Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg Twice Daily in Elderly Patients With Acute Coronary Syndrome (ACS)

Elderly individuals account for an increasing proportion of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) given the aging of the population and the lengthening of life expectancy.1, 2 Dual antiplatelet therapy with aspirin and an oral P2Y12 receptor inhibitor is the cornerstone of antithrombotic therapy in patients with ACS undergoing PCI, yet decision-making in older patients remains challenging because of a concomitantly increased risk of bleeding and ischemic complications burdening this population.3 Elderly status may be considered per se a condition at heightened risk of bleeding since, by applying available risk scores, patients aged 75 years or more who undergo PCI are classified as moderate-to-high risk of bleeding irrespective of other additional features.4 Current guidelines recommend DAPT in the setting of ACS and ticagrelor, an oral, reversible, direct-acting P2Y12 receptor inhibitor, should be preferred to clopidogrel and prasugrel among elderly patients.5 Nevertheless, observational studies have consistently shown that new P2Y12 receptor inhibitors continue to be withheld in more than one third of eligible patients with ACS and that aging is the most powerful predictor of undertreatment with clopidogrel.6 This occurs for several reasons, including adverse bleeding events or nonbleeding events, a perceived too high bleeding risk, and the higher risk profile of elderly patients seen in clinical practice compared with that in randomized trials. Therefore, alternative antithrombotic strategies should be pursued for elderly patients with ACS in order to minimize the harmful effects of more potent antiplatelet inhibition without withholding the established ischemic benefit. At this regard, a standard dose of prasugrel (10 mg daily) resulted in a negative net benefit among elderly patients with ACS and a lower dose of prasugrel (5 mg daily) did not prove safer or more effective than clopidogrel.7 8 Since the risk-benefit profile of a full dose of ticagrelor (90 mg twice daily) seemed more favorable among elderly individuals, a lower dose regimen of ticagrelor (60 mg twice daily) has the potential to improve the safety profile of potent P2Y12 receptor inhibition while providing an equally effective option.

A low-dose of ticagrelor has been evaluated in the PEGASUS-TIMI 54 trial, in which 21,162 patients, who were on aspirin and had a myocardial infarction 1 to 3 years earlier, were randomized to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg daily, or placebo. The primary efficacy endpoint of cardiovascular death, myocardial infarction, and stroke through 3 years was significantly reduced by 15% and 16% among patients randomized to standard and low-dose of ticagrelor compared with placebo. Patients randomly allocated to the standard and low dose of ticagrelor had a 169% and 132% relative risk increase in major bleeding compared with placebo. Of interest, ticagrelor 90 mg vs. placebo had the greatest benefit for the primary efficacy endpoint among younger than older patients (20% relative risk reduction vs. 2% relative risk increase, respectively), whereas ticagrelor 60 mg vs. placebo had the greatest benefit for the primary efficacy endpoint among older than younger patients (23% relative risk reduction vs. 14% relative risk reduction, respectively). For the safety profile, elderly patients had roughly a 2-fold higher incidence of bleeding compared with younger patients, with ticagrelor 90 mg being associated with the highest rate of bleeding (4.81%). Conversely, ticagrelor 60 mg was associated with a lower incidence of major bleeding (-0.7% absolute difference) compared with ticagrelor 90 mg, even though major bleeding events were increased compared with placebo (+2.43% absolute difference).9 Taken together, the data from the PEGASUS-TIMI 54 suggest ticagrelor 60 mg twice daily may present the best combination of efficacy and safety for elderly patients.

Although no specific data are available for ticagrelor 60 mg among elderly patients with ACS, a substudy of the PEGASUS- TIMI 54 trial showed that ticagrelor 60 mg twice daily achieved a platelet inhibition similar to that with 90 mg twice daily (PRU values: 59±63 and 47±43 for ticagrelor 60 and 90 mg twice daily, respectively).10 Noteworthy, these data have been observed in a relatively younger population (mean age 64 years) with stable coronary artery disease after nearly 2 years from the index myocardial infarction.10 Consequently, the findings of the PEGASUS-TIMI 54 trial cannot be directly extrapolated to our population with since both elderly status and ACS are associated with higher platelet reactivity.

Primary Objectives: the main aim of the trial is to determine whether the efficacy of ticagrelor 60 mg twice daily is not inferior to that of ticagrelor 90 mg twice daily among elderly patients with ACS undergoing PCI.

Secondary Objectives: To evaluate adverse events in patients treated with ticagrelor 60 mg and ticagrelor 90 mg. To determine the pharmacokinetic profile of ticagrelor 60 mg twice daily versus ticagrelor 90 mg twice daily.