BF066, a novel dual target antiplatelet agent without significant bleeding.
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ABSTRACT:
SUBMITTER: Pan C
PROVIDER: S-EPMC3398006 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
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BF066, a novel dual target antiplatelet agent without significant bleeding.
Pan ChangE C Wei Xunbin X Ye Jianqin J Liu Guangda G Zhang Si S Zhang Yan Y Du Hongguang H Ding Zhongren Z
PloS one 20120716 7
In this study, we report BF066, a novel adenine derivative, inhibits platelet activation and thrombosis via the adenosine receptor (A(2A)) activation and phosphodiesterase (PDE) inhibition. BF066 inhibits platelet aggregation and ATP releasing induced by multiple platelet agonists in a dose-dependent manner. The inhibition of BF066 on ADP-induced aggregation is potentiated by adenosine and can be dramatically antagonized by the A(2A) antagonist SCH58261. BF066 also inhibits the PDE activity and ...[more]
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Project description:This nationwide retrospective cohort study used the National Health Insurance Research Database of Taiwan to compare the impact of bleeding on clinical outcomes in patients with acute myocardial infarction (AMI) versus chronic coronary syndrome (CCS). Between July 2007 and December 2010, patients with AMI (n = 15,391) and CCS (n = 19,724) who received dual antiplatelet therapy after coronary stenting were identified from the database. AMI was associated with increased risks of MI (AMI vs. CCS: 0.38 vs. 0.16 per 100 patient-months; p < 0.01), all-cause death (0.49 vs. 0.32 per 100 patient-months; p < 0.01), and BARC type 3 bleeding (0.22 vs. 0.13 per 100 patient-months; p < 0.01) at 1 year compared with CCS, while the risk of BARC type 2 bleeding was marginally higher in the CCS patients than in the AMI patients (1.32 vs. 1.4 per 100 person-months; p = 0.06). Bleeding was an independent predictor of MI, stroke, and all-cause death in this East Asian population, regardless of the initial presentation. Among the patients with bleeding, AMI was associated with a higher risk of ischemic events at 1 year after bleeding compared with CCS (MI: 0.34 vs. 0.25 per 100 patient-months; p = 0.06; ischemic stroke: 0.22 vs. 0.13 per 100 patient-months; p = 0.02). The 1-year mortality after bleeding was comparable between the two groups after propensity score weighting. In conclusion, bleeding conferred an increased risk of adverse outcomes in East Asian patients with AMI and CCS.
| S-EPMC7721794 | biostudies-literature
Project description:Controversy persists regarding the perioperative management of clopidogrel among patients undergoing carotid endarterectomy (CEA). This study examined the effect of preoperative dual antiplatelet therapy (aspirin and clopidogrel) on in-hospital CEA outcomes.Patients undergoing CEA in the Vascular Quality Initiative were analyzed (2003-2014). Patients on clopidogrel and aspirin (dual therapy) were compared with patients taking aspirin alone preoperatively. Study outcomes included reoperation for bleeding and thrombotic complications defined as transient ischemic attack (TIA), stroke, or myocardial infarction. Secondary outcomes were in-hospital death and composite stroke/death. Univariate and multivariable analyses assessed differences in demographics and operative factors. Propensity score-matched cohorts were derived to control for subgroup heterogeneity.Of 28,683 CEAs, 21,624 patients (75%) were on aspirin and 7059 (25%) were on dual therapy. Patients on dual therapy were more likely to have multiple comorbidities, including coronary artery disease (P < .001), congestive heart failure (P < .001), and diabetes (P < .001). Patients on dual therapy were also more likely to have a drain placed (P < .001) and receive protamine during CEA (P < .001). Multivariable analysis showed that dual therapy was independently associated with increased reoperation for bleeding (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.20-2.42; P = .003) but was protective against TIA or stroke (OR, 0.61; 95% CI, 0.43-0.87; P = .007), stroke (OR, 0.63; 95% CI, 0.41-0.97; P = .03), and stroke/death (OR, 0.66; 95% CI, 0.44-0.98; P = .04). Propensity score matching yielded two groups of 4548 patients and showed that patients on dual therapy were more likely to require reoperation for bleeding (1.3% vs 0.7%; P = .004) but less likely to suffer TIA or stroke (0.9% vs 1.6%; P = .002), stroke (0.6% vs 1.0%; P = .04), or stroke/death (0.7% vs 1.2%; P = .03). Within the propensity score-matched groups, patients on dual therapy had increased rates of reoperation for bleeding regardless of carotid symptom status. However, asymptomatic patients on dual therapy demonstrated reduced rates of TIA or stroke (0.6% vs 1.5%; P < .001), stroke (0.4% vs 0.9%; P = .01), and composite stroke/death (0.5% vs 1.0%; P = .02). Among propensity score-matched patients with symptomatic carotid disease, these differences were not statistically significant.Preoperative dual antiplatelet therapy was associated with a 40% risk reduction for neurologic events but also incurred a significant increased risk of reoperation for bleeding after CEA. Given its observed overall neurologic protective effect, continued dual antiplatelet therapy throughout the perioperative period is justified. Initiating dual therapy in all patients undergoing CEA may lead to decreased neurologic complication rates.
| S-EPMC5065102 | biostudies-literature
Project description:AimsBleeding is a frequent complication in patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). An indication for dual antiplatelet therapy due to coronary stent implantation is present in a considerable number of these patients. The objective of this retrospective study was to evaluate if dual antiplatelet therapy (DAPT) significantly increases the high intrinsic bleeding risk in patients on VA-ECMO.Methods and resultsA total of 93 patients were treated with VA-ECMO between October 2010 and October 2013. Average time on VA-ECMO was 58.9 ± 1.7 hours. Dual antiplatelet therapy was given to 51.6% of all patients. Any bleeding was recorded in 60.2% of all patients. There was no difference in bleeding incidence in patients on DAPT when compared to those without any antiplatelet therapy including any bleeding (66.7% vs. 57.1%, p = 0.35), BARC3 bleeding (43.8% vs. 33.3%, p = 0.31) or pulmonary bleeding (16.7% vs. 19.0%, p = 0.77). This holds true after adjustment for confounders. Rate of transfusion of red blood cells were similar in patients with or without DAPT (35.4% vs. 28.6%, p = 0.488).ConclusionsBleeding on VA-ECMO is frequent. This registry recorded no statistical difference in bleeding in patients on dual antiplatelet therapy when compared to no antiplatelet therapy. When indicated, DAPT should not be withheld from VA ECMO patients.
| S-EPMC4965019 | biostudies-literature
Project description:ImportanceA decision to initiate aspirin therapy for primary prevention of cardiovascular disease (CVD) requires consideration of both treatment benefits and harms. The most significant harm associated with aspirin is major bleeding, yet there is a paucity of data on bleeding risk in suitable community populations.ObjectiveTo determine the risk of major bleeding among people without CVD who are not receiving antiplatelet therapy.Design, setting, and participantsProspective cohort study of 359 166 individuals aged 30 to 79 years receiving primary care in New Zealand who had CVD risk assessment between 2002 and 2015. Participants were censored at the earliest date on which they had a first major bleeding event, died, or met any baseline cohort exclusion criteria or the study end date of December 31, 2015. Analyses were repeated after excluding people with medical conditions associated with increased bleeding risk (non-high-risk cohort; n=305 057) and after further excluding people receiving other medications associated with increased bleeding risk (nonmedication cohort; n=240 254).ExposuresSex and age group in 10-year bands from 30 to 79 years.Main outcomes and measuresRisk of a major bleeding event (hospitalization or death associated with bleeding); nonfatal gastrointestinal tract bleeding; and gastrointestinal tract bleeding-related case fatality.ResultsMean participant age was 54 years (SD, 10 years), 44% were women, and 57% were European. Among the 359 166 individuals in the baseline cohort, 3976 had a major bleeding event during 1 281 896 person-years of follow-up. Most had gastrointestinal (GI) bleeding (n=2910 [73%]). There were 274 fatal bleeding events (7%), of which 153 were intracerebral. The risk of a nonfatal GI bleeding event per 1000 person-years was 2.19 (95% CI, 2.11-2.27), 1.77 (95% CI, 1.69-1.85) and 1.61 (95% CI, 1.52-1.69), in the baseline, non-high-risk, and nonmedication cohorts, respectively. Case fatality associated with GI bleeding was 3.4% (95% CI, 2.2%-4.1%), 4.0% (95% CI, 3.2%-5.1%), and 4.6% (95% CI, 3.6%-6.0%) in the baseline, non-high-risk, and nonmedication cohorts, respectively.Conclusions and relevanceIn a population not receiving antiplatelet therapy, the annual risk of major bleeding events and nonfatal major bleeding was estimated. These findings could inform population-level guidelines for primary prevention of CVD.
| S-EPMC6583689 | biostudies-literature
Project description:The risk for gastrointestinal bleeding from dual antiplatelet therapy (DAPT) with new antiplatelets (prasugrel/ticagrelor) compared to clopidogrel is unclear. AIM:To determine the risk and type of major (gastrointestinal bleeding requiring hospitalization) and minor (anemia and iron deficiency) gastrointestinal events with different types of DAPT. METHODS:Retrospective observational cohort study of patients who started DAPT after percutaneous coronary intervention. Follow-up was censored after 12 months of DAPT, when a major gastrointestinal event occurred, or when DAPT was discontinued. RESULTS:Among 1,327 patients (54.03% were treated with clopidogrel-based DAPT, 38.13% with ticagrelor-based DAPT, and 7.84% with prasugrel-based DAPT), 29.5% had at least one gastrointestinal event. Patients taking clopidogrel-DAPT were older, with more comorbidities, and higher gastrointestinal risk compared to those taking other DAPT regimens. Adjusted hazard ratios (HRs) showed no between-group differences in the risk for major (clopidogrel vs. new antiplatelets: HR 0.996; 95% confidence interval 0.497-1.996) and minor (HR 0.920; 0.712-1.189) gastrointestinal events. Most patients received proton pump inhibitors while on DAPT (93.3%) and after withdrawal (83.2%). CONCLUSION:Prasugrel- or ticagrelor-based DAPT was not associated with increased gastrointestinal bleeding risk when compared to clopidogrel-DAPT. New antiplatelets do not necessarily need to be restricted to patients with low gastrointestinal risk.
| S-EPMC7290690 | biostudies-literature
Project description:Background It is unknown whether contemporary drug-eluting stents have a similar safety profile in high bleeding risk patients treated with 1-month dual antiplatelet therapy following percutaneous coronary interventions. Methods and Results We performed an interventional, prospective, multicenter, single-arm trial, powered for noninferiority with respect to an objective performance criterion to evaluate the safety of percutaneous coronary interventions with Synergy bioresorbable-polymer everolimus-eluting stent followed by 1-month dual antiplatelet therapy in patients with high bleeding risk. In case of need for an oral anticoagulant, patients received an oral anticoagulant in addition to a P2Y12 inhibitor for 1 month, followed by an oral anticoagulant only. The primary end point was the composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis at 1-year follow-up. The study was prematurely interrupted because of slow recruitment. From April 2017 to October 2019, 443 patients (age, 74.8±9.2 years; women, 29.1%) at 10 Italian centers were included. The 1-year primary outcome occurred in 4.82% (95% CI, 3.17%-7.31%) of patients, meeting the noninferiority compared with the predefined objective performance criterion of 9.4% and the noninferiority margin of 3.85% (Pnoninferiority<0.001) notwithstanding the lower-than-expected sample size. The rates of cardiac death, myocardial infarction, and definite or probable stent thrombosis were 1.88% (95% CI, 0.36%-2.50%), 3.42% (95% CI, 2.08%-5.62%), and 0.94% (95% CI, 0.35%-2.49%), respectively. Conclusions Among high bleeding risk patients undergoing percutaneous coronary interventions with the Synergy bioresorbable-polymer everolimus-eluting stent, a 1-month dual antiplatelet therapy regimen is safe, with low rates of ischemic and bleeding events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03112707.
| S-EPMC9075308 | biostudies-literature
Project description:BackgroundLong-term antiplatelet treatment is associated with major bleeding.AimsTo determine the costs associated with major bleeding in patients treated with aspirin-based antiplatelet treatment for secondary prevention of vascular events without routine prescription of proton-pump inhibitors and to estimate the likely long-term savings from routine co-prescription.MethodsIn a prospective population-based cohort study of TIA, ischemic stroke, and MI treated with antiplatelet drugs, we evaluated hospital care costs associated with bleed management during 10-year follow-up. Bleeding-associated costs were averaged across all patients. For upper GI-bleeds, mean costs were compared with the cost of routine co-prescription of proton-pump inhibitor.ResultsAmong 3166 patients on antiplatelet therapy with 405 first bleeding events, the average cost of major bleeding was $13,093 (S.D. 20,501), with similar costs for upper GI bleeds and intracranial bleeds (p = 0.235). However, total costs among the 3166 patients were higher for upper GI bleeds ($1,158,385 vs. $740,123). Averaged across all patients, the 10-year cost of major bleeding was $838 (95%CI: 680-1007), $411 due to upper GI bleeding, the cost of which increased from $175 in those aged <75 years to $644 at age ≥75 years (p < 0.0001). The corresponding costs of routine life-long co-prescription of proton-pump inhibitor to those patients not on prior treatment were $85 (84-88) and $39 (38-42).ConclusionsIn secondary prevention with aspirin-based antiplatelet treatment without routine proton-pump inhibitor use, the long-term costs of upper-GI bleeding at age ≥75 years are much higher than at younger age groups, and are at least 10-fold greater than the drug cost of routine co-prescription of proton-pump inhibitor.
| S-EPMC7611493 | biostudies-literature
Project description:Cilostazol, a type-3 phosphodiesterase (PDE3) inhibitor, has become widely used as an antiplatelet drug worldwide. A recent second Cilostazol Stroke Prevention Study demonstrated that cilostazol is superior to aspirin for prevention of stroke after an ischemic stroke. However, its precise mechanisms of action remain to be determined. Here, we report that cilostazol, but not the PDE3 inhibitors cilostamide and milrinone, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, specific inhibitors for the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP(3)) receptors and several common signaling pathways (PLC-γ, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK), and the Ras/Raf/ERK/MAPK) significantly blocked the potentiation of NGF-induced neurite outgrowth by cilostazol. Using a proteomics analysis, we identified that levels of eukaryotic translation elongation factor eEF1A1 protein were significantly increased by treatment with cilostazol, but not cilostamide, in PC12 cells. Moreover, the potentiating effects of cilostazol on NGF-induced neurite outgrowth were significantly antagonized by treatment with eEF1A1 RNAi, but not the negative control of eEF1A1. These findings suggest that eEF1A1 and several common cellular signaling pathways might play a role in the mechanism of cilostazol-induced neurite outgrowth. Therefore, agents that can increase the eEF1A1 protein may have therapeutic relevance in diverse conditions with altered neurite outgrowth.
| S-EPMC3046984 | biostudies-literature
Project description:Dual antiplatelet treatment (DAPLT) for at least 12 months is recommended after drug eluting stent (DES) implantation, but concerns regarding the extended use of this treatment persist due to increased risk of bleeding. In this study are assessed the incidence, correlates, and clinical significance of bleeding complications in diabetic patients after long-term DAPLT post DES implantation.We studied 610 consecutive diabetic patients after DES implantation. The primary end point was the occurrence of any bleeding according to the BARC and TIMI definitions.The incidence of overall bleeding was higher in patients on DAPLT (21.1% vs. 4.4%, p < 0.001); minor/minimal according to the TIMI definition, and type 1 or 2 according to the BARC definition, were more frequently observed in patients on DAPLT (20.3% vs. 3.0%, p < 0.001, 15.6% vs. 2.0%, p < 0.001 and 4.4% vs. 0.5%, p = 0.034, respectively), whereas there was no effect on type 3 (3.5% vs. 2.0%, p = ns). DAPLT was an independent predictor for overall (HR 5.35, 95% CI: 2.69-10.67, p < 0.001), minor (HR 7.45, 95% CI: 3.25-17.12, p < 0.001, for TIMI classification) and type 1 or 2 bleeding (HR 8.17, 95% CI 3.29-20.25, p < 0.001); furthermore smoking was also predictor for overall bleeding (HR 1.65, 95% CI: 1.05-2.61, p = 0.030). Cardiovascular adverse events were not more frequent in patients with bleeding as compared with those without bleeding.Long-term DAPLT in diabetic patients after DES implantation is associated with higher risk of overall and minor but not major bleeding; smoking may have a significant role in the occurrence of bleeding complications.
| S-EPMC5497144 | biostudies-other
Project description:ImportanceVery short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option.ObjectiveTo test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events.Design, setting, and participantsMulticenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019.InterventionsPatients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522).Main outcomes and measuresThe primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding.ResultsAmong 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority).Conclusions and relevanceAmong patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations.Trial registrationClinicalTrials.gov Identifier: NCT02619760.
| S-EPMC6593641 | biostudies-literature