Impaired platelet P2Y12 inhibition by thienopyridines in chronic kidney disease: mechanisms, clinical relevance and pharmacological options

Patients with chronic kidney disease (CKD) represent an increasing proportion of the population undergoing percutaneous coronary intervention (PCI) and up to 40% of the patients treated for acute coronary syndrome (ACS). Several studies and registries in the setting of ACS and elective PCI have reported a negative association between CKD and mortality, stent thrombosis, post-procedural ischaemic events and bleeding events. Pharmacological inhibition of the adenosine diphosphate receptor by thienopyridines or ticagrelor and disruption of the cyclooxygenase pathway by aspirin constitute the current standards of care to prevent thrombotic complications following stent-based PCI. In CKD patients, the avoidance of anti-platelet therapy may be driven by the lack of clinical trial data to support its efficacy, by errors or omissions, or by a reluctance to use this therapy in a population characterized by its enhanced bleeding risk. However, there is growing evidence to suggest that a severely decreased glomerular filtration rate per se, independent of the presence of diabetes mellitus, is an important determinant of high residual platelet reactivity under a clopidogrel maintenance dose. Recent reports have emphasized that the impact of impaired platelet inhibition by thienopyridines is of paramount importance in CKD patients, with an enhanced mortality rate in low-responder patients. Pharmacodynamic studies indicate the phosphodiesterase 3 inhibitor, cilostazol, the third generation thienopyridine prasugrel and the reversible P2Y12 antagonist ticagrelor to be potent strategies to overcome this biological resistance. In clinical practice, platelet function testing should be considered in CKD patients undergoing PCI, especially in those who experience thrombotic events despite dual therapy. Newer agents should be contemplated in patients who display higher residual platelet aggregability after standard treatment. Among these, the non-thienopyridine P2Y12 receptor antagonist ticagrelor, which does not require biotransformation, could be the drug of choice in CKD patients with ACS. In this population, ticagrelor has been found to reduce mortality and ischaemic events with an acceptable bleeding risk.