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Impact of renal function on residual platelet reactivity and clinical outcomes in patients with acute coronary syndrome treated with clopidogrel

Abstract Background Chronic kidney disease (CKD) is a common comorbidity in patients with acute coronary syndrome (ACS) and may potentially influence platelet function. Hypothesis We explored the influence of renal function on platelet reactivity to investigate whether high residual platelet reactivity (HRPR) is associated with cardiovascular events. Methods ACS patients treated with aspirin and clopidogrel were prospectively enrolled. Patients were categorized into two groups on the basis of baseline estimated glomerular filtration rate (eGFR): non‐CKD (eGFR ≥60 mL/min/1.73 m2) and CKD (eGFR <60 mL/min/1.73 m2). Platelet function was measured by thromboelastography ≥5 days after maintenance dual antiplatelet therapy. Major adverse clinical events (MACEs) were collected at 1 year after discharge. Results There were 282 non‐CKD patients and 212 CKD patients. A significant difference in median MAADP value was observed between the two groups (15.0 mm vs. 31.3 mm, p < .001). HRPR was more prevalent in the CKD group than the non‐CKD group (27.4% vs 9.6%, p < .001). At 1‐year follow‐up, the incidence of MACEs was significantly higher for those with both CKD and HRPR compared with those with either CKD or HRPR (37.9% vs. 18.5%, p < .001). The relationship between HRPR and MACEs was consistent across CKD strata without evidence of interaction. Adding platelet reactivity to eGFR improved the model with area under the curve increasing from 0.703 to 0.734. Conclusion In patients with ACS, the risk of HRPR increased with declining eGFR. Both CKD and HRPR were associated with MACEs at 1‐year follow‐up.


| INTRODUCTION
Patients with coronary artery disease (CAD) and impaired renal function have a poor prognosis. 1,2 Despite the presence of strong epidemiological links between renal impairment and risk of thrombosis, underlying causal, and mechanistic insights have not been fully elucidated. Dual antiplatelet therapy (DAPT) including a P2Y 12 inhibitor and aspirin is standard treatment after acute coronary syndrome (ACS) or coronary drug-eluting stent implantation. 3,4 More potent P2Y 12 inhibitors have been shown to be more effective for reducing the risk of ischemic events, but are associated with a higher risk of bleeding events compared with clopidogrel. Clopidogrel thus remains a treatment option for preventing ischemia events and is widely used in patients with ACS, especially those with high-risk bleeding. 5,6 However, inadequate platelet inhibition is associated with a higher rate of ischemic events because of variations in response to clopidogrel, 7,8 with poorer response associated with CYP2C19 variant, gender, age, presence of diabetes mellitus, drug-drug interactions, and impaired renal function. [9][10][11] In ACS patients with low responsiveness to clopidogrel, one study demonstrated that thromboelastography (TEG)-guided antiplatelet therapy was shown to reduce the rate of a composite endpoint of all-cause death, target vessel revascularization, stroke, and myocardial infarction (MI). 12 Therefore, identifying predictors of impaired response to clopidogrel is beneficial for patients at high risk of thrombosis, especially for East Asian patients who may have a higher prevalence of CYP2C19 loss-of-function variants and a worse prognosis when treated with clopidogrel. 13 The correlation between high residual platelet reactivity (HRPR) and renal function remains controversial. To date, studies evaluating the relationship between chronic kidney disease (CKD) and HRPR have been restricted by modest sample size, limited follow-up, and inadequate multivariable adjustment. [14][15][16] Moreover, for patients with CKD, it remains unclear whether low response to clopidogrel has an implication on cardiovascular events. 15,17,18 We therefore investigated the influence of renal dysfunction on residual platelet reactivity and evaluated whether HRPR is related to higher incidence of adverse cardiovascular events in ACS patients with CKD.   logistic regression analysis model showed that there were more HRPR patients with age > 65 years, female gender, hypertension, hemoglobin <100 g/L, and CKD compared with patients without HRPR (Table   S1). Multivariate logistic regression analysis showed that CKD and female gender were significantly related to HRPR in response to clopidogrel ( Table 2).

| MACEs and bleeding events at 1 year
A total of 69 MACEs were observed (31 deaths, 11 ischemic stroke events, and 27 MI events) over 1 year of follow-up. The incidence of MACEs was significantly higher in the CKD group than in the non-CKD group at follow-up (24.1% vs. 6.4%, log-rank p < .001). Patients with renal dysfunction also experienced more bleeding events compared with those without CKD (6.6% vs. 2.1%, log-rank p = .007).
The incidence of MACEs was significantly higher in HRPR patients compared with those without HRPR, irrespective of CKD status (  (Table S4)

| DISCUSSION
The findings of this study provide important information about the impact of renal dysfunction on residual platelet reactivity and clinical outcomes in ACS patients receiving clopidogrel. Firstly, we showed that the prevalence of HRPR was more common in CKD patients in this cohort study, including patients on dialysis. Secondly, renal dysfunction was associated with a higher risk of mortality, ischemic events, and bleeding events among ACS patients with or without PCI.
Thirdly, HRPR was shown to be an independent risk factor for MACEs, regardless of renal function, with the highest risk observed among patients with both CKD and HRPR at 1-year follow-up.
Renal dysfunction was associated with a higher incidence of HRPR, which aligned with previous studies using a variety of platelet function tests. 15 A sub-analysis of the PLATO trial showed that ACS patients with CKD treated with ticagrelor had a greater reduction in ischemic events compared with non-CKD patients, without a significant increase in major bleeding events. 38 A single-center study showed that ticagrelor resulted in faster and greater platelet inhibition compared with clopidogrel in patients with kidney failure receiving hemodialysis. 39 Although low-dose prasugrel had a better antiplatelet effect than clopidogrel, it did not significantly improve the prevalence of HRPR in a study of Japanese hemodialysis patients. 40 However, randomized clinical trials of the use of platelet function tests to tailor antiplatelet therapy have failed to demonstrate any benefit, and were largely limited by the inclusion of low-risk populations. Baber et al.
suggested that additional risk markers may potentially allow clinicians to stratify patients to optimal antithrombotic therapy in clinical practice. 17 We suggest that further studies are needed to assess the benefit and risk of administering more potent P2Y 12 receptor antagonists to ACS patients with CKD.

| LIMITATIONS
The present study had several limitations, including the small sample size and single-center observational study design, which may have contributed to selection bias. Our study also had a relatively high proportion of patients with severe renal dysfunction who exhibited higher platelet reactivity than patients without CKD. 32

| CONCLUSION
Our findings demonstrated that renal dysfunction was associated with residual platelet reactivity and a high risk of 1-year MACEs in ACS patients treated with clopidogrel. HRPR was associated with risk of MACEs at 1-year follow up, independent of renal function. Antiplatelet treatment strategies in ACS patients with severe CKD require optimization using further studies.