potent platelet inhibition compared with clopidogrel,21,79,80 this improvement in clinical efficacy comes at the expense of excess bleeding among patients with ACS undergoing PCI.21 However, no such increase in bleeding was observed among subsets of patients with diabetes81 or ST-segment- elevation myocardial infarction (STEMI).82 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, 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 A Study of Platelet Inhibition and Patient Outcomes (PLATO) demonstrate significant reductions in the rate of cardiac death, MI or stroke with ticagrelor over clopidogrel among patients with 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, 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 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, which 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 its 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
The Utility of Platelet Function Assays
There is great interest in the role of platelet reactivity in risk stratification of patients with CAD, and several emerging studies suggest that platelet reactivity is a notable risk factor for the development of atherothrombotic disease. Using various risk scores, Marcucci et al. found that the incorporation of high residual platelet reactivity, as measured by the VerifyNow P2Y12 assay, as a clinical entity into a model significantly and independently increased the predictability of cardiovascular death and non-fatal MI.13 This model was adjusted for various clinical characteristics, including cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction (LVEF), multivessel disease, stent length, type of stent, bifurcation lesions, number of treated lesions and use of GP IIb/IIIa inhibitors. The POPular study was the first ever head-to-head comparison among eight platelet reactivity assays (see Table 2) to determine their capability to predict adverse clinical outcomes.64 According to the recently presented preliminary data, logistic regression modelling using clinical factors determined an area under the curve (AUC) of 0.64 for predicting the occurrence of major adverse atherothrombotic events at one year; this increased to an AUC of 0.72 with the addition of procedural risk factors (e.g. lesion and stent characteristics). However, the inclusion of high on-treatment platelet reactivity significantly increased AUC for LTA 5μmol/litre ADP, LTA 20μmol/litre ADP, VerifyNow P2Y12 and Plateletworks, thereby drawing an association between these tests and the predictability of atherothrombotic outcomes at one year. By comparison, the other platelet function tests provided no additional value and therefore no ability to predict outcomes based on platelet reactivity. It should be noted that several studies have reported negative predictive values for platelet function assays as being in the mid to high 90% range,23,101,102 suggesting that platelet function testing alone may not predict clinical events.
The increased predictability of cardiovascular events due to platelet reactivity has also been evaluated in other formats. Maximum plasma levels of the active metabolite of clopidogrel (600mg loading dose) in vivo has been strongly correlated with platelet function when measured by flow-cytometric VASP, VerifyNow P2Y12 and, to a lesser extent, LTA 20μmol/litre ADP.103 No significant association was observed with LTA 5μmol/litre ADP, whole-blood aggregometry or IMPACT-R. The results of this study suggest flowcytometric VASP and VerifyNow P2Y12 to be appropriate for monitoring peak plasma levels of the active metabolite of clopidogrel, with the greatest likelihood of accurate measurement of in vivo biological drug activity.
To date, no specific recommendations have been published for platelet function testing in routine clinical practice, largely because it is not clear whether modifications in antiplatelet therapy based on responsiveness as determined through these assays can reduce the occurrence of major adverse cardiovascular events.100 However, class IIB recommendations from the American College of Cardiology (ACC)/American Heart Association (AHA) have stated that platelet aggregation studies are warranted in patients undergoing PCI who are at risk of sub-acute stent thrombosis, with the option of increasing their maintenance dose of clopidogrel from 75 to 150mg/day in order to suppress platelet reactivity below 50%.104 Recent studies have evaluated the effect of modifying therapy on clinical outcome for patients deemed non-responsive as measured by platelet function tests.
In a multicentre prospective study with 429 patients, Bonello et al. demonstrated that patients who exhibit high on-treatment platelet reactivity as determined by VASP flow cytometry (platelet reactivity index >50%) were able to benefit from tailored clopidogrel loading dose therapy.11 The candidates for non-emergent PCI who were randomised to receive up to three additional 600mg loading doses of clopidogrel to achieve a platelet reactivity index <50% before PCI had a significantly lower rate of stent thrombosis (0.5 versus 4.2%; p<0.01). They also had a significantly lower rate of major adverse cardiovascular events (0.5 versus 8.9%; p<0.001) than patients undergoing immediate PCI. These benefits were achieved with no increased risk of bleeding.
In the 3T2R study by Valgimigli et al., patients who underwent elective coronary angioplasty while taking aspirin or clopidogrel or both and continued to exhibit high on-treatment platelet reactivity were randomised to receive the antiplatelet tirofiban or placebo.105 Patients who received tirofiban were found to have a lower rate of peri-procedural increases in troponin I/T ratio (20.4 versus 35.1%; p=0.009), indicative of MI, than those receiving placebo. They also had lower rates of major adverse cardiovascular events within 30 days based on serum creatinine kinase-MB (CK-MB) (3.8 versus 10.7%; p=0.031). The overall incidence of bleeding was low and did not differ between the treatment arms.
A study by Cuisset et al. has also explored the benefits of adjusting antiplatelet therapy according to platelet reactivity.106 A total of 149 patients with high on-clopidogrel platelet reactivity designated for elective PCI were randomised to the GPIIb/IIIa antagonist abciximab followed by heparin (active group) or heparin alone (conventional group), with the hypothesis that those receiving tailored antiplatelet therapy would experience greater benefits. At one month, patients in the active group exhibited a significantly lower rate of cardiovascular events than the conventional group (19 versus 40%; p=0.006, odds ratio [OR] 2.8, 95% confidence interval [CI] 1.4–6.0). These aforementioned studies provide some indication that a change of therapy based on measures of platelet function tests may be beneficial, but more evidence is required.
While many questions remain unanswered in terms of our understanding of the value of testing response to antiplatelet therapy, the growing body of evidence appears to be leading us further down the path of individualising treatment. Several studies, such as Guaging Responsiveness with A VerifyNow Assay Impact on Thrombosis And Safety (GRAVITAS) (NCT00645918), Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition (DANTE) (NCT00774475) and Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI) (NCT00910299), are currently planned or under way to evaluate the merit of changing therapy on the basis of platelet reactivity (see Table 3).107–111
The ARCTIC study (NCT00827411), which is currently recruiting, will be the first evaluation of the clinical relevance of platelet function tests. This randomised, open-label, active-control phase IV study has an estimated accrual of 2,500 patients undergoing drug-eluting stent implantation. Patients will be randomised to either the conventional arm of an active comparator group (i.e. fixed-dose regimen of both aspirin and clopidogrel after stent implantation) or the monitoring arm of an experimental group (i.e. modification of both aspirin and clopidogrel dose in sub-optimal responders identified by a point-of-care platelet function test). A composite end-point of death, MI, stroke, urgent coronary revascularisation and stent thrombosis will be assessed at one-year follow-up.
Future Perspectives
Studies show point-of-care platelet function tests to be promising for the measurement of patient response to antiplatelet therapy, with the potential to predict cardiovascular outcomes based on platelet reactivity. Among the tests that were able to predict events from the POPular study,64 the laboratory-based LTA assay is labour-intensive and requires trained technicians. By comparison, VerifyNow and Plateletworks are point-of-care assays, and the latter is highly time-sensitive, necessitating testing within 10 minutes of phlebotomy.112 The fact that these three tests are based on measures of platelet aggregation, whereas the tests that proved to be non-predictive (IMPACT-R, IMPACT-R ADP, PFA-100 and INNOVANCE PFA P2Y)64 employ platelet adhesion and/or shear stress, imply that measurements of platelet reactivity based on ADP-induced aggregation may be better suited for clinical decision-making. In the study by Bouman et al., VASP and VerifyNow were put forward as the preferred platelet function tests for monitoring clopidogrel responsiveness; however, VASP is relatively labour-intensive.103 Importantly, while aggregation tests correlate very well with each other, overall concordance is low (e.g. κ=0.20 between LTA and VerifyNow P2Y12 assay, 95% CI 0.06–0.40).113
The use of biological assays, whether in the form of genetic tests or platelet function tests, is not currently recommended for routine point-of-care practice in the setting of antiplatelet therapy. While genetic testing is limited by the fact that results can take at least three hours to obtain, the information yielded provides conclusive data – any information obtained is either a yes or a no. By contrast, the results from point-of-care platelet function tests can be obtained within minutes but may be highly variable from one time of testing to another. In future it may be that platelet genetic and functional testing are combined, but this would depend on a shortened genetic testing time, as well as guidance or recommendations on whether any one test should be performed, or both. Thus far, various studies have pointed towards an increased risk of atherothrombotic complications among patients with high on-treatment platelet reactivity, but the relationship between clinical outcomes and the polymorphisms underlying high on-clopidogrel platelet reactivity remains uncertain. However, the high degree of overlap observed between clinical, biochemical and genetic aspects of high on- clopidogrel platelet reactivity indicates the potential need to cross- correlate this information for greater accuracy. Any concordance between these aspects will require appropriately designed studies to evaluate one characteristic for subsequent cross-checking against the other. Aside from the limited but rapidly increasing data to correlate measures of platelet function to clinical outcomes, there is no single assay at the moment that accounts for both platelet biology and function. Moreover, the nature of platelets makes blood sample collection and handling a major challenge for platelet function testing in that results can be influenced by a variety of individual, chemical and mechanical factors during the collection, preparation and handling of blood samples.19 These issues suggest areas of improvement for many platelet function testing systems, as no point- of-care assay currently exists with sufficient validation to fulfil the necessary criteria for an ideal monitoring system, e.g. using small amounts of whole blood, lack of pipetting or handling of blood, reproducible results and rapidly available results. Nevertheless, it should be noted that of the available point-of-care tests to date, from a theoretical point of view the VerifyNow system addresses many of these criteria with its fully automated technique that allows for rapid assessment of platelet inhibition in whole blood in the absence of specially trained technicians.
There also remains an unresolved issue with bleeding in platelet inhibition therapy. Recent preliminary data suggest that peri-procedural platelet response to clopidogrel can predict the risk of spontaneous major bleeds.114 However, there are currently no available indications as to whether results from platelet function tests can guide antiplatelet treatment in avoiding bleeding events until specifically designed trials are conducted, especially in the area of planned invasive procedures. Although underpowered to assess the risk of bleeding, the recent POpular study found no association between the degree of platelet reactivity and bleeding.64 There is a high risk of major bleeding events among patients with cardiovascular disease receiving antiplatelet treatment, especially among the elderly; there is a definite urgency to address this issue, potentially by using reversible P2Y12 inhibitors, which are currently under investigation. With this in mind, the ideal scenario concerning antiplatelet therapy is platelet function tests that allow for the identification of poor responders, possibly guiding therapy towards optimal treatment regimens while potentially identifying whether hypo-responsiveness is in fact associated with excessive bleeding. If such circumstances can be achieved, the resulting prospects in antiplatelet therapy could provide greatly improved options for patients.