Andrew Elders

Mortality and quality of life in the five years after severe sepsis

IntroductionSevere sepsis is associated with high levels of morbidity and mortality, placing a high burden on healthcare resources. We aimed to study outcomes in the five years after severe sepsis.MethodsThis was a cohort study using data from a prospective audit in 26 adult ICUs in Scotland. Mortality was measured using clinical databases and quality of life using Short Form 36 (SF-36) at 3.5 and 5 years after severe sepsis.ResultsA total of 439 patients were recruited with a 58% mortality at 3.5 years and 61% mortality at 5 years. A total of 85 and 67 patients responded at 3.5 and 5 years follow-up, respectively. SF-36 physical component score (PCS) was low compared to population controls at 3.5 years (mean 41.8 (SD 11.8)) and at 5 years (mean 44.8 (SD 12.7)). SF-36 mental component score (MCS) was slightly lower than population controls at 3.5 years (mean 47.7 (SD 14.6)) and at 5 years after severe sepsis (mean 48.8 (SD 12.6)). The majority of patients were satisfied with their current quality of life (QOL) (80%) and all patients would be willing to be treated in an ICU again if they become critically ill despite many having unpleasant memories (19%) and recall (29%) of ICU events.ConclusionsPatients with severe sepsis have a high ongoing mortality after severe sepsis. They also have a significantly lower physical QOL compared to population norms but mental QOL scores were only slightly below population norms up to five years after severe sepsis. All survivors would be willing to be treated in an ICU again if critically ill. Mortality and QOL outcomes were broadly similar to other critically ill cohorts throughout the five years of follow-up.

A Randomized Trial Comparing Treatments for Varicose Veins

BACKGROUND Ultrasound-guided foam sclerotherapy and endovenous laser ablation are widely used alternatives to surgery for the treatment of varicose veins, but their comparative effectiveness and safety remain uncertain. METHODS In a randomized trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of foam, laser, and surgical treatments. Primary outcomes at 6 months were disease-specific quality of life and generic quality of life, as measured on several scales. Secondary outcomes included complications and measures of clinical success. RESULTS After adjustment for baseline scores and other covariates, the mean disease-specific quality of life was slightly worse after treatment with foam than after surgery (P=0.006) but was similar in the laser and surgery groups. There were no significant differences between the surgery group and the foam or the laser group in measures of generic quality of life. The frequency of procedural complications was similar in the foam group (6%) and the surgery group (7%) but was lower in the laser group (1%) than in the surgery group (P<0.001); the frequency of serious adverse events (approximately 3%) was similar among the groups. Measures of clinical success were similar among the groups, but successful ablation of the main trunks of the saphenous vein was less common in the foam group than in the surgery group (P<0.001). CONCLUSIONS Quality-of-life measures were generally similar among the study groups, with the exception of a slightly worse disease-specific quality of life in the foam group than in the surgery group. All treatments had similar clinical efficacy, but complications were less frequent after laser treatment and ablation rates were lower after foam treatment. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN51995477.).

Childbirth and prolapse : long-term associations with the symptoms and objective measurement of pelvic organ prolapse

To investigate prolapse symptoms and objectively measured pelvic organ prolapse, 12 years after childbirth, and association with delivery mode history.

Systematic Review of the Agreement of Tonometers with Goldmann Applanation Tonometry

OBJECTIVE To assess the agreement of tonometers available for clinical practice with the Goldmann applanation tonometer (GAT), the most commonly accepted reference device. DESIGN A systematic review and meta-analysis of directly comparative studies assessing the agreement of 1 or more tonometers with the reference tonometer (GAT). PARTICIPANTS A total of 11 582 participants (15 525 eyes) were included. METHODS Summary 95% limits of agreement (LoA) were produced for each comparison. MAIN OUTCOME MEASURES Agreement, recordability, and reliability. RESULTS A total of 102 studies, including 130 paired comparisons, were included, representing 8 tonometers: dynamic contour tonometer, noncontact tonometer (NCT), ocular response analyzer, Ocuton S, handheld applanation tonometer (HAT), rebound tonometer, transpalpebral tonometer, and Tono-Pen. The agreement (95% limits) seemed to vary across tonometers: 0.2 mmHg (-3.8 to 4.3 mmHg) for the NCT to 2.7 mmHg (-4.1 to 9.6 mmHg) for the Ocuton S. The estimated proportion within 2 mmHg of the GAT ranged from 33% (Ocuton S) to 66% and 59% (NCT and HAT, respectively). Substantial inter- and intraobserver variability were observed for all tonometers. CONCLUSIONS The NCT and HAT seem to achieve a measurement closest to the GAT. However, there was substantial variability in measurements both within and between studies.

The relative clinical effectiveness of ranibizumab and bevacizumab in diabetic macular oedema: an indirect comparison in a systematic review

Objective To indirectly compare the effectiveness of ranibizumab and bevacizumab in the treatment of diabetic macular oedema. Design Systematic review and indirect comparison. Data sources Medline (1996–September 2011), Embase (1996–September 2011), and the Cochrane Central Register of Controlled Trials (Issue 4, 2011). Selection criteria for studies Randomised trials evaluating ranibizumab or bevacizumab in diabetic macular oedema with a common comparator and sufficient methodological similarity to be included within an indirect comparison were eligible for inclusion. Main outcome measures The primary outcome was the proportion of patients with an improvement in best corrected visual acuity of more than two lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Secondary outcomes included mean changes in best corrected visual acuity and in central macular thickness, and adverse events. Best corrected visual acuity was converted to logMAR units, a linear scale of visual acuity with positive values representing increasing visual loss. Indirect comparisons were done using Bayesian methods to estimate relative treatment effects of bevacizumab and ranibizumab. Results Five randomised controlled trials with follow-up of 6–12 months and a common comparator (multiple laser treatment) were sufficiently similar to be included in the indirect comparison. Generally studies were small, resulting in wide credible intervals. The proportions of patients with an improvement in best corrected visual acuity of >2 lines were 21/77 participants (27%) for bevacizumab and 60/152 participants (39%) for ranibizumab (odds ratio 0.95 (95% credible interval 0.23 to 4.32)). The wide credible intervals cannot exclude a greater improvement, or worse outcome, for either drug. The mean change in best corrected visual acuity non-significantly favoured bevacizumab (treatment effect −0.08 logMAR units (−0.19 to 0.04)). The difference in mean change in central macular thickness was not statistically significant between ranibizumab and bevacizumab (treatment effect −6.9 μm (−88.5 to 65.4)). Conclusions Results suggest no difference in effectiveness between bevacizumab and ranibizumab, but the wide credible intervals cannot exclude the possibility that either drug might be superior. Sufficiently powered, direct head to head trials are needed.

Denosumab for treatment of bone metastases secondary to solid tumours:systematic review and network meta-analysis

AIM To evaluate the evidence for denosumab for the treatment of bone metastases secondary to solid tumours and, using a network meta-analysis, indirectly compare denosumab with bisphosphonates and best supportive care. DATA SOURCES MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), Cochrane Library (all sections) (issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011) and additional meeting abstracts (2010 and 2011) were searched. STUDY ELIGIBILITY, PARTICIPANTS AND INTERVENTIONS: Only randomised controlled trials assessing denosumab, bisphosphonates or best supportive care in patients with bone metastases from any solid tumour were included. SYNTHESIS Direct evidence comparing denosumab and zoledronic acid was assessed for breast cancer, prostate cancer and other solid tumours. Denosumab was compared with pamidronate and best supportive care through a network meta-analysis for each tumour type. The primary outcomes were time to first skeletal related event (SRE) and time to first and subsequent SRE. Secondary outcomes were skeletal morbidity rate, pain, quality of life (QoL) and overall survival. RESULTS Denosumab was found to be more effective in delaying the time to first SRE and reducing the risk of first and subsequent SRE compared to zoledronic acid, placebo and pamidronate. In breast and prostate cancer, denosumab was effective in reducing skeletal morbidity rate compared with placebo. The lack of published data on pain and QoL meant that firm conclusions could not be made. Denosumab did not appear to have an affect on overall survival. LIMITATIONS Network meta-analyses are subject to uncertainties and potential biases. CONCLUSIONS Denosumab is effective in preventing SRE, but the effect on pain and QoL is unclear.

Twelve-year follow-up of conservative management of postnatal urinary and faecal incontinence and prolapse outcomes: randomised controlled trial

To determine the long‐term (12‐year) effects of a conservative nurse‐led intervention for postnatal urinary incontinence.

Optical Coherence Tomography for the Monitoring of Neovascular Age-Related Macular Degeneration: A Systematic Review

TOPIC To compare the accuracy of optical coherence tomography (OCT) with alternative tests for monitoring neovascular age-related macular degeneration (nAMD) and detecting disease activity among eyes previously treated for this condition. CLINICAL RELEVANCE Traditionally, fundus fluorescein angiography (FFA) has been considered the reference standard to detect nAMD activity, but FFA is costly and invasive. Replacement of FFA by OCT can be justified if there is a substantial agreement between tests. METHODS Systematic review and meta-analysis. The index test was OCT. The comparator tests were visual acuity, clinical evaluation (slit lamp), Amsler chart, color fundus photographs, infrared reflectance, red-free images and blue reflectance, fundus autofluorescence imaging, indocyanine green angiography (ICGA), preferential hyperacuity perimetry, and microperimetry. We searched the following databases: MEDLINE, MEDLINE In-Process, EMBASE, Biosis, Science Citation Index, the Cochrane Library, Database of Abstracts of Reviews of Effects, MEDION, and the Health Technology Assessment database. The last literature search was conducted in March 2013. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias. RESULTS We included 8 studies involving more than 400 participants. Seven reported the performance of OCT (3 time-domain [TD] OCT, 3 spectral-domain [SD] OCT, 1 both types) and 1 reported the performance of ICGA in the detection of nAMD activity. We did not find studies directly comparing tests in the same population. The pooled sensitivity and specificity of TD OCT and SD OCT for detecting active nAMD was 85% (95% confidence interval [CI], 72%-93%) and 48% (95% CI, 30%-67%), respectively. One study reported ICGA with sensitivity of 75.9% and specificity of 88.0% for the detection of active nAMD. Half of the studies were considered to have a high risk of bias. CONCLUSIONS There is substantial disagreement between OCT and FFA findings in detecting active disease in patients with nAMD who are being monitored. Both methods may be needed to monitor patients comprehensively with nAMD.

Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours

BACKGROUND Denosumab offers an alternative, or additional, treatment for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumours. OBJECTIVES The aim of this review was to assess the clinical effectiveness and cost-effectiveness of denosumab, within its licensed indication, for the prevention of SREs in patients with bone metastases from solid tumours. DATA SOURCES Databases searched were MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), The Cochrane Library (all sections; Issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011). REVIEW METHODS Only randomised controlled trials (RCTs) assessing denosumab, bisphosphonates (BPs) or best supportive care (BSC) in patients with bone metastases were included. Systematic reviews and observational studies were used for safety and quality-of-life assessments. Study quality was assessed using the Cochrane risk of bias tool. Studies suitable for meta-analysis were synthesised using network meta-analysis (NMA). A systematic review was conducted for cost, quality-of-life and cost-effectiveness studies. The results of this informed the cost-utility modelling. This principally estimated the cost-effectiveness of denosumab relative to zoledronic acid for when BPs are currently recommended and relative to BSC when BPs are not recommended or are contraindicated. RESULTS A literature search identified 39 studies (eight suitable for NMA). Denosumab was effective in delaying time to first SRE and reducing the risk of multiple SREs compared with zoledronic acid. Generally speaking, denosumab was similar to zoledronic acid for quality of life, pain, overall survival and safety. The NMA demonstrated that denosumab was more effective in delaying SREs than placebo, but was limited by numerous uncertainties. Cost-utility modelling results for denosumab relative to zoledronic acid were driven by the availability of the patient access scheme (PAS) for denosumab. Without this, denosumab was not estimated to be cost-effective compared with zoledronic acid. With it, the cost-effectiveness ranged between dominance for breast and prostate cancer, to between £5400 and £15,300 per quality-adjusted life-year (QALY) for other solid tumours (OSTs) including non-small cell lung cancer (NSCLC) and £12,700 per QALY for NSCLC. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Denosumab was not estimated to be cost-effective compared with BSC. LIMITATIONS Only subgroup data were available for denosumab for NSCLC, and OSTs excluding NSCLC. The NMA was subject to numerous uncertainties. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. CONCLUSION Denosumab, compared with zoledronic acid and placebo, is effective in delaying SREs, but is similar with regard to quality of life and pain. Cost-effectiveness showed that without the PAS denosumab was not estimated to be cost-effective relative to either zoledronic acid or BSC. With the PAS, denosumab was estimated to be cost-effective relative to zoledronic acid but not BSC. STUDY REGISTRATION PROSPERO number CRD42011001418. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Optical coherence tomography for the diagnosis, monitoring and guiding of treatment for neovascular age-related macular degeneration: a systematic review and economic evaluation.

BACKGROUND Age-related macular degeneration is the most common cause of sight impairment in the UK. In neovascular age-related macular degeneration (nAMD), vision worsens rapidly (over weeks) due to abnormal blood vessels developing that leak fluid and blood at the macula. OBJECTIVES To determine the optimal role of optical coherence tomography (OCT) in diagnosing people newly presenting with suspected nAMD and monitoring those previously diagnosed with the disease. DATA SOURCES Databases searched: MEDLINE (1946 to March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 2013), EMBASE (1988 to March 2013), Biosciences Information Service (1995 to March 2013), Science Citation Index (1995 to March 2013), The Cochrane Library (Issue 2 2013), Database of Abstracts of Reviews of Effects (inception to March 2013), Medion (inception to March 2013), Health Technology Assessment database (inception to March 2013). REVIEW METHODS Types of studies: direct/indirect studies reporting diagnostic outcomes. INDEX TEST time domain optical coherence tomography (TD-OCT) or spectral domain optical coherence tomography (SD-OCT). COMPARATORS clinical evaluation, visual acuity, Amsler grid, colour fundus photographs, infrared reflectance, red-free images/blue reflectance, fundus autofluorescence imaging, indocyanine green angiography, preferential hyperacuity perimetry, microperimetry. Reference standard: fundus fluorescein angiography (FFA). Risk of bias was assessed using quality assessment of diagnostic accuracy studies, version 2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic curves. A Markov model was developed (65-year-old cohort, nAMD prevalence 70%), with nine strategies for diagnosis and/or monitoring, and cost-utility analysis conducted. NHS and Personal Social Services perspective was adopted. Costs (2011/12 prices) and quality-adjusted life-years (QALYs) were discounted (3.5%). Deterministic and probabilistic sensitivity analyses were performed. RESULTS In pooled estimates of diagnostic studies (all TD-OCT), sensitivity and specificity [95% confidence interval (CI)] was 88% (46% to 98%) and 78% (64% to 88%) respectively. For monitoring, the pooled sensitivity and specificity (95% CI) was 85% (72% to 93%) and 48% (30% to 67%) respectively. The FFA for diagnosis and nurse-technician-led monitoring strategy had the lowest cost (£ 39,769; QALYs 10.473) and dominated all others except FFA for diagnosis and ophthalmologist-led monitoring (£ 44,649; QALYs 10.575; incremental cost-effectiveness ratio £ 47,768). The least costly strategy had a 46.4% probability of being cost-effective at £ 30,000 willingness-to-pay threshold. LIMITATIONS Very few studies provided sufficient information for inclusion in meta-analyses. Only a few studies reported other tests; for some tests no studies were identified. The modelling was hampered by a lack of data on the diagnostic accuracy of strategies involving several tests. CONCLUSIONS Based on a small body of evidence of variable quality, OCT had high sensitivity and moderate specificity for diagnosis, and relatively high sensitivity but low specificity for monitoring. Strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective. Further research is required on (i) the performance of SD-OCT compared with FFA, especially for monitoring but also for diagnosis; (ii) the performance of strategies involving combinations/sequences of tests, for diagnosis and monitoring; (iii) the likelihood of active and inactive nAMD becoming inactive or active respectively; and (iv) assessment of treatment-associated utility weights (e.g. decrements), through a preference-based study. STUDY REGISTRATION This study is registered as PROSPERO CRD42012001930. FUNDING The National Institute for Health Research Health Technology Assessment programme.