10 Pharmacodynamic profiles of aspirin versus dual-pathway inhibition with either aspirin or clopidogrel among patients with stable atherosclerotic disease

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Mattia Galli ◽  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Latonya Been ◽  
Patrick Jaoude ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Antiplatelet Agents ◽  
Adenosine Diphosphate ◽  
Atherosclerotic Disease ◽  
Light Transmittance ◽  
Open Label ◽  
Cyclooxygenase 1 ◽  
Parallel Group ◽  
Dual Pathway ◽  
Pathway Inhibition

Abstract Aims Inhibition of thrombin-mediated signalling processes using a vascular dose of rivaroxaban in adjunct to single antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there is limited data on the pharmacodynamic (PD) effects of this strategy. Methods This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group PD study who were treated with either aspirin, aspirin plus rivaroxaban 2.5 mg/bid or clopidogrel plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. The primary endpoint was the comparison between groups of platelet-mediated global thrombogenicity by light transmittance aggregometry (LTA) following stimuli with collagen-related peptide + adenosine diphosphate + tissue factor (CATF). Results There were no differences in the primary endpoint between aspirin vs. aspirin plus rivaroxaban 2.5 mg/bid (P = 0.110), aspirin vs. clopidogrel plus rivaroxaban 2.5 mg/bid (P = 0.611) or aspirin plus rivaroxaban 2.5 mg/bid vs. clopidogrel plus rivaroxaban 2.5 mg/bid (P = 0.315). Rivaroxaban-based treatments significantly reduced markers of thrombin generation (peak thrombin and thrombin velocity index). Clopidogrel-based treatments reduced markers of P2Y12 signalling (LTA ADP 20 max and VerifyNow). Aspirin-based treatments reduced markers of markers of cyclooxygenase-1 activity (LTA collagen). Conclusions Compared with aspirin alone, DPI with either aspirin or clopidogrel might provide superior ischaemic protection by targeting pathways alternative to those affected by antiplatelet agents with only a moderate trade-off in bleeding as supported by similar platelet-mediated global thrombogenicity between treatments.

Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel vs dual antiplatelet therapy in patients with atherosclerotic disease

2022 ◽  
Author(s):  
Mattia Galli ◽  
Francesco Franchi ◽  
Fabiana Rollini ◽  
Latonya Been ◽  
Patrick Abou Jaoude ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Antiplatelet Therapy ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Adenosine Diphosphate ◽  
Atherosclerotic Disease ◽  
Light Transmittance ◽  
Dual Pathway ◽  
Pathway Inhibition

Aim: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy. Methods and Results: This investigation was conducted in selected cohorts of patients (n=40) with stable atherosclerotic disease enrolled within a larger prospective PD study who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI) or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays assessing of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF [collagen‐related peptide +adenosine diphosphate (ADP) +tissue factor (TF)], markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and TRAP), thrombin generation and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend towards reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP‐induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase‐1 mediated activity. Conclusions: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations support that modulating thrombin generation by means of factor Xa inhibition in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of DPI observed in clinical

scholarly journals Dual Pathway Inhibition for Vascular Protection in Patients with Atherosclerotic Disease: Rationale and Review of the Evidence

2020 ◽  
Vol 120 (08) ◽  
pp. 1147-1158 ◽  
Author(s):  
Jeffrey Ian Weitz ◽  
Dominick J. Angiolillo ◽  
Tobias Geisler ◽  
Stefan Heitmeier
Keyword(s):  
Secondary Prevention ◽  
Antiplatelet Therapy ◽  
Standard Of Care ◽  
Atherosclerotic Disease ◽  
Vascular Protection ◽  
Coronary Syndrome ◽  
Plaque Disruption ◽  
Dual Pathway ◽  
Artery Disease ◽  
Pathway Inhibition

AbstractDespite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease.

APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Martin Bendszus ◽  
Jürgen Debus ◽  
Wolfgang Wick ◽  
Grigory Kobyakov ◽  
Tobias Martens ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Recurrent Glioblastoma ◽  
Tumor Diameter ◽  
Synergistic Activity ◽  
Open Label ◽  
Flat Dose ◽  
Pathway Inhibition

2034 Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblastoma. Methods: Patients with recurrent glioblastoma after prior standard radiochemotherapy with temozolomide (± 1 second-line chemotherapy) were considered for re-irradiation provided a tumor diameter 1-4 cm and time since the end radiotherapy ≥ 8 months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat dose to be continued until progression. Radiotherapy plans were centrally evaluated. Primary endpoint was 6-months progression free survival (PFS-6). MRIs were performed every 6-weeks and centrally read. Sample size of the investigational treatment arm according to a two-stage design of Simon required 55 patients. A control arm of 28 patients was implemented to validate the assumptions on PFS-6 in a cohort of patients treated with reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 centers were randomized and treated, preliminary data of the current report are available on 71 patients (49 APG01 + irradiation, 22 irradiation alone). Median age was 57 years, median KPS 90%. The maximal tumor diameter was ≤ 2-5 cm in 34 patients and > 2.5 cm in 37 patients. No SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is the first trial evaluating CD95-mediated pathway inhibition as a therapeutic strategy. This trial is also the prospective trial on reirradiation in glioblastoma. Side effects of the combination were minimal, and treatment could be delivered as planned. The experimental arm met the primary endpoint. The approach to block rather than stimulate the CD95 system is breaking a paradigm. Our data suggest that CD95 inhibition by APG101 should be evaluated in the management of newly diagnosed glioblastoma in combination with standard radiochemotherapy. Further molecular data and updated results will be presented.

Daily consumption of fermented soymilk helps to improve facial wrinkles in healthy postmenopausal women in a randomized, parallel-group, open-label trial

2018 ◽  
Vol 8 (2) ◽  
pp. 107 ◽  
Author(s):  
Mitsuyoshi Kano ◽  
Kazuyoshi Haga ◽  
Kouji Miyazaki ◽  
Fumiyasu Ishikawa
Keyword(s):  
Postmenopausal Women ◽  
Maximum Depth ◽  
Liquid Chromatography Mass Spectrometry ◽  
Daily Consumption ◽  
Open Label ◽  
Facial Wrinkle ◽  
Crow’S Feet ◽  
Parallel Group ◽  
Secondary Endpoints ◽  
Open Label Trial

Background: Soymilk fermented by lactobacilli and/or bifidobacteria is attracting attention due to the excellent bioavailability of its isoflavones. We investigated the effects of fermented soymilk containing high amounts of isoflavone aglycones on facial wrinkles and urinary isoflavones in postmenopausal women in a randomized, parallel-group, open-label trial. Healthy Japanese women were randomly divided into active (n = 44, mean age 56.3 ± 0.5) or control (n = 44, mean age 56.1 ± 0.5) groups, who consumed or did not consume a bottle of soymilk fermented by Bifidobacterium breve strain Yakult and Lactobacillus mali for 8 weeks. Maximum depth of wrinkles around the crow’s feet area and other wrinkle parameters were evaluated as primary and secondary endpoints respectively at weeks 0, 4, and 8 during the consumption period. Urinary isoflavone levels were determined by liquid chromatography-mass spectrometry. Results: The active group demonstrated significant improvements in the maximum depth (p=0.015) and average depth (p=0.04) of wrinkles, and significantly elevated urinary isoflavones (daidzein, genistein, and glycitein; each p < 0.001) compared with the control during the consumption period. No serious adverse effects were recorded.Conclusion: These findings suggest that fermented soymilk taken daily may improve facial wrinkles and elevate urinary isoflavones in healthy postmenopausal women.Key words: postmenopausal women; isoflavone; fermented soymilk; phytoestrogen; facial wrinkle 

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