Optimization Of Stroke Prophylaxis Strategies In Nonvalvular AF -Drugs, Devices Or Both?
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ABSTRACT:
SUBMITTER: Noheria A
PROVIDER: S-EPMC4833393 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atrial fibrillation (AF) is the most common cardiac arrhythmia with the prevalence increasing over time. AF probably afflicts ?2% of worldwide adult population and increases with age.[1-3] In the Framingham Heart Study, the lifetime risk of having at least one episode of AF for 40-year-old men and women was 26% and 23% respectively.[4].
| S-EPMC5135161 | biostudies-other
Project description:The most dreaded complication of atrial fibrillation is stroke, and 70-80% of patients with AF-related stroke die or become disabled. The mechanisms of thromboembolism in AF are multifactorial, with evidence demonstrating that all three criteria of Virchow's triad are satisfied in AF: abnormal stasis of blood, endothelial damage, and hypercoagulability. Mechanistic insights into the latter two limbs have resulted in effective stroke prophylactic therapies (left atrial appendage occlusion and oral anticoagulants); however, despite these advances, there remains an excess of stroke in the AF population that may be due, in part, to a lack of mechanistic understanding of atrial hypocontractility resulting in abnormal stasis of blood within the atrium. These observations support the emerging concept of atrial cardiomyopathy as a cause of stroke. In this Review, we evaluate molecular, translational, and clinical evidence for atrial cardiomyopathy as a cause for stroke from AF, and present a rationale for further investigation of this largely unaddressed limb of Virchow's triad in AF.
| S-EPMC7039862 | biostudies-literature
Project description:ObjectiveThe aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke.BackgroundCardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden.Design, setting, and patientsA pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed.ResultsDuring a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3-14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22-3.64, P = 0.008).ConclusionsDevice-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.
| S-EPMC3930873 | biostudies-literature
Project description:BackgroundAntithrombotic prophylaxis with oral anticoagulation (OAC) substantially reduces stroke and mortality in patients with atrial fibrillation (AF).HypothesisAnalysis of data in the Global Registry on Long-Term Antithrombotic Treatments in Patients With Atrial Fibrillation (GLORIA-AF), an international, observational registry of patients with newly diagnosed AF, can identify factors associated with treatment decisions and outcomes.MethodsMultivariable regression identified patient, physician, and temporal factors associated with OAC prescription, compared with management with antiplatelet drugs or no antithrombotic drugs in North American patients enrolled between November 2011 and February 2014.ResultsOf 3320 eligible patients (mean age, 71 ± 11 years; 1879 males with CHA2 DS2 -VASc ≥1 and 1441 females with CHA2 DS2 -VASc ≥2), 79.3%, 12.5%, and 7.4% received OAC, antiplatelet drugs, or no antithrombotic therapy, respectively. Of those prescribed OAC, 66.4% received non-vitamin K antagonist oral anticoagulation and 24.5% received concomitant therapy with antiplatelet drugs. Independent predictors of OAC therapy were nonparoxysmal AF (odds ratio, 95% confidence interval: 2.02, 1.56-2.63), prior stroke/transient ischemic attack (2.00, 1.37-2.92), specialist care (1.50, 1.04-2.17), more concomitant medications (1.47, 1.13-1.92), commercial insurance (1.41, 1.07-1.85), and heart failure (1.44, 1.07-1.92). Antiplatelet drugs (0.18, 0.14-0.23), prior falls (0.41, 0.27-0.63), and prior bleeding (0.50, 0.35-0.72) were inversely associated with OAC prescription.ConclusionsIn GLORIA-AF, 20% of the population comprising males with CHA2 DS2 -VASc ≥1 and females with CHA2 DS2 -VASc ≥2 did not receive OAC therapy. Patient characteristics associated with a lower likelihood of OAC prescription were use of antiplatelet drugs, paroxysmal pattern of AF, history of falls, and prior bleeding.
| S-EPMC6032943 | biostudies-literature
Project description:Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bioisosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.
| S-EPMC4679534 | biostudies-other
Project description:The lack of evidence on the effectiveness and safety of interventions in chronic dialysis patients has been a subject of continuing criticism. New technologies are often introduced into the market without having specifically studied or even included patients with advanced kidney disease. Therefore, the need to generate valid effectiveness and safety data in this vulnerable subpopulation is of utmost importance. The US Food and Drug Administration has recently placed an increased focus on safety surveillance, and sponsors must now meet this additional postmarketing commitment. In patients with ESRD, the unique data collection environment in the United States allows for creative and efficient study designs to meet the needs of patients, providers, and sponsors. The purpose of this manuscript is to review the methodological and practical aspects of the different options for postmarketing study design in this field, with critical appraisal of their advantages and disadvantages.
| S-EPMC3848407 | biostudies-other
Project description:BACKGROUND:Oral HIV preexposure prophylaxis (PrEP) has been recommended as a means of HIV prevention among people who inject drugs (PWIDs) but, at current prices, is unlikely to be cost-effective for all PWID. OBJECTIVE:To determine the cost-effectiveness of alternative strategies for enrolling PWID in PrEP. DESIGN:Dynamic network model that captures HIV transmission and progression among PWID in a representative US urban center. OUTCOME MEASURES:HIV infections averted, discounted costs and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. INTERVENTION:We assume 25% PrEP coverage and investigate four strategies: first, random PWID are enrolled (Unselected Enrollment); second, individuals are randomly selected and enrolled together with their partners (Enroll Partners); third, individuals with the highest number of sexual and needle-sharing partnerships are enrolled (Most Partners); fourth, individuals with the greatest number of infected partners are enrolled (Most Positive Partners). RESULTS:PrEP can achieve significant health benefits: compared with the status quo of no PrEP, the strategies gain 1114 QALYs (Unselected Enrollment), 2194 QALYs (Enroll Partners), 2481 QALYs (Most Partners), and 3046 QALYs (Most Positive Partners) over 20 years in a population of approximately 8500 people. The incremental cost-effectiveness ratio of each strategy compared with the status quo (cost per QALY gained) is $272 000 (Unselected Enrollment), $158 000 (Enroll Partners), $124 000 (Most Partners), and $101 000 (Most Positive Partners). All strategies except Unselected Enrollment are cost-effective according to WHO criteria. CONCLUSION:Selection of high-risk PWID for PrEP can improve the cost-effectiveness of PrEP for PWID.
| S-EPMC5906044 | biostudies-literature
Project description:Simple Summary Although immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination. Abstract Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.
| S-EPMC8508444 | biostudies-literature
Project description:Background/aimsEfforts to reduce stroke in patients with atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines; however, the high early discontinuation rate of vitamin K antagonists (VKAs) is a limitation. Although non-VKA OACs (NOACs) are more convenient to administer than warfarin, their lack of monitoring may predispose patients to nonpersistence. We compared the persistence of NOAC and VKA treatment for AF in real-world practice.MethodsIn a prospective observational registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF] registry), 7,013 patients with nonvalvular AF (mean age 67.2 ± 10.9 years, women 36.4%) were consecutively enrolled between June 2016 and June 2017 from 10 tertiary hospitals in Korea. This study included 3,381 patients who started OAC 30 days before enrollment (maintenance group) and 572 patients who newly started OAC (new-starter group). The persistence rate of OAC was evaluated.ResultsIn the maintenance group, persistence to OAC declined during 6 months, to 88.3% for VKA and 95.5% for NOAC (p < 0.0001). However, the persistence rate was not different among NOACs. In the new-starter group, persistence to OAC declined during 6 months, to 78.9% for VKA and 92.1% for NOAC (p < 0.0001). The persistence rate was lower for rivaroxaban (83.7%) than apixaban (94.6%) and edoxaban (94.1%, p < 0.001). In the new-starter group, diabetes, valve disease, and cancer were related to nonpersistence of OAC.ConclusionNonpersistence was significantly lower with NOAC than VKA in both the maintenance and new-starter groups. In only the new-starter group, apixaban or edoxaban showed higher persistence rates than rivaroxaban.
| S-EPMC6960047 | biostudies-literature
Project description:Background & aimsProphylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.MethodsAnalytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.ResultsIt was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.ConclusionThe methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.
| S-EPMC5813962 | biostudies-literature