scholarly journals First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-986177/JNJ-70033093, a direct, reversible, small molecule Factor XIa inhibitor in healthy volunteers

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Perera ◽  
Z Wang ◽  
J Luettgen ◽  
J Wang ◽  
D Li ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Volunteers ◽  
Small Molecule ◽  
Healthy Subjects ◽  
Funding Source ◽  
Private Company ◽  
Factor Xia ◽  
Clinically Significant ◽  
Oral Doses ◽  
The Impact

Abstract Background Inhibition of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in many conditions predisposing to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits FXIa with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on therapy to current standard of care (SOC) antithrombotic agents or potentially as a replacement for current SOC. Purpose To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of BMS-177/JNJ-3093 in healthy subjects. Methods This was a 2-part, randomized, double-blind, placebo-controlled, sequential single- (Part A) and multiple- (Part B) ascending dose study to assess the safety, tolerability, PK, and PD of BMS-177/JNJ-3093 in healthy subjects. In Part A (SAD) of the study, 48 subjects were treated in 6 panels (8 subjects per panel). The 200 mg and 500 mg dose panels investigated the impact of a high fat diet on PK. In Part B (MAD), 56 subjects were treated in 7 panels (8 subjects per panel) on a once daily (QD) or twice daily (BID) regimen for a 14-day period. Within each panel in Parts A and B, subjects were randomized to receive either BMS-177/JNJ-3093 or matched placebo (3:1). Results Administration of single ascending doses of BMS-177/JNJ-3093 up to 500 mg and multiple ascending doses of BMS-177/JNJ-3093 up to 200 mg BID or 500 mg QD for 14 days were safe and well tolerated. No subjects had a clinically significant bleeding event. All treatment-emergent adverse events were mild in severity. After single doses of BMS-177/JNJ-3093 ranging from 4 to 500 mg in fasted status, BMS-177/JNJ-3093 plasma concentration reached Cmax at 3 h postdose in all panels, indicating a similar rate of absorption. The terminal half-life ranged from 8.26 to 13.8 h across SAD panels. Over 20 to 200 mg, a dose proportional increase was observed; however, saturable absorption was seen at higher doses of 300 and 500 mg. Food also increased the bioavailability of BMS-177/JNJ-3093. In the MAD portion of the study, based on visual inspection of trough plasma concentration profiles, BMS-177/JNJ-3093 plasma concentration steady state was reached between 1–3 dosing days (ie, Days 2–4) for the QD panels and 6 dosing days (ie, Day 7) for the 200 mg BID panel. Renal excretion was relatively low, ranging from 8–20%. After single oral dose or multiple oral doses, there is a clear trend that aPTT was prolonged and the magnitude of change was related to drug exposure. Conclusion BMS-177/JNJ-3093 was safe and well tolerated in healthy volunteers. The PK and PD profile demonstrates suitable dosing properties for further clinical studies. Currently, two Phase II studies are ongoing. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

Projecting the long-term benefits of single pill combination therapy for patients with hypertension in five countries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Borghi ◽  
J.G Wang ◽  
A.V Rodionov ◽  
M Rosas ◽  
I.S Sohn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
South Korea ◽  
Health Outcomes ◽  
Clinical Outcomes ◽  
Funding Source ◽  
Combination Therapies ◽  
Private Company ◽  
Treatment Pathways ◽  
Single Pill ◽  
The Impact

Abstract Background It is well established that single pill combination (SPC) therapies have the potential to improve patient adherence versus multi-pill regimens, thereby improving blood pressure control and clinical outcomes in populations with hypertension. Purpose To develop a microsimulation model, capturing different treatment pathways, to project the impact on clinical outcomes of using single pill combination therapies for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). Methods The model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices [CTP], single drug with dosage titration first then sequential addition of other agents [start low and go slow, SLGS], free choice combination with multiple pills [FCC] and combination therapy in the form of a single pill [SPC]. Model inputs were derived from Global Burden of Disease 2017 dataset, including demographics, health status/risk factors, transition probabilities and treatment attributes/healthcare utilization, and the model incorporated real-world challenges to healthcare delivery such as access to care, SBP measurement error, adherence and therapeutic inertia. Simulated outcomes of mortality, incidence of chronic kidney disease (CKD), stroke and ischemic heart disease (IHD), and disability-adjusted life years (DALYs) due to these conditions were estimated for population of 1,000,000 simulated patients for each treatment pathway and country. Results SPC therapy was projected to improve health outcomes over SLGS, FCC and CTP over 10 years in all five countries. SPC was forecast to reduce mortality by 5.4% (Italy), 4.9% (Russia), 4.5% (China), 2.3% (South Korea) and 3.6% (Mexico) versus CTP and showed greater projected reductions in mortality than SLGS and FCC. DALYs were projected to be reduced with SPC therapy by between 5.7% (Italy) and 2.2% (South Korea) compared with CTP and reductions in the incidence of clinical events were also projected with SPC therapy, with decreases in the range of 11.5% (Italy) to 4.9% (South Korea) versus CTP. Conclusions Ten-year projections of clinical outcomes associated with different anti-hypertensive treatment pathways in five countries indicated that both combination therapies (FCC and SPC) are likely to reduce the disease burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Gentilly, France

Artificial intelligence-guided image acquisition on patients with implanted electrophysiological devices: results from a pivotal prospective multi-center clinical trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Surette ◽  
A Narang ◽  
R Bae ◽  
H Hong ◽  
Y Thomas ◽  
...  
Keyword(s):  
Qualitative Assessment ◽  
Funding Source ◽  
Software Performance ◽  
Private Company ◽  
Diagnostic Quality ◽  
Icd Leads ◽  
Significant Difference ◽  
Level 3 ◽  
And Function ◽  
The Impact

Abstract Background A novel, recently FDA-authorized software uses deep learning (DL) to provide prescriptive transthoracic echocardiography (TTE) guidance, allowing novices to acquire standard TTE views. The DL model was trained by >5,000,000 observations of the impact of probe motion on image orientation/quality. This study evaluated whether novice-acquired TTE images guided by this software were of diagnostic quality in patients with and without implanted electrophysiological (EP) devices, focusing on RV size and function, which were thought to be sensitive to EP devices. Some aspects of the study have previously been presented. Methods 240 patients (61±16 years old, 58% male, 33% BMI >30 kg/m2, 91% with cardiac pathology) were recruited. 8 nurses without echo experience each acquired 10 view TTEs in 30 patients guided by the software. 235 of the patients were also scanned by a trained sonographer without assistance from the software. 5 Level 3 echocardiographers independently assessed the diagnostic quality of the TTEs acquired by the nurses and sonographers to evaluate the effect of EP devices on DL software performance. Results Nurses using the AI-guided acquisition software acquired TTEs of sufficient quality to make qualitative assessments of right ventricular (RV) size and function in greater than 80% of cases for patients with and without implanted EP devices (Table). There was no significant difference between nurse- and sonographer-acquired scans. Conclusion These results indicate that new DL software can guide novices to obtain TTEs that enable qualitative assessment of RV size even in the presence of implanted EP devices. The results of the comparison to sonographer-acquired exams indicate the software performance is robust to presence of pacemaker/ICD leads visible in the images (Figure). Nurse-acquired TTE with visible ICD lead Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Caption Health, Inc.

scholarly journals Reduced gastric injury with a novel, liquid lipid-aspirin formulation: results from a pooled, patient level analysis of two randomized endoscopy studies In healthy volunteers

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.L Bhatt ◽  
J Scheiman ◽  
D.J Angiolillo ◽  
P.G Steg ◽  
G.D Dangas ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Primary Outcome ◽  
Immediate Release ◽  
Platelet Inhibition ◽  
Gastric Injury ◽  
Funding Source ◽  
Private Company ◽  
Patient Level ◽  
Repeat Endoscopy ◽  
Initiation Of Therapy

Abstract Background Gastrointestinal (GI) toxicity from aspirin is high at the time of initiation of therapy. Objective The current analysis aimed to determine rates of endoscopically detected gastroduodenal erosions and ulcers after 7 days of either immediate release aspirin (IR-ASA) or a novel, pharmaceutical lipid-aspirin complex (PL-ASA) liquid formulation that has an antiplatelet effect similar to IR-ASA. Methods Two randomized, single blind, multicenter active control studies comparing upper GI damage after 7 days of 325 mg PL-ASA or IR-ASA in healthy volunteers not taking a gastroprotectant and who had a negative baseline endoscopy were pooled at the patient level. The primary outcome was the composite of >5 erosions and/or ≥1 ulcer (≥3 mm deep) assessed by a treatment-blinded reviewer at repeat endoscopy on day 7. Results Out of 451 randomized subjects (mean age 57 years, 47% males), 441 completed the 7-day endoscopy and represent the full analysis set. PL-ASA significantly reduced the primary outcome by 34% compared with IR-ASA (25.7% vs. 39%, p=0.0032) (figure). Notably, for ulcers there was a 61% reduction with PL-ASA (6.0% vs. 14.8%, p=0.0018) (Figure 1). The mean number of gastric erosions per patient was also reduced with PL-ASA (2.8±7.3 vs. 4.2±7.5, p<0.0001), while erosions in the duodenum were not different (1.4±7.1 vs. 0.9±2.3, p=0.45). Conclusion The novel PL-ASA liquid capsules reduced rates of GI injury compared with IR-ASA tablets. The combination of reliable platelet inhibition with less GI injury makes PL-ASA an attractive new aspirin therapy option. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PLx Pharma

Growth Differentation Factor 15 Is a Survival Factor for multiple myeloma cells and its plasma Concentration In Patients Is Related to Reduced Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 614-614
Author(s):  
Jill Corre ◽  
Elodie Labat ◽  
Nicolas Espagnolle ◽  
Hervé Avet-Loiseau ◽  
Murielle Roussel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Cell Line ◽  
Healthy Subjects ◽  
Univariate Analysis ◽  
Culture Conditions ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
The Impact

Abstract Abstract 614 We previously reported that bone marrow mesenchymal stem cells (BMMSCs) from newly diagnosed multiple myeloma (MM) patients were abnormal. In particular, we showed that Growth Differentiation 15 (GDF15) expression was higher in MM BMMSCs than in normal BMMSCs. GDF15 is a divergent member of the human TGFβ superfamily. GDF15 overexpression has been described in numerous malignancies and its concentration is increased in the serum of patients with glioma, prostate, colorectal or pancreatic cancers. Contradictory data prevent to understand clearly GDF15 implication in pathophysiology of tumors. Furthermore, GDF15 has never been studied in haematological malignancies. Our first objective was thus to determine the effect of human recombinant GDF15 (rGDF15) on MOLP-6 stroma-dependent cell line and MM1.S stroma-independent cell line under serum free culture conditions. rGDF15 could significantly increase cell survival in MOLP-6 but not in MM1.S. Interestingly, rGDF15 was able to induce Akt phosphorylation on Threonine 308 in MOLP-6 and primary MM cells but not in MM1.S cells. Furthermore, pre-treatment of MOLP-6 with Akt pharmacologic inhibitor abrogated the prosurvival effect of GDF15, suggesting an Akt-dependent mechanism. In the same culture conditions, we observed that rGDF15 could abrogate toxicity of drugs classically used in MM treatment (melphalan, bortezomid and lenalidomide) for both cell lines MOLP-6 and MM1.S, suggesting that this cytoprotective effect may be Akt-independent. Because of the in vitro effects of GDF15, our second objective was to determine whether the plasma concentration of GDF15 (pGDF15) in patients with MM may be indicative of the seriousness of the disease or correlate with the response to the treatment. Thus, we investigated the pGDF15 in 131 patients with newly diagnosed MM and 13 healthy subjects. We first found that it was significantly higher for patients with MM (0.90±1.10 ng/mL) than for healthy subjects (0.25±0.08 ng/mL) (P< .001). In patients with MM, pGDF15 correlated with the main prognostic factor of the disease (i.e. International Staging System, b2 microglobulin level, presence or absence of deletion of chromosome 13, and bone status). For the 81 patients with high pGDF15 level (≥ 0.50 ng/mL), the probabilities of event-free and overall survival 30 months after diagnosis were 50% and 75%. For the 50 patients with low pGDF15 level (< 0.5 ng/mL), the probabilities were 80% and 97% (P< .0045 and P< .013, respectively). However, we did not find a clear relationship between pGDF15 and response to treatment. We analysed the impact of prognostic factors on event-free survival for the 131 patients with MM. On univariate analysis, event-free survival was significantly related to age (P= .003), b2-microglobulin level (P= .02) and pGDF-15 level (P= .003). On multivariate analysis, event-free survival was significantly related to age (P= .001) and pGDF15 level (P= .04). Our study demonstrates that GDF15 is a survival and cytoprotective factor for MM cells and that pGDF15 is related to initial parameters of the disease and survival, which specifically implicates the MM microenvironment in the pathophysiology and the prognosis of the disease. Disclosures: No relevant conflicts of interest to declare.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of AG-519, an Allosteric Activator of Pyruvate Kinase-R, in Healthy Subjects

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1264-1264
Author(s):  
Ann J Barbier ◽  
Susan Bodie ◽  
Gary Connor ◽  
Elizabeth Merica ◽  
Charles Kung ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Healthy Volunteers ◽  
Pyruvate Kinase ◽  
Small Molecule ◽  
Healthy Subjects ◽  
Employment Equity ◽  
Multiple Doses ◽  
Equity Ownership ◽  
Dose Dependent ◽  
2,3 Dpg

Abstract BACKGROUND Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R) due to mutations in the PKLR gene. PK catalyzes the last enzymatic step in the glycolytic pathway and is the main source of adenosine triphosphate (ATP) production in red blood cells. PKLR mutations lead to defective proteins that are hypothesized to reduce ATP levels in red cells, leading to hemolysis. Small molecule allosteric activation of PK-R resulting in increases in ATP and decreases in 2,3-diphosphoglycerate (2,3-DPG) in healthy volunteers has been observed with an earlier molecule, AG-348, the first small molecule PK-R activator to enter clinical trials (Yang et al. EHA 2015, S138). AG-519 is the second small molecule PK-R activator to enter clinical trials. AG-519 is a potent, highly selective and orally bioavailable PK-R activator devoid of the aromatase inhibitory effects that were observed with AG-348. AIMS AG-519 is currently being tested in a randomized, double-blind, phase 1 study in healthy volunteers (NCT02630927), with the objective of identifying a safe and pharmacodynamically active dose and schedule to support potential ongoing development in patients with PK deficiency. Here we report the first 4 cohorts of the multiple ascending dose (MAD) phase of this study. The single ascending dose (SAD) phase of the study and the first two cohorts of the MAD phase of the study have been reported previously (Barbier et al. EHA 2016, P752). METHODS Healthymen and women (non-childbearing potential) aged 18-60 years who provided informed consent were eligible. The MAD phase of the study consisted of 5 dose cohorts. The dose levels administered were determined during interim data reviews of each completed MAD cohort, as well as data from completed SAD cohorts. At each dose level, 8 subjects were enrolled and randomized to receive AG-519 (n=6) or placebo (n=2) twice daily (BID; approximately every 12 hours) for 14 days. Safety assessments included adverse events (AEs), vital signs, electrocardiogram and clinical laboratory parameters. Serial blood samples were drawn to measure plasma concentrations of AG-519 and whole blood concentrations of 2,3-DPG and ATP for pharmacokinetic and pharmacodynamic (PD) assessments. RESULTS Data are available for 32 subjects enrolled across 4 dose cohorts in the MAD phase of the study: 8 subjects each in cohort 1 (125 mg BID), cohort 2 (375 mg BID), cohort 3 (25 mg BID), and cohort 4 (300 mg BID). Blinded safety reviews indicated that multiple doses up to 375 mg have been well tolerated with no serious AEs or dose-limiting toxicities reported to date. One case of probable drug-induced Grade 2 thrombocytopenia was previously reported in 1 subject in the 375 mg cohort; the event was rapidly reversible with no clinical sequelae. The protocol was amended to require daily monitoring of platelets in subsequent cohorts and no other subjects have developed thrombocytopenia during treatment. The preliminary analysis of free testosterone and estradiol confirmed the absence of aromatase inhibitory activity. AG-519 steady-state was reached the third day after the first dose based on trough concentration values. The clearance of AG-519 after multiple doses was similar to that observed after single doses in the SAD cohorts. Dose-dependent increases in ATP in blood (Figure 1) and decreases in 2,3-DPG in blood correlated with dose-dependent increases in exposure of AG-519, with a peak effect at or below 375 mg BID. ATP response at 25 mg appears to be greater than 50% of maximal response. Results from the fifth MAD cohort, which evaluated the PD results with 10 mg BID, will be presented. ATP = adenosine triphosphate; BID = twice daily CONCLUSION AG-519 is well tolerated in healthy subjects at doses ranging from 25 mg to 375 mg BID for 14 days. The robust dose-dependent changes in ATP and 2,3-DPG concentrations in blood from healthy volunteers are consistent with increased activity of PK-R, the expected PD effect of AG-519. These data support the hypothesis that AG-519 may be able to enhance glycolytic activity in red cells of patients with PK deficiency to address the underlying cause of the disease. Figure 1 Change of ATP concentration in blood from baseline Figure 1. Change of ATP concentration in blood from baseline Disclosures Barbier: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bodie:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Connor:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Le:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy.

Ten years of high-sensitivity cardiac troponin testing in the Netherlands: impact on the diagnosis of myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.M Kimenai ◽  
Y Appelman ◽  
H.M Den Ruijter ◽  
N.L Mills ◽  
S.J.R Meex
Keyword(s):  
Myocardial Infarction ◽  
The Netherlands ◽  
Cardiac Troponin ◽  
High Sensitivity ◽  
Funding Source ◽  
Private Company ◽  
Absolute Change ◽  
Before And After ◽  
One Year ◽  
The Impact

Abstract Introduction High-sensitivity cardiac troponin (hs-cTn) assays have enhanced sensitivity for myocardial injury and may lead to an increase in the diagnosis of myocardial infarction. Few real-world studies have investigated the transition from conventional cardiac troponin (cTn) to hs-cTn. We evaluated the impact of implementing hs-cTn assays and sex-specific thresholds in the Netherlands on the diagnosis of myocardial infarction in women and men. Methods Twelve Dutch hospitals were included (hs-cTnI assay [sex-specific thresholds], n=4; hs-cTnT assay [uniform threshold], n=8). Data from the health insurance claims of consecutive patients with anginal symptoms were collected before (cTn period) and after (hs-cTn period) implementation from January 2008 to December 2017. The proportion of patients with a diagnosis of myocardial infarction overall, and in men and women separately, and one-year mortality was compared before and after implementation of the hs-cTn assay. Results Across twelve hospitals, a total number of 77,464 patients presenting with anginal symptoms were included (cTn period: 35,409 [36.6% women]; hs-cTn period: 42,055 [34.6% women]). Following implementation of hs-cTn testing the proportion of patients with anginal symptoms diagnosed with myocardial infarction doubled from 24% (3,111/12,970) to 48% (7,014/14,560) in women, and from 25% (5,712/22,439) to 51% (13,912/27,495) in men, with similar increases in sites implementing hs-cTnI and hs-cTnT. The proportion of patients diagnosed with myocardial infarction who were women increased in sites implementing sex-specific thresholds (from 36.4% [1,435/3,941] to 37.5% [1,700/4,532], absolute change 1.1%), but did not increase in sites using a uniform threshold (from 34.3% [1,676/4,882] to 32.4% [5,314/16,394], absolute change −1.9%). In patients with a diagnosis of myocardial infarction, one-year mortality was 15.6% (485/3,111) and 11.6% (814/7,014) in women, and was 11.8% (673/5,712) and 9.4% (1,303/13,912) in men, before and after implementation of hs-cTn. Conclusions In patients presenting with anginal symptoms, the diagnosis of acute myocardial infarction doubled after implementation of hs-cTn testing in both women and men. Use of sex-specific thresholds increased the proportion of patients with myocardial infarction who were women compared to use of a uniform threshold. Implementation was associated with a reduction in one-year mortality, but further research is needed to understand whether this is due to differences in the risk profile of patients with myocardial infarction or improvements in treatment. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was supported by a grant from Abbott Laboratories to S.J.R.M.

Long-term prognostic benefit of beta-blockers use after discharge in patients with Tako-Tsubo syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Jamhour-Chelh ◽  
S Raposeiras-Roubin ◽  
I Nunez-Gil ◽  
E Abu-Assi ◽  
D Aritza Conty ◽  
...  
Keyword(s):  
Large Scale ◽  
Beta Blockers ◽  
Funding Source ◽  
Prognostic Impact ◽  
Private Company ◽  
Cox Analysis ◽  
The Impact ◽  
Long Term Mortality

Abstract Background Tako-tsubo Syndrome (TS) seems to be associated with a catecholamine-mediated mechanism. However, the impact of beta-blockers (BB) in-hospital and after discharge still remain uncertain. Objectives: The purpose of the study was to examine whether BB use after discharge in patients with TS, was associated with lower long-term mortality and recurrence. Methods Using a national multicentre large-scale inpatient database (RETAKO Registry), we analysed patients with a definitive TS diagnosis. Results A total of 970 patients were analysed (568 with BB therapy and 402 no-BB therapy). After discharge and over a median of follow-up of 1.1 years, treatment with BB have no shown prognostic effectiveness in terms of mortality and TS recurrence in unadjusted and adjusted Cox analysis (HR 0.86; 95% CI: 0.59 to 1.27; and 0.95; 95% CI: 0.57–1.13, respectively). Conclusions This data suggests that use of beta-blockers after hospital discharge has not shown long-term prognostic benefit in patients with Tako-tsubo Syndrome. Prognostic impact of BB in TS. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Retako webpage was funded by a non-conditioned Astrazeneca scholarship.

Impact of physical activity on all-cause mortality in European patients with atrial fibrillation: a report from the ESC-EHRA EORP AF General Long-Term Registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Vitolo ◽  
M Proietti ◽  
S Harrison ◽  
Z Kalarus ◽  
L Tavazzi ◽  
...  
Keyword(s):  
Physical Activity ◽  
Atrial Fibrillation ◽  
Funding Source ◽  
Private Company ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
All Cause Mortality ◽  
The Impact

Abstract Background Physical activity (PA) may have a beneficial contribution for outcomes in patients with atrial fibrillation (AF). Purpose We aimed to evaluate the impact of self-reported PA in a large contemporary cohort of European AF patients on the risk of all-cause mortality. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Self-reported PA was categorized, on the basis of reported time spent exercising, as follows: i) No PA; ii) Occasional PA; iii) Regular PA; iv) Intense PA. The primary outcome was all-cause death. Results Over 11096, a total of 8699 (78.4%) patients (mean age (SD) 69.1 (11.5); 40.7% female) had available data about PA and follow-up observation and were included in the analysis. Of these, 3703 (42.6%) reported no PA, 2829 (32.5%) occasional PA, 1824 (21.0%) regular PA, with only 343 (3.9%) reporting intense PA. With the 4 increasing PA categories, mean age, proportion of female patients, CHA2DS2-VASc and HAS-BLED scores were progressively lower (all p&lt;0.001). Use of vitamin K antagonist (VKA) declined across the classes of PA (53.1% vs. 52.2% vs. 44.5% vs. 33.9%, p&lt;0.001), while use of non-VKA OACs (NOACs) conversely increased. During a mean (SD) 680.6 (171.5) days of follow-up, there were a total of 848 (9.7%) all-cause death events. Based on Kaplan-Meier analysis, there was a progressively lower cumulative risk for all-cause death according to PA categories [Figure]. A multivariable Cox regression analysis, adjusting for CHA2DS2-VASc score, use of OAC at baseline and type of AF, found a lower risk of all-cause death associated with increasing levels of PA (Hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.59–0.81 for occasional PA, HR: 0.45, 95% CI: 0.35–0.58 for regular PA, HR: 0.41, 95% CI: 0.23–0.76 for intense PA, when compared to no PA). In a sensitivity analysis, a regular-intense PA was inversely associated with occurrence of cardiovascular (CV) death, after multivariable adjustments for comorbidities (HR: 0.54, 95% CI: 0.37–0.77). Conclusions In a large contemporary cohort of European AF patients, self-reported PA was found to be inversely associated with all-cause death and CV death. Kaplan-Meier Curves Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Since the start of EORP, several companies have supported the programme with unrestricted grants

scholarly journals Favorable therapeutic index of an orally-active small-molecule antagonist of the platelet protease-activated receptor-4, BMS-986141, compared with the P2Y12 antagonist ticagrelor in cynomolgus monkeys

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Wong ◽  
J Banville ◽  
R Wexler ◽  
E Priestley ◽  
A Marinier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Small Molecule ◽  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Thrombin Receptor ◽  
Funding Source ◽  
Private Company ◽  
Post Dose ◽  
Orally Active ◽  
P2y12 Antagonist

Abstract Introduction BMS-986141 is an orally-active small-molecule platelet thrombin receptor antagonist selective for the protease-activated receptor-4 (PAR4), a human platelet thrombin receptor. Purpose This study assessed effects of BMS-986141 vs. the P2Y12 antagonist ticagrelor, a standard of care antiplatelet agent, on arterial thrombosis (AT), mesenteric bleeding time (MBT) and platelet aggregation in monkeys. Methods Studies were conducted in models of electrically-mediated carotid artery thrombosis and MBT in anesthetized monkeys. Monkeys were given a single oral dose of BMS-986141 (0.05, 0.1, 0.5 mg/kg) or vehicle (n=8/group). At 2 hr post-dose, in vivo AT, MBT as well as ex vivo platelet aggregation were monitored in the same animal. Ticagrelor was studied as a comparator and given as IV bolus plus infusion at 0.0023+0.017 to 0.075+0.6 (mg/kg+mg/kg/h) (n=5–6/group). Thrombus weight reduction, MBT increase over vehicle, and platelet aggregation inhibition were determined. Peak platelet aggregation responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), to collagen (5 μg/ml) and to ADP (20 μM) were determined by whole blood aggregometry. Results BMS-986141 inhibited platelet aggregation induced by PAR4-AP in human and monkey blood in vitro with comparable IC50 of 1.8±0.3 and 1.2±0.3 nM, respectively. BMS-986141 at 0.5 mg/kg completely inhibited platelet aggregation induced by PAR4-AP but not PAR1-AP, ADP and collagen, suggesting PAR4 receptor selectivity. In the AT model, BMS-986141 at 0.05, 0.1 and 0.5 mg/kg reduced thrombus weight by 36±7*, 63±8*, and 88±3%*, respectively (*P&lt;0.05 vs. vehicle). BMS-986141 increased MBT by up to 1.2-fold. In a separate study, ticagrelor at 0.0023+0.017, 0.0068+0.055, 0.0255+0.18 and 0.075+0.6 (mg/kg+mg/kg/h IV) reduced thrombus weight by 19±8, 36±5*, 76±6* and 89±1%*, and increased MBT by respectively by 1.7-, 6.4-*, &gt;10-*, and &gt;10-fold*, respectively (*P&lt;0.05 vs. vehicle). Conclusion Comparable antithrombotic efficacy was observed between BMS-986141 and ticagrelor in monkeys. BMS-986141 exhibited lower MBT compared with ticagrelor at equivalent antithrombotic doses. This study suggests that PAR4 antagonism provides a potentially safer antiplatelet therapy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Research was supported by Bristol-Myers Squibb

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