Antiplatelet Therapy

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 may also play a role;28,29

and also increases with age.26,27 Genetic factors 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 acute coronary syndrome). 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 the occurrence of

42

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 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 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 the 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

EUROPEAN CARDIOLOGY

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 Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92