Clinical trial NCT04739384: Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg in Elderly Patients With ACS
Official title: Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg Twice Daily in Elderly Patients With Acute Coronary Syndrome (ACS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Coronary Syndrome
STEMI
NSTEMI
Coronary Artery Disease
Myocardial Infarction
Keywords: Platelet aggregation
Elderly patients
Ticagrelor
Lead sponsor: Federico II University
Sponsor class: OTHER
Collaborators: name: AdvicePharma Group
First posted: 2021-02-04
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Elderly individuals are increasingly represented among patients with acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 receptor inhibitor has an established role in the prevention of atherothrombotic events in ACS setting. However, DAPT in older patients is challenged by a concurrent heightened risk of ischemia and bleeding. Although guidelines recommend DAPT with aspirin and ticagrelor for elderly patients with ACS, clopidogrel, a less potent antiplatelet agent, continues to be used in more than one third of ACS patients with elderly status being the strongest predictor of undertreatment. A lower dose of ticagrelor may represent an alternative to the standard dose by conferring a similar efficacy and, potentially, a better safety profile. Our prospective, randomized, double-blind, crossover trial will test the hypothesis that a lower dose of ticagrelor provides similar antiplatelet effects compared with a standard dose among elderly patients with ACS.

The main aim of the trial is to determine the pharmacodynamic and pharmacokinetic profile of ticagrelor 60 mg twice daily versus ticagrelor 90 mg twice daily among elderly patients with ACS undergoing PCI.

This will be a prospective, randomized (1:1 ratio), non-inferiority, open-label, crossover trial to evaluate the level of platelet inhibition achieved with a low-dose of ticagrelor (60 mg twice daily) versus a standard dose of ticagrelor (90 mg twice daily) among elderly patients with ACS undergoing PCI.

Detailed description: 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.

This will be a prospective, randomized (1:1 ratio), non-inferiority, open-label, crossover trial to evaluate the level of platelet inhibition achieved with a low-dose of ticagrelor (60 mg twice daily) versus a standard dose of ticagrelor (90 mg twice daily) among elderly patients with ACS undergoing PCI. The study will have a 2 x 2 crossover design with 2-sequence, 2-period, and 2-treatments.

After signing the informed consent form, patients will be randomized to ticagrelor 60 mg twice daily vs. ticagrelor 90 mg twice daily in a 1:1 ratio through a web-based randomization system.

Each patient will be allocated to the following treatments in a open-label fashion:

* Ticagrelor 90 mg twice daily, followed by ticagrelor 60 mg twice daily;
* Ticagrelor 60 mg twice daily, followed by ticagrelor 90 mg twice daily;

The study duration for each individual patient will amount to 28 days consisting of:

* A 2-week first treatment period (from day 1 to day 14): randomly allocated treatment will be maintained for 14 days;
* A 2-week second treatment period (from day 15 to day 28): the patients will crossover to the alternative treatment, which is administered for 14 days.

Aspirin 100 mg once daily is maintained throughout all the study phases.

Blood sampling to evaluate adenosine diphosphate (ADP) e non-ADP platelet aggregation will be performed at 3 time points:

* Time 1 (baseline): before randomization;
* Time 2 (crossover): 14 days after randomization, including 2 samples, before and 2 hours after the last dose of the initial assigned treatment;
* Time 3 (end of study): 28 days after randomization, including 2 samples, before and 2 hours after the last dose of the second assigned treatment.

Platelet function will be assessed by using several platelet function tests: (i) VerifyNow P2Y12 (VN-P2Y12); (ii) Light transmittance aggregometry (LTA); (iii) Multiplate electrode aggregometry (MEA).

Eligibility criteria: Inclusion Criteria:

1. Ability to provide written informed consent in a time window 1 to 3 days after successful PCI;
2. Male or female, age ≥ 75 years at screening;
3. ACS at the time of the index hospitalization;
4. Use of a loading dose of 180 mg of ticagrelor administered after diagnosis of ACS or after PCI;
5. Use of a maintenance dose of 90 mg twice daily of ticagrelor of at least 48 hours after the loading dose;
6. Successful PCI (Thrombolysis In Myocardial Infarction \[TIMI\] flow 3 and residual coronary stenosis \<30%) for non-ST-segment elevation ACS or ST-segment elevation myocardial infarction

Exclusion Criteria:

1. Use of glycoprotein IIb/IIIa receptor inhibitors;
2. Need for chronic oral anticoagulant therapy;
3. Prior fibrinolysis;
4. Unstable clinical status (hemodynamic or electrical instability);
5. Planned surgery requiring DAPT discontinuation during the study;
6. Prior stroke, transient ischemic attack or intracranial bleeding;
7. Active bleeding;
8. Severe anemia (hemoglobin \< 8g/dL);
9. Platelet count ≤80x103/ml;
10. Renal failure (hemodialysis or creatinine clearance ≤ 30 ml/min calculated with Cockroft-Gault formula);
11. Severe hepatic dysfunction (baseline alanine aminotransferase ≥ 2.5 times the upper limit of normal);
12. Known hypersensitivity or contraindication to ticagrelor;
13. Under judicial protection, tutorship or curatorship;
14. Unable to understand and follow study-related instructions;
15. Enrollment in another investigational device or drug study.

Primary outcomes:
measure: P2Y12 reaction units (PRU) determined by VerifyNow assay.
timeFrame: 14 days
Secondary outcomes:
measure: High platelet reactivity (HPR) and ADP-induced platelet reactivity.
timeFrame: 28 days
measure: Non ADP-induced platelet reactivity.
timeFrame: 28 days
measure: The composite of all-cause death, myocardial infarction, or stroke.
timeFrame: 28 days
measure: The composite of cardiovascular death, myocardial infarction, urgent target-lesion revascularization.
timeFrame: 28 days
measure: Frequency of spontaneous myocardial infarction.
timeFrame: 28 days
measure: Frequency of unstable angina.
timeFrame: 28 days
measure: Frequency of any revascularization.
timeFrame: 28 days
measure: Frequency of bleeding events according to the BARC, TIMI and GUSTO classification.
timeFrame: 28 days
measure: Plasma levels of ticagrelor and its active metabolite AR-C124910XX.
timeFrame: 28 days
Other outcomes:
Locations:
city: Naples
country: Italy
facility: Professor Giovanni Esposito
Study officials:
affiliation: Federico II University
name: Giovanni Esposito, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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