Renal Function Affects Ticagrelor/Aspirin Impact on Recurrent Stroke: CHANCE-2

Ticagrelor and aspirin is the preferred combination for reducing the risk of recurrent stroke in clopidogrel nonresponders, but according to post hoc analysis of the CHANCE-2 trial, patients with mildly or moderate to severely decreased renal function may not see the same benefits.

“The findings suggest that renal function should be considered when deciding on the use of ticagrelor–aspirin versus clopidogrel–aspirin,” write Anxin Wang, PhD (Beijing Tiantan Hospital, Capital Medical University, and China National Clinical Research Center for Neurological Diseases, Beijing, China), and colleagues.

Past research has found conflicting results regarding renal function’s role in the efficacy of antiplatelet agents, so the investigators say they aimed to definitively determine the optimal regimen for carriers of the CYP2C19 loss-of-function allele across the spectrum of renal function.

Results by Renal Function

For the study, published online this week in the Annals of Internal Medicine, Wang and colleagues included 6,378 patients (median age 64.5 years; 33.9% female) from the randomized CHANCE-2 trial who had estimated glomerular filtration rate (eGFR) measurements available. Patients were stratified by renal function into three groups: normal (eGFR ≥ 90 mL/min/1.73m²; n = 4,050), mildly decreased (eGFR 60-89 mL/min/1.73m²; n = 2,010), and moderate to severely decreased (eGFR < 60 mL/min/1.73m²; n = 318).

The primary outcome of recurrent stroke within 90 days occurred in 5.9% and 7.6% of patients on aspirin plus ticagrelor or clopidogrel, respectively. Ticagrelor and aspirin compared with clopidogrel and aspirin led to a lower rate of recurrent stroke in patients with normal renal function (5.2% vs 8.1%; HR 0.63; 95% CI 0.49-0.81). However, this result was not seen for those with mildly decreased renal function (6.7% vs 6.9%; HR, 0.98; 95% CI 0.69-1.39) or those with moderate to severely decreased renal function (9.8% vs 6.1%; HR 1.31; 95% CI 0.48-3.55). Similar results were seen for the secondary outcomes of combined vascular events, ischemic stroke, and ordinal stroke or TIA.

A sensitivity analysis using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI) to calculate eGFR estimated a difference of 2.4 percentage points in the rate of recurrent stroke favoring aspirin plus ticagrelor versus clopidogrel in patients with normal renal function.

Severe or moderate bleeding (primary safety outcome) was similar for the ticagrelor and clopidogrel groups in patients regardless of whether renal function was normal (0.2% vs 0.3), mildly decreased (0.4% vs 0.3%), or moderate to severely decreased (0.7% vs 0.6%).

Prior studies like TWILIGHT-CKD have shown that patients with chronic kidney disease undergoing PCI benefit from ticagrelor monotherapy with less bleeding and no increase in ischemic events compared with dual antiplatelet therapy. Although the number of bleeding events in the current study was “relatively small,” the authors say, they highlight that ticagrelor plus aspirin did not lead to an absolute increase in severe or moderate bleeding across the different eGFR categories.

“However, it should be noted that the incidence of total bleeding, mainly mild bleeding, was greater with ticagrelor–aspirin in different eGFR categories,” Wang and colleagues write. “In addition, several previous studies have demonstrated that patients with impaired renal function have a higher bleeding tendency regardless of antiplatelet therapies. Taken together, these findings indicated that the bleeding risk should be carefully assessed and monitored in clinical utility of antiplatelet therapies.”

The main limitations of the study include the fact that renal function was only assessed by eGFR and not by the more precise method of evaluating for presence of albuminuria or proteinuria, the authors say, as well as the small number of patients with moderate to severely decreased renal function. Also, the fact that this was a post hoc analysis limited to only Chinese patients may limit its generalizability, they add.