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Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.
Singh, AK, Singh, R
Diabetes & metabolic syndrome. 2021;(1):351-359
Abstract
BACKGROUND AND AIMS We conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF. METHODS A systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model. RESULTS This meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69-0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78-0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62-0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF). CONCLUSIONS SGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant Pheterogenity for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF.
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The efficacy and safety of multiple versus single doses dexamethasone in unicompartmental knee arthroplasty: A protocol of randomized controlled trial.
Gao, D, Liu, X, Zhang, F, Ding, M
Medicine. 2020;(34):e21671
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BACKGROUND Concerns exist regarding the analgesia effect and safety of multiple versus single doses dexamethasone in unicompartmental knee arthroplasty. There is an urgent need of studies that efficiently control for confounding, conduct comprehensive and consecutive observation of potential risks of the dexamethasone administration, and investigate its clinical applicability. We thus further designed a randomized controlled study to assess the different dose of dexamethasone on postoperative pain and complications in patients undergoing unicompartmental knee arthroplasty. METHODS This randomized, prospective, controlled study was carried out between January 2018 and August 2019. It was approved by the institutional review board in our hospital (HBRM2020013). A total of 80 patients were randomly assigned to each group: the study group (n = 40) and the control group (n = 40). All surgical procedures were performed by a similar orthopedic surgeon. In the study group, patients received intravenously 20 mg dexamethasone (4 mL, Tianjin Kingyork group Co., Ltd., China) just after the anesthesia, and repeated at 24 hours after the surgery. Patients in the control group received intravenously 10 mg dexamethasone solution (2 mL) just after the anesthesia, and repeated at 24 hours after the surgery. CRP, IL-6, VAS pain scores at rest and walking, the VAS scores of nausea, and the incidence of postoperative vomiting and nausea (POVN) were recorded at 24, 48, and 72 hours postoperatively. CONCLUSION We hypothesized that patients receiving multiple doses of dexamethasone was associated with better outcomes compared with patients receiving single dose of dexamethasone. TRIAL REGISTRATION This study protocol was registered in Research Registry (researchregistry5770).
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Lurasidone, olanzapine, and quetiapine extended-release for bipolar depression: A systematic review and network meta-analysis of phase 3 trials in Japan.
Kishi, T, Yoshimura, R, Sakuma, K, Okuya, M, Iwata, N
Neuropsychopharmacology reports. 2020;(4):417-422
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AIM: This systematic review and random-effect model, network meta-analysis of the phase 3 trials in Japan assessed the efficacy and safety profile of lurasidone compared with olanzapine and quetiapine extended-release (QUE-XR) for the treatment of bipolar depression. METHODS The study included double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with bipolar depression. Outcomes included response rate (primary), remission rate (secondary), improvement of Montgomery-Åsberg Depression Rating Scale (MADRS) total score, discontinuation rates, and incidence of individual adverse events. RESULTS Three studies were included (n = 1223). Lurasidone and olanzapine but not QUE-XR were superior to placebo in response rate [risk ratio (95% credible interval): lurasidone = 0.78 (0.66, 0.92); olanzapine = 0.84 (0.71, 0.99); QUE-XR = 0.87 (0.73, 1.03)]. Lurasidone, olanzapine and QUE-XR were superior to placebo in remission rate [lurasidone = 0.90 (0.83, 0.98); olanzapine = 0.87 (0.77, 0.99); QUE-XR = 0.84 (0.73, 0.98)] and the improvement of MADRS total score. There were not differences in discontinuation rates between each antipsychotic and placebo. Compared with placebo, lurasidone was higher incidence of akathisia, and increased body weight and blood prolactin level; olanzapine was higher incidence of somnolence and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels; QUE-XR was higher incidence of extrapyramidal symptoms, akathisia, somnolence, dry mouth, constipation and ≥7% weight gain, and increased body weight, blood total cholesterol level, blood LDL cholesterol level, and blood triglyceride levels. CONCLUSIONS Our results suggested although the efficacy of three SGAs was similar, there were the differences in the safety profile among the SGAs.
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Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.
Jawitz, OK, Wang, TY, Lopes, RD, Chavez, A, Boyer, B, Kim, H, Anstrom, KJ, Becker, RC, Blackstone, E, Ruel, M, et al
American heart journal. 2020;:91-99
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Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin.
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The RICH LIFE Project: A cluster randomized pragmatic trial comparing the effectiveness of health system only vs. health system Plus a collaborative/stepped care intervention to reduce hypertension disparities.
Cooper, LA, Marsteller, JA, Carson, KA, Dietz, KB, Boonyasai, RT, Alvarez, C, Ibe, CA, Crews, DC, Yeh, HC, Miller, ER, et al
American heart journal. 2020;:94-113
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UNLABELLED Disparities in the control of hypertension and other cardiovascular disease risk factors are well-documented in the United States, even among patients seen regularly in the healthcare system. Few existing approaches explicitly address disparities in hypertension care and control. This paper describes the RICH LIFE Project (Reducing Inequities in Care of Hypertension: Lifestyle Improvement for Everyone) design. METHODS RICH LIFE is a two-arm, cluster-randomized trial, comparing the effectiveness of enhanced standard of care, "Standard of Care Plus" (SCP), to a multi-level intervention, "Collaborative Care/Stepped Care" (CC/SC), for improving blood pressure (BP) control and patient activation and reducing disparities in BP control among 1890 adults with uncontrolled hypertension and at least one other cardiovascular disease risk factor treated at 30 primary care practices in Maryland and Pennsylvania. Fifteen practices randomized to the SCP arm receive standardized BP measurement training; race/ethnicity-specific audit and feedback of BP control rates; and quarterly webinars in management practices, quality improvement and disparities reduction. Fifteen practices in the CC/SC arm receive the SCP interventions plus implementation of the collaborative care model with stepped-care components (community health worker referrals and virtual specialist-panel consults). The primary clinical outcome is BP control (<140/90 mm Hg) at 12 months. The primary patient-reported outcome is change from baseline in self-reported patient activation at 12 months. DISCUSSION This study will provide knowledge about the feasibility of leveraging existing resources in routine primary care and potential benefits of adding supportive community-facing roles to improve hypertension care and reduce disparities. TRIAL REGISTRATION Clinicaltrials.govNCT02674464.
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Comparison of two treatments on a covariate variable.
Lin, TY, Liao, CT, Li, CR, Tsai, JR, Liu, YT
Journal of biopharmaceutical statistics. 2020;(4):649-661
Abstract
In clinical trials, the efficacy of treatment might be dependent on the value of a covariate variable. Therefore, it might be possible to detect the region over the covariate variable where the two treatments under investigation do not have significantly different efficacy or the region of superiority of one treatment. The non-significant region can be verified to be a confidence interval for the abscissa of the intersection point of two regression lines, and each of the complementary regions of the confidence interval corresponds to a region of superiority. In this study, we develop a method of constructing the confidence interval based on the concept of a generalized pivotal quantity, so as to perform the task of detecting the possible three regions for a clinical trial. Two real-world examples are given to illustrate the application of our proposed method, and a simulation study is conducted to evaluate its performance.
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Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants.
Yebyo, HG, Aschmann, HE, Kaufmann, M, Puhan, MA
American heart journal. 2019;:18-28
Abstract
UNLABELLED The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations. METHODS We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes. RESULTS In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile. CONCLUSIONS All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.
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Evaluation of titanium mesh cranioplasty and polyetheretherketone cranioplasty: protocol for a multicentre, assessor-blinded, randomised controlled trial.
Yang, J, Sun, T, Yuan, Y, Li, X, Yu, H, Guan, J
BMJ open. 2019;(12):e033997
Abstract
INTRODUCTION Cranioplasty is a common surgery in neurosurgery department. However, restoring the integrity of skull brings many challenges to surgeons, and the selection of ideal implant materials is throughout the history of cranioplasty. Although titanium mesh was still preferred by many neurosurgeons in cranial reconstruction, the new polyetheretherketone (PEEK) material, for example, is gaining popularity for craniofacial reconstruction today. There remain limited data that compare the outcome of PEEK cranioplasty and titanium mesh cranioplasty. It is necessary to conduct a study to compare outcome of different materials for cranioplasty. METHODS/DESIGN In this multicentre, assessor-blinded, randomised controlled study, we will randomise 140 patients in a 1:1 ratio to PEEK cranioplasty versus titanium cranioplasty. Eligible patients are adults who were diagnosed with cranial defect (due to severe traumatic brain injury, ischaemic stroke, haemorrhagic stroke, infiltrative tumour and so on), the defect size is over 25 cm2, and they need to agree to participate in this trial. Instead of standard examinations, the enrolled patients receive neurological, motor, cognitive function and cerebral hemodynamics examinations as well as cosmetic evaluation. The procedures are repeated 3, 6 months after cranioplasty. The primary outcome, defined as infection or implant exposure after surgery, is the implant failure rate within 6 months. Secondary outcomes include postoperative complication rates, neurological outcomes, motor function, cerebral hemodynamics, cosmetic outcome and the total cost over a 6-month period. ETHICS AND DISSEMINATION This trial protocol has been approved by Biomedical Research Ethics Committee of West China Hospital of Sichuan University. All patients will be fully informed the implant materials, potential complications after surgery, responsibilities during the trial, and they will sign the informed consent before joining in this trial. If the patient's cognitive function is impaired, the patient's next of kin would be carefully informed. The results will be disseminated through academic conferences, student theses and will be published in a peer-reviewed journal. TRAIL REGISTRATION NUMBER ChiCTR1900024625; Pre-results.
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Evolution of Age and Female Representation in the Most-Cited Randomized Controlled Trials of Cardiology of the Last 20 Years.
Nguyen, QD, Peters, E, Wassef, A, Desmarais, P, Rémillard-Labrosse, D, Tremblay-Gravel, M
Circulation. Cardiovascular quality and outcomes. 2018;(6):e004713
Abstract
BACKGROUND Older adults and women have historically been underrepresented in randomized controlled trials of cardiology. Recent temporal evolution and factors influencing representation are incompletely investigated. We aimed to contrast age and female representation in the most influential randomized controlled trials in cardiology of the last 20 years to population prevalence and to assess the study factors affecting representation. METHODS AND RESULTS Using Web of Science, we selected the 25 most-cited cardiology articles each year between 1996 and 2015, and extracted mean age, percentage of women, funding source, sample size, disease condition, intervention type, and exclusion criteria. The outcomes were the evolution of the mean age and the percentage of women over time. Protocol design elements and year of publication were assessed as predictors of outcomes in multivariable regressions. A total of 500 studies were analyzed, where the mean age was 62.6±7.4 years and the median percentage of women was 28.6% (22.2-40.5). Compared with population prevalence derived from National Health and Nutrition Examination Survey 2015-2016, gaps in representation were apparent and more pronounced for coronary artery disease (-5.0 years; -27.2% women) and heart failure (-6.0 years; -25.4% women). The mean age (0.15 year per year; 95% confidence interval, 0.04-0.26) and percentage of women (+0.29% per year; 95% confidence interval, 0.07-0.50), slightly but significantly increased over time. Private funding, small sample size, and exclusions pertaining to maximal age, atrial fibrillation, and diabetes mellitus were associated with a decreased mean age in multivariable linear regressions. Age and life expectancy exclusions were associated with lower female percentage. CONCLUSIONS Although age and female representation increased over time, the modest trends are unlikely to resolve the persistently wide gaps with actual populational prevalence, especially for coronary artery disease and HF. Representation is modulated by the cardiovascular condition studied and some modifiable protocol elements.
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Characteristics and Treatments of Patients Enrolled in the CHAMP-HF Registry Compared With Patients Enrolled in the PARADIGM-HF Trial.
DeVore, AD, Mi, X, Thomas, L, Sharma, PP, Albert, NM, Butler, J, Hernandez, AF, Patterson, JH, Spertus, JA, Williams, FB, et al
Journal of the American Heart Association. 2018;(12)
Abstract
BACKGROUND The US Food and Drug Administration approved sacubitril/valsartan for patients with chronic heart failure (HF) with reduced ejection fraction in 2015 on the basis of the results of the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor Neprilysin Inhibitor] With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. There are limited data assessing the generalizability of PARADIGM-HF trial participants to a broader population of patients with HF with reduced ejection fraction routinely encountered in outpatient clinical practice. METHODS AND RESULTS We compared the baseline characteristics of patients in the PARADIGM-HF trial with those in the CHAMP-HF (Change the Management of Patients With Heart Failure) study a large US outpatient registry of patients with HF with reduced ejection fraction. Patients in the PARADIGM-HF trial (n=8442) were similar to those in the CHAMP-HF registry (n=3497) in terms of age (mean, 64 versus 66 years), sex (22% versus 29% women), New York Heart Association class III to IV (25% versus 32%), systolic blood pressure (mean, 121 versus 121 mm Hg), left ventricular ejection fraction (mean, 29% versus 29%), and other key baseline characteristics. The median (25th-75th percentile) Meta-Analysis Global Group in Chronic Heart Failure risk scores were similar for the 2 studies (20 [16-24] versus 22 [8-27]). Despite this, only 13% of patients in the CHAMP-HF registry were prescribed sacubitril/valsartan at baseline. CONCLUSIONS These data suggest participants randomized in the PARADIGM-HF trial have similar baseline characteristics to those encountered in routine outpatient clinical practice, but there is a substantial lag in the adoption of sacubitril/valsartan for patients with chronic HF with reduced ejection fraction.