Do We Need a New P2Y12 Receptor Antagonist?

Jean-Sébastien Hulot; Gilles Montalescot

Disclosures

Eur Heart J. 2020;41(33):3141-3143. 

Pharmacotherapy around the time of acute myocardial infarction (AMI) reperfusion is an area of intense research and continuous improvements. The different guidelines have highlighted the need for shortening the delay to treatment initiation as the pre-hospital phase appears to be the most critical in improving survival and cardiovascular outcomes.[1,2] Among the different targets, the rapid inhibition of platelet purinergic P2Y12 receptors is an undisputed objective. Following atherosclerotic plaque disruption, ADP is released and binds the platelet P2Y1 and P2Y12 receptors, which activates GPIIb/IIIa on platelets, and leads to sustained platelet aggregation and thrombus growth.[3] This mechanism amplifies within minutes after plaque disruption, thus supporting the need for fast-acting and fast-delivered pharmacotherapies that will specifically inhibit this prothrombotic process.

Two main classes of P2Y12 receptor antagonists are currently used for the treatment of AMI. First, thienopyridines (i.e. clopidogrel and prasugrel) are inactive prodrugs that are administered orally and metabolically converted in the liver to an active metabolite which irreversibly binds to and inactivates the P2Y12 receptor. In addition, clopidogrel activation requires a CYP2C19-dependent process which is variable between subjects, partly because of genetic polymorphism.[4] In order to speed up its onset of action, an intravenous formulation of clopidogrel (MDCO-157) was developed but failed to efficiently inhibit platelet aggregation.[5] Using prasugrel, near maximal inhibition of platelet aggregation (IPA) occurs within 4 h, and 1–2 h faster if the pills are crushed, but this is still a considerable delay, with efficacy occurring after percutaneous coronary intervention (PCI) is finished.

Secondly, ticagrelor (for oral use) and cangrelor (for intravenous use) are non-thienopyridine receptor antagonists that are directly active and can reversibly bind the P2Y12 receptor. Ticagrelor has a rapid onset of action but, even crushed or used with an orodispersible formulation, near maximal IPA occurs within 1–2 h after administration. Additional factors may further delay absorption and bioavailability, including the use of parenteral opiates which affect gastric emptying.[6,7] Cangrelor is a reversible intravenous short-acting P2Y12 receptor antagonist and could be seen as being an alternative to overcome these delays in action of the oral drugs. However, cangrelor requires a continuous intravenous infusion and is only used at the time of PCI in patients not pre-loaded with an oral P2Y12 receptor antagonist. No pre-hospital experience has been reported with cangrelor in contrast to prasugrel and ticagrelor.

There is thus a potential need for additional non-oral therapies that will provide rapid and reliable P2Y12 inhibition in AMI patients. Selatogrel (also known as ACT-246475) is a novel non-thienopyridine agent, a derivative of a 2-phenylpyrimidine-4-carboxamide analogue.[8] Selatogrel acts as a reversible, selective, and potent antagonist of the platelet P2Y12 receptor. It therefore represents another reversibly binding P2Y12 inhibitor that is, however, distinct from ticagrelor and cangrelor by being developed for subcutaneous administration. In a first study in healthy volunteers,[9] selatogrel was shown to be rapidly absorbed, with maximal platelet inhibition reached after ~30 min.

In this issue of the European Heart Journal, Storey and colleagues extend this study by reporting selatogrel pharmacodynamics (PD) and pharmacokinetics (PK) profiles in patients with stable coronary artery disease.[10] Selatogrel plasma concentrations peaked ~30 min post-dose which induced a potent IPA of ~90% as compared with 16% with placebo (P < 0.0001). This effect was already present 15 min after injection and was maintained for ≥8 h and reversible within 24 h. Two doses of selatogrel (i.e. 8 and 16 mg) were tested and provided similar PK and PD results, and the duration of platelet inhibition seemed modestly dose dependent. Selatogrel achieved additional platelet inhibition in patients already treated with oral P2Y12 inhibitors, which represents an important result for patients with recurrent thrombotic events under P2Y12 inhibitors. Selatogrel was safe and well tolerated, but induced dyspnoea, as already reported with reversibly binding P2Y12 inhibitors.

The results of this phase II trial are important in suggesting that this novel therapeutic strategy can achieve more rapid and more complete P2Y12 inhibition in patients with AMI than what is achievable with the currently available oral drugs. Additional information from a separate study in AMI patients will refine the optimal dose (8 or 16 mg) in patients presenting with AMI, the target population for phase III (ClinicalTrials.gov NCT03487445). A few issues remain, however. What benefit can we expect from selatogrel in patients already on prasugrel or ticagrelor? What is the strategy for transitioning from selatogrel to oral P2Y12 inhibitors without losing a potential initial benefit from selatogrel? Indeed, cangrelor was shown to impede the binding of thienopyridine active metabolites to the P2Y12 receptor, thereby creating a pharmacodynamic interaction.[11] Whether selatogrel displays the same effect needs to be determined.

In recent years, success has been achieved in decreasing the time from first medical contact to antiplatelet therapy preceding mechanical reperfusion of AMI. It has involved emergency departments and mobile intensive care units first in clinical trials and now in daily practice.[12–14] Stronger and faster platelet inhibition has also been obtained with the new generation of P2Y12 inhibitors as well as with the new modes of administration (crushed or orodispersible tablets, intravenous cangrelor). The chain of care cannot expect much better clinical outcomes with selatogrel. In contrast, the time from symptom onset to first medical contact, i.e. a waiting time free of any intervention to block the ongoing platelet-mediated event, has not changed much in the past years. This period belongs to the patients and their surroundings. Information and education should allow the patients to recognize the symptoms likely to correspond to the start of an MI and call for emergency help. Selatogrel, a P2Y12 inhibitor that can be self-administered subcutaneously, should be tested in the first minutes of AMI to see whether it aborts or at least reduces MI and possibly prevents cardiogenic shock, heart failure, arrythmias, or death (Take home figure). This will be the challenge of the phase III trial involving the patient directly in the process of coronary reperfusion. So, doctors may consider they do not need a new P2Y12 inhibitor like selatogrel whereas patients really need it and it may help to demonstrate that early self-administered antiplatelet therapy is an effective first-aid procedure in the case of a heart attack

Take home figure.

Timing of P2Y12 receptor antagonists in AMI management.

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