Randomized Comparison of Cangrelor, Tirofiban and Prasugrel in Patients With STEMI Referred for Primary PCI. (FABOLUS-FASTER)

Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over prasugreL: a mUlticenter Randomized Open-label Trial in patientS With ST-elevation Myocardial inFarction Referred for primAry percutaneouS inTERvention.FABOLUS FASTER Trial

Primary percutaneous coronary intervention (PCI) is the main reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI). The optimal platelet inhibition at the time of PCI is fundamental, however, the comparative speed of action of cangrelor as opposed to tirofiban and to chewed or integer loading dose of prasugrel is unknown.

The purpose of this trial is to assess the inhibition of platelet aggregation with different regimens on platelet inhibition (tirofiban bolus+infusion, cangrelor bolus+infusion, prasugrel chewed loading dose, prasugrel integer loading dose) in the early phase of primary PCI.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; STEMI - ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: Cangrelor; Drug: Tirofiban; Drug: Prasugrel

Detailed Description

Primary percutaneous coronary intervention (PCI) is the main reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI). Ancillary pharmacological therapy includes dual antiplatelet therapy with aspirin and an inhibitor of P2Y12 receptor, responsible of adenosine diphosphate(ADP)-mediated platelet activation.Prasugrel and ticagrelor are the most recent and efficient oral P2Y12 inhibitors available to date. However, in STEMI even prasugrel and ticagrelor could have a significant delay of onset of action. Early in-ambulance administration can increase the inhibition of P2Y12 receptor, however, the benefits versus risks balance remain uncertain. Recently, small-scale independent studies suggested that chewed or crushed loading dose of ticagrelor or prasugrel can achieve more pronounced platelet inhibition compared with standard whole tablets soon after drug administration. Yet, the delay in platelet inhibition remains considerable even after chewed or crushed loading dose of newer oral P2Y12 inhibitors and suboptimal modulation of platelet reactivity at the time of primary intervention may persist. Tirofiban and cangrelor are intravenous drugs with a more rapid onset and offset of action compared with oral agents. Both agents have been extensively tested in clinical trials including patients with STEMI. However, the comparative speed of action of cangrelor as opposed to tirofiban and to chewed or integer loading dose of prasugrel is unknown. The proposed investigation will have a prospective, randomized, design in which STEMI patients undergoing primary PCI will be randomized to receive Cangrelor or Tirofiban or Prasugrel (these patients will be further randomized to receive chewed or integer tablets). Pharmacodynamic testing will be performed at several time points to test the investigators' study hypotheses: 1) Cangrelor will have similar inhibitory effect to Tirofiban (non-inferiority of Cangrelor compared with Tirofiban); 2) Compared with Prasugrel, Cangrelor and Tirofiban will achieve more prompt and enhanced platelet inhibitory effects (superiority of both Tirofiban and Cangrelor to integer Prasugrel); 3) Compared with integer loading dose of Prasugrel, chewed Prasugrel regimen will achieve more prompt and enhanced platelet inhibitory effects (superiority of chewed Prasugrel to integer Prasugrel). This study will provide insights on the pharmacodynamic effects of these drugs and will help clinicians choose the most appropriate treatment to avoid complications related to inadequate platelet inhibition in the early phase of patients with STEMI undergoing primary PCI.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Ferrara, Italy, 44124
    • University of Ferrara
  • Naples, Italy, 80131
    • University of Naples Federico II
• Switzerland
  • Bern, Switzerland, 3010
    • Bern University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age greater than 18 years old
• ST-segment elevation myocardial infarction
• Referred for primary PCI either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia

Exclusion Criteria:

• Unconsciousness
• Other conditions that make the patient incapable receiving integer loading dose of prasugrel
• Any contraindication and/or known hypersensitivity or allergy to aspirin, prasugrel, intravenous unfractionated heparin, cangrelor, tirofiban
• Any contraindication to primary PCI
• Administration of glycoprotein IIb/IIIa inhibitors (GPI) or P2Y12-inhibitors or cangrelor < 7 days
• Chronic dialysis
• Recent (< 15 days) or current major bleeding
• Recent (< 15 days) major surgery
• Administration of fibrinolytics < 30 days
• Current use or indication to oral anticoagulant
• Previous stroke or transient ischemic attack (TIA)
• Inability to follow the procedures of the study (language problems, psychological disorders, dementia) or comorbidities associated with less than 6 months survival (active malignancies drug or alcohol abuse, etc.)
• Women who are pregnant or breast feeding or with potential to become pregnant during the course of the study (age < 55 years and last menstruation within the last 12 months) and did not undergo tubal ligation, ovariectomy or hysterectomy
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Enrolment of the investigator, his/her family members, employees and other dependent persons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cangrelor; Cangrelor bolus of 30 µg/Kg followed by infusion at 4 µg/Kg/min for 2 h (or to the end of PCI).	Drug: Cangrelor; Cangrelor will be administered as bolus of 30 µg/Kg followed by infusion at 4 µg/Kg/min for 2 h (or to the end of PCI); at the end of infusion, oral prasugrel at loading dose of 60 mg will be administrated, then 10 mg daily (5 mg daily if body weight < 60 kg or age > 75 years old).; Other Names: Kengreal; Kengrexal
ACTIVE_COMPARATOR: Tirofiban; Tirofiban bolus of 25 µg/Kg bolus followed by infusion at 0.15 µg/Kg/min for 2 h (or to the end of PCI) (infusion rate of 0.075 µg/Kg/min for patients with creatinine clearance < 60 ml/min).	Drug: Tirofiban; Tirofiban will be administrated as 25 µg/Kg bolus followed by infusion at 0.15 µg/Kg/min for 2 h (or to the end of PCI) (infusion rate of 0.075 µg/Kg/min for patients with creatinine clearance < 60 ml/min); at the end of infusion, oral prasugrel at loading dose of 60 mg will be administrated, then 10 mg daily (5 mg daily if body weight < 60 kg or age > 75 years old) .; Other Names: Aggrastat
ACTIVE_COMPARATOR: Prasugrel; Prasugrel oral integer or chewed at an identical loading dose of 60 mg	Drug: Prasugrel; In the prasugrel arm no intravenous anti-platelet drug will be administered. Patients will be randomized to oral integer prasugrel or chewed oral prasugrel at an identical loading dose of 60 mg, then 10 mg daily (5 mg daily if body weight < 60 kg or age > 75 years old).; Other Names: Efient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibition of platelet activity (IPA, %) with LTA-ADP 20 µmol/l	Primary outcome is platelet inhibition assessed with light transmission aggregometry (LTA) in platelet rich plasma with the addition of adenosine diphosphate (ADP) 20 µmol/l at 30 minutes from drug administration	30 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibition of platelet activity (IPA, %) with LTA-ADP 20 µmol/l	Platelet inhibition assessed with light transmission aggregometry (LTA) in platelet rich plasma with the addition of ADP 20 µmol/l at 15 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Inhibition of platelet activity (IPA, %) with LTA-ADP 5 µmol/l	Platelet inhibition assessed with light transmission aggregometry (LTA) in platelet rich plasma with the addition of ADP 5 µmol/l at 15 minutes, 30 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Inhibition of platelet activity (IPA, %) with LTA-TRAP 5 µmol/l	Platelet inhibition assessed with light transmission aggregometry (LTA) in platelet rich plasma with the addition of thrombin receptor-activating peptides (TRAP) 5 µmol/l at 15 minutes, 30 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Inhibition of platelet activity (IPA, %) with LTA-TRAP 15 µmol/l	Platelet inhibition assessed with light transmission aggregometry (LTA) in platelet rich plasma with the addition of TRAP 15 µmol/l at 15 minutes, 30 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Area under the curve (AUC) at Multiplate with ADP test	Platelet inhibition assessed with Multiplate ADP test at 15 minutes, 30 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Area under the curve (AUC) at Multiplate with TRAP test	Platelet inhibition assessed with Multiplate TRAP test at 15 minutes, 30 minutes, 1h, 2h, 3h and 4-6h from drug administration	15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4-6 hours
Angiographic result	Final angiographic result evaluated by proportion of patients with TIMI flow<3	immediately after PCI procedure
Electrocardiographic result	ST resolution at ECG recorded after PCI	immediately after PCI procedure and 90 minutes after PCI
Infarct size at Cardiac Magnetic Resonance Imaging (MRI)	Infarct size assessed at cardiac MRI	3 days and 4-6 months after PCI
Intramyocardial haemorrhage at Cardiac Magnetic Resonance Imaging (MRI)	Intramyocardial haemorrhage assessed at cardiac MRI	3 days and 4-6 months after PCI
Major adverse ischemic clinical events	Major adverse ischemic clinical events (including death, cardiac death, myocardial infarction, stroke, urgent target vessel revascularization, definite/probable stent thrombosis and their combinations in composite endpoints) will be evaluated 48 hours and 30 days from primary PCI.	48 h and 30 days after PCI
Bleeding events	Bleeding events according to Bleeding Academic Research Consortium (BARC), Thrombolysis in Myocardial Infarction (TIMI), Global Use of Strategies To Open occluded arteries (GUSTO) bleeding scales as well as Net adverse clinical events (NACE; defined as the composite of death, non-fatal myocardial infarction, definite/probable stent thrombosis, non-fatal stroke, and BARC 2, 3, or 5 bleeding) will be evaluated at 48 hours and 30 days from primary PCI	48 h and 30 days after PCI

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Study Chair: Marco Valgimigli, Prof, Department of Cardiology, Bern University Hospital; Principal Investigator: Giuseppe Gargiulo, MD, Department of Cardiology, Bern University Hospital

Publications and helpful links

General Publications

• Gargiulo G, Esposito G, Avvedimento M, Nagler M, Minuz P, Campo G, Gragnano F, Manavifar N, Piccolo R, Tebaldi M, Cirillo P, Hunziker L, Vranckx P, Leonardi S, Heg D, Windecker S, Valgimigli M. Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial. Circulation. 2020 Aug 4;142(5):441-454. doi: 10.1161/CIRCULATIONAHA.120.046928. Epub 2020 Jun 27. Erratum In: Circulation. 2020 Aug 4;142(5):e71.
• Gargiulo G, Esposito G, Cirillo P, Nagler M, Minuz P, Campo G, Gragnano F, Manavifar N, Piccolo R, Avvedimento M, Tebaldi M, Wahl A, Hunziker L, Billinger M, Heg D, Windecker S, Valgimigli M. Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over PrasugreL: a MUlticenter Randomized Open-label Trial in PatientS with ST-elevation Myocardial InFarction Referred for PrimAry PercutaneouS InTERvention (FABOLUS FASTER) Trial: Design and Rationale : The FABOLUS FASTER Trial. J Cardiovasc Transl Res. 2021 Feb;14(1):110-119. doi: 10.1007/s12265-020-09969-4. Epub 2020 Feb 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 4, 2017
• Primary Completion (ACTUAL): August 26, 2019
• Study Completion (ACTUAL): December 27, 2019

Study Registration Dates

• First Submitted: November 17, 2016
• First Submitted That Met QC Criteria: November 26, 2016
• First Posted (ESTIMATE): November 30, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 21, 2020
• Last Update Submitted That Met QC Criteria: February 20, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Acute Myocardial Infarction; Prasugrel; Antiplatelet therapy; Cangrelor; Tirofiban; Primary Percutaneous Coronary Intervention; Pharmacokinetic/Pharmacodynamic
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Infarction; Infarction; Coronary Artery Disease; ST Elevation Myocardial Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Tirofiban; Prasugrel Hydrochloride; Cangrelor
• Other Study ID Numbers: FABOLUS-FASTER

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No