Introduction on Current Concepts in the Clinical Utility of Platelet Reactivity Testing
The role of platelets in coronary artery thrombosis is well-established.1 They also play a critical role in a number of cardiovascular conditions including stroke, peripheral vascular disease and diabetes, and may be involved in the pathology underlying atherosclerotic changes.1 Antiplatelet agents such as clopidogrel, a platelet P2Y12 receptor antagonist, and aspirin are used for the prevention of thrombotic conditions in patients with acute coronary syndrome (ACS) or when undergoing percutaneous coronary intervention (PCI).2 Dual antiplatelet therapy (DAPT), with the combination of aspirin (75-325 milligrams [mg] daily) and clopidogrel (75 mg daily after a loading dose of 300/600 mg) has become the widely accepted regimen for stent-placement procedures. Use of these drugs is widespread - clopidogrel is one of the largest selling drugs worldwide.3
However, despite antiplatelet therapy following PCI with stent implantation, 1-5 % of patients develop stent thrombosis (ST), a feared complication that results in myocardial infarction (MI) in 80 % and mortality in up to 40 % of cases.4,5 Individuals receiving clopidogrel exhibit a wide variability in platelet responsiveness, resulting from a variable level of P2Y12 inhibition.6,7 A significant number (up to a third) of patients have no measurable effect of the medication, often referred to as having high on-treatment platelet activity (HTPR) to adenosine diphosphate (ADP).8 The presence of HTPR has been associated with increased rates of adverse effects, including cardiovascular death, MI and ST in patients undergoing PCI.9-11 Although less common, low response to aspirin has also been observed and has been associated with adverse effects.12-14
Alternative therapeutic options, such as prasugrel and ticagrelor, have been shown to be successful for ACS patients irrespective of HTPR status.15-18 These new therapeutic options have also demonstrated superiority to clopidogrel for the prevention of ischaemic events in patients undergoing PCI for ST-elevation MI (STEMI).19 However, these therapies may confer a higher risk of bleeding and are not available everywhere due to economic constraints. Another option is increasing the dose of clopidogrel; a randomised clinical trial found that a double-dose clopidogrel regimen is associated with a reduction in cardiovascular events and ST when PCI is performed, but also an elevated risk of major bleeding.20 A 'one-size-fits-all approach is therefore not appropriate in antiplatelet therapy and personalised strategies appear attractive, identifying those patients who would benefit most from therapeutic adjustment.
A subset of patients demonstrate low on-treatment platelet reactivity or a hyper-response to clopidogrel, which has been associated with an increased risk of haemorrhagic complications following coronary stent placement21 and after neurointerventional procedures.22-24 There is a need for larger studies to define thresholds for clopidogrel hyperresponse and examine the clinical effects of dose adjustments or treatment interruption in the setting of coronary artery bypass graft (CABG) surgery in particular.
Platelet reactivity testing enables the identification of patients with an inadequate response to antiplatelet agents who might benefit from a more intense antiplatelet regimen, as well as those exhibiting hyper-responsiveness. While large studies and registries have clearly defined a threshold for hypo-response,25,26 there remains a need to definitively define a threshold for hyper-response and the clinical effects of antiplatelet dosage adjustment. This article aims to discuss advances in platelet reactivity testing and to review clinical studies investigating their use.