Should we consider early de-escalation of maintenance dose of antiplatelet therapy post-ACS?

This editorial refers to ‘Platelet inhibition with standard vs. lower maintenance dose of ticagrelor early after myocardial infarction (ELECTRA): a randomized, open-label, active-controlled pharmacodynamic and pharmacokinetic study’, by J. Kubica et al., on page 139. Platelet activation plays a key role in the pathophysiology of acute coronary syndromes (ACS). Two decades ago, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial1 showed that dual antiplatelet therapy (DAPT) with the addition of clopidogrel, a P2Y12 inhibitor, to aspirin led to a significant reduction in major adverse cardiovascular events (MACE). With time, more effective platelet inhibitory drugs were developed, such as prasugrel and ticagrelor, with faster onset of action, more potent and consistent platelet inhibition,2 and no need for metabolic activation (ticagrelor). In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) study,3 prasugrel was more effective in reducing ischaemic events and stent thrombosis in patients with ACS undergoing percutaneous coronary interventions. However, major and fatal bleeding rates were significantly increased. Results from the large global study on platelet inhibition and patient outcomes (PLATO)4 demonstrated a significant benefit with a reduction in both MACE and mortality with ticagrelor 90 mg b.i.d. over clopidogrel, after almost 12 months median treatment duration with no overall increase in bleeding complications, but with higher rates of non-cardiopulmonary bypass graft (CABG)-related bleeding events. Thus, the current recommended antiplatelet treatment for ACS is a combination of aspirin and a P2Y12 inhibitor, preferably ticagrelor according to international guidelines,5 with a treatment duration of 12 months as default based on the treatment duration by design of the pivotal trials. There is general agreement that the risk of ischaemic events is highest in the first period post-ACS,6 and that bleeding events occur at a more steady rate depending on dose and treatment regimen of the antiplatelet therapy.7 In PEGASUS TIMI-54,8 prolonged duration of DAPT 1–3 years after a myocardial infarction (MI), with either a lower dose of ticagrelor 60 mg b.i.d. or the standard dose of 90 mg b.i.d. were tested over placebo. Both doses were found to be equally effective in further lowering the risk of cardiovascular events after the first year up to 3 years, but at the trade-off of a more than doubling of the risk of TIMI major bleedings. Bleeding rates were, however, lower with the 60 mg than with the 90 mg dose. Hence this dose is now approved for prolonged treatment after the first 12 months. The balance between risk of ischaemic events and risk of bleeding events is important, and clinicians often struggle with assessments of the net clinical benefit.9 The risk factors are often the same and overlapping. In this issue of the European Heart Journal – Cardiovascular Pharmacotherapy, Jacek Kubica and colleagues have taken this concept further and present the results from the ELECTRA study, a small mechanistic randomized open-label study on 52 patients, evaluating the effects on platelet reactivity of lowering the maintenance dose from ticagrelor 90 mg to 60 mg b.i.d., starting at 30 days in patients after an acute MI, treated with percutaneous coronary intervention (PCI).10 The main findings after 15 days of treatment were that no difference in platelet reactivity, assessed either by VASP (vasodilator-stimulated phosphoprotein) assay or by Multiplate, could be observed when comparing the two doses. It is important to keep in mind that the study was designed for evaluating the effects on platelet inhibition. Only a few bleeding events occurred during the study. Hence, no conclusion can be drawn from effects on bleeding events based on this small study, as well as on ischaemic outcomes, and the study is as such hypothesis generating. Other limitations may be that platelet function was assessed only at one time point, i.e. 4 h post-dosing. The authors suggest that the findings warrant further research in assessing the efficacy and safety between the two doses on clinical outcomes and safety aspects such as bleeding rates. A large-scale randomized prospective multicentre outcome study would be needed to answer this hypothesis. Early initiation of a lower maintenance dose has not previously been assessed with this strategy. However, efforts have been made to switch from a potent to a less potent platelet inhibitor after the acute phase. Most of these have been neutral. In one study, prasugrel was de-escalated to clopidogrel based on platelet function test,11 with non-inferior results. In the TOPIC study, DAPT with a newer P2Y12 inhibitor plus aspirin was changed to clopidogrel and aspirin at 1 month12 and resulted in fewer bleeding events but not at an increased rate of ischaemic events. A key question is where is the optimal time point after the ACS for a reduction in the maintenance dose of ticagrelor, to achieve sufficiently effective platelet inhibition. Where is the transfer point where a patient changes from unstable to stable? The Kaplan–Meier curves for both PLATO and TRITON show an increasing curve with a slight signal of levelling off after 30–60 days. More studies are needed in this respect. In summary, the authors have challenged the current concept of antiplatelet therapy with lowering the maintenance dose of antiplatelet therapy starting earlier than current recommendations, already at 30 days after the acute MI. They concluded that there were comparable levels of platelet reactivity with both 60 mg and 90 mg ticagrelor b.i.d. Thus, a potential clinical benefit of less bleeding but without an increased risk of ischaemic events would be clinically relevant. However, this needs to be tested in a prospective randomized large-scale controlled study. If this concept would hold true, it might affect future maintenance dosing strategies with antiplatelet drugs towards less intense platelet inhibition than current standards. However, as of today, we should base our recommendations on existing completed studies such as CURE, TRITON, and PLATO.