Chronic kidney disease (CKD) is an independent and powerful risk factor for adverse cardiovascular outcomes. Approximately 30% to 40% of patients presenting with acute coronary syndromes (ACS) have concurrent CKD, with prevalence rising sharply among the elderly and those with diabetes mellitus.1,2 The clinical significance of this overlap is profound: in-hospital mortality following acute myocardial infarction escalates dramatically with declining renal function, ranging from approximately 2% in patients with preserved kidney function to as high as 30% in those requiring dialysis.2 CKD doubles overall mortality and triples cardiovascular mortality in ACS patients, establishing renal dysfunction as the third most important predictor of mortality after cardiogenic shock and congestive heart failure.3
The pathophysiology underlying heightened cardiovascular risk in CKD is multifactorial. Uremia-related mechanisms include systemic chronic inflammation, oxidative stress, endothelial dysfunction, accelerated vascular and coronary calcification, and a prothrombotic milieu characterized by enhanced thrombin generation and impaired fibrinolysis.3 These processes accelerate atherosclerosis and predispose to plaque instability. From an interventional perspective, CKD substantially worsens outcomes following percutaneous coronary intervention (PCI), with significantly elevated rates of stent thrombosis following drug-eluting stent implantation.
Despite their elevated risk, CKD patients have been systematically underrepresented in landmark cardiovascular clinical trials. Many pivotal studies either excluded patients with advanced renal dysfunction or enrolled insufficient numbers to permit adequately powered subgroup analyses, creating a critical evidence gap that directly impacts clinical decision-making.2
Dual antiplatelet therapy (DAPT) combining aspirin with a P2Y12 receptor inhibitor is the standard of care following PCI for ACS. Three P2Y12 inhibitors are available: clopidogrel, prasugrel, and ticagrelor.12
Clopidogrel is a thienopyridine prodrug requiring hepatic conversion via cytochrome P450 enzymes (primarily CYP2C19) to its active metabolite, which irreversibly binds the P2Y12 receptor. In CKD, multiple factors impair clopidogrel’s efficacy. High on-treatment platelet reactivity (HTPR) occurs in a substantially greater proportion of CKD patients receiving clopidogrel compared with those with preserved renal function.4,5 The mechanism extends beyond impaired hepatic metabolism: uremia causes upregulation of P2Y12 receptor signaling itself, elevated circulating adenosine dinucleoside polyphosphates (endogenous P2Y12 agonists that accumulate due to impaired renal clearance), and enhanced thrombin generation — collectively creating a state of acquired biological resistance that standard clopidogrel doses cannot overcome.4-6
Prasugrel is a third-generation thienopyridine that also requires hepatic activation but undergoes more efficient and predictable conversion, producing approximately 10-fold higher plasma concentrations of its active metabolite compared with clopidogrel. Its binding to P2Y12 is irreversible. Pharmacodynamic studies demonstrate that prasugrel achieves significantly lower platelet reactivity in CKD patients compared with clopidogrel, effectively overcoming the P2Y12-mediated resistance characteristic of uremia.5,6
Ticagrelor is a cyclopentyl-triazolo-pyrimidine that directly and reversibly inhibits the P2Y12 receptor without requiring hepatic activation. This direct mechanism renders ticagrelor’s pharmacodynamic effect largely independent of CYP450 function. Like prasugrel, ticagrelor achieves potent P2Y12 inhibition in CKD patients.5 However, ticagrelor is approximately 80% hepatically metabolized and 20% renally excreted, and its plasma concentrations may increase modestly in severe renal impairment, raising theoretical concerns about excess bleeding in advanced CKD.7
The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18,624 patients with ACS to ticagrelor versus clopidogrel.8 The primary composite endpoint (cardiovascular death, MI, or stroke at 12 months) was significantly reduced with ticagrelor: 9.8% versus 11.7% (HR 0.84; 95% CI 0.77-0.92; p<0.001). All-cause mortality was also reduced (4.5% vs 5.9%; p<0.001). PLATO-defined major bleeding was similar between groups (11.6% vs 11.2%; p=0.43), though non-CABG-related bleeding was higher with ticagrelor (4.5% vs 3.8%; p=0.03).8
CKD Subgroup Analysis. James et al published a prespecified subgroup analysis examining outcomes by renal function.9 Among 3,237 patients with creatinine clearance <60 mL/min (17.4% of the trial population), ticagrelor reduced the primary endpoint from 22.0% to 17.3% (HR 0.77; 95% CI 0.65-0.90) — a 23% relative risk reduction, numerically greater than the 16% reduction observed in patients with preserved renal function. This interaction suggested that CKD patients may derive enhanced benefit from ticagrelor’s superior platelet inhibition. In the small subset with CrCl <30 mL/min (n=214), the point estimate remained favorable for ticagrelor (HR 0.77; 95% CI 0.49-1.30) though not statistically significant.9
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) randomized 13,608 ACS patients planned for PCI to prasugrel versus clopidogrel.10 The primary composite endpoint was significantly reduced with prasugrel: 9.9% versus 12.1% (HR 0.81; 95% CI 0.73-0.90; p<0.001), with particularly robust reductions in myocardial infarction (7.4% vs 9.7%; p<0.001) and stent thrombosis (1.1% vs 2.4%; p<0.001). However, TIMI major bleeding was higher with prasugrel (2.4% vs 1.8%; HR 1.32; p=0.03), including fatal bleeding (0.4% vs 0.1%; p=0.002).10
Regarding renal function, TRITON-TIMI 38 demonstrated that prasugrel’s superiority was independent of baseline creatinine clearance, though detailed stratified analyses across eGFR categories were not prominently reported, leaving a gap in evidence for prasugrel specifically in moderate-to-severe CKD.10
The Intracoronary Stenting and Antithrombotic Regimen 5 (ISAR-REACT 5) trial provided the first major head-to-head randomized comparison of prasugrel and ticagrelor in 4,018 ACS patients.11 Contrary to expectations based on PLATO, prasugrel significantly outperformed ticagrelor for the primary endpoint of death, MI, or stroke at 1 year: 6.9% versus 9.3% (p=0.006), a relative risk reduction of approximately 26%. Major bleeding (BARC 3-5) was numerically lower with prasugrel (4.8% vs 5.4%; p=NS).11
Critically, ISAR-REACT 5 did not provide stratified subgroup analyses by renal function, representing a major evidence gap for guiding P2Y12 inhibitor selection in CKD patients.
Real-world data have illuminated both practice patterns and outcomes in CKD patients undergoing PCI for ACS. The PROMETHEUS study, a multicenter U.S. registry of ACS-PCI patients, examined the association between CKD and outcomes with prasugrel versus clopidogrel.15 CKD was present in approximately 28% of patients and was independently associated with higher rates of MACE and myocardial infarction. Notably, PROMETHEUS found no significant interaction between CKD status and the treatment effect of prasugrel versus clopidogrel, suggesting that CKD patients’ residual risk may be driven by non-P2Y12 pathway mechanisms — including endothelial dysfunction, inflammation, and non-platelet-mediated thrombosis — that persist despite potent P2Y12 inhibition.15 Registry analyses also consistently show that potent P2Y12 inhibitors (prasugrel and ticagrelor) are prescribed substantially less frequently in CKD patients than in those with preserved renal function, suggesting clinicians may prioritize perceived bleeding risks over therapeutic efficacy.
The 2020 ESC guidelines for ACS management recommend prasugrel or ticagrelor in preference to clopidogrel for patients with ACS undergoing PCI (Class I, Level A), but do not provide specific recommendations stratified by renal function.12 This guideline silence on the comparative effectiveness of prasugrel versus ticagrelor in CKD reflects the absence of dedicated randomized trial data in this population and highlights the clinical relevance of registry-based evidence to inform practice.
Estimated glomerular filtration rate (eGFR) is the standard measure for classifying renal function in clinical practice and research. The CKD-EPI equation, originally developed by Levey et al in 2009, provides more accurate GFR estimation than the older MDRD equation, particularly at higher GFR values.13 The KDIGO guidelines define CKD stages based on eGFR: Stage 1-2 (eGFR ≥60), Stage 3a (45-59), Stage 3b (30-44), Stage 4 (15-29), and Stage 5 (<15 mL/min/1.73m²).14
Several critical knowledge gaps exist in the literature. No randomized trial has directly compared prasugrel and ticagrelor across defined CKD strata. ISAR-REACT 5 did not report renal subgroup analyses. Real-world data comparing all three P2Y12 inhibitors across the full spectrum of renal function (eGFR >60, 30-60, and <30) in ACS-PCI patients are limited. Whether eGFR modifies the comparative effectiveness of prasugrel versus ticagrelor (i.e., a drug × eGFR interaction) remains unclear. Finally, the relative performance of clopidogrel versus potent P2Y12 inhibitors specifically in severe CKD (eGFR <30) — where bleeding risk is highest — requires further characterization.
The present study addresses these gaps by leveraging a large, single-center PCI registry to compare all-cause mortality and MACE among prasugrel, ticagrelor, and clopidogrel recipients across three eGFR categories, with formal interaction testing to determine whether renal function modifies treatment effects.