Efficacy and safety of iGlarLixi versus IDegAsp: Results of a systematic literature review and indirect treatment comparison.

AIM: To assess the efficacy and safety of iGlarLixi, a fixed-ratio combination of basal insulin glargine 100 U/mL and lixisenatide (glucagon-like peptide-1 receptor agonist) versus IDegAsp, a co-formulation of basal insulin degludec 100 U/mL with rapid-acting insulin aspart. MATERIALS AND METHODS: A systematic literature search of randomized controlled trials (RCTs) was performed. Outcomes from eligible RCTs were compared by an indirect treatment comparison using a Bayesian framework. Subanalyses of Japanese and international trials were performed. RESULTS: Eight RCTs (duration 26-30 weeks) were included. Mean difference in HbA1c change with iGlarLixi exceeded that for IDegAsp: -0.64 (95% credible interval -1.01, -0.28) %-units (-7.0 [-11.0, -3.1] mmol/mol) for all trials, -0.39 (-0.55, -0.23) %-units (-4.3 [-6.0, -2.5] mmol/mol) for international, and -0.88 (-1.11, -0.64) %-units (-9.6 [-12.1, -7.0] mmol/mol) for Japanese trials. HbA1c target achievement (<7.0%-units [<53 mmol/mol]) was greater for iGlarLixi in all trials (odds ratio 2.50 [1.06, 5.56]) and Japanese trials (2.17 [1.27, 3.70]), but not in international trials (2.17 [0.42, 11.11]). Analyses suggesting differences in mean postmeal self-measured plasma glucose were significantly lower by 1.0-2.0 mmol/L (18-36 mg/dL) with iGlarLixi in all analyses. Bodyweight change was more favourable (1-2 kg) for iGlarLixi versus IDegAsp for all analyses (P < 0.05). Comparisons of hypoglycaemia were inconclusive owing to differences in definitions between studies. Adverse events were more frequent with iGlarLixi because of gastrointestinal intolerance. CONCLUSIONS: iGlarLixi appears to offer clinical benefit in glucose control and bodyweight change in people needing both basal and meal-time intervention.

Efficacy and safety of iGlarLixi versus IDegLira in adults with type 2 diabetes inadequately controlled by glucagon-like peptide-1 receptor agonists: a systematic literature review and indirect treatment comparison.

AIMS: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. MATERIALS AND METHODS: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. RESULTS: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was -0.36 (95% credible intervals -0.58, -0.14) % [-3.9 (-6.3, -1.5) mmol/mol] for HbA1c and -1.0 (-1.6, -0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial self-monitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). CONCLUSIONS: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches.

Efficacy and Safety of Patient-controlled Analgesia Compared With Epidural Analgesia After Open Hepatic Resection: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the efficacy and safety of patient-controlled analgesia (PCA) to epidural analgesia in adults undergoing open hepatic resection. BACKGROUND: Effective pain management in patients undergoing open hepatic resection is often achieved with epidural analgesia. However, associated risks have prompted investigation of alternative analgesic methods in this patient population. METHODS: A comprehensive systematic literature review via Medline, Embase, and the Cochrane databases from inception until December 2, 2017 was conducted, followed by meta-analysis. Abstract and full-text screening, data extraction, and quality assessment were conducted by 2 investigators. Odds ratios (OR), mean differences (MD), and 95% confidence intervals were calculated using RevMan 5.3. RESULTS: Four randomized controlled trials with 278 patients were identified. All studies compared the use of PCA to epidural, with differing regimens. Pooled MD and 95% confidence interval for pain score were higher for PCA at rest 24 hours postoperatively (0.59 [0.30, 0.88]), and with movement at 48 hours postoperatively (0.95 [0.31, 1.60]. Pooled MD for hospital length of stay was 1.23 days (-2.72, 5.19). Pooled OR was 0.68 (0.36, 1.3) and 0.24 (0.04, 1.36) for overall and analgesia-related complications, respectively. Need for blood transfusion had a pooled OR of 1.14 (0.31, 4.18). CONCLUSIONS: Epidural analgesia was observed to be superior to PCA for pain control in patients undergoing open hepatic resection, with no significant difference in hospital length of stay, complications, or transfusion requirements. Thus, epidural analgesia should be the preferred method for the management of postoperative pain in this patient population.

Humanistic burden of pediatric type 1 diabetes on children and informal caregivers: systematic literature reviews.

BACKGROUND: Diagnosis of children with type 1 diabetes (T1D) imposes an unprecedented burden on children and their caregivers. OBJECTIVE: To assess the burden of T1D on children and their informal caregivers, both after a recent diagnosis or after a longer duration of disease. METHODS: A series of systematic literature reviews were performed to explore the burden of T1D on children with the disease and their primary informal caregivers, based on the time of diagnosis. After the extraction of the qualitative and quantitative data from the included studies, two literature-based conceptual frameworks were developed: on the burden of pediatric T1D on children, and on informal caregivers. A third conceptual framework on the shared burden of pediatric T1D on both children and informal caregivers as part of the same family unit was also developed. RESULTS: The review of literature has identified a series of factors that affect the quality of life of children with T1D and their informal caregivers, with a direct impact on physical, emotional, and social outcomes. Generally, female patients and older adolescents experience more worry and stress that affects their quality of life. Other categories of factors affecting the child's and caregiver's burden include social, emotional, and physical factors, treatment-related and disease-related factors, as well as their coping abilities. Anxiety, depression, stress, and worry were commonly found among children and caregivers, starting with the diagnosis of T1D and continuing over time in relation to new challenges pertaining to aging or the disease duration. CONCLUSION: T1D causes a significant burden to affected children and their caregivers, both independently and through transactional interaction within the family unit. Disease burden can be reduced by strengthening individuals for the benefit of the whole family.

Disease-free survival as a surrogate endpoint for overall survival in adults with resectable esophageal or gastroesophageal junction cancer: A correlation meta-analysis.

OBJECTIVES: To evaluate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) using aggregate-level data from resectable esophageal or gastroesophageal junction cancer (EC/GEJC) trials assessing therapies in (neo)adjuvant and perioperative settings. METHODS: A systematic literature review was conducted to identify trials reporting OS and DFS, or compatible progression-free survival (PFS). Bivariate random-effects meta-analysis was used to estimate correlation between the treatment effects on DFS/PFS and OS, and weighted linear regression models assuming trial sample sizes as weights were used to estimate surrogacy equations. The primary analysis consisted of trials across all treatment settings, and secondary analysis consisted of trials only in the adjuvant setting. Leave-one-out cross-validation (LOOCV) was performed to measure the stability and predictive accuracy of the surrogacy equations while surrogate threshold effects (STE)-the minimum treatment effect on DFS/PFS that would translate into a positive OS benefit-were derived to measure their usefulness. RESULTS: The primary analysis included 26 trials. The estimated correlation coefficient between the hazard ratio (HR) of DFS/PFS (HRDFS/PFS) and HR of OS (HROS) was 0.83 (95% confidence interval [CI]: 0.70-0.90). The estimated surrogacy equation was log(HROS) = 0.80 × log(HRDFS/PFS) with a corresponding STE of 0.82. Reported HROS was within the 95% prediction interval of the predicted HROS from the model for more than 95% of the trials in the LOOCV, indicating a valid model. Secondary analysis included 7 trials with an estimated correlation coefficient of 0.76 (95% CI: 0.18-0.95). Through LOOCV, the surrogacy equation in the adjuvant setting was deemed valid. CONCLUSIONS: Our meta-analysis suggests that HRDFS/PFS -where DFS/PFS is defined as time from resection to disease recurrence (local, locoregional, or distant) or death-is correlated to HROS, and a valid and useful surrogate predictor for HROS in the neoadjuvant, perioperative, or adjuvant settings.

Perspectives of Persons With Arthritis on the Use of Wearable Technology to Self Monitor Physical Activity: A Qualitative Evidence Synthesis.

OBJECTIVE: We aimed to broaden understanding of the perspectives of persons with arthritis on their use of wearables to self-monitor physical activity, through a synthesis of evidence from qualitative studies. METHODS: We conducted a systematic search of 5 databases (including Medline, CINAHL, and Embase) from inception to 2018. Eligible studies qualitatively examined the use of wearables from the perspectives of persons with arthritis. All relevant data were extracted and coded inductively in a thematic synthesis. RESULTS: Of 4,358 records retrieved, 7 articles were included. Participants used a wearable during research participation in 3 studies and as part of usual self-management in 2 studies. In remaining studies, participants were shown a prototype they did not use. Themes identified were: 1) the potential to change dynamics in patient-health professional communication: articles reported a common opinion that sharing wearable data could possibly enable patients to improve communication with health professionals; 2) wearable-enabled self-awareness, whether a benefit or downside: there was agreement that wearables could increase self-awareness of physical activity levels, but perspectives were mixed on whether this increased self-awareness motivated more physical activity; 3) designing a wearable for everyday life: participants generally felt that the technology was not obtrusive in their everyday lives, but certain prototypes may possibly embarrass or stigmatize persons with arthritis. CONCLUSION: Themes hint toward an ethical dimension, as participants perceive that their use of wearables may positively or negatively influence their capacity to shape their everyday self-management. We suggest ethical questions pertinent to the use of wearables in arthritis self-management for further exploration.

Health state utility values by cancer stage: a systematic literature review.

OBJECTIVES: Cancer diagnoses at later stages are associated with a decrease in health-related quality of life (HRQOL). Health state utility values (HSUVs) reflect preference-based HRQOL and can vary based on cancer type, stage, treatment, and disease progression. Detecting and treating cancer at earlier stages may lead to improved HRQOL, which is important for value assessments. We describe published HSUVs by cancer type and stage. METHODS: A systematic review was conducted using Embase, MEDLINE®, EconLit, and gray literature to identify studies published from January 1999 to September 2019 that reported HSUVs by cancer type and stage. Disutility values were calculated from differences in reported HSUVs across cancer stages. RESULTS: From 13,872 publications, 27 were eligible for evidence synthesis. The most frequent cancer types were breast (n = 9), lung (n = 5), colorectal (n = 4), and cervical cancer (n = 3). Mean HSUVs decreased with increased cancer stage, with consistently lower values seen in stage IV or later-stage cancer across studies (e.g., - 0.74, - 0.44, and - 0.51 for breast, colorectal, and cervical cancer, respectively). Disutility values were highest between later-stage (metastatic or stage IV) cancers compared to earlier-stage (localized or stage I-III) cancers. CONCLUSIONS: This study provides a summary of HSUVs across different cancer types and stages that can inform economic evaluations. Despite the large variation in HSUVs overall, a consistent decline in HSUVs can be seen in the later stages, including stage IV. These findings indicate substantial impairment on individuals' quality of life and suggest value in early detection and intervention.

Cardiovascular Disease in Rheumatoid Arthritis: Risk Factors, Autoantibodies, and the Effect of Antirheumatic Therapies.

OBJECTIVE: To scope the current published evidence on cardiovascular risk factors in rheumatoid arthritis (RA) focusing on the role of autoantibodies and the effect of antirheumatic agents. METHODS: Two reviews were conducted in parallel: A targeted literature review (TLR) describing the risk factors associated with cardiovascular disease (CVD) in RA patients; and a systematic literature review (SLR) identifying and characterizing the association between autoantibody status and CVD risk in RA. A narrative synthesis of the evidence was carried out. RESULTS: A total of 69 publications (49 in the TLR and 20 in the SLR) were included in the qualitative evidence synthesis. The most prevalent topic related to CVD risks in RA was inflammation as a shared mechanism behind both RA morbidity and atherosclerotic processes. Published evidence indicated that most of RA patients already had significant CV pathologies at the time of diagnosis, suggesting subclinical CVD may be developing before patients become symptomatic. Four types of autoantibodies (rheumatoid factor, anti-citrullinated peptide antibodies, anti-phospholipid autoantibodies, anti-lipoprotein autoantibodies) showed increased risk of specific cardiovascular events, such as higher risk of cardiovascular death in rheumatoid factor positive patients and higher risk of thrombosis in anti-phospholipid autoantibody positive patients. CONCLUSION: Autoantibodies appear to increase CVD risk; however, the magnitude of the increase and the types of CVD outcomes affected are still unclear. Prospective studies with larger populations are required to further understand and quantify the association, including the causal pathway, between specific risk factors and CVD outcomes in RA patients.

Efficacy and Safety of Hylan G-F 20 Versus Intra-Articular Corticosteroids in People with Knee Osteoarthritis: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Direct injection of corticosteroids into the joint is a standard treatment for knee osteoarthritis (OA). However, the treatment is somewhat controversial with regard to the benefit of both single and repeated injections; evidence that they are beneficial comes from small studies that show only modest improvements. The aim of this study was to estimate the short- and long-term clinical efficacy and safety of hylan G-F 20 versus intra-articular corticosteroids (IACS) for the treatment of pain in knee OA using Bayesian network meta-analysis. METHODS: Based on a pre-specified protocol, MEDLINE, Embase, and CENTRAL were searched from inception to June 2018 to identify randomized controlled trials. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used to assess the included studies. Hylan G-F 20 and IACS were compared using Bayesian network meta-analysis. Efficacy was evaluated at 1, 3, and 6 months, and at the final follow-up for safety outcomes. A pain hierarchy was used to select 1 pain outcome per study. RESULTS: Forty-two trials were included for analysis. The network meta-analysis of pain showed that hylan G-F 20 may be equivalent to IACS in the short-term, but by 6 months the benefit relative to IACS was statistically significant, standardized mean difference (95% credible interval): -0.13 (-0.26, -0.01). There were no statistical differences in adverse events. CONCLUSIONS: Hylan G-F 20 may perform better in relieving pain at 6 months post-injection compared to IACS. Both agents were relatively well tolerated, with no clear differences in safety.

The Effect of Massage on the Cardiac Autonomic Nervous System and Markers of Inflammation in Night Shift Workers: a Pilot Randomized Crossover Trial.

BACKGROUND: Shift work is a necessary part of many industries; however, it can have detrimental effects on health over time. PURPOSE: This study investigated the effect of a massage intervention on the cardiac autonomic activity and blood inflammatory markers of healthy medical residents working night shifts. SETTING: This trial was conducted at British Columbia Children's and Women's Hospital between February 2014 and June 2016. PARTICIPANTS: Included participants were generally healthy medical residents and were working rotating night shifts on a regular basis. RESEARCH DESIGN: This was a randomized, controlled, crossover, open-label trial (NCT02247089). INTERVENTIONS: Participants received either a 30-min massage intervention or reading control after consecutive periods of night shift. MAIN OUTCOME MEASURES: The primary outcome was high frequency, a proxy for the cardiac parasympathetic activity, measured via heart rate variability. Secondary outcomes included other heart rate variability measures, blood markers of inflammation, and blood pressure. RESULTS: Twelve participants were recruited (nine female) with median age of 28 years. There was no significant difference between the massage intervention and the reading control for the primary outcome, (median relative change between pre- and postmassage [interquartile range]: 62% [-1 to 150], pre- and postreading: 14% [-10 to 51], p = .16). Similarly, there was no difference with respect to blood inflammatory markers and blood pressure. Median high frequency significantly increased between pre- and postmassage (185 vs. 358 ms2, p = .04). CONCLUSION: This pilot study found no statistically significant difference between the massage intervention and the reading control; however, we did observe a significant increase in median high frequency from before massage to after massage, indicative of increased parasympathetic activity. This study may help inform planning of larger trials evaluating massage interventions on the activity of the autonomic nervous system and managing shift work stress.

The effects of antimuscarinic agents on the activity of the cardiac autonomic nervous system in children with functional overactive bladder.

BACKGROUND: Functional overactive bladder disorder is one of the most prevalent presentations of bladder and bowel dysfunction in children, and it is associated with lower overall cardiac autonomic and parasympathetic activity. Antimuscarinics are the most frequently used pharmacological agents for treatment of children with functional overactive bladder disorder; however, there is a gap in the literature in describing the effect of antimuscarinics on the autonomic profile of this population. OBJECTIVE: The aim of the study was to assess the cardiac parasympathetic activity before and after 12 weeks of oxybutynin treatment in children with overactive bladder. METHODS: This was a single-institution prospective cohort study. Cardiac autonomic activity was assessed during storage and voiding phases of the bladder function via spectral analysis of heart rate variability and impedance cardiography. The primary outcome measure was high frequency, a proxy for parasympathetic nervous system activity. Parameters of uroflow study, severity of symptoms, and quality of life outcomes were also assessed. RESULTS: Ten children (7 females) diagnosed with overactive bladder with a median age of 10 years (range = 6-14) were followed up for a median treatment duration of 11.8 weeks (range = 6-19.4). After treatment, there was a significant reduction in high frequency during the storage phase (median change = -24.17%, p = 0.047). No change was observed in the other outcome measures except for the overall Symptom Score for Dysfunctional Elimination Syndrome after treatment (5-point decrease, p = 0.034) (Summary Table). DISCUSSION: The findings of the present follow-up study suggest that the use of oxybutynin in children with overactive bladder is associated with a significant reduction in the activity of the parasympathetic nervous system. The clinical implications of this finding are important because similar autonomic profiles (as markers of chronic stress) have been shown to be associated with increased inflammation and are found in major chronic diseases. The authors caution making a clinical connection between the heart rate variability profile of the patients in this study and patients with chronic diseases because oxybutynin is usually not administered as long-term treatment for overactive bladder. CONCLUSION: Use of oxybutynin was associated with reduction in cardiac parasympathetic activity of children with functional overactive bladder. Further investigation into the role of the autonomic nervous system as a treatment target in the management of these children is warranted.

The Effect of Head Massage on the Regulation of the Cardiac Autonomic Nervous System: A Pilot Randomized Crossover Trial.

OBJECTIVES: To evaluate the effect of a single 10-minute session of Chinese head massage on the activity of the cardiac autonomic nervous system via measurement of heart rate variability (HRV). DESIGN: In this pilot randomized crossover trial, each participant received both head massage and the control intervention in a randomized fashion. SETTINGS/LOCATION: The study was conducted at Children's & Women's Health Centre of British Columbia between June and November 2014. PARTICIPANTS: Ten otherwise healthy adults (6 men and 4 women) were enrolled in this study. INTERVENTIONS: The intervention comprised 10 minutes of head massage therapy (HMT) in a seated position compared with a control intervention of sitting quietly on the same chair with eyes closed for an equal amount of time (no HMT). OUTCOME MEASURES: The primary outcome measures were the main parameters of HRV, including total power (TP), high frequency (HF), HF as a normalized unit, pre-ejection period, and heart rate (HR). RESULTS: A single short session (10 minutes) of head massage demonstrated an increase in TP continuing up to 20 minutes after massage and reaching statistical significance at 10 minutes after massage (relative change from baseline, 66% for HMT versus -6.6% for no HMT; p = 0.017). The effect on HF also peaked up to 10 minutes after massage (59.4% for HMT versus 4% for no HMT; p = 0.139). Receiving head massage also decreased HR by more than three-fold compared to the control intervention. CONCLUSION: This study shows the potential benefits of head massage by modulating the cardiac autonomic nervous system through an increase in the total variability and a shift toward higher parasympathetic nervous system activity. Randomized controlled trials with larger sample size and multiple sessions of massage are needed to substantiate these findings.