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1.
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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The Effects of Novel Antidiabetic Drugs on Albuminuria in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Luo, Y, Lu, K, Liu, G, Wang, J, Laurent, I, Zhou, X
Clinical drug investigation. 2018;(12):1089-1108
Abstract
BACKGROUND AND OBJECTIVE The effects of novel antidiabetic drugs, including sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors, on albuminuria in patients with type 2 diabetes mellitus (T2DM) are still controversial. Therefore, we performed a meta-analysis to evaluate the effects of novel antidiabetic drugs on albuminuria in patients with T2DM. METHODS We conducted a random-effects meta-analysis of randomized controlled trials (RCTs) by searching the MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases up to 16 August 2018. The effects of novel antidiabetic drugs on albuminuria were evaluated as percent changes from baseline to follow-up urinary albumin excretion/urinary albumin to creatinine ratio (UAE/UACR) levels in both the intervention and control groups. Data regarding percent changes were used to generate weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS In this meta-analysis, 26 RCTs involving 14,929 patients were included. Pooled analysis suggested that SGLT-2 inhibitors (WMD - 26.23%, 95% CI - 35.90 to - 16.56; p < 0.00001) and GLP-1 receptor agonists (WMD - 13.85%, 95% CI - 15.96 to - 11.74; p < 0.00001) were associated with a significant reduction in albuminuria compared with other conventional therapies or placebo. DPP-4 inhibitors (WMD - 6.19%, 95% CI - 14.03 to 1.66; p = 0.12) were not significantly associated with lower albuminuria than other conventional therapies or placebo. CONCLUSION This meta-analysis indicates that SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a reduction in albuminuria compared with other conventional therapies or placebo, while DPP-4 inhibitors were not associated with albuminuria-reducing effects compared with other conventional therapies or placebo.
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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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Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data.
Campbell, BCV, van Zwam, WH, Goyal, M, Menon, BK, Dippel, DWJ, Demchuk, AM, Bracard, S, White, P, Dávalos, A, Majoie, CBLM, et al
The Lancet. Neurology. 2018;(1):47-53
Abstract
BACKGROUND General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. METHODS For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. FINDINGS Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14-2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. INTERPRETATION Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons. FUNDING Medtronic.
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Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota: A Systematic Review.
Bafeta, A, Koh, M, Riveros, C, Ravaud, P
Annals of internal medicine. 2018;(4):240-247
Abstract
BACKGROUND Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood. PURPOSE To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics. DATA SOURCES Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018. STUDY SELECTION RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition. DATA EXTRACTION 4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results. DATA SYNTHESIS Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators. LIMITATION Journal publication processes may have affected the completeness of reporting; only English-language publications were examined. CONCLUSION Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data. PRIMARY FUNDING SOURCE No specific funding.
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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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Effectiveness of contrast-associated acute kidney injury prevention methods; a systematic review and network meta-analysis.
Ahmed, K, McVeigh, T, Cerneviciute, R, Mohamed, S, Tubassam, M, Karim, M, Walsh, S
BMC nephrology. 2018;(1):323
Abstract
BACKGROUND Different methods to prevent contrast-associated acute kidney injury (CA-AKI) have been proposed in recent years. We performed a mixed treatment comparison to evaluate and rank suggested interventions. METHODS A comprehensive Systematic review and a Bayesian network meta-analysis of randomised controlled trials was completed. Results were tabulated and graphically represented using a network diagram; forest plots and league tables were shown to rank treatments by the surface under the cumulative ranking curve (SUCRA). A stacked bar chart rankogram was generated. We performed main analysis with 200 RCTs and three analyses according to contrast media and high or normal baseline renal profile that includes 173, 112 & 60 RCTs respectively. RESULTS We have included 200 trials with 42,273 patients and 44 interventions. The primary outcome was CI-AKI, defined as ≥25% relative increase or ≥ 0.5 mg/dl increase from baseline creatinine one to 5 days post contrast exposure. The top ranked interventions through different analyses were Allopurinol, Prostaglandin E1 (PGE1) & Oxygen (0.9647, 0.7809 & 0.7527 in the main analysis). Comparatively, reference treatment intravenous hydration was ranked lower but better than Placebo (0.3124 VS 0.2694 in the main analysis). CONCLUSION Multiple CA-AKI preventive interventions have been tested in RCTs. This network evaluates data for all the explored options. The results suggest that some options (particularly allopurinol, PGE1 & Oxygen) deserve further evaluation in a larger well-designed RCTs.
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Recruitment of New Immigrants Into a Randomized Controlled Prevention Trial: The Live Well Experience.
Metayer, N, Boulos, R, Tovar, A, Gervis, J, Abreu, J, Hval, E, Kamins, CL, Tofuri, K, Economos, CD
The journal of primary prevention. 2018;(5):453-468
Abstract
Minority populations are hard to reach with prevention interventions because of cultural and logistical barriers to recruitment. Understanding how to overcome these barriers is pertinent to reducing the elevated burden of obesity within these underserved communities. To inform this literature gap, we explore the processes and outcomes of recruitment for Live Well-a randomized controlled obesity prevention intervention targeting new immigrant mothers and children from Brazil, Latin America, and Haiti who were residing in the greater Somerville, MA area. We employed community-based participatory research principles to develop and implement five culturally-adapted recruitment activities (posters and flyers, media announcements, church outreach, participant referrals, and community organization partnerships) and tracked enrollment for the total and stratified samples of 406 dyads (37% Brazilian, 29% Latino, 33% Haitian). We describe how strategic partnerships were built and sustained within the intervention community, and detail the key adjustments that contributed to our success. Ultimately, community organization partnerships and participant referrals enrolled a collective majority of participants (34% and 25%, respectively); however, stratified analyses revealed variation by ethnicity: Haitian immigrants responded best to ethnic-based media announcements (44%), whereas Latino and Brazilian immigrants were most responsive to community organization outreach (45% and 38%, respectively). Implications from our findings enhance the literature on recruiting hard-to-reach communities into prevention research: some less integrated communities may respond more to grassroots activities with direct engagement, whereas communities with more social capital may be more responsive to top-down, community-wide collaborations. Furthermore, we suggest that strategic and trusting partnerships are key facilitators of recruitment, and future researchers must understand communities' culture and social networks when building relationships. Our analyses provide rare insight into best practices to overcome specific cultural barriers to recruitment which future investigators can use to better reach underserved communities with prevention research.