Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

Vagus nerve stimulation in patients with Lennox-Gastaut syndrome: A meta-analysis.

OBJECTIVES: Lennox-Gastaut syndrome (LGS) is among the most severe epileptic and developmental encephalopathies. A meta-analysis was performed to evaluate the effectiveness of adjunctive vagus nerve stimulation (VNS Therapy) in patients with LGS. MATERIALS & METHODS: PubMed database was queried (January 1997 to September 2018) to identify publications reporting on the efficacy of VNS Therapy in patients with LGS, with or without safety findings. Primary endpoint of the meta-analysis was the proportion of responders (≥50% reduction in seizure frequency). Random-effects analysis was used to calculate weighted mean estimates and confidence intervals. Heterogeneity was evaluated by statistical tests including I2 . RESULTS: Of 2752 citations reviewed, 17 articles (480 patients) were eligible including 10 retrospective studies and seven prospective studies. A random-effects model produced a pooled proportion of 54% (95% confidence intervals [CI]: 45%, 64%) of patients with LGS who responded to adjunctive VNS Therapy (p for heterogeneity <0.001, I2 =72.9%). Per an exploratory analysis, the calculated incidence of serious adverse events associated with VNS Therapy was 9% (95% CI: 5%, 14%); the rate was higher than in long-term efficacy studies of heterogeneous cohorts with drug-resistant epilepsy and likely attributed to variable definitions of serious adverse events across studies. CONCLUSIONS: The meta-analysis of 480 patients with LGS suggests that 54% of patients responded to adjunctive VNS Therapy and that the treatment option was safe and well-tolerated. The response in patients with LGS was comparable to heterogeneous drug-resistant epilepsy populations. A clinical and surgical overview has been included to facilitate the use of VNS in LGS.

Preoperative intra-aortic balloon pump to reduce mortality in coronary artery bypass graft: a meta-analysis of randomized controlled trials.

INTRODUCTION: The intra-aortic balloon pump is routinely used in cardiac surgery; however, its impact on outcome is still a matter of debate and several randomized trials have been published recently. We perform an updated meta-analysis of randomized controlled trials that investigated the use of preoperative intra-aortic balloon pump in adult patients undergoing coronary artery bypass grafting. METHODS: Potentially eligible trials were identified by searching the Medline, Embase, Scopus, ISI Web of Knowledge and The Cochrane Library. Searches were not restricted by language or publication status and were updated in August 2014. Randomized controlled trials on preoperative intra-aortic balloon pump in patients undergoing coronary artery bypass grafting either with or without cardiopulmonary bypass were identified. The primary end point was mortality at the longest follow-up available and the secondary end point was 30-day mortality. RESULTS: The eight included randomized clinical trials enrolled 625 patients (312 to the intra-aortic balloon pump group and 313 to control). The use of intra-aortic balloon pump was associated with a significant reduction in the risk of mortality (11 of 312 (3.5%) versus 33 of 313 (11%), risk ratio = 0.38 (0.20 to 0.73), P for effect = 0.004, P for heterogeneity = 0.7, I-square = 0%, with eight studies included). The benefit on mortality reduction was confirmed restricting the analysis to trials with low risk of bias, to those reporting 30-day follow-up and to patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. CONCLUSIONS: Preoperative intra-aortic balloon pump reduces perioperative and 30-day mortality in high-risk patients undergoing elective coronary artery bypass grafting.

Application of the Bayesian network theory in clinical trial data: Severity shift in spasticity numeric rating scale in patients with multiple sclerosis.

BACKGROUND: Data digitization expands data collection opportunities, representing both a chance to understand interrelationships between variables and a challenge to identify the most appropriate clinical factors. Applications of causal inference techniques to clinical trial data is becoming very attractive, especially with the intent to provide insights into the relationships between baseline characteristics and outcomes. Graphical representations of model structures and conditional probabilities can be powerful tools to illustrate relationships in a high-dimensional data setting. METHODS: We review and apply Bayesian network theory to a clinical case study, presenting an analytical approach to investigating and visualizing causal relationships. We propose the use of the adherence score to compare data networks' patterns based on different variables' discretization. Data from adult patients with spasticity related to multiple sclerosis (MSS) from two randomized placebo-controlled clinical trials of nabiximols were used as analysis sets. The training and validation sets included 106 (53 treated, 53 placebo) and 155 (76 treated, 79 placebo) participants, respectively. The primary objective was to create a network and estimate the causal dependencies between participants' characteristics, changes in MSS severity as reflected by shifts in the patient-reported numeric rating scale (NRS), and changes in symptoms, functional abilities, and quality of life factors. RESULTS: A causal network was identified between the key factors of assigned treatment, end of study spasticity NRS, and mental health/vitality subscales of the 36-Item Short Form Health Survey questionnaire (4 nodes and 3 edges; adherence score = 93%). In patients with mild spasticity, the impact of nabiximols on mental health or vitality subscales resulted in a probability ratio of 1.63. The decomposed mediation effect of spasticity NRS was observed through a mediation analysis between treatment and mental health (99.4%) or vitality (93.7%) subscales. CONCLUSIONS: The use of innovative methods such as causal networks is highly encouraged to identify dependent relationships among key factors in clinical trial data and drive insights for additional research.

Spray-Drying Microencapsulation of Bauhinia ungulata L. var. obtusifolia Aqueous Extract Containing Phenolic Compounds: A Comparative Study Using Different Wall Materials.

Species belonging to the Bauhinia genus, usually known as "pata-de-vaca", are popularly used to treat diabetes. Bauhinia ungulata var. obtusifolia (Ducke) Vaz is among them, of which the leaves are used as a tea for medicinal purposes in the Amazon region. A microencapsulation study of lyophilized aqueous extract from Bauhinia ungulata leaves, which contain phenolic compounds, using five different wall materials (maltodextrin DE 4-7, maltodextrin DE 11-14; ß-cyclodextrin; pectin and sodium carboxymethylcellulose) is described in this paper. The microstructure, particle size distribution, thermal behavior, yield, and encapsulation efficiency were investigated and compared using different techniques. Using high-performance liquid chromatography, phenolics, and flavonoids were detected and quantified in the microparticles. The microparticles obtained with a yield and phenolics encapsulation efficiency ranging within 60-83% and 35-57%, respectively, showed a particle size distribution between 1.15 and 5.54 µm, spherical morphology, and a wrinkled surface. Among them, those prepared with sodium carboxymethylcellulose or pectin proved to be the most thermally stable. They had the highest flavonoid content (23.07 and 21.73 mg RUTE/g Extract) and total antioxidant activity by both the DPPH (376.55 and 367.86 µM TEq/g Extract) and ABTS (1085.72 and 1062.32 µM TEq/g Extract) assays. The chromatographic analyses allowed for quantification of the following substances retained by the microparticles, chlorogenic acid (1.74-1.98 mg/g Extract), p-coumaric acid (0.06-0.08 mg/g Extract), rutin (11.2-12.9 mg/g Extract), and isoquercitrin (0.49-0.53 mg/g Extract), compounds which considered to responsible for the antidiabetic property attributed to the species.

Risk of stroke with percutaneous coronary intervention compared with on-pump and off-pump coronary artery bypass graft surgery: Evidence from a comprehensive network meta-analysis.

BACKGROUND: Although some trials have reported that on-pump coronary artery bypass graft (CABG) surgery may be associated with higher rates of stroke than percutaneous coronary intervention (PCI), whether stroke is more common after off-pump CABG compared with PCI is unknown. We therefore sought to determine whether off-pump CABG is associated with an increased risk of stroke compared with PCI by means of network meta-analysis. METHODS: Randomized controlled trials (RCTs) comparing CABG vs PCI were searched through MEDLINE, EMBASE, Cochrane databases, and proceedings of international meetings. RESULTS: Eighty-three RCTs with 22,729 patients randomized to on-pump CABG (n = 10,957), off-pump CABG (n = 7,119), or PCI (n = 4,653) were analyzed. Thirty-day rates of stroke were significantly lower in patients treated with PCI compared with either off-pump CABG (odds ratio [OR]; 0.39, 95% CI, 0.19-0.83) or on-pump CABG (OR, 0.26; 95% CI, 0.12-0.47). Compared with on-pump CABG, off-pump CABG was associated with significantly lower 30-day risk of stroke (OR, 0.67; 95% CI, 0.41-0.95). However, in sensitivity analyses restricted to high-quality studies, studies with more than either 100 or 1,000 patients, or studies with protocol definition or adjudication of stroke by a clinical events committee, the precision of the point estimate for the 30-day risk of stroke between off-pump vs on-pump CABG was markedly reduced. CONCLUSIONS: Percutaneous coronary intervention is associated with lower 30-day rates of stroke than both off-pump and on-pump CABG. Further studies are required to determine whether the risk of stroke is reduced with off-pump CABG compared with on-pump CABG.

Meta-analysis of randomized trials of effect of milrinone on mortality in cardiac surgery: an update.

OBJECTIVE: The long-term use of milrinone is associated with increased mortality in chronic heart failure. A recent meta-analysis suggested that it might increase mortality in patients undergoing cardiac surgery. The authors conducted an updated meta-analysis of randomized trials in patients undergoing cardiac surgery to determine if milrinone impacted survival. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: One thousand thirty-seven patients from 20 randomized trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomed, Central, PubMed, EMBASE, the Cochrane central register of clinical trials, and conference proceedings were searched for randomized trials that compared milrinone versus placebo or any other control in adult and pediatric patients undergoing cardiac surgery. Authors of trials that did not include mortality data were contacted. Only trials for which mortality data were available were included. Overall analysis showed no difference in mortality between patients receiving milrinone versus control (12/554 [2.2%] in the milrinone group v 10/483 [2.1%] in the control arm; relative risk [RR] = 1.15; 95% confidence interval [CI], 0.55-2.43; p = 0.7) or in analysis restricted to adults (11/364 [3%] in the milrinone group v 9/371 [2.4%] in the control arm; RR = 1.17; 95% CI, 0.54-2.53; p = 0.7). Sensitivity analyses in trials with a low risk of bias showed a trend toward an increase in mortality with milrinone (8/153 [5.2%] in the milrinone arm v 2/152 [1.3%] in the control arm; RR = 2.71; 95% CI, 0.82-9; p for effect = 0.10). CONCLUSIONS: Despite theoretic concerns for increased mortality with intravenous milrinone in patients undergoing cardiac surgery, the authors were unable to confirm an adverse effect on survival. However, sensitivity analysis of high-quality trials showed a trend toward increased mortality with milrinone.

Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygenation: a case-control study.

OBJECTIVE: Heparin-based anticoagulation for patients undergoing extracorporeal membrane oxygenation has many limitations, including a high risk of heparin-induced thrombocytopenia. However, little experience with other anticoagulants in these patients has been described. The aim of this study was to compare bivalirudin-based anticoagulation with heparin-based protocols in a population of patients treated with venovenous or venoarterial extracorporeal membrane oxygenation. DESIGN: In this case-control study, 10 patients received bivalirudin (cases) and 10 heparin (controls). The target activated partial thromboplastin time (aPTT) was 45 to 60 seconds. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: aPTT variations >20% of the previous value were much more frequent in patients treated with heparin than in patients receiving bivalirudin (52 v 24, p < 0.001). The number of corrections of the anticoagulant dose was higher in the heparin group compared with the bivalirudin group (58 v 51), although it did not reach statistical significance. Bleeding, thromboembolic complications, extracorporeal membrane oxygenation (ECMO) support duration, mortality, and the number of episodes of aPTT >80 seconds were not different between the 2 groups. A further analysis was performed in the bivalirudin group according to the presence of acute renal failure requiring continuous venovenous hemofiltration. The median bivalirudin dose in patients with or without hemofiltration was 0.041 (0.028-0.05) mg/kg/h and 0.028 (0-0.041) mg/kg/h, respectively (p = 0.2). CONCLUSIONS: Bivalirudin-based anticoagulation may represent a new method of anticoagulation for reducing thromboembolic and bleeding complications, which still jeopardize the application of extracorporeal membrane oxygenation. Moreover, bivalirudin is free from the risk of heparin-induced thrombocytopenia. Higher doses of bivalirudin may be needed in patients undergoing hemofiltration.

The effect of isoflurane on survival and myocardial infarction: a meta-analysis of randomized controlled studies.

OBJECTIVE: The aim of this meta-analysis was to investigate the cardioprotective properties of isoflurane versus any comparator in terms of the rate of myocardial infarction and all-cause mortality. DESIGN: Pertinent studies were searched independently in Biomed, Central, PubMed, Embase, and the Cochrane Central Register of clinical trials. The primary endpoint was mortality at the longest follow-up available. SETTING: A hospital. PARTICIPANTS: Randomized controlled trials. INTERVENTION: A meta-analysis of 37 trials. MEASUREMENTS AND MAIN RESULTS: The 37 included trials randomized 3,539 patients in cardiac (16 studies) and in noncardiac surgery (21 studies) with noninhalation comparators in 55% of trials. The overall analysis showed no difference in mortality between the isoflurane and control groups (16/1,602 [1.0%] v 23/1,937 [1.2%], odds ratios (OR) = 0.76 [0.39-1.47], p = 0.4 with 37 studies included) and no difference in the rate of myocardial infarction (3/1,312 [0.2%] v 1/1,532 [0.07%], OR = 2.03 [0.27-15.49], p = 0.5 with 30 studies included). Mortality was reduced in the isoflurane group when only studies with a low risk of bias were included in the analyses (0/540 [0%] v 5/703 [0.7%] in the control arm, OR = 0.13 [0.02-0.76], p = 0.02) with 4 cardiac and 6 noncardiac trials included and 5 noninhalation and 5 inhalation agents as the comparator. A trend was noted when a subanalysis was performed with propofol as a comparator (1/544 [0.2%] v 6/546 [1.1%], p = 0.05, with 16 studies included). CONCLUSIONS: Isoflurane reduced mortality in high-quality studies and showed a trend toward a reduction in mortality when it was compared with propofol. No differences in the rates of overall mortality and myocardial infarction were noted.

Does response to vagus nerve stimulation for drug-resistant epilepsy differ in patients with and without Lennox-Gastaut syndrome?

INTRODUCTION: Literature on outcomes of patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types. METHODS: The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response. RESULTS: A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, "other" seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic-clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p = .015. CONCLUSIONS: Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs.

A post hoc evaluation of the shift in spasticity category in individuals with multiple sclerosis-related spasticity treated with nabiximols.

Background: Over 80% of individuals with multiple sclerosis (MS) experience MS-associated spasticity (MSS). In many European countries, after failure of first-line treatments, moderate or severe MSS can be treated with nabiximols, a cannabis-based add-on treatment. Objective: This post hoc analysis assessed the shift of participants treated with nabiximols from higher (severe or moderate) to lower (moderate or mild/none) spasticity. Methods: Previously published data from two randomised controlled trials (RCTs), GWSP0604 (NCT00681538) and SAVANT (EudraCT2015-004451-40), and one large real-world study (consistent with EU label), all enriched for responders, were re-analysed. Spasticity severity, measured using the 0-10 numerical rating scale (spasticity NRS), was categorised as none/mild (score <4), moderate (score ⩾4-7), or severe (score ⩾7). Results: In the two RCTs, the shift of participants with severe MSS into a lower category was significantly greater at week 12 for those receiving nabiximols versus placebo [GWSP0604: OR (95% CI), 4.4 (1.4, 14.2), p = 0.0125; SAVANT: 5.2 (1.2, 22.3), p = 0.0267]. In all three studies, over 80% of assessed patients with severe spasticity at baseline reported a shift into a lower category of spasticity after 12 weeks. Conclusions: A meaningful proportion of MSS patients treated with nabiximols shifted to a lower category of spasticity severity, typically maintained to the end of the 12-week study period.

Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies.

OBJECTIVE: Catecholaminergic inotropes have a place in the management of low output syndrome and decompensated heart failure but their effect on mortality is debated. Levosimendan is a calcium sensitizer that enhances myocardial contractility without increasing myocardial oxygen use. A meta-analysis was conducted to determine the impact of levosimendan on mortality and hospital stay. DATA SOURCES: BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for pertinent studies. International experts and the manufacturer were contacted. STUDY SELECTION: Articles were assessed by four trained investigators, with divergences resolved by consensus. Inclusion criteria were random allocation to treatment and comparison of levosimendan vs. control. There were no restrictions on dose or time of levosimendan administration or on language. Exclusion criteria were: duplicate publications, nonadult studies, oral administration of levosimendan, and no data on main outcomes. DATA EXTRACTION: Study end points, main outcomes, study design, population, clinical setting, levosimendan dosage, and treatment duration were extracted. DATA SYNTHESIS: Data from 5,480 patients in 45 randomized clinical trials were analyzed. The overall mortality rate was 17.4% (507 of 2,915) among levosimendan-treated patients and 23.3% (598 of 2,565) in the control group (risk ratio 0.80 [0.72; 0.89], p for effect <.001, number needed to treat = 17 with 45 studies included). Reduction in mortality was confirmed in studies with placebo (risk ratio 0.82 [0.69; 0.97], p = .02) or dobutamine (risk ratio 0.68 [0.52-0.88]; p = .003) as comparator and in studies performed in cardiac surgery (risk ratio 0.52 [0.35; 0.76] p = .001) or cardiology (risk ratio 0.75 [0.63; 0.91], p = .003) settings. Length of hospital stay was reduced in the levosimendan group (weighted mean difference = -1.31 [-1.95; -0.31], p for effect = .007, with 17 studies included). A trend toward a higher percentage of patients experiencing hypotension was noted in levosimendan vs. control (risk ratio 1.39 [0.97-1.94], p = .053). CONCLUSIONS: Levosimendan might reduce mortality in cardiac surgery and cardiology settings of adult patients.

Remifentanil in cardiac surgery: a meta-analysis of randomized controlled trials.

OBJECTIVE: The authors conducted a review of randomized controlled trials to identify advantages in clinically relevant outcomes in patients undergoing cardiac surgery with remifentanil. DESIGN: Meta-analysis. SETTING: Hospitals. PARTICIPANTS: A total of 1,473 patients from 16 randomized trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULT: PubMed, BioMedCentral, and conference proceedings were searched (updated May 2010) for randomized trials that compared remifentanil with fentanyl or sufentanil in cardiac anesthesia. Four independent reviewers performed data extraction, with divergences resolved by consensus. Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = -139 min [-244, -32], p for effect = 0.01, p for heterogeneity < 0.001, I(2) = 89%); length of hospital stay (WMD = -1.08 days [-1.60, -0.57], p for effect < 0.0001, p for heterogeneity = 0.004, I(2) = 71%); and cardiac troponin-I release (WMD = -2.08 ng/mL [-3.93, -0.24], p for effect = 0.03, p for heterogeneity < 0.02, I(2) = 74%). No difference was noted in mortality (3/344 [0.87%] in the remifentanil group vs [1.06%] the control group, OR 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I(2) = 5%). CONCLUSIONS: Remifentanil reduces cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery.

Quantifying the burden of disease in patients with Lennox Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy but there is limited literature characterizing the disease burden despite this being crucial for disease management strategies, and for designing and interpreting clinical trials. We searched the Vagus Nerve Stimulation (VNS) Therapy Patient Outcome Registry including over 7000 patients with drug­resistant epilepsy (DRE). Propensity Score Matching (PSM) matched LGS-DRE patients and non-LGS-DRE patients and frequencies of individual seizure types were assessed. The PSM population included 705 and 1410 DRE patients with and without LGS. 40% of the LGS-DRE group had polypharmacy with 3 antiseizure medications (ASM) while 42% in non-LGS-DRE had polypharmacy with 2 ASMs. Median total monthly seizure frequency was over double in the LGS group: 90 (IQR, 28-312) versus 40 (IQR, 10-150); p < 0.001. This analysis suggests that seizure frequency in LGS patients who later receive VNS is more than double than in non-LGS DRE patients with mostly bilateral tonic-clonic seizures contributing to this difference. Furthermore, ASM burden with poorer seizure control may be greater in LGS patients, however data collection ceased in 2003 and therefore does not take recent ASMs approved for LGS into account. This analysis offers quantitative insight into the burden of disease in patients with LGS.

The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry.

BACKGROUND: To compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone. METHODS: Response was defined as ≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 3, 6, 9, or 12 months post-baseline. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan-Meier (KM) analysis and compared using log-rank test. Suicidality was assessed using the MADRS Item 10 score. RESULTS: At baseline (entry into registry), the VNS + TAU group (N = 97) had more episodes of depression, psychiatric hospitalizations, lifetime suicide attempts and higher suicidality score, more severe symptoms (based on MADRS and other scales), and higher rate of prior electroconvulsive therapy than TAU group (N = 59). Lifetime use of medications was similar between the groups (a mean of 9) and was consistent with the severe treatment-resistant nature of their depression. Over 5 years, 63% (61/97) in VNS + TAU had an initial response compared with 39% (23/59) in TAU. The time-to-initial response was significantly quicker for VNS + TAU than for TAU (p < 0.03). Among responders in the first year after implant, the KM estimate of the median time-to-relapse from initial response was 15.2 vs 7.6 months for VNS + TAU compared with TAU (difference was not statistically significant). The mean reduction in suicidality score across the study visits was significantly greater in the VNS + TAU than in the TAU group (p < 0.001). CONCLUSIONS: The patients who received VNS + TAU included in this analysis had severe bipolar depression that had proved extremely difficult to treat. The TAU comparator group were similar though had slightly less severe illnesses on some measures and had less history of suicide attempts. Treatment with VNS + TAU was associated with a higher likelihood of attaining a response compared to TAU alone. VNS + TAU was also associated with a significantly greater mean reduction in suicidality. LIMITATIONS: In this registry study, participants were not randomized to the study treatment group, VNS Therapy stimulation parameters were not controlled, and there was a high attrition rate over 5 years. Trial registration ClinicalTrials.gov NCT00320372. Registered 3 May 2006, https://clinicaltrials.gov/ct2/show/NCT00320372 (retrospectively registered).

Concomitant implantation of Impella® on top of veno-arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock.

AIMS: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support stabilizes patients with cardiogenic shock. Despite improved oxygenation and peripheral circulation, LV unloading may be impeded due to the increased afterload, resulting in a failing static left ventricle and in high mortality. METHODS AND RESULTS: We describe for the first time a large series of patients treated with the combination of VA-ECMO and Impella® compared with patients with VA-ECMO only. We retrospectively collected data on patients from two tertiary critical care referral centres. We enrolled 157 patients treated with VA-ECMO from January 2013 to April 2015: 123 received VA-ECMO support and 34 had concomitant treatment with VA-ECMO and Impella. A propensity-matching analysis was performed in a 2:1 ratio, resulting in 42 patients undergoing VA-ECMO alone (control group) compared with 21 patients treated with VA-ECMO and Impella. Patients in the VA-ECMO and Impella group had a significantly lower hospital mortality (47% vs. 80%, P < 0.001) and a higher rate of successful bridging to either recovery or further therapy (68% vs. 28%, P < 0.001) compared with VA-ECMO patients. A higher need for continuous veno-venous haemofiltration (48% vs. 19%, P = 0.02) and increased haemolysis (76% vs. 33%, P = 0.004) were reported in the study group due to higher survival. There was no difference in major bleeding rates between the two groups (VA-ECMO and Impella 38% vs. VA-ECMO 29%, P = 0.6). CONCLUSIONS: Concomitant treatment with VA-ECMO and Impella may improve outcome in patients with cardiogenic shock compared with VA-ECMO only. Nevertheless, randomized studies are needed to validate these promising results further.

A Bayesian network meta-analysis for binary outcome: how to do it.

This study presents an overview of conceptual and practical issues of a network meta-analysis (NMA), particularly focusing on its application to randomised controlled trials with a binary outcome of interest. We start from general considerations on NMA to specifically appraise how to collect study data, structure the analytical network and specify the requirements for different models and parameter interpretations, with the ultimate goal of providing physicians and clinician-investigators a practical tool to understand pros and cons of NMA. Specifically, we outline the key steps, from the literature search to sensitivity analysis, necessary to perform a valid NMA of binomial data, exploiting Markov Chain Monte Carlo approaches. We also apply this analytical approach to a case study on the beneficial effects of volatile agents compared to total intravenous anaesthetics for surgery to further clarify the statistical details of the models, diagnostics and computations. Finally, datasets and models for the freeware WinBUGS package are presented for the anaesthetic agent example.

The attractiveness of network meta-analysis: a comprehensive systematic and narrative review.

Network meta-analysis provides a global estimate of comparative treatment effectiveness combining both direct and indirect evidence. In the past decade, the medical literature has witnessed a rapid increase in the possibility to combine evidence from different treatment comparisons. This opportunity is attractive for clinicians since their major concern is to identify the single best available treatment. In addition, despite the sudden increase of publications concerning network meta-analysis, only a limited number focus on methodological and statistical aspects, and many issues remain unclear. The aim of our work was to explore and emphasize the potential attractiveness of network meta-analyses. We performed a systematic and narrative review (last updated on April 15, 2014) in order to assess the scholarly diffusion of network meta-analyses. The following data were collected: author identification, year and journal of publication, PubMed index, number of treatments and studies included, characteristics of network configuration, nature of primary outcome, clinical indication, type of intervention investigated and medical area. Since 2003 there has been an exponential increase in the number of published network meta-analyses. Out of 340 articles included according to our selection criteria, encompassing 248 treatment networks, cardiovascular and pulmonary diseases were the most prevalent topics, with an average of 5 treatments being compared stemming from an average of 10 controlled trials. In conclusion, network meta-analyses are becoming increasingly attractive as they offer a comprehensive framework for decision-making. Whether they will also contribute to improvements in patient outlook remains to be proven.

A multilevel approach to network meta-analysis within a frequentist framework.

Meta-analysis is a powerful tool to summarize knowledge. Pairwise or network meta-analysis may be carried out with multivariate models that account for the dependence between treatment estimates and quantify the correlation across studies. From a different perspective, meta-analysis may be viewed as a special case of multilevel analysis having a hierarchical data structure. Hence, we introduce an alternative frequentist approach, called multilevel network meta-analysis, which also allows to account for publication bias and the presence of inconsistency. We propose our approach for a three-level data structure set-up: arms within studies at the first level, studies within study designs at the second level and design configuration at the third level. This strategy differs from the traditional frequentist modeling because it works directly on an arm-based data structure. An advantage of using multilevel analysis is its flexibility, since it naturally allows to add further levels to the model and to accommodate for multiple outcome variables. Moreover, multilevel modeling may be carried out with widely available statistical programs. Finally, we compare the results from our approach with those from a Bayesian network meta-analysis on a binary endpoint which examines the effect on mortality of some anesthetics at the longest follow-up available. In addition, we compare results from the Bayesian and multilevel network meta-analysis approaches on a publicly available "Thrombolytic drugs" database. We also provide the reader with a blueprint of SAS codes for fitting the proposed models, although our approach does not rely on any specific software.