TREAT: Ticagrelor noninferior to clopidogrel for TIMI major bleeding in STEMI patients after fibrinolysis

Pearl Toh
20 Mar 2018
Otavio Berwanger
Dr Otavio Berwanger

Delayed administration of ticagrelor after fibrinolysis appears to be as safe as clopidogrel with regards to TIMI* major bleeding risk at 30 days in patients younger than 75 years with ST-segment elevation myocardial infarction (STEMI), according to the TREAT** trial.

However, there were more minor and minimal bleeding events with ticagrelor than with clopidogrel. 

While percutaneous coronary intervention (PCI) is well established as the preferred reperfusion strategy for patients with acute MI, timely access to the procedure is not always available worldwide. As such, many patients ended up receiving fibrinolytics as the initial reperfusion strategy.

“I think doctors, some of whom are already using ticagrelor off-label, will find the results reassuring because they suggest that you can use ticagrelor in this population without causing more major bleeding or fatal bleeding than clopidogrel,” said Dr Otavio Berwanger from the Brazilian Clinical Research Institute in Sao Paulo, Brazil.

Although ticagrelor has been shown to be superior to clopidogrel in acute coronary syndrome in the PLATO*** study, patients treated with fibrinolytics in the past 24 hours were excluded in the study. Therefore, TREAT is an investigator-initiated study specifically to address this gap in knowledge.

“Because most of the included patients [in TREAT] were pretreated with clopidogrel, these findings reflect mostly the noninferiority of switching from clopidogrel to ticagrelor in patients already treated with clopidogrel,” according to Berwanger and co-authors.

TREAT with ticagrelor or clopidogrel?

The phase III, multinational, open-label study included 3,799 patients younger than 75 years (mean age 58 years, 77.1 percent men) presenting with STEMI within 24 hours of symptom onset and treated with fibrinolytics. They were randomized 1:1 to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300–600 mg loading dose, 75 mg daily thereafter) at a median of 11.4 hours after receiving fibrinolytics. [ACC.18, abstract 404-12; JAMA Cardiol 2018;doi:10.1001/jamacardio.2018.0612]

At 30 days, the primary outcome of TIMI major bleeding occurred in similar proportion of patients in the ticagrelor vs the clopidogrel arms (0.73 percent vs 0.69 percent; p<0.001 for noninferiority).

The secondary endpoint of major bleeding rates based on PLATO and BARC# type 3–5 criteria were also similar between the two treatment groups (1.20 percent vs 1.38 percent; p=0.001 for noninferiority for both criteria).

Furthermore, comparable rates of fatal (0.16 percent vs 0.11 percent; p=0.67) and intracranial bleeding (0.42 percent vs 0.37 percent; p=0.82) were seen in both groups.

“For patients who may be resistant to clopidogrel, or for those in whom it may be desirable to use the more potent drug, at least from our results doctors can know it is safe to do so,” said Berwanger.

However, the rates of minor and minimal bleeding, the other secondary endpoints, were significantly higher with ticagrelor than with clopidogrel.   

“Minor bleeding was increased with ticagrelor, and there was no benefit on efficacy outcomes,” said Berwanger, referring to the comparable rates of the composite outcome of CV death, MI, or stroke in the two treatment arms (4.0 percent vs 4.3 percent; hazard ratio, 0.91; p=0.57). “However, we will have to wait until next year … to have a clearer picture [on efficacy].”

Unanswered questions

This trial answers some questions, but critical others remain,” wrote Drs Clyde Yancy and Robert Harrington of Northwestern University, Chicago, Illinois and Stanford University in Stanford, California, US, respectively in an accompanying editorial. [JAMA Cardiol 2018;doi:10.1001/jamacardio.2018.0644]

“The crucial question that needs to be addressed—concomitant use of ticagrelor with lytic therapy for acute revascularization—remains unanswered in this trial.”

“We also await further data addressing short-term and long-term outcomes in this lower-risk population of patients with STEMI,” they added.

As bleeding risk increases with age and the trial excluded patients older than 75 years, Berwanger cautioned against generalizing the results to older patients.   



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