Prasugrel Tops Ticagrelor in ACS Across the eGFR Spectrum: ISAR-REACT 5

When choosing between potent P2Y12 inhibitors in ACS patients managed with an invasive strategy, renal function should not be a deciding factor, a prespecified analysis of the ISAR-REACT 5 trial suggests.

The main findings of the trial—showing that prasugrel carried a lower risk of all-cause death, MI, or stroke, and a similar risk of major bleeding compared with ticagrelor—were consistent regardless of whether patients had a low, intermediate, or high estimated glomerular filtration rate (eGFR), according to researchers led by Jochen Wöhrle, MD, and Julia Seeger, MD (both Medical Campus Lake Constance, Friedrichshafen, Germany).

These latest results were published online in JACC: Cardiovascular Interventions and will be presented as part of the virtual European Society of Cardiology Congress 2021 starting later this week.

The study “is the first renal function-based analysis of patients with ACS randomly assigned to prasugrel or ticagrelor,” co-author Adnan Kastrati, MD (Deutsches Herzzentrum München and Technische Universität München, Germany), told TCTMD via email. It’s important to look at the potential influence of impaired renal function in patients taking antiplatelet drugs, both because it’s a major risk factor for ischemic and bleeding events and because it can alter the pharmacokinetics of the medications, he explained.

And in the case of prasugrel and ticagrelor in this setting, “the results show that the choice between these two drugs should not be influenced by the individual patient’s renal function,” Kastrati said.

Advantage Greatest at Low eGFR

For this analysis, the investigators divided 4,012 trial participants (after excluding six for missing serum creatinine levels) into three eGFR groups:

• Low (< 60 mL/min/1.73 m²): 760 patients
• Intermediate (60 to < 90 mL/min/1.73 m²): 1,968 patients
• High (≥ 90 mL/min/1.73 m²): 1,284 patients

As expected based on prior research, the rate of the primary endpoint (all-cause death, MI, or stroke) at 1 year was highest in patients with low eGFR (17.6%), followed by those with intermediate and high eGFR (7.1% and 4.0%, respectively). After adjustment, low eGFR was associated with greater risk compared with both intermediate eGFR (HR 1.89; 95% CI 1.46-2.46) and high eGFR (HR 2.33; 95% CI 1.57-3.46).

Similar patterns were seen in regard to the secondary safety endpoint of BARC types 3 to 5 bleeding at 1 year, with the rates declining across eGFR groups (10.1% to 5.3% to 3.6%).

Renal function, however, didn’t significantly affect the relative efficacy (P = 0.41 for interaction) or safety (P = 0.92 for interaction) of prasugrel versus ticagrelor, although the magnitude of prasugrel’s advantage was greatest in patients with low eGFR. In that subset, the rate of all-cause death, MI, or stroke was significantly higher in patients treated with ticagrelor versus prasugrel (20.5% vs 14.7%; HR 1.47; 95% CI 1.04-2.08), with no significant difference in BARC types 3 to 5 bleeding (10.4% vs 8.4%; HR 1.24; 95% CI 0.73-2.09).

Asked about an explanation for prasugrel’s advantage, Kastrati pointed to a pharmacodynamic substudy showing that it provides more-potent platelet inhibition compared with ticagrelor. “This is one of the reasons for its greater clinical efficacy,” he said.

He said the fact that the more-powerful effect of prasugrel was not associated with more bleeding could be explained by two factors. “First, differently from ticagrelor, we used an adapted, reduced dose of prasugrel in patients with a particularly increased risk of bleeding (elderly, low-weight patients),” he said. “Second, in patients who underwent a PCI (the large majority of the patients in this trial) ticagrelor but not prasugrel was administered as a pretreatment. Pretreatment with antiplatelet drugs increases the risk of bleeding especially in the immediate postprocedural period, the period with highest risk for this complication.”

‘Not Necessarily Surprising’

Commenting for TCTMD, Khaled Ziada, MD (Cleveland Clinic, OH), a deputy editor of JACC: Cardiovascular Interventions, said “it is not necessarily surprising” to see greater efficacy with prasugrel versus ticagrelor across eGFR groups because that’s consistent with the overall trial results.

It’s also not unexpected to see that the absolute benefit was greatest in patients with low eGFR, because that group carries the highest risk to start with, Ziada said. “It may not be that any of these findings is novel, but the combination of all of them in a nice analysis of a good data set is valuable.”

Overall, ISAR-REACT 5 “gives prasugrel a chance,” said Ziada, noting that ticagrelor was initially billed as a better option because it was thought to carry a lower bleeding risk based on indirect comparisons of pivotal trial results. The results also address a major concern many physicians have regarding use of potent antiplatelet agents in patients with reduced renal function, he added. “This study gives them a little bit of reassurance that actually there is a benefit in doing that and that the risk of bleeding may not be higher with a drug as potent as prasugrel.”

Still, Ziada indicated, the findings may not be definitive. A major limitation, he pointed out, is that roughly 20% of patients in the trial were not discharged on the assigned study drug, a “pretty whopping percentage.”

Nevertheless, the trial “suggests that prasugrel is not dead, that prasugrel has a place, and it may in fact be a better antiplatelet agent in patients with acute coronary syndrome undergoing PCI regardless of their renal function,” Ziada said.

In an accompanying editorial, Ovidio De Filippo, MD (A.O.U Città della Salute e della Scienza di Torino, Turin, Italy), and colleagues say that despite its limitations, “the ISAR-REACT 5 trial and its subanalyses are a reminder of the importance of clinical trials in generating evidence.”

They add that this new analysis in particular “has a further merit of focusing back the scientific attention on the risk of recurrent ischemic events among chronic kidney disease patients, thus helping physicians to face the crossroad of dual antiplatelet therapy intensity in patients with impaired renal function.”