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Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial.
Gargiulo, G, Esposito, G, Avvedimento, M, Nagler, M, Minuz, P, Campo, G, Gragnano, F, Manavifar, N, Piccolo, R, Tebaldi, M, et al
Circulation. 2020;(5):441-454
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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.
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Relationship Between Platelet Reactivity and Culprit Lesion Morphology: An Assessment From the ADAPT-DES Intravascular Ultrasound Substudy.
Yun, KH, Mintz, GS, Witzenbichler, B, Inaba, S, Shimizu, T, Metzger, DC, Rinaldi, MJ, Mazzaferri, EL, Duffy, PL, Weisz, G, et al
JACC. Cardiovascular imaging. 2016;(7):849-854
Abstract
OBJECTIVES This study evaluated the relationship between platelet reactivity and plaque morphology using grayscale and radiofrequency intravascular ultrasound (IVUS) virtual histology (VH). BACKGROUND Recent studies have reported that high on-treatment platelet reactivity (HPR) is associated with higher plaque volume and the presence of multivessel disease; however, the association between HPR and plaque morphology has not been evaluated. METHODS The ADAPT-DES (Dual AntiPlatelet Therapy With Drug Eluting Stents) intravascular ultrasound substudy was a prospective, multicenter, observational study of 8,582 patients undergoing percutaneous coronary intervention with drug-eluting stents in whom platelet reactivity on clopidogrel was assessed routinely. The current analysis included 909 culprit lesions from 773 patients with pre-intervention grayscale IVUS and IVUS-VH. HPR was defined as platelet reactivity >208 P2Y12 reaction unit in point-of-care P2Y12 testing by the VerifyNow assay, measured during steady-state platelet inhibition in patients receiving an antiplatelet agent. RESULTS HPR was associated with 3-vessel coronary artery disease (31.0% vs. 24.4%; p = 0.04). The incidence of fibroatheroma was higher in patients with HPR than those without HPR (77.1% vs. 68.9%; p = 0.01). The HPR group had larger percent plaque and media volume (plaque and media/external elastic membrane volume: 58.1% [95% confidence interval (CI): 57.1% to 59.0%] vs. 56.6% [95% CI: 55.8% to 57.5%]; p = 0.03) and plaque burden at the minimum lumen site (76.7% [95% CI: 75.7% to 77.8%] vs. 75.0% [95% CI: 74.0% to 76.0%]; p = 0.02). Despite a similar prevalence of attenuated plaque, patients with HPR had longer culprit lesion attenuated plaque length (8.0 [95% CI: 7.0 to 9.1] mm vs. 6.5 [95% CI: 5.9 to 7.1] mm; p = 0.01). On multivariate analysis, the presence of angiographic calcium (odds ratio [OR]: 1.85: 95% CI: 1.33 to 2.56; p = 0.0002) and HPR (OR: 1.45; 95% CI: 1.05 to 2.01; p = 0.02) were independent predictors for a culprit lesion fibroatheroma. CONCLUSIONS HPR was associated with increased culprit lesion atherosclerotic burden and adverse plaque morphology among patients undergoing percutaneous coronary intervention. Platelet reactivity might be associated with not only blood clot formation, but also severity of atherosclerosis. (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents [ADAPT-DES]; NCT00638794).
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Influence of statin treatment on platelet inhibition by clopidogrel - a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment.
Malmström, RE, Ostergren, J, Jørgensen, L, Hjemdahl, P, ,
Journal of internal medicine. 2009;(5):457-66
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Abstract
OBJECTIVES Possible interactions between clopidogrel and atorvastatin, simvastatin or rosuvastatin (a 'non-CYP3A4' metabolized statin) were investigated in a randomized prospective study using sensitive and specific ex vivo platelet function tests. METHODS Patients with coronary artery disease participating in a double-blind study comparing lipid-lowering effects of atorvastatin (20-80 mg OD; n = 22) and rosuvastatin (10-40 mg OD; n = 24) were studied before and after 2 weeks treatment with clopidogrel 75 mg OD after completed statin dose titration. In addition, 23 patients were randomized to open-label simvastatin 40 mg OD. RESULTS Clopidogrel inhibited 10 mumol L(-1) ADP-induced platelet aggregation by 40 +/- 27%, 57 +/- 28% and 51 +/- 29%, respectively, in patients on rosuvastatin, atorvastatin and simvastatin treatment. The other platelet tests yielded similar results. No dose-dependent effects of rosuvastatin or atorvastatin co-treatment on clopidogrel efficacy were observed. CONCLUSIONS Treatment with CYP3A4 metabolized statins, atorvastatin or simvastatin, did not attenuate the platelet inhibitory effect of clopidogrel maintenance treatment compared with the non-CYP3A4 metabolized, rosuvastatin.
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Iron-induced platelet aggregation measurement: a novel method to measure platelet function in stenting for ST segment elevation myocardial infarction.
Smit, JJ, van Oeveren, W, Ottervanger, JP, Slingerland, RJ, Remijn, JA, Zijlstra, F, van 't Hof, AW
European journal of clinical investigation. 2009;(2):103-9
Abstract
BACKGROUND Iron and (stainless) steel are potent platelet aggregation activators, and may be involved in stent thrombosis, a serious complication after intracoronary stenting. Current platelet function tests are suboptimal, because of inappropriate agonists and/or lack of reproducibility. We tested the feasibility and reproducibility of a novel platelet function test using stainless steel as an agonist and compared it with other platelet function tests. MATERIALS AND METHODS In 111 patients with acute ST segment elevation myocardial infarction (STEMI), duplo measurements of iron (Fe)-induced platelet aggregation (FIPA) were performed after clopidogrel, acetylsalicylic acid and/or tirofiban treatment. Within 1 h, citrated blood samples drawn from the femoral sheath before primary percutaneous coronary intervention were added to 100 mg of low carbon steel and after 5 s mixing with vortex, the samples were incubated for 15 min. The ratio between the non-aggregated platelets in the agonist sample and platelets in a reference sample was calculated as the platelet aggregation inhibition. RESULTS FIPA measurement was highly reproducible (correlation coefficient (R)=0.942, P<0.001 between duplo samples). FIPA correlated well with adenosine diphosphate-induced platelet aggregation (R=0.83, P<0.001) but weakly with platelet function analyser-100 bleeding time (R=0.56, P<0.001). FIPA could be measured in patients in which platelet aggregation could not be measured by platelet function analyser-100 or after adenosine diphosphate. CONCLUSION This study showed good reproducibility of a novel platelet function test using stainless steel as an agonist and showed correlation with validated platelet function tests. We found that the novel platelet function test is a suitable test for measurement of platelet aggregation inhibition in patients undergoing stenting for STEMI, even when they are taking multiple antiplatelet regimens.
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Comparative pharmacodynamic evaluation of eptifibatide and tirofiban HCl in patients undergoing percutaneous coronary intervention (the TAM1 Study).
Saucedo, JF, Garza, L, Wolford, DC, Cook, SL, Ramanathan, KB, Matin, Z, McGrew, FA, Jacoski, MV, Jennings, LK, ,
The American journal of cardiology. 2004;(10):1279-82
Abstract
We performed a comparative analysis of platelet aggregation inhibition achieved with the glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban HCl in patients who underwent percutaneous coronary intervention and used light transmission aggregometric assays with D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone as an anticoagulant and 20 micromol of adenosine diphosphate as an agonist. Taking into account the differences in clinical efficacy of these 2 drugs in large trials investigating percutaneous coronary intervention, we hypothesized that the variable clinical effects might be related to variability in the magnitude and consistency of platelet aggregation inhibition achieved with dosing regimens of these glycoprotein IIb/IIIa inhibitors.
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Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).
Tcheng, JE, Talley, JD, O'Shea, JC, Gilchrist, IC, Kleiman, NS, Grines, CL, Davidson, CJ, Lincoff, AM, Califf, RM, Jennings, LK, et al
The American journal of cardiology. 2001;(10):1097-102
Abstract
This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.