Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers

NCT ID: NCT02618837

Last Updated: 2020-12-02

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 2520 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-14
• Study Completion Date: 2022-08-31

Brief Summary

To evaluate the impact on outcomes of the currently accepted antithrombotic strategies based on the administration of newer P2Y12 receptor blockers (prasugrel and ticagrelor) in a population of non ST elevated ACS (NSTEACS) patients with an initial invasive indication.

Furthermore, to evaluate the effects of bivalirudin administration in comparison to standard therapy with unfractioned heparin (plus provisional anti-GPIIbIIIa) in NSTEACSpatients who undergo PCI and will thus receive these potent antiplatelet agents which may theoretically favor the occurrence of bleedings.

A combined measure of efficacy and safety endpoints, the so-called net clinical benefit (NACE), will be considered at early (30 days) and mid term (12 months) follow-up.

Conditions

Unstable Angina or Non ST Elevated Myocardial Infarction

Keywords

NSTEMI; NSTEACS; prasugrel; ticagrelor; Downstream versus Upstream strategy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Downstream strategy arm

downstream administration strategy of P2Y12 receptor blockers (prasugrel or ticagrelor)

Group Type: ACTIVE_COMPARATOR

Downstream strategy

Intervention Type: PROCEDURE

At diagnosis:

Subjects receive a loading dose of aspirin (150-300mg). Administration of clopidogrel is allowed only for patients already receiving clopidogrel

Pre-procedure:

Until PCI is performed, all subjects will be maintained at a minimum of 75mg of aspirin (Subjects with clopidogrel may be maintained at a minimum of 75mg of clopidogrel)

Peri- and post-procedure:

For all the patients undergoing PCI, both the use of unfractioned heparin and of bivalirudin will be allowed at the time of PCI; choice based upon clinical judgement.

In this case, subject will be randomized in a 1:1 fashion to prasugrel vs ticagrelor

At the time of PCI, the loading doses required (according to randomization):

• Ticagrelor 180mg, maintained at 90mg b.i.d. for at least 12 months
• Prasugrel 60mg, maintained at a minimum of 75mg of aspirin for at least 12 months plus 10mg of prasugrel* daily for at least 12 months

• If subject is >75 years old or <60 kg, daily dose of prasugrel should be 5mg

Upstream strategy arm

upstream administration strategy (ticagrelor only)

Group Type: ACTIVE_COMPARATOR

Upstream strategy

Intervention Type: PROCEDURE

At the time of diagnosis:

Subjects randomized in this arm must receive a loading dose of aspirin (150-300 mg) and ticagrelor (180 mg) at admission as soon as possible.

Pre-procedure:

All subjects will be maintained at a minimum of 90 mg of ticagrelor b.i.d. and a minimum of 75 mg of aspirin, until coronary angiography is performed.

Peri- and post-procedure:

For all the patients undergoing PCI, both the use of unfractioned heparin and of bivalirudin will be allowed at the time of PCI; the choice of the anticoagulant at the time of PCI will be based upon clinical judgement.

All subjects randomized to the upstream strategy arm will be maintained at a minimum of 90 mg of ticagrelor b.i.d. and a minimum of 75 mg of aspirin, for at least 12 months. If the subject develops hypersensitivity or intolerance to ticagrelor, clopidogrel may be used as a substitute at a dose in accordance with standard hospital practice (to be documented in the eCRF).

Interventions

Downstream strategy

At diagnosis:

Subjects receive a loading dose of aspirin (150-300mg). Administration of clopidogrel is allowed only for patients already receiving clopidogrel

Pre-procedure:

Until PCI is performed, all subjects will be maintained at a minimum of 75mg of aspirin (Subjects with clopidogrel may be maintained at a minimum of 75mg of clopidogrel)

Peri- and post-procedure:

For all the patients undergoing PCI, both the use of unfractioned heparin and of bivalirudin will be allowed at the time of PCI; choice based upon clinical judgement.

In this case, subject will be randomized in a 1:1 fashion to prasugrel vs ticagrelor

At the time of PCI, the loading doses required (according to randomization):

• Ticagrelor 180mg, maintained at 90mg b.i.d. for at least 12 months
• Prasugrel 60mg, maintained at a minimum of 75mg of aspirin for at least 12 months plus 10mg of prasugrel* daily for at least 12 months

• If subject is >75 years old or <60 kg, daily dose of prasugrel should be 5mg

Intervention Type: PROCEDURE

Upstream strategy

At the time of diagnosis:

Subjects randomized in this arm must receive a loading dose of aspirin (150-300 mg) and ticagrelor (180 mg) at admission as soon as possible.

Pre-procedure:

All subjects will be maintained at a minimum of 90 mg of ticagrelor b.i.d. and a minimum of 75 mg of aspirin, until coronary angiography is performed.

Peri- and post-procedure:

For all the patients undergoing PCI, both the use of unfractioned heparin and of bivalirudin will be allowed at the time of PCI; the choice of the anticoagulant at the time of PCI will be based upon clinical judgement.

All subjects randomized to the upstream strategy arm will be maintained at a minimum of 90 mg of ticagrelor b.i.d. and a minimum of 75 mg of aspirin, for at least 12 months. If the subject develops hypersensitivity or intolerance to ticagrelor, clopidogrel may be used as a substitute at a dose in accordance with standard hospital practice (to be documented in the eCRF).

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 and < 85
• Non ST elevated acute coronary syndrome (unstable angina, non ST elevated myocardial infarction), with an onset of symptoms during the previous 24 hours.
• An initial invasive strategy is chosen (the patient is expected to undergo coronary angiography within 72 h from admission).
• Subject is able to start therapy with a new P2Y12 inhibitor (prasugrel or ticagrelor) OR is on a maintenance dose of clopidogrel or ticlopidine and is able to switch to a new P2Y12 inhibitor (prasugrel or ticagrelor).
• Subject is able to verbally confirm understanding of risks and benefits of dual antiplatelet therapy in coronary acute syndromes and he/she or his/her legally authorized representative provides written informed consent prior to any Clinical Investigation related procedure, as approved by the appropriate Ethics Committee.
• Patient agrees to comply with follow-up evaluations.

Exclusion Criteria

• Known hypersensitivity/contraindication to aspirin, clopidogrel, prasugrel, ticagrelor, heparin or bivalirudin, or sensitivity to contrast media, which can't be adequately pre-medicated.
• Platelet count <100,000 cells/mm³ or >700,000 cells/mm³, or a white blood cell (WBC) count <3,000 cells/mm³ within 7 days prior to index procedure.
• Shock.
• Have severe hepatic impairment defined as Child Pugh Class C.
• Pregnant or nursing subjects and those who plan pregnancy in the period up to 3 years following screening. (Female subjects of child-bearing potential must have a negative pregnancy test done within 28 days prior to enrollment).
• Other medical illness (e.g., cancer or congestive heart failure) or known history of substance abuse (alcohol, cocaine, heroin etc.) as per physician judgment that may cause non-compliance with the protocol or confound the data interpretation or is associated with a limited life expectancy.
• Subject is belonging to a vulnerable population (per investigator's judgment, e.g., subordinate hospital staff or sponsor staff) or subject unable to read or write.
• Currently participating in investigational drug or device trial that has not completed the primary endpoint or that clinically interferes with current trial endpoints. Subject must agree not to participate in any other clinical investigation for a period of three years following the index procedure, including clinical trials of medication and invasive procedures. Questionnaire-based studies, or other studies that are non-invasive and do not require medication are allowed.
• Prior history of hemorrhagic or ischemic stroke, a transient ischemic attack (TIA), or sub-arachnoid hemorrhage.
• History of intracranial neoplasm, arterovenous malformation, or aneurysm.
• Have received fibrinolytic therapy within 48 hours of entry or randomization into the study.
• Have active pathological bleeding or history of bleeding diathesis.
• Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding.
• Have had recent surgery (within 4 weeks of entry into the study) or are scheduled to undergo surgery within the next 2 months.
• Have received a loading dose of a thienopyridine (ticlopidine, clopidogrel or prasugrel) or a maintenance dose of prasugrel or Ticlopidine or Ticagrelor within 7 days of entry into the study.
• Are receiving a GPIIb/IIIa inhibitor (eptifibatide, tirofiban, or abciximab).
• Are receiving warfarin or other coumarin derivatives.
• Are receiving or will receive oral anticoagulation or other oral antiplatelet therapy (except aspirin [ASA]) that cannot be safely discontinued within the next 3 months.
• Are receiving daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX2) inhibitors that cannot be discontinued or are anticipated to require >2 weeks of daily treatment with NSAID or COX2 inhibitors during the study.
• Concomitant therapy with a strong cytochrome P-4503A inhibitor or inducer.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 84 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Azienda Ospedaliera di Padova

OTHER

Sponsor Role: collaborator

University of Padova

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Azienda Ospedaliera di Padova

Padua, Veneto, Italy

Countries

Italy

References

Tarantini G, Mojoli M, Varbella F, Caporale R, Rigattieri S, Ando G, Cirillo P, Pierini S, Santarelli A, Sganzerla P, De Cesare N, Limbruno U, Lupi A, Ricci R, Cernetti C, Favero L, Saia F, Roncon L, Gasparetto V, Ferlini M, Ronco F, Ferri L, Trabattoni D, Russo A, Guiducci V, Penzo C, Tarantino F, Mauro C, Marchese A, Castiglioni B, La Manna A, Martinato M, Gregori D, Angiolillo DJ, Musumeci G. Downstream or upstream administration of P2Y12 receptor blockers in non-ST elevated acute coronary syndromes: study protocol for a randomized controlled trial. Trials. 2020 Nov 24;21(1):966. doi: 10.1186/s13063-020-04859-1.

Reference Type: DERIVED

PMID: 33234137 (View on PubMed)

Tarantini G, Mojoli M, Varbella F, Caporale R, Rigattieri S, Ando G, Cirillo P, Pierini S, Santarelli A, Sganzerla P, Cacciavillani L, Babuin L, De Cesare N, Limbruno U, Massoni A, Rognoni A, Pavan D, Belloni F, Cernetti C, Favero L, Saia F, Fovino LN, Masiero G, Roncon L, Gasparetto V, Ferlini M, Ronco F, Rossini R, Canova P, Trabattoni D, Russo A, Guiducci V, Penzo C, Tarantino F, Mauro C, Corrada E, Esposito G, Marchese A, Berti S, Martinato M, Azzolina D, Gregori D, Angiolillo DJ, Musumeci G; DUBIUS Investigators; Italian Society of Interventional Cardiology. Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. J Am Coll Cardiol. 2020 Nov 24;76(21):2450-2459. doi: 10.1016/j.jacc.2020.08.053. Epub 2020 Aug 31.

Reference Type: DERIVED

PMID: 32882390 (View on PubMed)

Other Identifiers

DUBIUS - 0015746

Identifier Type: -

Identifier Source: org_study_id