Vagus nerve stimulation (VNS) therapy in patients with treatment resistant depression: A systematic review and meta-analysis.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is approved for treatment-resistant depression (TRD). A recent 5-year comparative study prompted this review of its impact in this very severe population. Previous systematic literature reviews (SLR) cited concerns in terms of missing studies or patient duplication. METHODS: This SLR addressed these criticisms, assessed all outcomes of longer-term adjunctive VNS in all studies, irrespective of TRD severity, comparing where feasible with treatment-as-usual (TAU). We searched for adult VNS+TAU studies (January 1, 2000 to June 24, 2019). Comparative and single-arm studies were eligible. All reported efficacy, safety and quality of life (QOL) outcomes were assessed. Where possible, meta-analysis was used to calculate overall pooled effect estimates across studies at several time points. RESULTS: Of 22 identified studies, there were two randomized controlled (RCT), sixteen single-arm and four non-randomized comparative studies. Numerous depression-specific, safety and QOL measures were reported. Meta-analysis was possible for three efficacy [Montgomery-Asberg Depression Rating Scale, Clinician Global Impression-Improvement, Hamilton Rating Scale for Depression] and three safety [serious adverse events, study drop-outs and all-cause mortality] but no QOL measures. Data beyond 2 years was not poolable. Analyses demonstrated that antidepressant benefits improved to 24 months and safety issues were minimal. Heterogeneity was high and statistically significant. CONCLUSIONS: Despite limitations in the evidence base, our comprehensive summary of VNS+TAU outcomes suggests that this treatment provides improving benefit and hope for this very hard-to-treat chronic population. More comparative TRD studies should describe safety and QOL.

Systematic review of the epidemiology of urinary incontinence and detrusor overactivity among patients with neurogenic overactive bladder.

BACKGROUND: The prevalence and incidence of neurogenic overactive bladder (nOAB) are poorly defined. This systematic literature review identified nOAB epidemiological data and estimated the incidence and prevalence of urinary incontinence (UI) and detrusor overactivity (DO) in patients with multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD), stroke and spina bifida. An initial search of MEDLINE, Embase, PubMed, and the Cochrane library was supplemented by an internet search for grey literature and manual searching of the bibliographies of retrieved articles. Additional study selection identified comparable studies for statistical analysis. A descriptive statistical analysis, single-arm meta-analysis and stratified analysis were conducted using predefined criteria. SUMMARY: Initial selection identified 189 articles containing prevalence data. Secondary selection for statistical analysis identified 39 and 52 articles with prevalence of UI and DO, respectively. Random-effect meta-analysis found the prevalence of UI was 50.9% in patients with MS, 52.3% with SCI, 33.1% with PD and 23.6% with stroke. Spina bifida was excluded due to insufficient data. The prevalence of DO may be biased and artificially elevated because it can only be measured with urodynamic investigations. KEY MESSAGES: A substantial proportion of patients with neurological conditions develop UI that may be attributable to nOAB.

A cost analysis of robotic vs. video-assisted thoracic surgery: The impact of the learning curve and the COVID-19 pandemic.

Introduction: Robot-assisted thoracoscopic surgery (RATS) is an alternative to video-assessed thoracoscopic surgery (VATS) for the treatment of lung cancer but concern exists regarding the high associated costs. The COVID-19 pandemic added further financial pressure to healthcare systems. This study investigated the impact of the learning curve on the cost-effectiveness of RATS lung resection and the financial impact of the COVID-19 pandemic on a RATS program. Methods: Patients undergoing RATS lung resection between January 2017 and December 2020 were prospectively followed. A matched cohort of VATS cases were analyzed in parallel. The first 100 and most recent 100 RATS cases performed at our institution were compared to assess the learning curve. Cases performed before and after March 2020 were compared to assess the impact of the COVID-19 pandemic. A comprehensive cost analysis of multiple theatre and postoperative data points was performed using Stata statistics package (v14.2). Results: 365 RATS cases were included. Median cost per procedure was £7,167 and theatre cost accounted for 70%. Major contributing factors to overall cost were operative time and postoperative length of stay. Cost per case was £640 less after passing the learning curve (p < 0.001) largely due to reduced operative time. Comparison of a post-learning curve RATS subgroup matched to 101 VATS cases revealed no significant difference in theatre costs between the two techniques. Overall cost of RATS lung resections performed before and during the COVID-19 pandemic were not significantly different. However, theatre costs were significantly cheaper (£620/case; p < 0.001) and postoperative costs were significantly more expensive (£1,221/case; p = 0.018) during the pandemic. Discussion: Passing the learning curve is associated with a significant reduction in the theatre costs associated with RATS lung resection and is comparable with the cost of VATS. This study may underestimate the true cost benefit of passing the learning curve due to the effect of the COVID-19 pandemic on theatre costs. The COVID-19 pandemic made RATS lung resection more expensive due to prolonged hospital stay and increased readmission rate. The present study offers some evidence that the initial increased costs associated with RATS lung resection may be gradually offset as a program progresses.

Targeted systemic therapies for psoriatic arthritis: a systematic review and comparative synthesis of short-term articular, dermatological, enthesitis and dactylitis outcomes.

INTRODUCTION: Randomised controlled trials (RCTs) have compared biological and targeted systemic disease-modifying antirheumatic drugs (DMARDS) against placebo in psoriatic arthritis (PsA); few have compared them head to head. OBJECTIVES: To compare the efficacy and safety of all evaluated DMARDs for active PsA, with a special focus on biological DMARDs (bDMARDs) licensed for PsA or psoriasis. METHODS: A systematic review identified RCTs and Bayesian network meta-analysis (NMA) compared treatments on efficacy (American College of Rheumatology (ACR) response, Psoriasis Area and Severity Index (PASI) response, resolution of enthesitis and dactylitis) and safety (patients discontinuing due to adverse events (DAE)) outcomes. Subgroup analyses explored ACR response among patients with and without prior biological therapy exposure. RESULTS: The NMA included 46 studies. Results indicate that some tumour necrosis factor inhibitors (anti-TNFs) may perform numerically, but not significantly, better than interleukin (IL) inhibitors on ACR response but perform worse on PASI response. Few significant differences between bDMARDs on ACR response were observed after subgrouping for prior bDMARD exposure. Guselkumab and IL-17A or IL-17RA inhibitors-brodalumab, ixekizumab, secukinumab-were best on PASI response. These IL-inhibitors and adalimumab were similarly efficacious on resolution of enthesitis and dactylitis. Infliximab with and without methotrexate, certolizumab 400 mg every 4 weeks and tildrakizumab showed the highest rates of DAE; abatacept, golimumab and the IL-inhibitors, the lowest. CONCLUSIONS: Despite similar efficacy for ACR response, IL-17A and IL-17RA inhibitors and guselkumab offered preferential efficacy to anti-TNFs in skin manifestations, and for enthesitis and dactylitis, thereby supporting drug selection based on predominant clinical phenotype.

A meta-analysis of placebo-controlled clinical trials assessing the efficacy and safety of incretin-based medications in patients with type 2 diabetes.

AIMS: A systematic review of the literature, in combination with a meta-analysis of randomized controlled trials comparing treatments with placebo, was conducted to provide an update on the clinical efficacy and safety of incretin-based medications in adult patients with type 2 diabetes. METHODS: A literature search (2000-2009) identified 38 placebo-controlled trials (phase II or later - parallel design) comparing exenatide (n = 8), liraglutide (n = 7), vildagliptin (n = 11) and sitagliptin (n = 12) with placebo. Outcomes were change from baseline in HbA(1c) and in weight, and the number of patient-reported hypoglycemic episodes. HbA(1c) and weight outcomes were analyzed as weighted mean differences (WMD), and the number of hypoglycemic episodes as relative risks (RR). RESULTS: Patients receiving liraglutide showed greater reduction in HbA(1c) in comparison to placebo (WMD = -1.03, 95% confidence interval, CI = -1.16 to -0.90, p < 0.001) than those on sitagliptin (WMD = -0.79, 95% CI = -0.93 to -0.65, p < 0.001), exenatide (WMD = -0.75, 95% CI = -0.83 to -0.67, p < 0.001) or vildagliptin (WMD = -0.67, 95% CI = -0.83 to -0.52, p < 0.001). Weight was statistically significantly negatively associated with exenatide (WMD = -1.10, 95% CI = -1.32 to -0.87, p < 0.001) and positively associated with sitagliptin (WMD = 0.60, 95% CI = 0.33-0.87, p < 0.001) and vildagliptin (WMD = 0.56, 95% CI = 0.27-0.84, p < 0.001). The number of patient-reported hypoglycemic episodes was statistically significantly associated with the use of sitagliptin (RR = 2.56, 95% CI = 1.23-5.33, p = 0.01) and exenatide (RR = 2.40, 95% CI = 1.30-4.11, p = 0.002). CONCLUSION: Incretin-based therapies are effective in glycemic control and also offer other advantages such as weight loss (exenatide and liraglutide). This may have an important impact on patient adherence to medication.

Influence of Idiopathic Pulmonary Fibrosis Progression on Healthcare Resource Use.

BACKGROUND: Disease progression and acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF) are associated with high morbidity and mortality. They usually require a visit to a specialist or a general practitioner (GP) in less severe cases or hospitalisation in more severe cases. OBJECTIVE: The objective of this study was to identify factors that influence resource use in IPF. METHODS: Clinical and healthcare resource use data were collected in two large, international, multi-centre, randomised controlled trials (RCTs) that studied nintedanib for the treatment of IPF (INPULSIS-1 and -2). The pooled data of nintedanib and placebo included 1014 patients followed for 12 months. The trial data were analysed in 3-month intervals. We studied two dependent variables: the occurrence of all-cause hospitalisation and visits to a physician (GP or specialist). The independent variables included the change in forced vital capacity percent predicted (FVC%pred), investigator-reported acute exacerbation events, age, time since diagnosis, smoking status, and sex. RESULTS: Hospitalisation during a 3-month interval was significantly associated with a drop of at least 5 or 10 points in FVC%pred (odds ratios [ORs] 1.58 [p = 0.009] and 2.62 [p < 0.001]) and associated with the occurrence of at least one acute exacerbation (OR 14.44; p < 0.001) during the same interval. The above factors remained significant when repeating the analysis for hospitalisation based on change in FVC%pred or events occurring during the previous 3 months interval. Smoker status and a unit change in FVC%pred during the previous interval were added to the significant factors. Physician visits during a 3-month interval were significantly associated with a lower FVC%pred at the start of the interval (per 10-point decrement, OR 1.05; p = 0.040) and with the change in FVC%pred during the same interval (per 10-point loss, OR 1.13; p = 0.042). Visits were also associated with a 5-point drop in FVC%pred (OR 1.23; p = 0.020), age (per 5-year increments OR 1.07; p = 0.028), and female sex (OR 1.32; p = 0.017). Nevertheless, the predictive power of the models was considered poor for both outcomes (hospitalisation and physician visits). CONCLUSIONS: Disease progression and acute exacerbation events are significantly associated with hospitalisation of patients with IPF. Outpatient visits to physicians are associated with disease progression, baseline FVC%pred, age and sex.

Tofacitinib for the treatment of moderately to severely active ulcerative colitis: a systematic review, network meta-analysis and economic evaluation.

BACKGROUND AND AIMS: In the UK, treatments for patients with moderately to severely active ulcerative colitis who have an inadequate response to conventional therapies comprise four biological therapies-the tumour necrosis factor inhibitor (TNFi) agents adalimumab, golimumab and infliximab and the anti-integrin vedolizumab-and an orally administered small molecule therapy, tofacitinib. However, there have been few head-to-head studies of these therapies. This study aimed to compare the clinical and cost-effectiveness of tofacitinib with biological therapies. METHODS: A systematic literature review was conducted to identify all relevant randomised controlled trial (RCT) evidence. Clinical response, clinical remission and serious infection rates were synthesised using network meta-analysis (NMA). The results were used to compare the cost-effectiveness of tofacitinib and biologics with conventional therapy, using a Markov model, which incorporated lifetime costs and consequences of treatment from a UK National Health Service perspective. Analyses were conducted separately for TNFi-naïve and TNFi-exposed populations. RESULTS: Seventeen RCTs were used in the NMAs. There were no statistically significant differences among biological therapies and tofacitinib for either TNFi-naïve or TNFi-exposed patients. In TNFi-naïve patients, all therapies were more efficacious than placebo. In TNFi-exposed patients, only tofacitinib was significantly more efficacious than placebo as induction therapy, and only tofacitinib and vedolizumab were significantly more efficacious than placebo as maintenance therapies. There were no significant differences in serious infection rates among therapies. The incremental cost-effectiveness ratios for tofacitinib versus conventional therapy were £21 338 and £22 816 per quality-adjusted life year (QALY) in the TNFi-naïve and TNFi-exposed populations, respectively. TNFi therapies were dominated or extendedly dominated in both populations. Compared with vedolizumab, tofacitinib was associated with a similar number of QALYs, at a lower cost. CONCLUSION: Tofacitinib is an efficacious treatment for moderately to severely active ulcerative colitis and is likely to be a cost-effective use of NHS resources.

Indirect comparison of once daily insulin detemir and glargine in reducing weight gain and hypoglycaemic episodes when administered in addition to conventional oral anti-diabetic therapy in patients with type-2 diabetes.

AIMS: Basal insulin administered to type-2 diabetic patients with poor glycaemic control when managed with oral anti-diabetics (OADs) alone can lead to an increased risk of weight gain and hypoglycaemia. In the absence of head-to-head trials, an indirect comparison of the once-daily insulin detemir with insulin glargine was conducted on the following outcomes: weight gain, hypoglycaemic episodes, and HbA(1c). METHODS: Parallel-group randomised controlled trials of at least 20 weeks duration that compared once-daily evening glargine or detemir with a common comparator, neutral protamine Hagedorn insulin (evening), were selected. Trials focused on insulin-naïve, type-2 diabetic patients poorly controlled with OAD. Five open-label trials were identified (n = 2,092 patients; n = 1 detemir and n = 4 glargine trials), with an indirect comparison of glargine (n = 869 patients) and detemir trials (n = 169 patients) carried out using meta-regression to control for covariates. Weight gain was analysed as weighted mean differences (WMD), hypoglycaemic episodes as odds ratios (OR), and HbA(1c) at the end of study as standardised mean differences (SMD). RESULTS: Patients receiving evening detemir gained significantly less weight (unadjusted WMD -1.22 kg, 95% CI -2.15, -0.29 kg; p = 0.010) and significantly fewer of them experienced hypoglycaemic episodes versus evening glargine (unadjusted OR 0.52, 95% CI 0.28, 0.98; p = 0.044). There was no significant difference between treatments for the mean HbA(1c) level at study endpoint (unadjusted SMD 0.09, 95% CI -0.16, 0.33; p = 0.480). CONCLUSIONS: Once-daily use of insulin detemir resulted in significantly less weight gain and fewer hypoglycaemic episodes than glargine, while maintaining clinically appropriate HbA(1c) levels in type-2 diabetic patients currently receiving OAD.

Cerebrovascular events post-transcatheter aortic valve replacement in a large cohort of patients: a FRANCE-2 registry substudy.

OBJECTIVES: The aim of this study was to analyze the incidence, impact, and predictors of cerebrovascular events (CVEs) in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Several issues remain unresolved post-TAVR, including CVEs. METHODS: The FRANCE-2 (French Aortic Nation CoreValve and Edwards-2) registry prospectively included all patients who underwent TAVR in France and Monaco from January 2010 to October 2011. A total of 3,191 patients were analyzed. Six-month follow-up data were obtained. Events were adjudicated according to Valve Academic Research Consortium (VARC)-1 definition. RESULTS: Of the cohort, 3.98% experienced a CVE: 55% were major strokes, 14.5% minor strokes, and 30.5% transient ischemic attacks. The mean delay for CVE occurrence was 2 days (interquartile range: 0 to 7 days) with 48.5% of CVEs occurring within 2 days. There was no statistically significant difference in CVE rate with regard to the type of valve (p = 0.899) and the access route (p = 0.128). Patients with a CVE more frequently had new-onset paroxysmal atrial fibrillation (13.6% vs. 7.6%; p = 0.015). During follow-up, the unadjusted mortality rate was higher in patients with a CVE (26% vs. 16.5%; p = 0.002). By multivariate analysis, only advanced age (odds ratio: 1.05; 95% confidence interval: 1.02 to 1.08; p = 0.02) and having 2 valves implanted (odds ratio: 3.13; 95 confidence interval: 1.40 to 7.05; p = 0.006) were associated with a significant risk of CVEs. CONCLUSIONS: CVEs occur frequently after TAVR and are associated with an increased mortality rate. No difference exists in the CVE rate when exploring the type of valve or the access route. Advanced age and multiple valves implanted during the same procedure are predictors of CVE.

Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study.

OBJECTIVES: The purpose of this study was to evaluate the prevalence of aortic stenosis (AS) in the elderly and to estimate the current and future number of candidates for transcatheter aortic valve replacement (TAVR). BACKGROUND: Severe AS is a major cause of morbidity and mortality in the elderly. A proportion of these patients is at high or prohibitive risk for surgical aortic valve replacement, and is now considered for TAVR. METHODS: A systematic search was conducted in multiple databases, and prevalence rates of patients (>75 years) were pooled. A model was based on a second systematic literature search of studies on decision making in AS. Monte Carlo simulations were performed to estimate the number of TAVR candidates in 19 European countries and North America. RESULTS: Data from 7 studies (n = 9,723 subjects) were used. The pooled prevalence of all AS in the elderly was 12.4% (95% confidence interval [CI]: 6.6% to 18.2%), and the prevalence of severe AS was 3.4% (95% CI: 1.1% to 5.7%). Among elderly patients with severe AS, 75.6% (95% CI: 65.8% to 85.4%) were symptomatic, and 40.5% (95% CI: 35.8% to 45.1%) of these patients were not treated surgically. Of those, 40.3% (95% CI: 33.8% to 46.7%) received TAVR. Of the high-risk patients, 5.2% were TAVR candidates. Projections showed that there are approximately 189,836 (95% CI: 80,281 to 347,372) TAVR candidates in the European countries and 102,558 (95% CI: 43,612 to 187,002) in North America. Annually, there are 17,712 (95% CI: 7,590 to 32,691) new TAVR candidates in the European countries and 9,189 (95% CI: 3,898 to 16,682) in North America. CONCLUSIONS: With a pooled prevalence of 3.4%, the burden of disease among the elderly due to severe AS is substantial. Under the current indications, approximately 290,000 elderly patients with severe AS are TAVR candidates. Nearly 27,000 patients become eligible for TAVR annually.

Update on the need for a permanent pacemaker after transcatheter aortic valve implantation using the CoreValve® Accutrak™ system.

AIMS: High rates of permanent pacemaker (PPM) implantation are reported after transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve® system. The Accutrak™ catheter is designed to allow a more predictable landing zone. Little is known about the real clinical impact of this catheter. The aims of this paper were to describe the potential impact of the Accutrak™ catheter on the accuracy of positioning a 26 or 29 mm CoreValve® across the aortic annulus and its impact on the need for a pacemaker. METHODS AND RESULTS: A total of 134 patients were treated with the CoreValve® Accutrak™ system at two French centres (Lille and Toulouse). Mean age was 82.4 ± 4.7 years; logistic EuroSCORE was 24.3 ± 9.5%. Procedural success rate was 99.2%; mean depth of implantation was 4.9 mm. A final position between 0 and 6 mm was achieved in 85.8% of the patients. All-cause mortality at 30 days was 6%. The PPM implantation rate was 10.6%. Due to a limited number of events, we could not identify any predictor of need for a PPM: pre-existing right bundle branch block (RBBB) (OR 2.72 [0.63-11.87], p=ns), use of a 29 mm prosthesis (OR 2.73 [0.33-22.90], p=ns) and left ventricular septal hypertrophy (OR 2.63 [0.08-83.32], p=ns). CONCLUSIONS: In this cohort of patients treated with the CoreValve® Accutrak™ system, the incidence of permanent pacemaker implantation was low, which may be a consequence of an average small implantation depth. The Accutrak™ catheter seems to be helpful in achieving higher and more predictable implants. Operators could standardise their technique to place the CoreValve® prostheses less than 6 mm below the aortic annulus.

An indirect comparison, via enoxaparin, of rivaroxaban with dabigatran in the prevention of venous thromboembolism after hip or knee replacement.

OBJECTIVE: To compare the efficacy, in the prevention of venous thromboembolism (VTE), and safety, of rivaroxaban and dabigatran relative to the common comparator enoxaparin. METHODS: Two randomized clinical trials of dabigatran, one after total hip replacement (THR), RE-NOVATE, and one after total knee replacement (TKR), RE-MODEL, were identified as using the same enoxaparin regimen (40 mg once daily given the evening before surgery) and being of comparable duration to two rivaroxaban trials, RECORD1 and RECORD3. Indirect comparisons were performed on both efficacy and safety endpoints. To enable comparisons, symptomatic VTE results were based on the total study duration period, i.e. including the follow-up period. Major bleeding included surgical-site bleeding events. RESULTS: After THR, rivaroxaban 10 mg once daily significantly reduced total VTE and symptomatic VTE relative to dabigatran 220 mg once daily (relative risk 0.34 and 0.19, respectively). After TKR, rivaroxaban significantly reduced total VTE versus dabigatran (relative risk 0.53); symptomatic VTE was not different between dabigatran and rivaroxaban. There was no significant difference in the rates of major bleeding for patients receiving rivaroxaban or dabigatran. CONCLUSIONS: Based on the indirect comparisons, rivaroxaban was estimated to be more efficacious than dabigatran in the prevention of total VTE after THR and TKR. Our analysis relied upon published data for dabigatran and did not have the advantages of more detailed comparative data obtained directly from a randomized trial, as was the case with rivaroxaban. Further comparative research may be of value, but until available our conclusions represent the best available evidence.