• ISAR-REACT 5 Substudy Confirms Prasugrel ACS Benefit Over Ticagrelor Irrespective of eGFR

    A new substudy of the ISAR-REACT 5 trial has confirmed the surprise original finding – that prasugrel was more effective at reducing ischemic events in acute coronary syndrome (ACS) patients over the more potent antiplatelet drug ticagrelor – irrespective of estimated glomerular filtration rates (eGFR).

    The findings suggest that renal function should not be used to guide the selection of adjunct P2Y12 inhibitors in patients with ACS, the authors, led by Jochen Wöhrle, MD, and Julia Seeger, MD, from Medical Campus Lake Constance, Friedrichshafen, Germany, said.

    The study was published online Monday, ahead of the Sept. 13. issue of JACC: Cardiovascular Interventions.

    ISAR-REACT 5 first returned its unexpected overall findings on the two antiplatelet therapies at the European Society of Cardiology Congress 2019, confounding investigator assumptions that ticagrelor would be superior to prasugrel.

    In the 4,018 ACS patients with and without ST-elevation myocardial infarction (STEMI) randomized across 19 centers in Germany and Italy, just 6.9% of the prasugrel arm had a primary endpoint event – death, myocardial infarction or stroke at 1 year – versus 9.3% on ticagrelor (hazard ratio [HR] 1.36; 95% confidence interval [CI] 1.09-1.70; p=0.006).

    No significant difference was observed in the secondary endpoints of major bleeding, mortality, stroke or stent thrombosis, although myocardial infarction was also significantly lower in prasugrel patients (3%) versus those on ticagrelor (4.8%).

    In the current study, the investigators set out to assess safety and efficacy of the two drugs according to patients’ kidney function, based on estimated eGFRs, the outcomes of which were previously undefined. Six of the original cohort were excluded because serum creatinine level was not available.

    The remaining 4,012 were categorized into three groups; low eGFR of <60 mL/min/1.73m2, intermediate eGFR of ≥60 and <90 mL/min/1.73m2, and high eGFR of  ≥90 mL/min.1.73m2. Those with low eGFR tended to be older than patients in the other two categories, and – though still majority male – accounted for a greater number of women.

    Overall, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel, the researchers said.

    In those with low eGFR – who were overall found to be at higher risk of the all-cause death, myocardial infarction, and stroke primary endpoint – the risk was lowered with prasugrel (low vs. intermediate eGFR: adjusted HR, 1.89; 95% CI: 1.46-2.46; low vs. high eGFR: adjusted HR, 2.33; 95% CI: 1.57-3.46) –.

    The primary endpoint occurred for 20.5% of the low eGFR patients on ticagrelor and 14.7% of those on prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029).

    Although a “risk excess” for low eGFR patients across the entire cohort was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs. intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs. high eGFR), there was no significant difference in bleeding between the two treatment groups.

    “Prasugrel is superior to ticagrelor with respect to reduction of ischemic events irrespective of eGFR,” the researchers concluded.

    “Our results demonstrate that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events. However, eGFR did not affect significantly the relative efficacy and safety of ticagrelor versus prasugrel in patients with ACS managed with an invasive treatment strategy.”

    Corroboration from specifically designed and sufficiently powered randomized trials in patients with ACS and chronic kidney disease (CKD) is now needed, the researched urged.

    In an accompanying editorial, A.O.U Città della Salute e della Scienza di Torino’s Ovidio De Filippo, MD, and colleagues welcomed the paper’s aim 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 [dual antiplatelet therapy] in patients with impaired renal function.”


    Wöhrle J, Seeger J, Lahu S et al. Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate. JACC Cardiovasc Interv 2021;14:1857-1866.

    De Filippo O, D’Ascenzo F, De Ferrari GM. Antiplatelet Therapy in Acute Coronary Syndrome Patients With Impaired Renal Function: The Destination Matters! JACC Cardiovasc Interv 2021;14:1867-1869.

    Image Credit: eddows – stock.adobe.com

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