Subcutaneous selatogrel inhibits platelet aggregation in patients with acute myocardial infarction

Selected in JACC by F. Gragnano , S. Brugaletta

This study sought to assess the antiplatelet response to selatogrel, a novel subcutaneous reversible P2Y12 receptor antagonist, in patients with AMI.

Reviewers

Felice Gragnano

@FeliceGragnano

Coronary interventions

Inselspital, Universitätsspital Bern - Bern, Switzerland

Salvatore Brugaletta

@sbrugaletta

Interventional cardiologist / Cardiologist

Barcelona, Spain

Our Comment

Why this study? – the rationale/objective

Early platelet inhibition is a key step in the treatment of patients with acute myocardial infarction (AMI). Oral P2Y12 receptor antagonists, namely clopidogrel, ticagrelor, or prasugrel, have a delayed antiplatelet effect in AMI mainly due to delayed absorption. Cangrelor – an intravenous P2Y12 inhibitor – requires a continuous infusion and is used at the time of PCI only. Therefore, no P2Y12 inhibitor with a fast onset of action is available in the pre-hospital or emergency department setting.

This study sought to assess the antiplatelet response to selatogrel – a novel subcutaneous reversible P2Y12 receptor antagonist – in patients with AMI.

How was it executed? – the methodology

This was a prospective, open-label, multicentre, randomised, phase 2 study evaluating the safety and early antiplatelet effect of selatogrel in patients with AMI undergoing invasive management.

Patients were eligible if they had type 1 AMI (with or without ST-segment elevation) with symptoms onset from 30 min to 6 hours, and a bodyweight >40 kg. The use of loading doses of ticagrelor was permitted but only after selatogrel injection. Concomitant use of irreversible oral P2Y12 inhibitors (i.e., clopidogrel or prasugrel) and/or cangrelor infusion was not allowed. Patients were randomly allocated (1:1) to receive a single subcutaneous dose of selatogrel (8 or 16 mg), injected into the thigh as soon as possible after randomization.

The primary endpoint was the response to treatment, defined for each subject as a P2Y12 reaction units (PRU) <100 at 30 min post-dose (measured by VerifyNow, which corresponds to an inhibition of ADP-induced platelet aggregation >80%), with a pre-defined target proportion of responders >85%. Safety was assessed up to 48 hours post-injection.

What is the main result?

Of 48 patients randomised in the study, 47 patients received selatogrel and completed the study (8 mg, n=24; 16 mg, n=23). At randomisation, patients had a median age of 69 years, STEMI in 62% of cases, and Killip class I in 94%.

Among 45 patients with valid VerifyNow measurements 30 min post selatogrel, 91% and 96% of patients receiving the 8 mg and 16 mg doses, respectively, responded to the drug (PRU <100). The proportion of responders was significantly higher than the predefined target response threshold of 85% in the 16 mg group (p=0.009) but not in the 8-mg group (p=0.142). The response rate did not vary by age, sex, or AMI presentation. The proportion of responders was consistent at 15 min (8 mg: 75%; 16 mg: 91%), and 60 min post-dose (8 mg: 75%; 16 mg: 96%), and resulted significantly higher than the 85% target response threshold for selatogrel 16 mg at 60 min only (p=0.006). The study drug was well tolerated, and no major bleeding occurred.

Illustration credit: JACC

Illustration credit: JACC

Critical reading and the relevance for clinical practice

This is the first study assessing the safety of and early antiplatelet response to selatogrel (8 and 16 mg) administered subcutaneously in the setting of AMI. Although the study was underpowered for clinical outcomes and limited by the small sample size, open-label design, and absence of a placebo group, the results have an attractive outlook and potentially relevant implications.

To date, there is an unmet need for a fast P2Y12 receptor antagonism before cath-lab admission in patients presenting with AMI. Selatogrel can induce profound platelet inhibition 15 min after subcutaneous administration, resulting in a PRU below 100 in more than 90% of cases irrespective of the dose. In this perspective, selatogrel may potentially offer several advantages over oral P2Y12 inhibitors, including a faster onset profile and almost complete inhibition of the P2Y12 pathway. Noteworthy, the pronounced antiplatelet effect was well tolerated and appeared to be safe.

It is important to consider that the use of loading doses of ticagrelor post selatogrel injection by study design complicates the assessment of the pharmacodynamics effect of selatogrel per se. Nevertheless, the strong P2Y12-mediated platelet inhibition observed at 15 and 30 min is likely to be principally related to selatogrel, in view of pharmacokinetic data. In addition, irreversible P2Y12 inhibitors were forbidden per protocol to avoid interaction with selatogrel; therefore, study conclusions do not apply in patients receiving loading doses of clopidogrel or prasugrel.

As often in research, the most exciting piece of the story is probably what comes next. A phase III trial is upcoming to investigate the clinical efficacy and safety of a single self-administration of selatogrel 16 mg in patients with suspected recurrent AMI. This trial will pioneer the completely new paradigm of early self-medication in acute coronary patients, which could also be extended to other drugs (i.e., subcutaneous lipid-lowering agents). Certainly, this approach – targeting the patient-related treatment delay – poses a number of challenges, including how to educate patients to self-administer the drug at the right time, and whether the early drug self-administration would be enough to provide a net clinical benefit in this setting.

In the meantime, we have learned that selatogrel administered subcutaneously can save time in the early P2Y12 inhibition during AMI. Whether this novel drug will expand modern antiplatelet armamentarium against acute coronary thrombosis remains an open challenge.

What is your feeling about this novel antiplatelet agent? Where do you see an indication for selatogrel in clinical practice?