Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial

Abstract

Background: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention.

Methods: The FABOLUS-FASTER trial (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) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 μmol/L adenosine diphosphate.

Results: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016).

Conclusions: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.

Keywords: cangrelor; percutaneous coronary intervention; platelet aggregation; prasugrel hydrochloride; tirofiban.

Conflict of interest statement

Dr Gargiulo reports consultant fees from Daiichi-Sankyo outside the submitted work. Dr Gragnano reports research grant support from the European Society of Cardiology. Dr Vranckx reports personal fees from Daiichi-Sankyo, AstraZeneca, Bayer Health Care, and Terumo outside the submitted work. Dr Leonardi reports personal fees from Bayer, Bristol-Myers Squibb SA, Chiesi, Daiichi-Sankyo, and AstraZeneca outside the submitted work. Dr Windecker reports research and educational grants to the institution from Abbott, Amgen, Bayer, BMS, Biotronik, Boston Scientific, CSL Behring, Edwards Lifesciences, Medtronic, Polares, and Sinomed outside the submitted work. Dr Valgimigli reports a grant to the institution from Medicure and grants and personal fees from Abbott, Alvimedica, Amgen, Bayer, Bristol-Myers Squibb SA, Coreflow, Daiichi-Sankyo, Vifor, Idorsia, Terumo, iVascular, and AstraZeneca outside the submitted work. The other authors report no disclosures.

Figures

Figure 1.

Flow chart of the FABOLUS-FASTER trial. *For 2 hours or to the end of the PCI. FABOLUS-FASTER indicates 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; PCI, percutaneous coronary intervention; and STEMI, ST-segment–elevation myocardial infarction.

Figure 2.

Pharmacodynamic effects of drugs measured by LTA after ADP 20 µmol/L stimulation.A, Percentage of inhibition of platelet aggregation (IPA). B, IPA >80%. C, IPA >90%. ADP indicates adenosine diphosphate; CI, confidence interval; LS, least square; and LTA, light transmittance aggregometry.

Figure 3.

Rates of high residual platelet reactivity defined by platelet aggregation >59% at LTA after ADP 20 µmol/L stimulation. °P<0.001 versus cP; *P<0.001 versus C and cP; **P<0.05 versus cP; #P<0.001 versus C; §P<0.05 versus cP; ¶P<0.01 versus C. ADP indicates adenosine diphosphate; and LTA, light transmittance aggregometry.

Figure 4.

Pharmacodynamic effects of drugs measured by LTA. Pharmacodynamic effects of drugs measured by LTA after stimulation with ADP 5 µmol/L (A) and TRAP 15 (B) and 5 (C) µmol/L. ADP indicates adenosine diphosphate; CI, confidence interval; IPA, inhibition of platelet aggregation; LS, least square; LTA, light transmittance aggregometry; and TRAP, thrombin receptor agonist peptide.

Figure 5.

Pharmacokinetic analysis comparing PAM concentrations between chewed and integral prasugrel groups. CI indicates confidence interval; and PAM, prasugrel active metabolite.

Figure 6.

Pharmacodynamic and pharmacokinetic effects of cangrelor, tirofiban, and prasugrel (chewed or integral) in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention 30 minutes after drug administration. ADP indicates adenosine diphosphate; and TRAP, thrombin receptor agonist peptide.