Prasugrel a better choice to improve outcomes in ACS patients with CKD, JACC study.

Chronic kidney disease (CKD) represents a puzzling dilemma for physicians who care for patients experiencing acute coronary syndrome (ACS). The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. In this context, latest pre-specified analysis from ISAR-REACT 5 trial by Wohrle et al has shown that reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel.

Prasugrel was indeed associated with a lower occurrence of the primary endpoint in patients with low as well as high eGFR without increasing the bleeding risk in comparison to ticagrelor. This analysis was recently published in JACC Cardiovascular Interventions.

Kidney disease may have two opposing effects on the hemostatic milieu of body. It may increase the risk of thrombosis by multiple mechanisms, including compromise of coagulation cascade, enhanced platelet reactivity, and endothelium injury resulting in loss of its antithrombotic properties. At the same time, altered pathways of platelet function in CKD patients result in aggregation and adhesion disturbance, entailing an increased risk of bleeding events both spontaneous and associated with antiplatelet agents.

Both ticagrelor and prasugrel have been linked to a superior outcomes in patients with ACS compared with clopidogrel, which has also been shown in the subgroup of patients with CKD. However result of a direct comparison of the two drugs is lacking.

The analysis of the relative merits of ticagrelor versus prasugrel according to renal function was part of the protocol-defined prespecified analyses of the ISAR-REACT 5 trial.

Patients were categorized into 3 groups:

1. Low eGFR (<60 mL/min/1.73 m 2 ),

2. Intermediate eGFR (≥60 and <90 mL/min/1.73 m 2 ), and

3. High eGFR (≥90 mL/min/1.73 m 2 ).

The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium (BARC) types 3 to 5 bleeding, both at 1 year.

The authors found that:

1. Patients with low eGFR (defined as eGFR <60 ml/min/1.73 m2) have a 4.5-fold increased risk of stroke, myocardial infarction, or all-cause death  as compared with patients with preserved eGFR.

2. An excess of risk, albeit less marked, was also noted for major bleeding events for patients with low versus high eGFR.

3. Further, the relative efficacy and safety of prasugrel vs ticagrelor was not affected by eGFR.

4. Prasugrel was indeed associated with a lower occurrence of the primary endpoint in patients with low as well as high eGFR while no difference in bleeding was observed between the 2 drugs across all eGFR strata.

5. Of note, the benefit of prasugrel with respect to the primary outcome was driven by a reduction in myocardial infarction and all-cause death among patients with low and high eGFR, respectively.

In an accompanying editorial Fillipo et al note that "The concordance between the results of the main trial and of this subanalysis could be partly expected based on available pharmacokinetic evidence. Ticagrelor metabolism indeed minimally depends on renal function, while previous studies observed that the levels of the active metabolites of prasugrel were not affected by moderate renal impairment."

"In particular, the paper by Wöhrle et al (11) has a further merit of focusing back the scientific attention on the risk of recurrent ischemic events among CKD patients, thus helping physicians to face the crossroad of DAPT intensity in patients with impaired renal function", add Fillipo et al.

Recent findings from the largest platelet function study to date, carried out in 598 patients enrolled in the ISAR-REACT 5 trial, showed significantly higher inhibition of platelet aggregation with prasugrel compared with ticagrelor, which may at least partly explain the clinical superiority of prasugrel.

Source: JACC Cardiovascular Interventions:

1. DOI: 10.1016/j.jcin.2021.06.028

2. DOI: 10.1016/j.jcin.2021.07.026