Cangrelor, Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST-Segment Elevation Myocardial Infarction: Primary Results of the FABOLUS FASTER Trial
Selected in Circulation by L. Biasco
The results of the FABOLUS FASTER trial clearly highlight that a high residual platelet reactivity persists when targeting platelet activation by inhibition of the P2Y12 receptor either with Prasugrel or Cangrelor, while tackling the mechanism of platelet adhesion thought the inhibition of GPIIB/IIIA might almost completely inhibit platelet aggregation soon after drug administration.
References
Authors
Giuseppe Gargiulo, Giovanni Esposito, Marisa Avvedimento, Michael Nagler, Pietro Minuz, Gianluca Campo, Felice Gragnano, Negar Manavifar, Raffaele Piccolo , Matteo Tebaldi, Plinio Cirillo, Lukas Hunziker, Pascal Vranckx, Sergio Leonardi, Dik Heg, Stephan Windecker, and Marco Valgimigl
Published
June 2020
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Read the abstractOur comment
Why this study? – the rationale/objective
Rapid and complete inhibition of platelet function is of paramount importance when managing patients with acute coronary sindromes. This becomes fundamental in those presenting with ST segment elevation myocardial infarction (STEMI) undergoning primary percutaneous coronary interventions (PPCI). As the presence of residual platelet reactivity correlates with higher rates of procedural failures as well as worse outcomes among STEMI patients, therapeutic strategies able to achieve a rapid and stable suppression of platelet reactivity are warranted.
The “Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over PrasugreL: a MUlticenter Randomized Open-label Trial in PatientS with STelevation Myocardial InFarction Referred for PrimAry PercutaneouS InTERvention (FABOLUS FASTER)” is an investigator initiated, multicenter open label randomized trial evaluating the pharmacodynamic of three different strategies based on Tirofiban, a parenteral GP IIb/IIIa inhibitor, Cangrelor (direct parenteral) or Prasugrel (oral prodrug) inhibitors of the adenosine diphosphate (ADP)-activated platelet P2Y12 receptor. The effects of integral vs chewed administration of Prasugrel on pharmacokynetics and platelet reactivity were also assessed.
How was it executed? – the methodology
Study population:
- 122 P2Y12-naïve STEMI patients with a mean age of 65 years (73% males) undergoing PPCI randomly allocated to cangrelor (40 pts), tirofiban (40 pts) and prasugrel (60 mg, chewed tablets in 21 pts, integral administration in the remaining).
- In both parenteral arms a bolus + short (2 hours) infusion protocol was followed by a loading dose of 60 mg of prasugrel.
- Enrollment was performed at three different centers (Bern, Naples and Ferrara University Hospitals).
- Aspirin, Heparin and other medications prescribed as percurrent clinical practice with dose reductions wheter deemed clinically indicated.
Methodology:
Blood samples were collected at baseline and repeated at 15, 30 min,1h, 2h, 3h, and between 4 to 6h after administration of either tirofiban, cangrelor or prasugrel.
Serial assessment of platelet function on platelet rich plasma with light transmittance aggregometry (LTA) stimulated with Adenosine Diphosphate (ADP at 5 and 20 ɥmol/L) and Trombin Receptor Agonist Peptide (TRAP at 5 and 15 ɥmol/L). Multiple electrode aggregometry was also used to assess platelet aggregation in whole blood in two centers.
Measurement of Prasugrel’s active metabolite was also implemented following a specific request of the Italian Drug Agency.
The primary endpoint was set as the percent of inhibition of platelet aggregation (%IPA, defined as the percent of platelet aggregation compared to the basal measure) assessed with LTA at 30 minutes after stimulation with ADP (20 ɥmol/L), while all residual measurements considered as secondary endpoints.
The study was designed to test the non-inferiority of Cangrelor compared to Tirofiban, superiority of both Tirofiban and Cangrelor compared to chewed Prasugrel and superiority of chewed vs integral Prasugrel. A prespecified secondary conditional endpoint of superiority of Tirofiban vs Cangrelor was also chosen.
What is the main result?
Evaluation of percent of IPA as assessed with LTA at 30 minutes after stimulation with ADP (20 ɥmol/L) yelded the following results: Tirofiban 95.0±9.0, Cangrelor 34.1±22.5, chewed 10.5±11.0 and integral 6.3±11.4 Prasugrel. The primary endopoint of non-inferiority of cangrelor vs tifofiban was not met while the secondary conditional endpoint of superiority of Tirofiban was met. Both parenteral drugs proved to be superior to oral prasugrel while superiority of chewed vs integral prasugrel was not proven.
Time trend analysis clearly show that parenteral administration of tirofiban yelded a fast and persistent platelet inhibition until end of the infusion protocol. When comparing cangrelor to prasugrel, a greater degree of inhibition of platelet aggregation was evident with cangrelor up to the first hour after drug administration, while being comparable at 2 hours. From 3 hours onward, prasugrel showed higher rates of platelet inhibition. About half of patients in the cangrelor arm showed a high residual platelet reactivity (HRPR, defined as platelet reactivity >59% after ADP 20 μmol/L) throughout the whole time of drug infusion.
Chewed prasugrel, while not reaching the endpoint of superior % IPA over the integral administration at 30 minutes, showed to be associated with a greater seric concentration of it its active metabolite up to 1 hour after administration (68.836±87.797 vs 27.861±52.841 ng/ml, p=0.029) but without significant differences in terms of time for the maximum plasma concentration (1.441±1.316 vs 1.933±1.033 hours; p=0.244).
Illustration credit: FABOLUS FASTER presentation by Marco Valmigli at PCR e-Course 2020
Critical reading and the relevance for clinical practice:
In the context of STEMI, obtaining fast, reliable and stable inhibition of platelet reactivity is a mainstay of medical therapy. This concept derives from the observation that risk of early thrombotic complications, such as re-infarction or acute stent thrombosis, is directly related to the residual level of platelet reactivity.
Prasugrel, a prodrug requiring conversion to an active metabolite through a one-step cytochrome P450-dependant reaction, and Ticagrelor, orally active drug requiring no metabolic activation, have been developed and used in ACS patients to allow a faster onset of action and a more predictable clinical effect than with clopidogrel.
Nonetheless, a high residual on treatment platelet reactivity has been reported with both drugs up to 6 hours after administration, a crucial time window when mechanical reperfusion is considered. Then, given the lack of clear alternatives such as more rapid antiplatelet drugs or clear effects of preloading, the use of alternative drugs regimes thus including parenteral administration routes might help in achieving a earlier and complete suppression of platelet reactivity in STEMI patients, this representing the rationale of the FABOLUS trials family. The results of the FABOLUS FASTER trial represent a step forward with respect to the previously published FABOLUS PRO trial comparing Prasugrel versus Tirofiban and the first head to head comparison between Tirofiban and Cangrelor, the latter comparison being of particular clinical interest.
The results of the FABOLUS FASTER trial clearly highlight that a high residual platelet reactivity persist when targeting platelet activation by inhibition of the P2Y12 receptor either with Prasugrel or Cangrelor, while tackling the mechanism of platelet adhesion thought the inhibition of GPIIB/IIIA might almost completely inhibit platelet aggregation soon after drug administration. The proposal of a short infusion protocol for the parenteral GP IIb/IIIa inhibitor might represent newer, and safer, therapeutic possibility for this class of drugs which is administered nowadays almost exclusively as a bailout strategy in the context of slow flow-no reflow phenomena.
Results of the present analysis are hypothesis generating. While clinical event being properly collected and analysed, the study was clearly not powered to assess clinical endpoints that have to be evaluated in a properly designed randomized trial. In the meanwhile, even if not finally proven, I will reconsider the utility of GP IIb/IIIa inhibitors and, while loading with a P2Y12 inhibitor my STEMI patients, suggest to chew their tablets.
Related reading:
- PCR e-Course 2020: view this presentation of the FABOLUS FASTER trial by Marco Valmigli
- Read this trial review of the FABOLUS FASTER trial by Luis Ortega Paz
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