Abdullah Pandor

Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials

Objectives.  To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non‐familial) hypercholesterolaemia.

Remote monitoring after recent hospital discharge in patients with heart failure: a systematic review and network meta-analysis

Context Readmission to hospital for heart failure is common after recent discharge. Remote monitoring (RM) strategies have the potential to deliver specialised care and management and may be one way to meet the growing needs of the heart failure population. Objective To determine whether RM strategies improve outcomes for adults who have been recently discharged (<28 days) following an unplanned admission due to heart failure. Study design Systematic review and network meta-analysis. Data sources Fourteen electronic databases (including MEDLINE, EMBASE and PsycINFO) were searched to January 2012, and supplemented by hand-searching relevant articles. Study selection All randomised-controlled trials (RCTs) or observational cohort studies with a contemporaneous control group were included. RM interventions included home telemonitoring (TM) (including implanted monitoring devices) with medical support provided during office hours or 24/7 and structured telephone support (STS) programmes delivered via human-to-human contact (HH) or human-to-machine interface (HM). Data Extraction Data were extracted and validity was assessed independently by two reviewers. Results Twenty-one RCTs that enrolled 6317 patients were identified (11 studies evaluated STS (10 of which were HH, while 1 was HM), 9 studies assessed TM, and 1 study assessed both STS and TM). No trial of implanted monitoring devices met the inclusion criteria. Compared with usual care, although not reaching statitistical significance, RM trended to reduce all-cause mortality for STS HH (HR: 0.77, 95% credible interval (CrI): 0.55, 1.08), TM during office hours (HR: 0.76, 95% CrI: 0.49, 1.18) and TM24/7 (HR: 0.49, 95% CrI: 0.20, 1.18). Exclusion of one trial that provided better-than-usual support to the control group rendered each of the above comparisons statistically significant. No beneficial effect on mortality was observed with STS HM. Reductions were also observed in all-cause hospitalisations for TM interventions but not for STS interventions. Care packages generally improved health-related quality-of-life and were acceptable to patients. Conclusions STS HH and TM with medical support provided during office hours showed beneficial trends, particularly in reducing all-cause mortality for recently discharged patients with heart failure. Where ‘usual’ care is less good, the impact of RM is likely to be greater.

Home telemonitoring or structured telephone support programmes after recent discharge in patients with heart failure: systematic review and economic evaluation

BACKGROUND Remote monitoring (RM) strategies have the potential to deliver specialised care and management to patients with heart failure (HF). OBJECTIVE To determine the clinical effectiveness and cost-effectiveness of home telemonitoring (TM) or structured telephone support (STS) strategies compared with usual care for adult patients who have been recently discharged (within 28 days) from acute care after a recent exacerbation of HF. DATA SOURCES Fourteen electronic databases (including MEDLINE, EMBASE, PsycINFO and The Cochrane Library) and research registers were searched to January 2012, supplemented by hand-searching relevant articles and contact with experts. The review included randomised controlled trials (RCTs) or observational cohort studies with a contemporaneous control group that included the following RM interventions: (1) TM (including cardiovascular implanted monitoring devices) with medical support provided during office hours or 24/7; (2) STS programmes delivered by human-to-human contact (HH) or human-to-machine interface (HM). REVIEW METHODS A systematic review and network meta-analysis (where appropriate) of the clinical evidence was carried out using standard methods. A Markov model was developed to evaluate the cost-effectiveness of different RM packages compared with usual care for recently discharged HF patients. TM 24/7 or using cardiovascular monitoring devices was not considered in the economic model because of the lack of data and/or unsuitability for the UK setting. Given the heterogeneity in the components of usual care and RM interventions, the cost-effectiveness analysis was performed using a set of costing scenarios designed to reflect the different configurations of usual care and RM in the UK. RESULTS The literature searches identified 3060 citations. Six RCTs met the inclusion criteria and were added to the 15 trials identified from the previous systematic reviews giving a total of 21 RCTs included in the systematic review. No trials of cardiovascular implanted monitoring devices or observational studies met the inclusion criteria. The methodological quality of the studies varied widely and reporting was generally poor. Compared with usual care, RM was beneficial in reducing all-cause mortality for STS HH [hazard ratio (HR) 0.77, 95% credible interval (CrI) 0.55 to 1.08], TM during office hours (HR 0.76, 95% CrI 0.49 to 1.18) and TM 24/7 (HR 0.49, 95% CrI 0.20 to 1.18); however, these results were statistically inconclusive. The results for TM 24/7 should be treated with caution because of the poor methodological quality of the only included study in this network. No favourable effect on mortality was observed with STS HM. Similar reductions were observed in all-cause hospitalisations for TM interventions, whereas STS interventions had no major effect. A sensitivity analysis, in which a study was excluded because it provided better-than-usual support to the control group, showed larger beneficial effects for most outcomes, particularly for TM during office hours. In the cost-effectiveness analyses, TM during office hours was the most cost-effective strategy with an estimated incremental cost-effectiveness ratio (ICER) of £11,873 per quality-adjusted life-year (QALY) compared with usual care, whereas STS HH had an ICER of £228,035 per QALY compared with TM during office hours. STS HM was dominated by usual care. Similar results were observed in scenario analyses performed using higher costs of usual care, higher costs of STS HH and lower costs of TM during office hours. LIMITATIONS The RM interventions included in the review were heterogeneous in terms of monitored parameters and HF selection criteria and lacked detail in the components of the RM care packages and usual care (e.g. communication protocols, routine staff visits and resources used). As a result, the economic model developed scenarios for different RM classifications and their costs were estimated using bottom-up costing methods. Although the users can decide which of these scenarios is most representative of their setting, uncertainties still remain about the assumptions made in the estimation of these costs. In addition, the model assumed that the effectiveness of the interventions was constant over time, irrespective of the duration of deployment, and that the intervention was equally effective in different age/severity groups. CONCLUSION Despite wide variation in usual care and RM strategies, cost-effectiveness analyses suggest that TM during office hours was an optimal strategy (in most costing scenarios). However, clarity was lacking among descriptions of the components of RM packages and usual care and there was a lack of robust estimation of costs. Further research is needed in these areas. STUDY REGISTRATION PROSPERO registration no. CRD42011001368. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Febuxostat for the management of hyperuricaemia in patients with gout: a NICE single technology appraisal.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of febuxostat (Adenuric®; Ipsen, UK) was invited to submit evidence for the clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were commissioned to act as the independent Evidence Review Group (ERG).This article provides details of the company’s initial submission, the ERG’s clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced by a substantially different model, which were presented by the manufacturer after the production of the appraisal consultation document.The ERG produced a critical review of the evidence for the clinical evidence and cost effectiveness of the technology based upon the manufacturer’s submission to NICE.The clinical evidence was derived from two head-to-head, phase III, multiarm, randomized, double blind, controlled trials comparing the efficacy and safety of febuxostat with fixed-dose allopurinol (300/100mg/day) in patients with hyperuricaemia and gout. The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. Although a simple pooled analysis of the individual patientlevel data from the two trials was undertaken, the statistical approach for combining the data was considered inappropriate by the ERG as it failed to preserve randomization and introduced bias and confounding. There was substantial uncertainty in the relationships reported by the manufacturer regarding serum uric acid levels and the incidence of gout flares and underlying patient utility. The mathematical model developed was flawed and was not corrected despite ERG comments. It focused only on patients receiving febuxostat (80mg/day titrated to 120mg/day if necessary) with fixed-dose allopurinol (300/100mg/day). Sequential treatment was not modeled, nor was titrating allopurinol to 900mg/day, which is regarded as best practice. Numerous other errors were identified, which included the uncertain price of febuxostat being sampled within the probabilistic sensitivity analyses. Supplementary exploratory modelling addressing the position of febuxostat where patients were intolerant or contraindicated to allopurinol was provided to the NICE Appraisal Committee following the release of the appraisal consultation document.The NICE Appraisal Committee concluded that febuxostat be recommended as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant to allopurinol or for whom allopurinol is contraindicated.

Clinical decision rules for children with minor head injury: a systematic review

Introduction Clinical decision rules aid clinicians with the management of head injured patients. This study aimed to identify clinical decision rules for children with minor head injury and compare their diagnostic accuracy for detection of intracranial injury (ICI) and injury requiring neurosurgical intervention (NSI). Methods Relevant studies were identified by an electronic search of key databases. Papers in English were included with a cohort of at least 20 children suffering minor head injury (GCS 13–15). Studies of a decision rule derived to identify patients at risk of ICI or NSI had to include a proportion of the cohort undergoing imaging. Study quality was assessed using the QUADAS checklist. Results 16 publications, representing 14 cohorts, with 79 740 patients were included. Only four rules were tested in more than one cohort. Of the validated rules the paediatric emergency care applied research network (PECARN) rule was most consistent (sensitivity 98%; specificity 58%). For neurosurgical injury all had high sensitivity (98–100%) but the childrens head injury algorithm for the prediction of important clinical events (CHALICE) rule had the highest specificity (86%) in its derivation cohort. Conclusion Of the current decision rules for minor head injury the PECARN rule appears the best for children and infants, with the largest cohort, highest sensitivity and acceptable specificity for clinically significant ICI. Application of this rule in the UK would probably result in an unacceptably high rate of CT scans per injury, and continued use of the CHALICE-based NICE guidelines represents an appropriate alternative.

Clinical Decision Rules for Adults With Minor Head Injury: A Systematic Review

BACKGROUND There are many clinical decision rules for adults with minor head injury, but it is unclear how they compare in terms of diagnostic accuracy. This study aimed to systematically identify clinical decision rules for adults with minor head injury and compare the estimated diagnostic accuracies for any intracranial injury and injury requiring neurosurgical intervention. METHODS Several electronic bibliographic databases covering biomedical, scientific, and gray literature were searched from inception to March 2010. At least two independent reviewers determined the eligibility of cohort studies that described a clinical decision rule to identify adults with minor head injury (Glasgow Coma Scale score, 13-15) at risk of intracranial injury or injury requiring neurosurgical intervention. RESULTS Twenty-two relevant studies were identified. Differences existed in patient selection, outcome definition, and reference standards used. Nine rules stratified patients into high- and moderate-risk categories (to identify neurosurgical or nonsurgical intracranial lesions). The Canadian Computed Tomography Head Rule (CCHR) high-risk criteria have sensitivity of 99% to 100% with specificity of 48% to 77% for injury requiring neurosurgical intervention. Other rules such as New Orleans criteria, National Emergency X-Radiography Utilization Study II, Neurotraumatology Committee of the World Federation of Neurosurgical Societies, Scandinavian, and Scottish Intercollegiate Guidelines Network produce similar sensitivities for injury requiring neurosurgical intervention but with lower and more variable specificity values. DISCUSSION The most widely researched decision rule is the CCHR, which has consistently shown high sensitivity for identifying injury requiring neurosurgical intervention with an acceptable specificity to allow considered use of cranial computed tomography. No other decision rule has been as widely validated or demonstrated as acceptable results, but its exclusion criteria make it difficult to apply universally.

Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: a systematic review and cost-effectiveness analysis

BACKGROUND Gene expression profiling (GEP) and expanded immunohistochemistry (IHC) tests aim to improve decision-making relating to adjuvant chemotherapy for women with early breast cancer. OBJECTIVE The aim of this report is to assess the clinical effectiveness and cost-effectiveness of nine GEP and expanded IHC tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer in England and Wales. The nine tests are BluePrint, Breast Cancer Index (BCI), IHC4, MammaPrint, Mammostrat, NPI plus (NPI+), OncotypeDX, PAM50 and Randox Breast Cancer Array. DATA SOURCES Databases searched included MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. Databases were searched from January 2009 to May 2011 for the OncotypeDX and MammaPrint tests and from January 2002 to May 2011 for the other tests. REVIEW METHODS A systematic review of the evidence on clinical effectiveness (analytical validity, clinical validity and clinical utility) and cost-effectiveness was conducted. An economic model was developed to evaluate the cost-effectiveness of adjuvant chemotherapy treatment guided by four of the nine test (OncotypeDX, IHC4, MammaPrint and Mammostrat) compared with current clinical practice in England and Wales, using clinicopathological parameters, in women with oestrogen receptor-positive (ER+), lymph node-negative (LN-), human epidermal growth factor receptor type 2-negative (HER2-) early breast cancer. RESULTS The literature searches for clinical effectiveness identified 5993 citations, of which 32 full-text papers or abstracts (30 studies) satisfied the criteria for the effectiveness review. A narrative synthesis was performed. Evidence for OncotypeDX supported the prognostic capability of the test. There was some evidence on the impact of the test on decision-making and to support the case that OncotypeDX predicts chemotherapy benefit; however, few studies were UK based and limitations in relation to study design were identified. Evidence for MammaPrint demonstrated that the test score was a strong independent prognostic factor, but the evidence is non-UK based and is based on small sample sizes. Evidence on the Mammostrat test showed that the test was an independent prognostic tool for women with ER+, tamoxifen-treated breast cancer. The three studies appeared to be of reasonable quality and provided data from a UK setting (one study). One large study reported on clinical validity of the IHC4 test, with IHC4 score a highly significant predictor of distant recurrence. This study included data from a UK setting and appeared to be of reasonable quality. Evidence for the remaining five tests (PAM50, NPI+, BCI, BluePrint and Randox) was limited. The economic analysis suggests that treatment guided using IHC4 has the greatest potential to be cost-effective at a £20,000 threshold, given the low cost of the test; however, further research is needed on the analytical validity and clinical utility of IHC4, and the exact cost of the test needs to be confirmed. Current limitations in the evidence base produce significant uncertainty in the results. OncotypeDX has a more robust evidence base, but further evidence on its impact on decision-making in the UK and the predictive ability of the test in an ER+, LN-, HER- population receiving current drug regimens is needed. For MammaPrint and Mammostrat there were significant gaps in the available evidence and the estimates of cost-effectiveness produced were not considered to be robust by the External Assessment Group. LIMITATIONS Methodological weaknesses in the clinical evidence base relate to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence. Further evidence is required on the clinical utility of all of the tests and on UK-based populations. A key area of uncertainty relates to whether the tests provide prognostic or predictive ability. CONCLUSIONS The clinical evidence base for OncotypeDX is considered to be the most robust. The economic analysis suggested that treatment guided using IHC4 has the most potential to be cost-effective at a threshold of £20,000; however, the evidence base to support IHC4 needs significant further research. STUDY REGISTRATION PROSPERO 2011:CRD42011001361, available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001361.

Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation

OBJECTIVE To evaluate the cost-effectiveness of high-dose statins (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) versus simvastatin 40 mg/day in individuals with acute coronary syndrome (ACS). DATA SOURCES Eleven bibliographic databases, including MEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, DARE and NHS EED, were searched from inception to 2008. REVIEW METHODS Data relating to study design, baseline patient characteristics, clinical or surrogate outcome, and adverse events were abstracted, and methodological quality was assessed according to standard methods. A synthesis of the available evidence was performed using a Bayesian mixed treatment meta-analysis using both direct and indirect evidence. An existing Markov model was modified to explore the costs and benefits associated with a lifetime of the differing treatment regimens. RESULTS A total of 3345 titles and abstracts were screened for inclusion in the review of clinical effectiveness and 125 full papers retrieved and assessed in detail. Of these, 30 papers met the inclusion criteria for the review, describing 28 trials. The Bayesian mixed treatment meta-analysis demonstrated a clear dose-response relationship in terms of reductions in low-density lipoprotein cholesterol (LDL-c), with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%) from baseline, followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). Although serious adverse events with statins are rare, their incidence is likely to be greater with higher doses. Several clinical scenarios were used to explore the effect of adherence on the cost-effectiveness of the treatment regimens. Using a threshold of 20,000 pounds per quality-adjusted life-year (QALY) and assuming that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting and that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. Simvastatin 80 mg/day is not well tolerated because of the high incidence rates of less severe adverse events such as myopathy (26-fold higher than rates in those receiving simvastatin 20 mg/day), which are likely to affect adherence levels in clinical practice. The reference case shows that rosuvastatin is the optimal treatment for individuals with a recent history of ACS using a threshold of 20,000 pounds per QALY. However, this is based on the assumption that the additional incremental reductions in LDL-c observed in patients treated with rosuvastatin 40 mg/day compared with atorvastatin will transfer into corresponding changes in relative risks of cardiovascular events. CONCLUSIONS Simvastatin 80 mg/day cannot be recommended because of the high incidence rates of adverse events. If the cost of atorvastatin decreases in line with that observed for simvastatin when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment for all thresholds; if the cost reduces to 25% of the current value, atorvastatin 80 mg/day will be the most cost-effective treatment for thresholds between 5000 pounds and 30,000 pounds per QALY. Large long-term RCTs reporting effects in terms of clinical events are required to determine the optimum statin use for subgroups.

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.

Modelling the long term cost effectiveness of clopidogrel for the secondary prevention of occlusive vascular events in the UK

ABSTRACT Objective: To assess the long term cost effectiveness of clopidogrel monotherapy compared with acetylsalicylic acid (aspirin; ASA) monotherapy in patients at risk of secondary occlusive vascular events (OVEs) in the UK. Design: Cost utility analysis based on clinical data from CAPRIE (a multicentre randomised controlled trial, involving 19 185 patients); long-term effects were extrapolated beyond the trial period using a Markov model populated with data from UK observational studies. Health economic evaluation carried out from the perspective of the UK National Health Service. Participants: A representative cohort of 1000 UK patients aged 60 years (approximate mean age of the CAPRIE population), with the qualifying diagnoses of myocardial infarction, ischaemic stroke and peripheral arterial disease, who are at risk of secondary OVEs (non-fatal myocardial infarction, non-fatal stroke or vascular death). Interventions: Patients were assumed to receive treatment with either clopidogrel (75 mg/day) for 2 years followed by ASA (325 mg/day, average) for their remaining lifetime, or ASA alone (325 mg/day, average) for life. Main outcome measures: Incremental cost per life year gained and incremental cost per quality-adjusted life year (QALY) gained. Results: In the base case, the incremental cost effectiveness of clopidogrel versus ASA in this population is estimated at £18 888 per life year gained and £21 489 per QALY gained. Multiple deterministic and probabilistic sensitivity analyses suggest the model is robust to variations in a wide range of input parameters. Conclusion: Two years of treatment with clopidogrel can be considered a cost effective intervention in patients at risk of secondary OVEs in the UK.