Difference In Serious Adverse Events Research Articles

Efficacy and tolerability of duloxetine in patients with knee osteoarthritis: a meta-analysis of randomised controlled trials.

Knee osteoarthritis (OA) is one of the most common joint diseases, and pharmacotherapy is necessary to control its symptoms. To evaluate efficacy and tolerability of duloxetine in patients with knee OA. PubMed, Web of Science, Embase, Cochrane Library and ClinicalTrials.gov were searched to identify randomised controlled trials comparing duloxetine with placebo for knee OA. Data including pain, stiffness, physical function, and adverse events were extracted for meta-analysis. The protocol was prospectively registered in PROSPERO (CRD42018097110). Data from six randomised controlled trials including 2059 participants were pooled. Duloxetine achieved significant reductions in primary outcomes including Brief Pain Inventory 24-h average pain score (weighted mean difference (WMD) = -0.74, 95% confidence interval (CI) = -0.92 to -0.57), weekly mean of the 24-h average pain score (WMD = -0.76, 95% CI = -0.96 to -0.56), WOMAC stiffness score (WMD = -0.47, 95% CI = -0.60 to -0.34) and WOMAC physical function score (WMD = -4.44, 95% CI = -5.24 to -3.64). Furthermore, duloxetine demonstrated a higher number of treatment-emergent adverse events (risk ratio (RR) = 1.31, 95% CI = 1.20-1.44) and discontinuations (RR = 2.26, 95% CI = 1.63-3.12); however, no difference in serious adverse events (RR = 0.92, 95% CI = 0.40-2.11) was observed. Duloxetine is effective in the management of chronic pain and loss of physical function in knee OA with acceptable adverse events despite having no advantage in treating joint stiffness. Future trials should focus on determining the optimal treatment regimen.

Users Guide to Pitfalls and Lessons Learned About HBOC-201 During Clinical Trials, Expanded Access, and Clinical Use in 1,701 Patients.

Lessons learned during 1,701 clinical uses of HBOC-201, a polymerized bovine hemoglobin-based oxygen carrier (HBOC), were identified to provide management lessons and training material for future clinical trials and use. HBOC-201 contains 13 g/dL hemoglobin (Hb), is iso-oncotic, stable at 2°C to 30°C with shelf-life of 3 years, requires no cross-matching with half-life of 19 h, and plasma volume distribution. Adverse effects include increased blood pressure, oliguria, gastrointestinal (GI) symptoms, yellow skin and scleral discoloration, decreased pulse oximetry measurements, and transient increases in methemoglobin, hepatic, and pancreatic enzymes. There was no cardiotoxicity. Elevations in blood pressure were transient and were managed with vasodilators. Oliguria was of limited duration. GI symptoms were treated with smooth muscle relaxants. Yellow skin and sclera were self-limiting, caused by Hb metabolism. The most important clinical management errors were lack of understanding of volume expansion effects and the half-life properties of HBOC-201, and failure to repeat infusions. Early use of HBOC-201 for Expanded Access when Hb less than 5 g/dL optimized survival and minimized advanced resource utilization. For phase 3 trials, there was transfusion avoidance of 96% for 24 h, 70% for 1 week, with no difference in serious adverse events or mortality whether patients received at most 10 bags HBOC-201 or at most 3 units blood. More nonserious events occurred with HBOC-201. Age, history of cardiac disease, and Hb deficit, but not randomization to HBOC-201, were significantly predictive of cardiac ischemic events. Administration of HBOC-201 in1,701 humans showed it was well tolerated in a wide range of doses and clinical settings. HBOC-201 should be considered when blood is not available or an option.

Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)\u2014a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

BackgroundPart of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome.MethodThe CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 μg/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test.ResultsWe included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group.Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality.ConclusionOur results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial.Trial registrationClinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41

Targeted Therapeutics for Transthyretin amyloid cardiomyopathy: Time to Move Forward

Introduction Deposition of wild type or mutant transthyretin (TTR) amyloid fibrils causes TTR cardiac amyloidosis (ATTR-CA). Targeted therapeutics (TT) for ATTR-CA include TTR stabilizers (tafamidis, dilfunisal) and oligonucleotide drugs (Revusiran, Patisiran and Inotersen).TTR stabilizers prevent dissociation of amyloid tetramers and thereby limit the deposition of amyloid fibrils. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin. Recent studies have demonstrated improved outcomes with TT in patients with ATTR-CA. Hypothesis We performed a pooled analysis to study the safety and efficacy of TT in patients with ATTR-CA. Methods We searched PubMed for all studies comparing the safety and efficacy of targeted therapeutics (TT) with placebo in patients with ATTR-CA. Primary outcomes were 1) all-cause mortality, 2) cardiac hospitalizations, 3) serious adverse events and 4) change in global longitudinal strain. Random effects model with Mantel-Haenszel method was used to analyze the data. Results We identified six studies which reported at least one of the outcomes comparing TT and placebo. One study was stopped prematurely due to increased mortality in the TT arm. Pooled analysis included 1164 patients, of which 691 patients received TT and 473 patients received placebo. When compared to placebo, TT significantly reduced all-cause mortality [OR 0.39 (95% CI: 0.16 - 0.97, P =0.04)]. Pooled analysis after exclusion of aforementioned prematurely terminated study also showed decrease in all-cause mortality with TT[OR 0.27 (95% CI: 0.10 - 0.71, P =0.008)]. There was no difference in serious adverse events with TT [OR 1.06 (95% CI: 0.78 - 1.44, P =0.72)]. A trend towards improvement in global longitudinal strain with TT (mean difference -0.69 (95% CI: -1.44 - 0.05, P =0.07) was noted. Only two studies reported the effect on cardiac hospitalizations. Conclusions In patients with ATTR-CA, TT reduced all-cause mortality and were well-tolerated as compared to placebo.

Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT

BackgroundCombination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease.ObjectiveThe objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease.DesignA Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control).SettingRecruitment was from 19 HIV specialist centres in the UK.ParticipantsA total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria.Interventions20-, 40- and 80-mg tablets of telmisartan.Main outcome measuresThe primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan.ResultsAt the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg;n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642;p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019;p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms.LimitationsThe patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time.ConclusionsUsing a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals.Future workThe mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions.Trial registrationCurrent Controlled Trials ISRCTN51069819.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

BACKGROUND: Anti-tumor necrosis factor (TNF) agents are effective in treating patients with rheumatoid arthritis (RA), but they are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation or disease activity guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) on disease activity, functioning, costs, safety and radiographic damage compared with usual care in patients with RA and low disease activity. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 8, 2013; Ovid MEDLINE (1946 to 8 September 2013); EMBASE (1947 to 8 September 2013); Science Citation Index (Web of Science); and conference proceedings of the American College of Rheumatology (2005 to 2012) and European League against Rheumatism (2005 to 2013). We contacted authors of the seven included studies to ask for additional information on their study; five responded. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in patients with RA and a low disease activity state. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. MAIN RESULTS: Six RCTs and one CCT (total 1203 participants), reporting anti-TNF down-titration, were included. Three studies (559 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Five studies (732 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (two studies assessed both anti-TNF discontinuation and dose reduction), and one study assessed disease activity-guided anti-TNF dose tapering (137 participants). These studies include only adalimumab and etanercept; controlled data on other anti-TNF agents are absent. Two studies were available in full text; one was assessed as having low risk of bias and the other high risk. Five studies were available only as one or more abstracts. Because data provided in these abstracts were limited, risk of bias was unclear. Clinical heterogeneity between the trials was high.Dose reduction of anti-TNF (etanercept data only) showed no statistically significant or clinical relevant difference in disease activity score in 28 joints (DAS28) (mean difference (MD) 0.10, 95% confidence interval (CI) -0.11 to 0.31) (scale 0.9 to 8; higher score indicates worse disease activity). The proportion of participants who maintained low disease activity was slightly lower among participants given reduced doses of the anti-TNF agent (risk ratio (RR) 0.87, 95% CI 0.78 to 0.98, absolute risk difference (ARD) 9%). Radiographic outcome was slightly worse, but this was not clinically meaningful, compared with continuation of anti-TNF (MD 0.11, 95% CI 0.08 to 0.14) (scale 0 to 448; higher score indicates greater joint damage). Function was not statistically different between anti-TNF dose reduction and continuation (MD 0.10, 95% CI 0.00 to 0.20) (scale 0 to 3; higher score indicates worse functioning). Reinstalment of anti-TNF after failure of dose reduction showed a 5% risk of persistent flare. Data on numbers of serious adverse events (SAEs) (RR 0.58, 95% CI 0.23 to 1.45, ARD -2%) and withdrawals due to adverse events (AEs) (RR 0.57, 95% CI 0.17 to 1,92, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.Participants who discontinued anti-TNF (adalimumab and etanercept data) had higher mean DAS28 (DAS28-erythrocyte sedimentation rate (ESR): MD 1.10, 95% CI 0.86 to 1.34) and DAS28-C-reactive protein (CRP): MD 0.57 95% CI -0.09 to 1.23) and were less likely to maintain a low disease activity state (RR 0.43, 95% CI 0.27 to 0.68, ARD 40%). Also, radiographic and functional outcomes are worse after anti-TNF discontinuation (MD 0.66, 95% CI 0.63 to 0.69, and MD 0.30, 95% CI 0.19 to 0.41, respectively). Data on numbers of SAEs (RR 1.26, 95% CI 0.61 to 2.63, ARD 2%) and withdrawals due to AEs (RR 0.72, 95% CI 0.23 to 2.24, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.The one study comparing disease activity-guided anti-TNF dose tapering (adalimumab and etanercept data) reported no statistically significant differences in functional outcomes (MD 0.20, 95% CI -0.02 to 0.42). Significantly higher mean disease activity was found amon

Clinical Benefit of Hospitalization for Older Adults With Unexplained Syncope: A Propensity-Matched Analysis

Many adults with syncope are hospitalized solely for observation and testing. We seek to determine whether hospitalization versus outpatient management for older adults with unexplained syncope is associated with a reduction in postdisposition serious adverse events at 30 days. We performed a propensity score analysis using data from a prospective, observational study of older adults with unexplained syncope or near syncope who presented to 11 emergency departments (EDs) in the United States. We enrolled adults (≥60 years) who presented with syncope or near syncope. We excluded patients with a serious diagnosis identified in the ED. Clinical and laboratory data were collected on all patients. The primary outcome was rate of post-ED serious adverse events at 30days. We enrolled 2,492 older adults with syncope and no serious ED diagnosis from April 2013 to September 2016. Mean age was 73 years (SD 8.9 years), and 51% were women. The incidence of serious adverse events within 30 days after the index visit was 7.4% for hospitalized patients and 3.19% for discharged patients, representing an unadjusted difference of 4.2% (95% confidence interval 2.38% to 6.02%). After propensity score matching on risk of hospitalization, there was no statistically significant difference in serious adverse events at 30 days between the hospitalized group (4.89%) and the discharged group (2.82%) (risk difference 2.07%; 95% confidence interval -0.24% to 4.38%). In our propensity-matched sample of older adults with unexplained syncope, for those with clinical characteristics similar to that of the discharged cohort, hospitalization was not associated with improvement in 30-day serious adverse event rates.

P116: Impact of young age on outcomes of emergency department procedural sedation

Introduction: Procedural sedation in the emergency department (ED) for children undergoing painful procedures is common practice, however little is known about sedation in very young children. We examined the effect of young age on sedation outcomes. Methods: This is a secondary analysis of an observational cohort study of children 0-18 years undergoing procedural sedation in six pediatric EDs across Canada. We compared presedation state, indication for sedation, medications, sedation efficacy and four main post-sedation outcomes (serious adverse events (SAE), significant interventions, oxygen desaturation and vomiting) between patients who ≤2 years with those >2 years. Pre-sedation state, medications, indication for sedation and time intervals were summarized using frequency and percentage and compared with chi2 test. Logistic regression was used to examine associations between age group and outcomes. Results: 6295 patients were included; 5349 (85%) were >2 years and 946 (15%) were ≤2 years. Children ≤2 years were sedated most commonly for laceration repair (n = 450; 47.6%), orthopedic reduction (165; 17.4%) and abscess incision and drainage (136; 14.4%). Children >2years were sedated most commonly for orthopedic reductions (3983; 74.5%). Ketamine was the most common medication in both groups, but was used most frequently in children ≤2 years (80.9% vs 58.9%; p < 0.001). There was no difference in the incidence of SAE, significant interventions or oxygen desaturation between age groups, however children ≤2 years were less likely to vomit (Table 1). Young children had decreased odds of a successful sedation (OR 0.48; 95%CI: 0.37 to 0.63). On average, patients ≤2 years were sedated for 7 minutes less (74.1 vs 81.0 p < 0.001) and discharged 10 minutes sooner (90.1 vs 100.8 p < 0.001). Table 1 ≤2 years (n = 946) >2 years (n = 5349) OR (95%CI)* p-value n(%) n(%) Serious Adverse Event 8 (0.85) 59 (1.0) 0.76 (0.43-1.7) 0.477 Significant intervention 10 (1.0) 76 (1.4) 0.74 (0.34-1.4) 0.374 Oxygen Desaturation 50 (5.3) 303 (5.6) 0.93 (0.67-1.3) 0.640 Vomiting 14 (1.5) 314 (5.9) 0.24 0.13-0.41) <0.001 *Reference category: ≤2 years. Conclusion: Children ≤2 years most commonly received ED sedation for laceration repair using ketamine. Young age was not associated with a significant difference in SAEs, significant intervention or desaturation but was associated with decreased odds of vomiting and of successful sedation.

Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial

Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS. PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov, number NCT01587378, and EudraCT, number 2011-002203-15. The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0·50, 95% CI 0·22-1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1·09, 95% CI 0·69-1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23-0·79; p=0·004). In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes. Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.

Exercise-based cardiac rehabilitation for adult patients with an implantable cardioverter defibrillator.

An effective way of preventing sudden cardiac death is the use of an implantable cardioverter defibrillator (ICD). In spite of the potential mortality benefits of receiving an ICD device, psychological problems experienced by patients after receiving an ICD may negatively impact their health-related quality of life, and lead to increased readmission to hospital and healthcare needs, loss of productivity and employment earnings, and increased morbidity and mortality. Evidence from other heart conditions suggests that cardiac rehabilitation should consist of both exercise training and psychoeducational interventions; such rehabilitation may benefit patients with an ICD. Prior systematic reviews of cardiac rehabilitation have excluded participants with an ICD. A systematic review was therefore conducted to assess the evidence for the use of exercise-based intervention programmes following implantation of an ICD. To assess the benefits and harms of exercise-based cardiac rehabilitation programmes (exercise-based interventions alone or in combination with psychoeducational components) compared with control (group of no intervention, treatment as usual or another rehabilitation programme with no physical exercise element) in adults with an ICD. We searched CENTRAL, MEDLINE, Embase and four other databases on 30 August 2018 and three trials registers on 14 November 2017. We also undertook reference checking, citation searching and contacted study authors for missing data. We included randomised controlled trials (RCTs) if they investigated exercise-based cardiac rehabilitation interventions compared with no intervention, treatment as usual or another rehabilitation programme. The trial participants were adults (aged 18 years or older), who had been treated with an ICD regardless of type or indication. Two review authors independently extracted data and assessed risk of bias. The primary outcomes were all-cause mortality, serious adverse events and health-related quality of life. The secondary outcomes were exercise capacity, antitachycardia pacing, shock, non-serious adverse events, employment or loss of employment and costs and cost-effectiveness. Risk of systematic errors (bias) was assessed by evaluation of predefined bias risk domains. Clinical and statistical heterogeneity were assessed. Meta-analyses were undertaken using both fixed-effect and random-effects models. We used the GRADE approach to assess the quality of evidence. We identified eight trials published from 2004 to 2017 randomising a total of 1730 participants, with mean intervention duration of 12 weeks. All eight trials were judged to be at overall high risk of bias and effect estimates are reported at the end of the intervention with a follow-up range of eight to 24 weeks.Seven trials reported all-cause mortality, but deaths only occurred in one trial with no evidence of a difference between exercise-based cardiac rehabilitation and control (risk ratio (RR) 1.96, 95% confidence interval (CI) 0.18 to 21.26; participants = 196; trials = 1; quality of evidence: low). There was also no evidence of a difference in serious adverse events between exercise-based cardiac rehabilitation and control (RR 1.05, 95% CI 0.77 to 1.44; participants = 356; trials = 2; quality of evidence: low). Due to the variation in reporting of health-related quality of life outcomes, it was not possible to pool data. However, the five trials reporting health-related quality of life at the end of the intervention, each showed little or no evidence of a difference between exercise-based cardiac rehabilitation and control.For secondary outcomes, there was evidence of a higher pooled exercise capacity (peak VO2) at the end of the intervention (mean difference (MD) 0.91 mL/kg/min, 95% CI 0.60 to 1.21; participants = 1485; trials = 7; quality of evidence: very low) favouring exercise-based cardiac rehabilitation, albeit there was evidence of substantial statistical heterogeneity (I2 = 78%). There was no evidence of a difference in the risk of requiring antitachycardia pacing (RR 1.26, 95% CI 0.84 to 1.90; participants = 356; trials = 2; quality of evidence: moderate), appropriate shock (RR 0.56, 95% CI 0.20 to 1.58; participants = 428; studies = 3; quality of evidence: low) or inappropriate shock (RR 0.60, 95% CI 0.10 to 3.51; participants = 160; studies = 1; quality of evidence: moderate). Due to a lack of evidence, we were unable to definitively assess the impact of exercise-based cardiac rehabilitation on all-cause mortality, serious adverse events and health-related quality of life in adults with an ICD. However, our findings do provide very low-quality evidence that patients following exercise-based cardiac rehabilitation experience a higher exercise capacity compared with the no exercise control. Further high-quality randomised trials are needed in order to assess the impact of exercise-based cardiac rehabilitation in this population on all-cause mortality, serious adverse events, health-related quality of life, antitachycardia pacing and shock.

Delivering the Thinking Healthy Programme for perinatal depression through peers: an individually randomised controlled trial in India

The Thinking Healthy Programme (THP) is a psychological intervention recommended for the treatment of perinatal depression. However, efforts to integrate the intervention at scale into the routines of community health workers who delivered the THP when it was first evaluated were compromised by the competing responsibilities of community health workers. We aimed to assess the effectiveness and cost-effectiveness of THP peer-delivered (THPP) in Goa, India. In this single-blind, individually randomised controlled trial, we recruited pregnant women aged 18 years or older who scored at least 10 on the Patient Health Questionnaire-9 (PHQ-9) from antenatal clinics in Goa. Participants were randomly allocated (1:1) to receive enhanced usual care (EUC; so-called because, in India, perinatal depression is not typically treated) only (control group) or THPP in addition to EUC (intervention group) in randomly sized blocks that were stratified by area of residence (urban or rural). Group allocations were concealed from participants and researchers before assignments were made by use of sequentially numbered opaque envelopes. The primary outcomes were the severity of depressive symptoms (assessed by PHQ-9 score) and the prevalence of remission (defined as a PHQ-9 score of less than 5) in participants with available data 6 months after childbirth, which was assessed by researchers who were masked to treatment allocations. We analysed outcomes by intention to treat, adjusting for covariates that were defined a priori or that showed imbalance at baseline. The trial is registered with ClinicalTrials.gov, number NCT02104232. Between Oct 24, 2014, and June 24, 2016, we assessed 118 260 women for their eligibility for screening, of whom 111 851 (94·6%) women were ineligible. 6409 (5·4%) women were eligible for screening and 6369 (99·4%) of these women consented to be screened with the PHQ-9 (40 women did not consent), of whom 333 (5·2%) screened positive for depression (defined as a PHQ-9 score of at least 10). We enrolled 280 (84·1%) women with perinatal depression; 140 women were assigned to the THPP and EUC group and 140 women to the EUC only group. The final treatment was given on May 27, 2017. The final 6-month outcome assessment was completed on June 9, 2017. At 6 months after birth, 122 (87%) women in the THPP and EUC group and 129 (92%) women in the EUC only group were assessed for the primary outcome. There was a higher prevalence of remission at 6 months after birth in the THPP and EUC group compared with the EUC only group (89 [73%] women in the intervention group vs 77 [60%] women in the control group; prevalence ratio 1·21, 95% CI 1·01 to 1·45; p=0·04), but there was no evidence of a difference in symptom severity between the groups (mean PHQ-9 score 3·47 [SD 4·49] in the intervention group vs 4·48 [5·11] in the control group; standardised mean difference -0·18, 95% CI -0·43 to 0·07; p=0·16). There was no evidence of significant differences in serious adverse events between the groups. THPP had a moderate effect on remission from perinatal depression over the 6-month postnatal period. THPP is relatively cheap to deliver and is cost-saving through reduced health-care, time and productivity costs. National Institute of Mental Health (USA).

Delivering the Thinking Healthy Programme for perinatal depression through volunteer peers: a cluster randomised controlled trial in Pakistan

The Thinking Healthy Programme (THP), which is endorsed by WHO, is an evidence-based intervention for perinatal depression. We adapted THP for delivery by volunteer peers (laywomen from the community) to address the human resource needs in bridging the treatment gap, and we aimed to assess its effectiveness and cost-effectiveness in Rawalpindi, Pakistan. In this cluster randomised controlled trial, we randomly assigned 40 village clusters (1:1) to provide either THP peer-delivered (THPP) and enhanced usual care (EUC; intervention group) or EUC only (control group) to the participants within clusters. These villages were randomly selected from eligible villages by an independent researcher. The participants were pregnant women aged 18 years or older who had scored at least 10 on the Patient Health Questionnaire-9 (PHQ-9), who we recruited from households within communities in Rawalpindi, Pakistan. The research teams who were responsible for recruiting trial participants were masked to treatment allocations. Participants attended follow-up visits at 3 and 6 months after childbirth. The primary outcomes were the severity of depressive symptoms (assessed by PHQ-9 score) and the prevalence of remission (defined as a PHQ-9 score of less than 5) in participants with available data 6 months after childbirth, which was assessed by researchers who were masked to treatment allocations. We analysed outcomes by intention to treat, adjusting for covariates that were defined a priori or that showed imbalance at baseline. The trial was registered with ClinicalTrials.gov, number NCT02111915. Between April 15 and July 30, 2014, we randomly selected 40 of 46 eligible village clusters for assessment, as per sample size calculations. Between Oct 15, 2014, and Feb 25, 2016, we identified and screened 971 women from 20 village clusters that had been randomly assigned to the THPP and EUC group and 939 women from 20 village clusters that had been randomly assigned to the EUC only group. In the intervention group, 79 women were ineligible for inclusion, 11 women refused screening, 597 women screened negative on the PHQ-9, and one woman did not consent to participate. In the control group, 75 women were ineligible for inclusion, 14 women refused screening, 562 women screened negative on the PHQ-9, and one woman did not consent to participate. We enrolled 283 (29%) women in the intervention group and 287 (31%) women in the control group. At 6 months after childbirth, 227 (80%) women in the THPP and EUC group and 226 (79%) women in the EUC only group were assessed for the primary outcome. The severity of depression (assessed by PHQ-9 scores; standardised mean difference -0·13, 95% CI -0·31 to 0·06; p=0·07) and prevalence of remission (49% in the intervention group vs 45% in the control group; prevalence ratio 1·12, 95% CI 0·95 to 1·29; p=0·14) did not significantly differ between the groups 6 months after childbirth. There was no evidence of significant differences in serious adverse events between the groups. THPP had no effect on symptom severity or remission from perinatal depression at 6 months after childbirth, but we found that it was beneficial on some other metrics of severity and disability and that it was cost-effective. THPP could be a step towards use of an unused human resource to address the treatment gap in perinatal depression. National Institute of Mental Health (USA).

Network meta-analysis: a comparison of effectiveness and safety of partial agonists of nicotinic acetylcholine receptors varenicline and cytisine for smoking cessation

Background. Partial agonists of α4b2 nicotinic acetylcholine receptors are the most effective treatment strategy for tobacco smoking cessation. They are able to alleviate withdrawal symptoms and to reduce smoking satisfaction.
 The aim of this study was to review the efficacy and safety of nicotinic receptor partial agonists varenicline and cytisine, for smoking cessation.
 Methods. A search for randomized controlled trials was done using the terms (“cytisine”, “tabex”, “varenicline” or 'partial agonists of nicotinic receptors’) in MEDLINE, EMBASE, eLibrary in May 2018. Types of participants, the doses and duration of the treatments, efficacy and safety parameters, quality of randomization and blinding procedures were evaluated. Bayesian network meta-analysis was performed.
 Results. Cytisine overcame placebo in the 12, 24 and 52 weeks of therapy with the following odds ratios (ORs) for abstinence: 3.3 (95% CrI 1.8–5.8), 3.9 (2.4–6.7), 3.8 (CrI 1.3–11,9) accordingly. Varenicline in 2 mg/day dose overcame placebo in the 12, 24 and 52 weeks of therapy with the ORs: 4.0 (3.3–4.7), 3.1 (2.5–3.7), 2.9 (2.2–4.1) accor dingly. Varenicline in 1 mg/day dose overcame placebo in 12 and 52 weeks of therapy, the ORs were 3.0 (2.0–4.7) and 2.3 (1.3–4.4) accordingly. Varenicline in 0.5 mg/day dose overcame placebo in 12 weeks of therapy only with the OR 2.4 (1.3–4.4). Cytisine and varenicline 2 mg/day were associated with more gastrointestinal disturbances than placebo with the ORs 6.2 (2.1–22.8) and 2.4 (2.0–2.8) accordingly. Cytisine and varenicline 2 mg/day were associated with more psychiatric problems than placebo with ORs 5.2 (1.9–15.1) and 1.6 (1.3–1.9) accordingly. There was no difference in serious adverse events between the investigated drugs and placebo: OR for cytisine was 2.4 (0.8–6.8), varenicline 0.5 mg/day – 2.0 (0.5–6.6), varenicline 1.0 mg/day – 1.0 (0.3–2.7), varenicline 2 mg/day – 1.0 (0.7–1.4).
 Conclusion. Cytisine was proved to be as effective and safe aid for smoking cessation as varenicline.

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis

The efficacy and safety of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis.

Background:Several randomized controlled trials (RCTs) have been investigated the benefits of soluble guanylate cyclase (sGC) stimulators in the treatment of heart failure, but a comprehensive evaluation is lacking. We performed a meta-analysis to evaluate the efficacy and safety of oral sGC stimulators (vericiguat and riociguat) in patients with heart failure.Methods:Studies were searched and screened in PubMed, Embase, and Cochrane Library. Eligible RCTs were included that reported mortality, the change of EuroQol Group 5-Dmensional Self-report Questionnaire (EQ-5D) US index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), or serious adverse events (SAEs). Relative risk or weight mean difference (WMD) was estimated using fixed effect model or random effect model. Analysis of sensitivity and publication bias was conducted.Results:Five trials with a total of 1200 patients were included. sGC stimulators had no impact on the mortality (1.25; 95% confidence interval 0.50–3.11) and significantly improved EQ-5D US index (0.04; 95% confidence interval 0.020–0.05). Furthermore, in comparison with control group, NT-proBNP was statistically decreased in riociguat group (−0.78; 95% confidence interval −1.01 to −0.47), but not in vericiguat group (0.04, 95% confidence interval −0.18 to 0.25). There were not obverse differences in SAEs between sGC stimulators and control groups (0.90; 95% confidence interval 0.72–1.12).Conclusion:Our meta-analysis suggests that sGC stimulators could improve the quality of life in patients with heart failure with good tolerance and safety, but their long-term benefits need to be observed in the future. sGC stimulators are likely to be promising add-on strategies for the treatment of heart failure.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

This is the first update of the review published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2018: Cochrane Hypertension Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. We included randomized controlled trials (RCTs) that included more than 50 participants per group and provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard targets for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. We included six RCTs that involved a total of 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data.We found no change in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; moderate-quality evidence). Similarly, we found no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; low-quality evidence). Studies reported more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower target group by 8.9/4.5 mmHg. More drugs were needed in the lower target group, but blood pressure targets were achieved more frequently in the standard target group. We found no evidence of a difference in total mortality, serious adverse events, or total cardiovascular events between people with hypertension and cardiovascular disease treated to a lower or to a standard blood pressure target. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on adverse events, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to examine this topic.

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia.

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma‐derived C3A cells express anti‐inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End‐Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3‐5 days of continuous ELAD treatment plus SOC. After a minimum follow‐up of 91 days, overall survival (OS) was assessed by using a Kaplan‐Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent‐to‐treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380–393 2018 AASLD.

1-Year Results of a Multicenter Randomized Controlled Trial Comparing Heparin-Bonded Endoluminal to Femoropopliteal Bypass

ObjectivesThis study sought to compare heparin-bonded endografts with femoropopliteal bypass, including quality of life, using general health and disease-specific questionnaires as well as patency rates. BackgroundEndovascular treatment continues to advance and is gaining acceptance as primary treatment for long occlusive or stenotic lesions in the superficial femoral artery. Heparin-bonded expanded polytetrafluoroethylene endografts have been related to outcomes comparable to bypass surgery, but this has not been tested in a randomized fashion. MethodsA multicenter randomized-controlled trial was performed comparing femoropopliteal bypass with heparin-bonded expanded polytetrafluoroethylene endografts. Data were analyzed on an intention-to-treat and per-protocol manner. ResultsA total of 129 patients were randomized and 125 patients were treated, 63 in the endoluminal and 62 in the surgical group (42 venous, 20 prosthetic). Enrollment was terminated before reaching the predefined target number for patency. Baseline characteristics and anatomical data were similar. Patients were treated for critical limb ischemia in 38.1% and 32.2% in the endoluminal and surgical arms, respectively. Mean lesion length was 23 cm in both groups and lesions were largely TransAtlantic Inter-Society Consensus II D. Hospitalization time and 30-day morbidity were significantly lower in the endoluminal group, without differences in serious adverse events (n = 5 each; surgical: 4 venous and 1 polytetrafluoroethylene bypass). There were no significant differences in Rutherford category between groups at any time point. At 30 days the endoluminal group showed a greater improvement in quality-of-life scores. At 1 year, these differences had largely disappeared and no differences in primary (endoluminal: 64.8%; surgical: 63.6%), assisted primary (endoluminal: 78.1%; surgical: 79.8%), secondary patency (endoluminal: 85.9%; surgical: 83.3%), and target vessel revascularization (endoluminal: 72.1%; surgical: 71.0%) were observed. Limb salvage rate was 100% in both groups. ConclusionsHeparin-bonded endoluminal bypass for long segment lesions shows promising results (less morbidity, faster recovery, and improvement in quality of life with indistinguishable patency rates at 1 year) compared with surgical bypass. Long-term results have to be awaited.