Marrissa Martyn-St James

Meta-analysis of walking for preservation of bone mineral density in postmenopausal women

Whilst exercise is recommended for optimum bone health in adult women, there are few systematic reviews of the efficacy of walking as singular exercise therapy for postmenopausal bone loss. The aim of this study was to assess the effects of prescribed walking programmes on bone mineral density (BMD) at the hip and spine in postmenopausal women and to determine if effects are modified by variations in protocol design. We undertook a systematic review and meta-analysis of randomised (RCTs) and non-randomised controlled trials. Electronic bibliographic databases, key journals and reference lists of reviews and articles were searched to identify studies for inclusion. Randomised and non-randomised controlled trials assessing the effects of walking on lumbar spine, femoral neck and total hip BMD, measured by radiographic techniques, among sedentary postmenopausal women were eligible for inclusion. Two independent reviewers assessed studies for eligibility. Reported absolute BMD outcomes were combined in the analysis. Weighted mean differences (WMD) were calculated using a fixed and random-effects models. Heterogeneity among trials was examined using the Q statistic and I2 methods. Potential publication bias was assessed through funnel plot inspection. Assessment of trial quality was also performed using the widely used instrument devised by Jadad et al. [Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Cont Clin Trials 1996; 17:1-12]. Eight trials were eligible for inclusion. Treatment duration ranged from 6 to 24 months. All eight trials reported BMD data at the lumbar spine following walking interventions among postmenopausal women. Meta-analysis showed no significant change in BMD at this site [WMD (fixed-effect) 0.007 g/cm2 95% CI (-0.001 to 0.016); P=0.09)]. BMD data at the femoral neck were available from five trials among postmenopausal women. Results were inconsistent (I2=51.4%) in showing a positive effect of walking on BMD at this site [WMD (random-effects) 0.014 g/cm2 95% CI (0.000 to 0.028); P=0.05). Insufficient data were available for meta-analysis of the total hip site. Funnel plots showed some asymmetry for negative lumbar spine BMD outcomes. Trial quality scores ranged from 0 to 3 from the Jadad scale of 0 to 5. We conclude that regular walking has no significant effect on preservation of BMD at the spine in postmenopausal women, whilst significant positive effects at femoral neck are evident. However, diverse methodological and reporting discrepancies are apparent in the published trials on which these conclusions are based. Other forms of exercise that provide greater targeted skeletal loading may be required to preserve bone mineral density in this population.

A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes

Objectives: To assess the effects of differing impact exercise protocols on postmenopausal bone loss at the hip and spine. Design: Systematic review and meta-analysis. Data sources: Electronic bibliographic databases, key journals and reference lists of reviews and articles. Review methods: Two independent reviewers assessed controlled trials evaluating effects of impact exercise on lumbar spine, femoral neck and total hip bone mineral density (BMD) in postmenopausal women for inclusion. Heterogeneity amongst trials and publication bias were assessed. Trial quality assessment was also performed. Results: Impact protocols that included jogging mixed with walking and stair climbing, and protocols that incorporated impact exercise with high-magnitude loading (resistance exercises), were effective at lumbar spine (weighted mean difference (random effects) 0.025 g/cm2 95% CI (0.004 to 0.046) and 0.016 g/cm2 95% CI (0.005 to 0.027); p = 0.02 and p = 0.005 respectively), although heterogeneity was evident (I2 = 88% and I2 = 73%, where I2 measures the extent of inconsistency among the trials). Effects on femoral neck BMD following these types of protocols were significant (weighted mean difference (fixed effect) 0.022 g/cm2 95% CI (0.014 to 0.030); p<0.001 and 0.005 g/cm2 95% CI (0.001 to 0.010); p = 0.03 respectively). High-impact only and odd-impact only protocols were ineffective in increasing BMD at any site. Conclusion: Mixed loading exercise programmes combining jogging with other low-impact loading activity and programmes mixing impact activity with high-magnitude exercise as resistance training appear effective in reducing postmenopausal bone loss at the hip and spine. Other forms of impact exercise appear less effective at preserving BMD in this population. However, diverse methodological and reporting discrepancies are evident in current published trials.

Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects.

Regular weight-bearing physical activity has been widely recommended for adult women and may be beneficial in preserving bone mineral density (BMD). However, there is conflicting evidence regarding the effects of resistance training on BMD in premenopausal women.Novel systematic review and meta-analysis evidence is presented on the effects of progressive high-intensity resistance training on BMD in premenopausal women. Structured computer searches of MEDLINE, EMBASE, PubMed, Web of Science, SportDiscus and Evidence Based Medicine Reviews Multifile were undertaken along with hand-searching of key journals and reference lists to locate relevant studies published up to September 2004. Criteria for included studies were published controlled studies and randomised controlled trials (RCTs) evaluating the effects of progressive, high-intensity resistance training studies on BMD in premenopausal women. Two authors reached consensus on all included and excluded studies. Study outcomes for analysis were radiographic BMD assessment from first follow-up at lumbar spine and femoral neck. Primary outcomes for analysis were absolute changes in BMD g/cm2 at lumbar spine and femoral neck. Relative changes (percentage change) in BMD at lumbar spine were also assessed. Data were extracted from studies including study design, participant characteristics and treatment mode, intensity and duration, using electronic data extraction forms. Where necessary, relevant information was obtained by contacting study authors. Methodological quality of studies was assessed using a well recognised three-question instrument designed to assess bias. Informal assessment for small sample study effects and potential bias was undertaken through visual inspection of funnel plots. The weighted mean difference method (inverse of the variances) was used for combining study group estimates. Quantification of the effect of heterogeneity among study outcomes was assessed using the I2 statistic. Random effects and fixed-effect models were applied according to observed study heterogeneity. Comparisons resulting in I2 > 50.0% were considered heterogeneous. Where heterogeneity was observed, a random effects model was applied. Pooled estimates of effect were calculated using the Cochrane Collaboration’s Review Manager (RevMan) 4.2.1 software.High-intensity progressive resistance training was shown to be efficacious in increasing absolute BMD at the lumbar spine (p < 0.00001) but not the femoral neck (p = 0.78) in premenopausal women. The weighted mean difference (WMD) using a fixed-effect model for six controlled trials investigating the lumbar spine BMD change was 0.014 g/cm2 (95% CI 0.009, 0.019; p < 0.00001). The relative BMD change for this site was 0.98% (WMD [random effects], 95% CI 0.49, 3.91%; p = 0.04). In contrast, studies evaluating femoral neck BMD changes showed no significant BMD change (WMD [fixed effect], 0.001 g/cm2 95% CI -0.006, 0.008; p = 0.78). Funnel plot inspection of lumbar spine effects indicated that smaller studies demonstrated larger treatment effects. An asymmetry towards studies with positive BMD outcomes was also noted. The methodological quality score of all included studies was low and no study presented a valid intention-to-treat accounting for participant drop-out (attrition). As such, the modest overall treatment effects for resistance training on BMD among premenopausal women observed in this review may be biased and should be interpreted with caution.It is concluded that further RCTs of resistance training of sufficiently long duration and providing optimum type, intensity and volume of loading, with intention-to-treat analysis are now required.

Sepsis: the LightCycler SeptiFast Test MGRADE®, SepsiTest™ and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi – a systematic review and economic evaluation

BACKGROUND Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity. OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of three tests [LightCycler SeptiFast Test MGRADE(®) (Roche Diagnostics, Risch-Rotkreuz, Switzerland); SepsiTest(TM) (Molzym Molecular Diagnostics, Bremen, Germany); and the IRIDICA BAC BSI assay (Abbott Diagnostics, Lake Forest, IL, USA)] for the rapid identification of bloodstream bacteria and fungi in patients with suspected sepsis compared with standard practice (blood culture with or without matrix-absorbed laser desorption/ionisation time-of-flight mass spectrometry). DATA SOURCES Thirteen electronic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched from January 2006 to May 2015 and supplemented by hand-searching relevant articles. REVIEW METHODS A systematic review and meta-analysis of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. A decision tree was used to estimate the costs and quality-adjusted life-years (QALYs) associated with each test; all other parameters were estimated from published sources. The model was populated with evidence from the systematic review or individual studies, if this was considered more appropriate (base case 1). In a secondary analysis, estimates (based on experience and opinion) from seven clinicians regarding the benefits of earlier test results were sought (base case 2). A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Scenario analyses were used to assess uncertainty. RESULTS For the review of diagnostic test accuracy, 62 studies of varying methodological quality were included. A meta-analysis of 54 studies comparing SeptiFast with blood culture found that SeptiFast had an estimated summary specificity of 0.86 [95% credible interval (CrI) 0.84 to 0.89] and sensitivity of 0.65 (95% CrI 0.60 to 0.71). Four studies comparing SepsiTest with blood culture found that SepsiTest had an estimated summary specificity of 0.86 (95% CrI 0.78 to 0.92) and sensitivity of 0.48 (95% CrI 0.21 to 0.74), and four studies comparing IRIDICA with blood culture found that IRIDICA had an estimated summary specificity of 0.84 (95% CrI 0.71 to 0.92) and sensitivity of 0.81 (95% CrI 0.69 to 0.90). Owing to the deficiencies in study quality for all interventions, diagnostic accuracy data should be treated with caution. No randomised clinical trial evidence was identified that indicated that any of the tests significantly improved key patient outcomes, such as mortality or duration in an intensive care unit or hospital. Base case 1 estimated that none of the three tests provided a benefit to patients compared with standard practice and thus all tests were dominated. In contrast, in base case 2 it was estimated that all cost per QALY-gained values were below £20,000; the IRIDICA BAC BSI assay had the highest estimated incremental net benefit, but results from base case 2 should be treated with caution as these are not evidence based. LIMITATIONS Robust data to accurately assess the clinical effectiveness and cost-effectiveness of the interventions are currently unavailable. CONCLUSIONS The clinical effectiveness and cost-effectiveness of the interventions cannot be reliably determined with the current evidence base. Appropriate studies, which allow information from the tests to be implemented in clinical practice, are required. STUDY REGISTRATION This study is registered as PROSPERO CRD42015016724. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: A systematic review and indirect comparison

INTRODUCTION Retigabine (RTG) is now approved in Europe and the US for the adjunctive treatment of partial-onset seizures in adults with epilepsy. To support submissions to EU reimbursement authorities, we explored its efficacy and tolerability relative to selected antiepileptic drugs (AEDs). METHODS A systematic review was conducted to identify placebo-controlled trials of RTG and selected AEDs approved for use in a similar position in the management pathway of partial epilepsy (eslicarbazepine acetate [ESL], lacosamide [LCM], pregabalin [PGB], tiagabine [TGB] and zonisamide [ZNS]). Using conventional and network meta-analyses as appropriate, we report efficacy and tolerability outcomes for each AED versus placebo and the performance of RTG relative to other AEDs. RESULTS Twenty studies met the inclusion criteria: three each for RTG, ESL, LCM, TGB and ZNS; five for PGB. Comparisons comprised 1-5 studies per AED. In the network meta-analysis, RTG was not found to be different from the other AEDs for responder rate (maintenance period), seizure freedom (maintenance period and double-blind period), withdrawals due to adverse events, and incidences of ataxia, dizziness, fatigue and nausea. Differences between RTG and other AEDs were found for a few comparisons, which did not reveal any trends: RTG was associated with a lower responder rate than PGB during the double-blind period, higher withdrawal rate due to any reason than ESL and a higher incidence of somnolence than TGB. CONCLUSIONS Findings suggest that the risk/benefit for RTG is similar to that for comparator AEDs. However, results should be interpreted in the context of the limitations of the analyses.

Interventions to treat premature ejaculation: a systematic review short report

BACKGROUND Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130-4). Treatments include behavioural and pharmacological interventions. OBJECTIVE To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. DATA SOURCES The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. METHODS Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). RESULTS A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics - eutectic mixture of local anaesthetics (EMLA(®), AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) - citalopram (Cipramil(®), Lundbeck), escitalopram (Cipralex(®), Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy(®), Menarini), 30 mg or 60 mg; serotonin-noradrenaline reuptake inhibitors - duloxetine (Cymbalta(®), Eli Lilly & Co Ltd); tricyclic antidepressants - inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors - vardenafil (Levitra(®), Bayer), tadalafil (Cialis(®), Eli Lilly & Co Ltd); opioid analgesics - tramadol (Zydol SR(®), Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies - improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers - terazosin (Hytrin(®), AMCO) not significantly different to antidepressants in ejaculation control; acupuncture - improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine - improvements over treatment as usual; delay device - improvements in IELT when added to stop-start technique; yoga - improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. LIMITATIONS Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. CONCLUSIONS Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005289. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Tramadol for premature ejaculation: a systematic review and meta-analysis

BackgroundTramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation (PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE is yet not supported by a high level of evidence. The purpose of this study was to systematically review the evidence from randomised controlled trials (RCT) for tramadol in the management of PE.MethodsWe searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-group differences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trial heterogeneity was assessed.ResultsA total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were of unclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, a high level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol is significantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is not assessed in the current evidence base.ConclusionsTramadol appears effective in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence. The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration does not permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, including addiction potential, for men with PE have not been evaluated in the current evidence base.Trial registrationThe review is registered on PROSPERO 2013:CRD42013005289.

Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: A systematic review and network meta-analysis.

OBJECTIVES To assess the relative efficacy of bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) for the treatment of osteoporosis using network meta-analysis (NMA). METHODS A systematic review of the literature was conducted using PRISMA guidelines. A network meta-analysis was used to determine the relative efficacy of treatments on four fracture outcomes (vertebral, non-vertebral, hip and wrist) and percentage change in femoral neck bone mineral density (BMD). Treatment effects were modelled using an exchangeable treatment effects model. Heterogeneity in treatment effects was explored by considering potential treatment effect modifiers using meta-regression. Where appropriate, inconsistency between direct and indirect evidence was assessed using node-splitting. RESULTS 46 randomised controlled trials (RCTs) were identified. Twenty seven RCTs provided fracture data and 35 RCTs provided BMD data for analysis. Zoledronic acid was associated with the greatest treatment effect on vertebral fractures (HR 0.41, 95% CrI: 0.28, 0.56) and percentage change in BMD (3.21, 95%: CrI 2.52, 3.86) compared to placebo. The greatest treatment effect on non-vertebral and wrist fractures was given by risedronate (HR 0.72, 95%: CrI 0.53, 0.89 and HR 0.77, 95%: CrI 0.44, 1.24, respectively). For hip fractures the greatest treatment effect was given by alendronate (HR 0.78, 95% CrI: 0.44, 1.30). CONCLUSIONS All treatments examined were associated with beneficial effects on fractures and femoral neck BMD relative to placebo. For vertebral fractures and percentage change in femoral neck BMD the treatment effects were statistically significant for all treatments. Pairwise comparisons between treatments indicated that no active treatment was statistically significantly more effective than any other active treatment for fracture outcomes. There was some heterogeneity in treatment effects between studies suggesting differential treatment effects according to study characteristics; however, there was no evidence of differential treatment effects with respect to gender and age.

A Model-Based Economic Evaluation of Biologic and Non-Biologic Options for the Treatment of Adults with Moderately-to-Severely Active Ulcerative Colitis after the Failure of Conventional Therapy

BackgroundUlcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. Medical management aims to induce and maintain remission and to avoid complications and the necessity for surgical intervention. Colectomy removes the source of inflammation but is associated with morbidity and mortality. Newer anti-tumour necrosis factor (TNF)-α therapies may improve medical outcomes, albeit at an increased cost.ObjectiveOur objective was to assess the incremental cost effectiveness of infliximab, adalimumab and golimumab versus conventional therapy and surgery from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon.MethodsA Markov model was developed with health states defined according to whether the patient is alive or dead, current treatments received, history of colectomy and level of disease control. Transition probabilities were derived from network meta-analyses (NMAs) of trials of anti-TNF-α agents in the moderate-to-severe UC population. Health utilities, colectomy rates, surgical complications and resource use estimates were derived from literature. Unit costs were drawn from standard costing sources and literature and were valued at year 2013/2014 values.ResultsFor patients in whom surgery is an option, colectomy is expected to dominate all medical treatment options. For patients in whom colectomy is not an option, infliximab and golimumab are expected to be ruled out due to dominance, whilst the incremental cost-effectiveness ratio (ICER) for adalimumab versus conventional treatment is expected to be approximately £50,278 per quality-adjusted life-year (QALY) gained.ConclusionsBased on the NMAs, the ICERs for anti-TNF-α therapy versus conventional treatment or surgery are expected to be at best, in excess of £50,000 per QALY gained. The cost effectiveness of withdrawing biologic therapy upon remission and re-treating relapse is unknown.

Behavioral Therapies for Management of Premature Ejaculation: A Systematic Review

Introduction Premature ejaculation (PE) is defined by short ejaculatory latency and inability to delay ejaculation causing distress. Management may involve behavioral and/or pharmacological approaches. Aim To systematically review the randomized controlled trial (RCT) evidence for behavioral therapies in the management of PE. Methods Nine databases including MEDLINE were searched up to August 2014. Included RCTs compared behavioral therapy against waitlist control or another therapy, or behavioral plus drug therapy against drug treatment alone. [Correction added on 10 September 2015, after first online publication: Search period has been amended from August 2013 to August 2014.] Main Outcome Measure Intravaginal ejaculatory latency time (IELT), sexual satisfaction, ejaculatory control, and anxiety and adverse effects. Results Ten RCTs (521 participants) were included. Overall risk of bias was unclear. All studies assessed physical techniques, including squeeze and stop-start, sensate focus, stimulation device, and pelvic floor rehabilitation. Only one RCT included a psychotherapeutic approach (combined with stop-start and drug treatment). Four trials compared behavioral therapies against waitlist control, of which two (involving squeeze, stop-start, and sensate focus) reported IELT differences of 7–9 minutes, whereas two (web-based sensate focus, stimulation device) reported no difference in ejaculatory latency posttreatment. For other outcomes (sexual satisfaction, desire, and self-confidence), some waitlist comparisons significantly favored behavioral therapy, whereas others were not significant. Three trials favored combined behavioral and drug treatment over drug treatment alone, with small but significant differences in IELT (0.5–1 minute) and significantly better results on other outcomes (sexual satisfaction, ejaculatory control, and anxiety). Direct comparisons of behavioral therapy vs. drug treatment gave mixed results, mostly either favoring drug treatment or showing no significant difference. No adverse effects were reported, though safety data were limited. Conclusions There is limited evidence that physical behavioral techniques for PE improve IELT and other outcomes over waitlist and that behavioral therapies combined with drug treatments give better outcomes than drug treatments alone. Further RCTs are required to assess psychotherapeutic approaches to PE.