Ticagrelor safe after fibrinolysis – and now there’s a reversal agent

Ticagrelor represents a safe treatment option after fibrinolysis for ST-elevation myocardial infarction (STEMI), with 12-month results from the TREAT study showing it was noninferior to clopidogrel.

The primary endpoint (major bleeding at 30 days) was previously reported in 2018 showing comparable safety between ticagrelor and clopidogrel.

Now the results for 12 months have been released at the American College of Cardiology meeting 2019 in New Orleans, with researchers reporting that the primary outcome of TIMI major bleeding occurred in 0.73% of the ticagrelor group vs. 0.69% of the clopidogrel group (p < 0.001 for noninferiority).

Ticagrelor was also non-inferior to clopidogrel in the secondary outcomes of fatal bleeding: (0.16% vs 0.11%, p = 0.67); intracranial bleeding (0.42% vs 0.37%,p = 0.82); major adverse cardiovascular events (4.0% vs 4.3% p = 0.57) and the composite endpoint of cardiovascular mortality, MI, stroke/transient ischaemic attack, recurrent ischaemia, or other arterial thrombotic events at 12 months: (8.0% vs 9.1% p = 0.25).

The study involved almost 3800 patients under 75 who received fibrinolytic therapy for STEMI and were then randomised to delayed ticagrelor (n = 1,913) or clopidogrel (n = 1,886). It was conducted in 15 centres including the South Australian Health and Medical Research Institute, University of Adelaide.

“In spite of the fact that ticagrelor is more potent than clopidogrel, we found that it is safe to use ticagrelor in this population,” said Dr Otavio Berwanger, Chair of the Steering Committee and the study’s lead author.

He noted that ticagrelor had a faster onset of antiplatelet effect than clopiogrel and a previous study – the PLATO  trial – found ticagrelor was superior to clopidogrel at preventing adverse cardiac events in patients with acute coronary syndromes.

Dr Berwanger said the TREAT study was much smaller than PLATO, which had more than 18,000 participants, and the risk reductions of ticagrelor as compared with the clopidogrel groups were identical in both studies; however, the gap was considered statistically significant in PLATO due to that trial’s larger size.

When the researchers analysed pooled data combining PLATO and TREAT, they found ticagrelor significantly improved outcomes compared to clopidogrel.

“By combining both trials, we can say that ticagrelor is beneficial across the whole spectrum of patients with acute coronary syndromes, regardless of how they are managed in terms of fibrinolytic therapy,” he said.

Meanwhile, another study presented at ACC19 described the evaluation of a potential reversal agent for ticagrelor.

Researchers said a reversal agent for oral P2Y12 receptor antagonists such as ticagrelor was desirable because an increased bleeding risk persisted for several days after drug cessation.

“Establishment of haemostasis can be challenging in patients with major bleeding, such as intracranial or gastrointestinal haemorrhage. In addition … if an emergency procedure is indicated, the surgeon or proceduralist must proceed while accepting the increased bleeding risk, often after empirically providing platelet transfusions, despite the ineffectiveness of such transfusions in reversing the antiplatelet effects of P2Y12 inhibitors.”

In a preliminary study, researchers from Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, investigated the effects of PB2452, a novel recombinant human monoclonal antibody antigen-binding fragment, on platelet function in 64 healthy volunteers before and after 48 hours of ticagrelor pretreatment.

They found that after 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12 or 16 hours) was found to be associated with a significantly greater increase in platelet function than placebo. Furthermore, ticagrelor reversal occurred within five minutes after the initiation of PB2452 and was sustained for more than 20 hours.

The researchers noted there was no evidence of a rebound in platelet activity after drug cessation, and adverse events related to the trial drug were limited mainly to issues involving the infusion site.

However they cautioned that “it remains unclear whether reversal of the antiplatelet effects of ticagrelor by PB2452 would lead to more rapid haemostasis in patients with bleeding or to prevention of bleeding in patients who are undergoing urgent invasive procedures.

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