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An appraisal of the SDIR as an estimate of true individual differences in training responsiveness in parallel-arm exercise randomized controlled trials.
Bonafiglia, JT, Brennan, AM, Ross, R, Gurd, BJ
Physiological reports. 2019;(14):e14163
Abstract
Calculating the standard deviation of individual responses (SDIR ) is recommended for estimating the magnitude of individual differences in training responsiveness in parallel-arm exercise randomized controlled trials (RCTs). The purpose of this review article is to discuss potential limitations of parallel-arm exercise RCTs that may confound/complicate the interpretation of the SDIR . To provide context for this discussion, we define the sources of variation that contribute to variability in the observed responses to exercise training and review the assumptions that underlie the interpretation of SDIR as a reflection of true individual differences in training responsiveness. This review also contains two novel analyses: (1) we demonstrate differences in variability in changes in diet and physical activity habits across an intervention period in both exercise and control groups, and (2) we examined participant dropout data from six RCTs and found that significantly (P < 0.001) more participants in control groups (12.8%) dropped out due to dissatisfaction with group assignment compared to exercise groups (3.4%). These novel analyses raise the possibility that the magnitude of within-subject variability may not be equal between exercise and control groups. Overall, this review highlights that potential limitations of parallel-arm exercise RCTs can violate the underlying assumptions of the SDIR and suggests that these limitations should be considered when interpreting the SDIR as an estimate of true individual differences in training responsiveness.
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2.
Ethical Issues in Pragmatic Cluster-Randomized Trials in Dialysis Facilities.
Goldstein, CE, Weijer, C, Taljaard, M, Al-Jaishi, AA, Basile, E, Brehaut, J, Cook, CL, Grimshaw, JM, Lacson, E, Lindsay, C, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019;(5):659-666
Abstract
A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution.
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Hidradenitis Suppurativa: A Systematic Review and Meta-analysis of Therapeutic Interventions.
Tchero, H, Herlin, C, Bekara, F, Fluieraru, S, Teot, L
Indian journal of dermatology, venereology and leprology. 2019;(3):248-257
Abstract
Hidradenitis suppurativa is a chronic inflammatory condition that affects skin regions bearing apocrine glands. Although hidradenitis suppurativa is difficult to treat and cure, the currently available treatments are directed toward managing the lesions and associated symptoms. This review presents an evidence-based outline of the available treatment options. We searched four electronic databases and extracted data from retrieved studies for qualitative or quantitative analysis. Meta-analysis was conducted using the comprehensive meta-analysis software to generate pooled standardized mean differences or risk ratios. Numerous medical treatments are available for hidradenitis suppurativa such as antibiotics, retinoids, antiandrogens, immunosuppressive and anti-inflammatory agents and radiotherapy for early lesions. Adalimumab, an anti-tumor necrosis factor antibody, was superior to placebo in reducing Sartorius score (standardized mean difference = -0.32, confidence interval [-0.46, -0.18], P < 0.0001) and pain (risk ratio = 1.42, confidence interval [1.07, 1.9], P = 0.02), when given weekly (not every other week). Combination therapies (such as antibiotics and hyperbaric oxygen therapy) have been tested, which have shown promising results that are yet to be confirmed. Based on the quality of evidence, the most recommended treatments for hidradenitis suppurativa include adalimumab and laser therapy. Surgery (either by simple excision or complete local excision followed by skin graft) is the first choice for intractable disease presenting in the late stages. However, the evidence on most of these treatments is deficient and further randomized trials are needed to establish the most efficient therapies for hidradenitis suppurativa management.
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4.
Trials and Tribulations of CETP Inhibitors.
Tall, AR, Rader, DJ
Circulation research. 2018;(1):106-112
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Abstract
The development of CETP (cholesteryl ester transfer protein) inhibitors has had a long and difficult course with 3 compounds failing in phase III clinical trials. Finally, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid modification) trial has shown that the CETP inhibitor anacetrapib decreased coronary heart disease when added to statin therapy. Although the result is different to earlier studies, this is likely related to the size and duration of the trial. The benefit of anacetrapib seems to be largely explained by lowering of non-HDL-C (high-density lipoprotein cholesterol), rather than increases in HDL-C. Although the magnitude of benefit for coronary heart disease appeared to be moderate, in part this may have reflected aspects of the trial design. Anacetrapib treatment was associated with a small increase in blood pressure, but was devoid of major side effects and was also associated with a small reduction in diabetes mellitus. Treatment with CETP inhibitors, either alone or in combination with statins, could provide another option for patients with coronary disease who require further reduction in LDL (low-density lipoprotein) and non-HDL-C.
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Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.
Nicholls, SJ, Lincoff, AM, Bash, D, Ballantyne, CM, Barter, PJ, Davidson, MH, Kastelein, JJP, Koenig, W, McGuire, DK, Mozaffarian, D, et al
Clinical cardiology. 2018;(10):1281-1288
Abstract
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.
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SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials.
Puckrin, R, Saltiel, MP, Reynier, P, Azoulay, L, Yu, OHY, Filion, KB
Acta diabetologica. 2018;(5):503-514
Abstract
AIMS: There is concern about the infection-related safety profile of sodium-glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models. RESULTS Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89-3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14-4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96-1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93-1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10-1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20-0.72, I2 0%) but did not affect the risk of respiratory tract infections. CONCLUSIONS/INTERPRETATION SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.
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Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: a meta-analysis of randomized controlled trials.
Huang, X, Wang, F, Wang, K
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018;(16):2216-2222
Abstract
BACKGROUND Paracetamol has been suggested as an effective treatment for patent ductus arteriosus (PDA). However, the comparative efficacy and safety between paracetamol and ibuprofen were not determined. METHODS A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant studies were identified via database searching. A fixed or random effect model was applied depending on the extent of heterogeneity. RESULTS Five RCTs with 677 neonates were included. The efficacies for the primary (risk ratio [RR]: 1.03, p = .56) and overall PDA closure were comparable between the two medications (RR: 1.02, p = .62). Neonates of the two groups were comparable for the incidence of PDA complications, including necrotizing enterocolitis (RR: 0.86, p = .70), intraventricular hemorrhage (RR: 0.84, p = .55), bronchopulmonary dysplasia (RR: 0.69, p = .16), and retinopathy of prematurity (RR: 0.58, p = .15), and the risks of sepsis (RR = 0.88, p = .48) and death (RR: 1.45, p = .45) within hospitalization. However, treatment with paracetamol was associated with a trend of reduced risk of renal failure (RR: 0.20, p = .07), and a significantly reduced risk of gastrointestinal bleeding (RR: 0.28, p = .009). CONCLUSIONS Paracetamol may confer comparable treatment efficacy for the closure of PDA as ibuprofen, although paracetamol is associated with lower risk of adverse events.
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Economic Impact of Third-Wave Cognitive Behavioral Therapies: A Systematic Review and Quality Assessment of Economic Evaluations in Randomized Controlled Trials.
Feliu-Soler, A, Cebolla, A, McCracken, LM, D'Amico, F, Knapp, M, López-Montoyo, A, García-Campayo, J, Soler, J, Baños, RM, Pérez-Aranda, A, et al
Behavior therapy. 2018;(1):124-147
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Abstract
The term third-wave cognitive behavioral therapy (CBT) encompasses new forms of CBT that both extend and innovate within CBT. Most third-wave therapies have been subject to randomized controlled trials (RCTs) focused on clinical effectiveness; however, the number and quality of economic evaluations in these RCTs has been unknown and may be few. Evidence about efficiency of these therapies may help support decisions on efficient allocation of resources in health policies. The main aim of this study was to systematically review the economic impact of third-wave therapies in the treatment of patients with physical or mental conditions. We conducted a systematic literature search in PubMed, PsycINFO, EMBASE, and CINALH to identify economic evaluations of third-wave therapies. Quality and Risk of Bias (RoB) assessment of economic evaluations was also made using the Drummond 35-item checklist and the Cochrane Collaboration's tool for assessing risk of bias, respectively. Eleven RCTs were included in this systematic review. Mindfulness-Based Cognitive Therapy (MBCT), Mindfulness-Based Stress Reduction (MBSR), Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), and extended Behaviour Activation (eBA) showed acceptable cost-effectiveness and cost-utility ratios. No study employed a time horizon of more than 3 years. Quality and RoB assessments highlight some limitations that temper the findings. There is some evidence that MBCT, MBSR, ACT, DBT, and eBA are efficient from a societal or a third-party payer perspective. No economic analysis was found for many third-wave therapies. Therefore, more economic evaluations with high methodological quality are needed.
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Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study.
Pradhan, AD, Paynter, NP, Everett, BM, Glynn, RJ, Amarenco, P, Elam, M, Ginsberg, H, Hiatt, WR, Ishibashi, S, Koenig, W, et al
American heart journal. 2018;:80-93
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Abstract
Observational, genetic, and experimental data indicate that triglyceride rich lipoproteins (TRLs) likely participate causally in atherothrombosis. Yet, robust clinical trial evidence that triglyceride (TG) lowering therapy reduces cardiovascular events remains elusive. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM-α), pemafibrate, will be used to target residual cardiovascular risk remaining after treatment to reduce low-density lipoprotein cholesterol (LDL-C) in individuals with the dyslipidemia of type 2 diabetes mellitus (T2). The PROMINENT study will randomly allocate approximately 10,000 participants with T2D, mild-to-moderate hypertriglyceridemia (TG: 200-499 mg/dl; 2.26-5.64 mmol/l) and low high-density lipoprotein cholesterol levels (HDL-C: ≤40 mg/dl; 1.03 mmol/l) to either pemafibrate (0.2 mg twice daily) or matching placebo with an average expected follow-up period of 3.75 years (total treatment phase 5 years; 24 countries). At study entry, participants must be receiving either moderate-to-high intensity statin therapy or meet specified LDL-C criteria. The study population will be one-third primary and two-thirds secondary prevention (established cardiovascular disease). The primary endpoint is a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for unstable angina requiring urgent coronary revascularization, and cardiovascular death. This event-driven study will complete when 1092 adjudicated primary endpoints have accrued with at least 200 occurring in women. Statistical power is at least 90% to detect an 18% reduction in the primary endpoint. Pre-specified secondary and tertiary endpoints include all-cause mortality, hospitalization for heart failure, new or worsening peripheral artery disease, new or worsening diabetic retinopathy and nephropathy, and change in biomarkers including select lipid and non-lipid biomarkers, inflammatory and glycemic parameters.
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Phosphocreatine in Cardiac Surgery Patients: A Meta-Analysis of Randomized Controlled Trials.
Mingxing, F, Landoni, G, Zangrillo, A, Monaco, F, Lomivorotov, VV, Hui, C, Novikov, M, Nepomniashchikh, V, Fominskiy, E
Journal of cardiothoracic and vascular anesthesia. 2018;(2):762-770
Abstract
OBJECTIVE There is experimental evidence that phosphocreatine (PCr) can decrease ischemia/reperfusion injury of the heart. The authors investigated if PCr would improve heart performance as compared with standard treatment in cardiac surgery. DESIGN Meta-analysis of randomized controlled trials. SETTING Hospitals. PARTICIPANTS Adult and pediatric patients undergoing cardiac surgery. INTERVENTIONS The ability of PCr to improve cardiac outcomes as compared with standard treatment was investigated. MEASUREMENTS AND MAIN RESULTS PubMed/Medline, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, WANGFANG DATA, and VIP Paper Check System were searched to March 1 2017. The authors included 26 randomized controlled trials comprising 1,948 patients. Random and fixed-effects models were used to estimate odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI). PCr use was associated with reduced rates of intraoperative inotropic support (27% v 44%; OR 0.47, 95% CI 0.35-0.61; p < 0.001), major arrhythmias (16% v 28%; OR 0.44, 95% CI 0.27-0.69; p < 0.001), as well as increased spontaneous recovery of the cardiac rhythm immediately after aortic declamping (50% v 34%; OR 2.45, 95% CI 1.82-3.30; p < 0.001) as compared with standard treatment. The use of PCr decreased myocardial damage and augmented left ventricular ejection fraction in the postoperative period; however, MD for these outcomes were small and do not seem to be clinically significant. CONCLUSIONS In randomized trials, PCr administration was associated with reduced rates of intraoperative inotropic support and major arrhythmias, and increased spontaneous recovery of the cardiac rhythm after aortic declamping. Large multicenter evidence is needed to validate these findings.