Reduced-Dose Prasugrel Works Well in Older, Low-Weight ACS Patients

A subgroup analysis of the ISAR-REACT 5 trial, which compared prasugrel and ticagrelor in ACS patients managed with an invasive approach, shows that using a half dose of prasugrel in older or low-weight patients conserves the drug’s ability to prevent ischemic events while avoiding excess bleeding.

In patients who were age 75 and older or weighed less than 60 kg (132 lbs), the rate of the primary composite endpoint of death, MI, or stroke at 1 year was 12.7% with reduced-dose prasugrel and 14.6% with standard-dose ticagrelor (HR 0.82; 95% CI 0.60-1.14). Rates of BARC type 3 to 5 bleeding were 8.1% and 10.6%, respectively (HR 0.72; 95% CI 0.46-1.12), lead author Maurizio Menichelli, MD (Ospedale Fabrizio Spaziani, Frosinone, Italy), and colleagues report.

Among patients who didn’t fall into either one of those categories, full-dose prasugrel was more effective at preventing ischemic events compared with ticagrelor (4.8% vs 7.3%; HR 0.65; 95% CI 0.48-0.88), with no difference in major bleeding (3.7% vs 3.8%; HR 0.98; 95% CI 0.65-1.47).

Ticagrelor has gained greater acceptance in clinical practice compared with prasugrel, based at least in part on safety concerns stemming from indirect comparisons made between the PLATO and TRITON-TIMI 38 trials, which established the advantage of the two P2Y12 inhibitors over clopidogrel in ACS patients undergoing PCI.

In TRITON-TIMI 38, no net clinical benefit was seen for prasugrel over clopidogrel in patients 75 and older because of an increased risk for intracranial and fatal bleeding; an excess bleeding risk was observed in younger patients with low body weight as well. After the trial, the US Food and Drug Administration warned of increased bleeding risks—and a reduced maintenance dose of prasugrel 5 mg was subsequently recommended—in these categories of patients.

For ticagrelor, on the other hand, a subgroup analysis of PLATO showed the efficacy and safety of ticagrelor versus clopidogrel was not influenced by patient age.

ISAR-REACT 5, conducted at 23 centers in Germany and Italy, compared the two drugs head-to-head, showing that contrary to prevailing belief based on indirect comparisons, prasugrel was more effective than ticagrelor for preventing death, MI, or stroke without increasing major bleeding risk. The half dose of prasugrel was used in older patients and those with low body weight.

The overall trial already pointed to the superiority of prasugrel over ticagrelor, said Adnan Kastrati, MD (Deutsches Herzzentrum München and Technische Universität München, Munich, Germany), senior author of this new analysis. And this current substudy is the first comparison of the two drugs in these high-risk categories, eliminating concerns about using prasugrel if used at a reduced dose, he told TCTMD: “It makes things easier. Just use prasugrel in acute coronary syndromes irrespective of the patient age and patient weight if you reduce dose in these patients.”

High Ischemic and Bleeding Risks

This subanalysis of ISAR-REACT 5, published July 21, 2020, ahead of print in the Annals of Internal Medicine, confirmed that patients who were older or had a low body weight—about 27% of the entire trial population—had heightened risks of both ischemic and bleeding events when compared with the rest of the patients, no matter which P2Y12 inhibitor they received, Kastrati pointed out.

The findings also suggest that the reduced-dose prasugrel regimen used in the trial in these high-risk patients explains the “lower-than-expected” rates of bleeding complications seen in the entire prasugrel arm, he said.

We should really advocate for direct comparisons, large trials that are well powered that really provide a clear answer. David Conen

Indeed, in a sensitivity analysis evaluating the risk of all bleeding—BARC type 1 to 5—there was a numerically lower risk with prasugrel versus ticagrelor in the older and low-weight patients (29.5% vs 32.9%) but a numerically greater risk with prasugrel in the rest of the patients (19.8% vs 16.5%).

“Thus, age- and weight-based dose adaptation of prasugrel may at least partly explain why prasugrel did not increase the bleeding risk in the whole population, although it significantly reduced ischemic complications compared with ticagrelor in the ISAR-REACT 5 trial,” the authors write in their paper. “An additional explanation may be that the loading dose of prasugrel was first given after diagnostic angiography in the majority of trial participants, whereas ticagrelor was always given in the form of preloading. This might have had a differential effect on immediate postprocedural bleeding, which is a major contributor to the overall incidence of bleeding.”

They acknowledge, however, that these subgroup analyses were underpowered for efficacy or safety outcomes, so the findings “should be considered exploratory and hypothesis-generating.”

The Importance of Head-to-head Trials

Commenting for TCTMD, David Conen, MD, who wrote an accompanying editorial with P.J. Devereaux, MD, PhD (both Population Health Research Institute and McMaster University, Hamilton, Canada), said this subanalysis “confirms this algorithm with prasugrel dose reduction to 5 mg per day” in older patients and those with low body weight. ISAR-REACT 5 is “one of the few prospective randomized studies that actually used that dose reduction scheme that has been implemented post hoc after the initial randomized trial suggested an increased risk of bleeding in that population.”

There are limitations to subgroup analyses, Conen added, “but it doesn’t suggest any problems using that specific dosing in those subgroups.”

The study also “highlights that in these elderly, underweight patients, event rates are still much higher than in those who are not elderly and [who are] normal weight,” Conen said.

But most importantly, it “highlights really the importance of large, well-powered, head-to-head trials,” he said, noting that prasugrel usage fell so low based safety concerns derived from indirect comparisons with ticagrelor that it was pulled from the market in some countries. This direct comparison “shows that prasugrel is not as dangerous as it was supposed to be and thought to be and it seems to be pretty safe when used correctly,” Conen said.

“We should really advocate for direct comparisons, large trials that are well powered that really provide a clear answer,” he argued. “And I think that is the main contribution of ISAR-REACT 5—that they have provided an answer to a question that is important.”