Acute Coronary SyndromePhase 3PlinytheElderNCT04739384
Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg in Elderly Patients With ACS
A Phase 3 study testing Ticagrelor 90mg and Ticagrelor 60 mg in people with Acute Coronary Syndrome and STEMI, run by Federico II University at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Coronary Syndrome, STEMI, NSTEMI
- What is being tested?
- Ticagrelor 90mg and Ticagrelor 60 mg
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteItaly
- Study dates
- 1 Apr 2021to 20 Jun 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Ability to provide written informed consent in a time window 1 to 3 days after successful PCI;
- Male or female, age ≥ 75 years at screening;
- ACS at the time of the index hospitalization;
- Use of a loading dose of 180 mg of ticagrelor administered after diagnosis of ACS or after PCI;
- Use of a maintenance dose of 90 mg twice daily of ticagrelor of at least 48 hours after the loading dose;
- 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
Who cannot join
- Use of glycoprotein IIb/IIIa receptor inhibitors;
- Need for chronic oral anticoagulant therapy;
- Prior fibrinolysis;
- Unstable clinical status (hemodynamic or electrical instability);
- Planned surgery requiring DAPT discontinuation during the study;
- Prior stroke, transient ischemic attack or intracranial bleeding;
Show all 15Show fewer
- Active bleeding;
- Severe anemia (hemoglobin < 8g/dL);
- Platelet count ≤80x103/ml;
- Renal failure (hemodialysis or creatinine clearance ≤ 30 ml/min calculated with Cockroft-Gault formula);
- Severe hepatic dysfunction (baseline alanine aminotransferase ≥ 2.5 times the upper limit of normal);
- Known hypersensitivity or contraindication to ticagrelor;
- Under judicial protection, tutorship or curatorship;
- Unable to understand and follow study-related instructions;
- Enrollment in another investigational device or drug study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg Twice Daily in Elderly Patients With Acute Coronary Syndrome (ACS)
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.
Read the 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).
- Being tested
- Ticagrelor 90mg, Ticagrelor 60 mg
- Keywords
- Platelet aggregation, Elderly patients, Ticagrelor
- Medical subject headings
- Acute Coronary Syndrome, ST Elevation Myocardial Infarction, Non-ST Elevated Myocardial Infarction, Coronary Artery Disease, Myocardial Infarction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ticagrelor 90mgDrug
Also called Ticagrelor 60 mg
Ticagrelor 90 mg followed by Ticagrelor 60 mg
Ticagrelor 60 mgDrug
Also called Ticagrelor 90 mg
Ticagrelor 60 mg followed by Ticagrelor 90 mg
| Study group | Role | What they receive |
|---|---|---|
| Standard dose of ticagrelor (90 mg twice daily). | Experimental | Standard dose of ticagrelor (90 mg twice daily) followed by lower dose of ticagrelor (60 mg twice daily). Receives: Drug: Ticagrelor 90mg; Drug: Ticagrelor 60 mg |
| Low dose of ticagrelor (60 mg twice daily). | Experimental | Low dose of ticagrelor (60 mg twice daily) followed by standard dose of ticagrelor (90 mg twice daily). Receives: Drug: Ticagrelor 90mg; Drug: Ticagrelor 60 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
P2Y12 reaction units (PRU) determined by VerifyNow assay.
Comparison of pre-dose P2Y12 reaction units (PRU) determined by VerifyNow- P2Y12 assay at 14 days after treatment with ticagrelor 60 mg or 90 mg.
Measured: 14 days
Secondary outcomes (9)
High platelet reactivity (HPR) and ADP-induced platelet reactivity.
High platelet reactivity (HPR) and ADP-induced platelet reactivity evaluated through light transmittance aggregometry (LTA) and Multiplate Analyzer.
Measured: 28 days
Non ADP-induced platelet reactivity.
Non ADP-induced platelet reactivity (arachidonic acid and thrombin receptor-activating test).
Measured: 28 days
The composite of all-cause death, myocardial infarction, or stroke.
Measured: 28 days
The composite of cardiovascular death, myocardial infarction, urgent target-lesion revascularization.
Measured: 28 days
Frequency of spontaneous myocardial infarction.
Measured: 28 days
Frequency of unstable angina.
Measured: 28 days
Frequency of any revascularization.
Measured: 28 days
Frequency of bleeding events according to the BARC, TIMI and GUSTO classification.
Measured: 28 days
Plasma levels of ticagrelor and its active metabolite AR-C124910XX.
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2021
- Study start1 Apr 2021
- Primary completion20 Jun 2022
- Study completion20 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Acute Coronary SyndromeStudies of the same condition, open and under way.
- More trials run by Federico II UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Federico II University
- Sponsor type
- University, hospital or other
- Collaborators
- AdvicePharma Group
- Responsible party
- Principal investigator, Giovanni Esposito, Federico II University
- Investigators
- Giovanni Esposito, MD, PhD, Principal investigator, Federico II University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04739384
- Sponsor's protocol ID
- 16520
- Acronym
- PlinytheElder
- Status last verified
- Jul 2022
- First submitted
- 28 Dec 2020
- Last updated
- 7 Jul 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Andreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, Huber K, Hylek EM, Lip GY, Montalescot G, Morais J, Patrono C, Verheugt FW, Wallentin L, Weiss TW, Storey RF; ESC Thrombosis Working Group. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2015 Dec 7;36(46):3238-49. doi: 10.1093/eurheartj/ehv304. Epub 2015 Jul 9. No abstract available.
PubMed 26163482Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJ. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015 Apr 2;372(14):1333-41. doi: 10.1056/NEJMoa1406656.
PubMed 25830423Capodanno D, Angiolillo DJ. Antithrombotic therapy in the elderly. J Am Coll Cardiol. 2010 Nov 16;56(21):1683-92. doi: 10.1016/j.jacc.2010.04.063.
PubMed 21070918Varenne O, Cook S, Sideris G, Kedev S, Cuisset T, Carrie D, Hovasse T, Garot P, El Mahmoud R, Spaulding C, Helft G, Diaz Fernandez JF, Brugaletta S, Pinar-Bermudez E, Mauri Ferre J, Commeau P, Teiger E, Bogaerts K, Sabate M, Morice MC, Sinnaeve PR; SENIOR investigators. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet. 2018 Jan 6;391(10115):41-50. doi: 10.1016/S0140-6736(17)32713-7. Epub 2017 Nov 1.
PubMed 29102362Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260. doi: 10.1093/eurheartj/ehx419. No abstract available.
PubMed 28886622Calabro P, Gragnano F, Di Maio M, Patti G, Antonucci E, Cirillo P, Gresele P, Palareti G, Pengo V, Pignatelli P, Pennacchi M, Granatelli A, De Servi S, De Luca L, Marcucci R; for EYESHOT Study and Start Antiplatelet Register. Epidemiology and Management of Patients With Acute Coronary Syndromes in Contemporary Real-World Practice: Evolving Trends From the EYESHOT Study to the START-ANTIPLATELET Registry. Angiology. 2018 Oct;69(9):795-802. doi: 10.1177/0003319718760917. Epub 2018 Mar 15.
PubMed 29544348Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.
PubMed 17982182Savonitto S, Ferri LA, Piatti L, Grosseto D, Piovaccari G, Morici N, Bossi I, Sganzerla P, Tortorella G, Cacucci M, Ferrario M, Murena E, Sibilio G, Tondi S, Toso A, Bongioanni S, Ravera A, Corrada E, Mariani M, Di Ascenzo L, Petronio AS, Cavallini C, Vitrella G, Rogacka R, Antonicelli R, Cesana BM, De Luca L, Ottani F, De Luca G, Piscione F, Moffa N, De Servi S; Elderly ACS 2 Investigators. Comparison of Reduced-Dose Prasugrel and Standard-Dose Clopidogrel in Elderly Patients With Acute Coronary Syndromes Undergoing Early Percutaneous Revascularization. Circulation. 2018 Jun 5;137(23):2435-2445. doi: 10.1161/CIRCULATIONAHA.117.032180. Epub 2018 Feb 19.
PubMed 29459361Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791-800. doi: 10.1056/NEJMoa1500857. Epub 2015 Mar 14.
PubMed 25773268Storey RF, Angiolillo DJ, Bonaca MP, Thomas MR, Judge HM, Rollini F, Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R, Braunwald E, Sabatine MS. Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol. 2016 Mar 15;67(10):1145-1154. doi: 10.1016/j.jacc.2015.12.062.
PubMed 26965534Piccolo R, Avvedimento M, Canonico ME, Gargiulo P, Paolillo R, Conti V, Dal Piaz F, Filippelli A, Morisco C, Simonetti F, Leone A, Marenna A, Bruzzese D, Gargiulo G, Stabile E, Di Serafino L, Franzone A, Cirillo P, Esposito G. Platelet Inhibition with Ticagrelor 60 mg Versus 90 mg Twice Daily in Elderly Patients with Acute Coronary Syndrome: Rationale and Design of the PLINY THE ELDER Trial. Cardiovasc Drugs Ther. 2023 Oct;37(5):1031-1038. doi: 10.1007/s10557-021-07302-y. Epub 2022 Jan 20.
PubMed 35048203
Study at a glance
From the registry record, last updated by the sponsor on 7 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Platelet Inhibition With Ticagrelor 60 mg Versus Ticagrelor 90 mg Twice Daily in Elderly Patients With Acute Coronary Syndrome (ACS)
- ClinicalTrials.gov ID
- NCT04739384
- Acronym / sponsor ID
- PlinytheElder / 16520
- Keywords
- Platelet aggregation, Elderly patients, Ticagrelor
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Federico II UniversityUniversity, hospital or other
- Collaborators
- AdvicePharma Group
- Study start
- 1 Apr 2021 (actual)
- Primary completion
- 20 Jun 2022 (actual)
- Study completion
- 20 Jun 2022 (actual)
- First posted
- 4 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard dose of ticagrelor (90 mg twice daily). | Experimental | Drug: Ticagrelor 90mg, Drug: Ticagrelor 60 mgStandard dose of ticagrelor (90 mg twice daily) followed by lower dose of ticagrelor (60 mg twice daily). |
| Low dose of ticagrelor (60 mg twice daily). | Experimental | Drug: Ticagrelor 90mg, Drug: Ticagrelor 60 mgLow dose of ticagrelor (60 mg twice daily) followed by standard dose of ticagrelor (90 mg twice daily). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Ability to provide written informed consent in a time window 1 to 3 days after successful PCI;
- Male or female, age ≥ 75 years at screening;
- ACS at the time of the index hospitalization;
- Use of a loading dose of 180 mg of ticagrelor administered after diagnosis of ACS or after PCI;
- Use of a maintenance dose of 90 mg twice daily of ticagrelor of at least 48 hours after the loading dose;
Key exclusion criteria (15 listed)
- Use of glycoprotein IIb/IIIa receptor inhibitors;
- Need for chronic oral anticoagulant therapy;
- Prior fibrinolysis;
- Unstable clinical status (hemodynamic or electrical instability);
- Planned surgery requiring DAPT discontinuation during the study;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ticagrelor 90mgAlso: Ticagrelor 60 mgTicagrelor 90 mg followed by Ticagrelor 60 mg | Drug | Low dose of ticagrelor (60 mg twice daily)., Standard dose of ticagrelor (90 mg twice daily). |
| Ticagrelor 60 mgAlso: Ticagrelor 90 mgTicagrelor 60 mg followed by Ticagrelor 90 mg | Drug | Low dose of ticagrelor (60 mg twice daily)., Standard dose of ticagrelor (90 mg twice daily). |
Primary outcome
P2Y12 reaction units (PRU) determined by VerifyNow assay.
Time frame: 14 days
Comparison of pre-dose P2Y12 reaction units (PRU) determined by VerifyNow- P2Y12 assay at 14 days after treatment with ticagrelor 60 mg or 90 mg.
9 secondary outcomes
High platelet reactivity (HPR) and ADP-induced platelet reactivity.
Time frame: 28 days
Non ADP-induced platelet reactivity.
Time frame: 28 days
The composite of all-cause death, myocardial infarction, or stroke.
Time frame: 28 days
The composite of cardiovascular death, myocardial infarction, urgent target-lesion revascularization.
Time frame: 28 days
Frequency of spontaneous myocardial infarction.
Time frame: 28 days
Frequency of unstable angina.
Time frame: 28 days
Frequency of any revascularization.
Time frame: 28 days
Frequency of bleeding events according to the BARC, TIMI and GUSTO classification.
Time frame: 28 days
Plasma levels of ticagrelor and its active metabolite AR-C124910XX.
Time frame: 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jul 2022.
- Background: PubMed 26163482Andreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, Huber K, Hylek EM, Lip GY, Montalescot G, Morais J, Patrono C, Verheugt FW, Wallentin L, Weiss TW, Storey RF; ESC Thrombosis Working Group. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2015 Dec 7;36(46):3238-49. doi: 10.1093/eurheartj/ehv304. Epub 2015 Jul 9. No abstract available.
- Background: PubMed 25830423Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJ. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015 Apr 2;372(14):1333-41. doi: 10.1056/NEJMoa1406656.
- Background: PubMed 21070918Capodanno D, Angiolillo DJ. Antithrombotic therapy in the elderly. J Am Coll Cardiol. 2010 Nov 16;56(21):1683-92. doi: 10.1016/j.jacc.2010.04.063.
- Background: PubMed 29102362Varenne O, Cook S, Sideris G, Kedev S, Cuisset T, Carrie D, Hovasse T, Garot P, El Mahmoud R, Spaulding C, Helft G, Diaz Fernandez JF, Brugaletta S, Pinar-Bermudez E, Mauri Ferre J, Commeau P, Teiger E, Bogaerts K, Sabate M, Morice MC, Sinnaeve PR; SENIOR investigators. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet. 2018 Jan 6;391(10115):41-50. doi: 10.1016/S0140-6736(17)32713-7. Epub 2017 Nov 1.
- Background: PubMed 28886622Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260. doi: 10.1093/eurheartj/ehx419. No abstract available.
- Background: PubMed 29544348Calabro P, Gragnano F, Di Maio M, Patti G, Antonucci E, Cirillo P, Gresele P, Palareti G, Pengo V, Pignatelli P, Pennacchi M, Granatelli A, De Servi S, De Luca L, Marcucci R; for EYESHOT Study and Start Antiplatelet Register. Epidemiology and Management of Patients With Acute Coronary Syndromes in Contemporary Real-World Practice: Evolving Trends From the EYESHOT Study to the START-ANTIPLATELET Registry. Angiology. 2018 Oct;69(9):795-802. doi: 10.1177/0003319718760917. Epub 2018 Mar 15.
- Background: PubMed 17982182Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi: 10.1056/NEJMoa0706482. Epub 2007 Nov 4.
- Background: PubMed 29459361Savonitto S, Ferri LA, Piatti L, Grosseto D, Piovaccari G, Morici N, Bossi I, Sganzerla P, Tortorella G, Cacucci M, Ferrario M, Murena E, Sibilio G, Tondi S, Toso A, Bongioanni S, Ravera A, Corrada E, Mariani M, Di Ascenzo L, Petronio AS, Cavallini C, Vitrella G, Rogacka R, Antonicelli R, Cesana BM, De Luca L, Ottani F, De Luca G, Piscione F, Moffa N, De Servi S; Elderly ACS 2 Investigators. Comparison of Reduced-Dose Prasugrel and Standard-Dose Clopidogrel in Elderly Patients With Acute Coronary Syndromes Undergoing Early Percutaneous Revascularization. Circulation. 2018 Jun 5;137(23):2435-2445. doi: 10.1161/CIRCULATIONAHA.117.032180. Epub 2018 Feb 19.
- Background: PubMed 25773268Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791-800. doi: 10.1056/NEJMoa1500857. Epub 2015 Mar 14.
- Background: PubMed 26965534Storey RF, Angiolillo DJ, Bonaca MP, Thomas MR, Judge HM, Rollini F, Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R, Braunwald E, Sabatine MS. Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol. 2016 Mar 15;67(10):1145-1154. doi: 10.1016/j.jacc.2015.12.062.
- Derived from this study: PubMed 35048203Piccolo R, Avvedimento M, Canonico ME, Gargiulo P, Paolillo R, Conti V, Dal Piaz F, Filippelli A, Morisco C, Simonetti F, Leone A, Marenna A, Bruzzese D, Gargiulo G, Stabile E, Di Serafino L, Franzone A, Cirillo P, Esposito G. Platelet Inhibition with Ticagrelor 60 mg Versus 90 mg Twice Daily in Elderly Patients with Acute Coronary Syndrome: Rationale and Design of the PLINY THE ELDER Trial. Cardiovasc Drugs Ther. 2023 Oct;37(5):1031-1038. doi: 10.1007/s10557-021-07302-y. Epub 2022 Jan 20.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giovanni Esposito, MD, PhD principal investigator
Federico II University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ticagrelor 90mg and Ticagrelor 60 mg in people with Acute Coronary Syndrome and STEMI, run by Federico II University at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
P2Y12 reaction units (PRU) determined by VerifyNow assay. (time frame: 14 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04739384, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jul 2022.