G Rogers

The harmful health effects of recreational ecstasy: a systematic review of observational evidence

OBJECTIVES To investigate the harmful health effects of taking ecstasy (3,4-methylenedioxymethamphetamine, MDMA) for recreational purposes. DATA SOURCES MEDLINE, EMBASE, PsycINFO and Web of Knowledge were searched. Additional information on deaths was collected from the General Mortality Register (GMR) and the Special Mortality Register collated by the National Programme on Substance Abuse Deaths (np-SAD). REVIEW METHODS Studies were categorised according to design, with systematic research syntheses (Level I evidence) the most valid and least open to bias. Where Level I evidence was not available, controlled observational studies (Level II evidence) were systematically reviewed. If neither Level I nor Level II evidence was available, uncontrolled case series and case reports (Level III evidence) were systematically surveyed. Data were extracted by one reviewer and a sample checked by a second. The heterogeneity of Level II evidence was addressed by undertaking stratified analyses for current and former ecstasy users and comparing them either with control groups using other illegal drugs but not ecstasy (polydrug controls) or with controls naïve to illegal drugs (drug-naïve controls). Statistical heterogeneity was minimised by using a random-effects model throughout and investigated using study-level regression analysis (metaregression). RESULTS Five Level I syntheses were identified; for each it was difficult to ascertain the exact methods adopted and evidence included. Small but significant deficits for ecstasy users compared to controls were reported in areas relating to attention, memory, psychomotor speed, executive systems functioning, and self-reported depressive symptoms. Data from Level II studies were directly pooled for seven individual outcomes, suggesting that ecstasy users performed worse than controls on common measures of immediate and delayed verbal recall (RAVLT, RBMT, digit span). No difference was seen in IQ (NART). The 915 outcome measures identified in Level II studies were analysed in broad domains: immediate and delayed verbal and visual memory, working memory, two measures of attention, three measures of executive function, perceptual organisation, self-rated depression, memory and anxiety, and impulsivity measured objectively and subjectively. Ecstasy users performed significantly worse than polydrug controls in 13/16 domains and significantly worse than drug-naïve controls in 7/12 domains for which sufficient data were available. The largest, most consistent exposure effects were seen in meta-analyses of memory (especially verbal and working memory, with less marked effects seen in visual memory). Former ecstasy users frequently showed deficits that matched or exceeded those seen amongst current users. At aggregate level, the effects do not appear to be dose-related, but are variably confounded by other drug use, particularly alcohol. Of Level III evidence, in the 10 years to 2006, the np-SAD and the GMR recorded an average of around 50 drug-related deaths per year involving ecstasy; it was the sole drug implicated in around 10 cases per year. Retrospective case series, based on hospital emergency department records, reported a death rate of 0-2% from emergency admissions related to ecstasy. Two major syndromes are most commonly reported as the immediate cause of death in fatal cases: hyperthermia and hyponatraemia. CONCLUSIONS A broad range of relatively low-quality literature suggests that recreational use of ecstasy is associated with significant deficits in neurocognitive function (particularly immediate and delayed verbal memory) and increased psychopathological symptoms. The clinical significance of the exposure effect in individual cases will be variable but, on average, deficits are likely to be relatively small. Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.OBJECTIVES To provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better. DATA SOURCES Eight electronic bibliographic databases were searched during March-April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language. METHODS Selected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results. RESULTS In total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8-34.3, p < 0.001) in men with an annual PSA velocity of more than 2 ng/ml versus an annual PSA velocity of 2 ng/ml or less; similarly, the hazard ratio was 12.8 (95% CI 3.7-43.7, p < 0.001) in the pathological model. The quality of the prognostic model studies was adequate and overall better than the quality of the prognostic marker studies. Two issues were poorly dealt with in most or all of the prognostic model studies: inclusion of established markers and consideration of the possible biases from study attrition. Given the heterogeneity of the models, they cannot be considered comparable. Only two models did not include a novel marker, and one of these included several demographic and co-morbidity variables to predict all-cause mortality. Only two models reported a measure of model performance, the C-statistic, and for neither was it calculated in an external data set. It was not possible to assess whether the models that included novel markers performed better than those without. CONCLUSIONS This review highlighted the poor quality and heterogeneity of studies, which render much of the results inconclusive. It also pinpointed the small proportion of models reported in the literature that are based on patient cohorts with a mean or median follow-up of at least 5 years, thus making long-term predictions unreliable. PSA velocity, however, stood out in terms of the strength of the evidence supporting its prognostic value and the relatively high hazard ratios. There is great interest in PSA velocity as a monitoring tool for active surveillance but there is as yet no consensus on how it should be used and, in particular, what threshold should indicate the need for radical treatment.

The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of Technology Appraisal No. 111): A Systematic Review and Economic Model

BACKGROUND Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY. LIMITATIONS Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Dasatinib and Nilotinib for Imatinib-Resistant or -Intolerant Chronic Myeloid Leukaemia: A Systematic Review and Economic Evaluation

BACKGROUND Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

Surveillance of cirrhosis for hepatocellular carcinoma: a cost–utility analysis

Using a decision-analytic model, we evaluated the effectiveness and cost-effectiveness of surveillance for hepatocellular carcinoma (HCC) in individuals with cirrhosis. Separate cohorts with cirrhosis due to alcoholic liver disease, hepatitis B and hepatitis C were simulated. Results were also combined to approximate a mixed aetiology population. Comparisons were made between a variety of surveillance algorithms using α-foetoprotein (AFP) assay and/or ultrasound at 6- and 12-monthly intervals. Parameter estimates were obtained from comprehensive literature reviews. Uncertainty was explored using one-way and probabilistic sensitivity analyses. In the mixed aetiology cohort, 6-monthly AFP+ultrasound was predicted to be the most effective strategy. The model estimates that, compared with no surveillance, this strategy may triple the number of people with operable tumours at diagnosis and almost halve the number of people who die from HCC. The cheapest strategy employed triage with annual AFP (incremental cost-effectiveness ratio (ICER): £20 700 per quality-adjusted life-year (QALY) gained). At a willingness-to-pay threshold of £30 000 per QALY the most cost-effective strategy used triage with 6-monthly AFP (ICER: £27 600 per QALY gained). The addition of ultrasound to this strategy increased the ICER to £60 100 per QALY gained. Surveillance appears most cost-effective in individuals with hepatitis B-related cirrhosis, potentially due to younger age at diagnosis of cirrhosis. Our results suggest that, in a UK NHS context, surveillance of individuals with cirrhosis for HCC should be considered effective and cost-effective. The economic efficiency of different surveillance strategies is predicted to vary markedly according to cirrhosis aetiology.

Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness

Background:Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-α (IFN-α)) in the treatment of advanced metastatic RCC.Methods:Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-α) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator.Results:Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63–1.0; P=0.0272).Conclusion:There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.

Cost-effectiveness of dasatinib and nilotinib for imatinib-resistant or -intolerant chronic phase chronic myeloid leukemia

OBJECTIVES To estimate the cost-effectiveness of dasatinib and nilotinib compared with high-dose imatinib for people with chronic phase chronic myeloid leukemia, which are resistant to normal-dose imatinib and compared with interferon-α for people intolerant to imatinib, from the perspective of the UK National Health Service. METHODS An an area under the curve partitioned survival model was developed to estimate the cost-effectiveness of dasatinib and nilotinib. Clinical effectiveness evidence was taken mostly from single-arm trials. RESULTS Both progression-free survival and overall survival are highly uncertain. In the base case, patients take nilotinib for much less time than dasatinib. Nilotinib is expected to dominate high-dose imatinib, yielding slightly more (0.32) quality-adjusted life years (QALYs) at slightly less cost (£11,100 [pound sterling]) per person. Dasatinib is predicted to provide slightly more (0.53) QALYs at substantially greater cost (£48,900), yielding a very high incremental cost-effectiveness ratio of £91,500 QALY against high-dose imatinib. Cost-effectiveness, however, changes radically under the plausible assumption that the drugs are taken for the same time. For people intolerant to imatinib, nilotinib is expected to yield an incremental cost-effectiveness ratio of £104,700/QALY, and dasatinib £82,600/QALY compared with interferon-α. Further, both drugs represent poor value for money for a range of plausible structural assumptions. CONCLUSIONS The model should be viewed as an exploratory analysis of the cost-effectiveness of dasatinib and nilotinib because it relies on many assumptions. Whilst clinical data remains immature, the cost-effectiveness of dasatinib and nilotinib for imatinib-resistant people is highly uncertain. Both nilotinib and dasatinib are highly unlikely to be cost-effective versus interferon-α for people intolerant to imatinib.

Patient self-assessment of hospital pain, mood and health-related quality of life in adults with sickle cell disease.

Introduction Acute pain is a hallmark of sickle cell disease (SCD) for which frequent hospital admissions may be required, affecting the quality of life of patients. Objectives To characterise the relationship between adult patient self-reported sickle cell pain, mood and quality of life during and after hospital admissions. Design Longitudinal study across three time-points. Setting Secondary care, single specialist sickle cell centre. Participants 510 adult patients with SCD admitted to hospital daycare or inpatient units. Outcome measures Self-assessments of pain, mood and health-related quality of life with health utility (measured on the EQ-5D) on admission, before discharge and at 1-week postdischarge. Results Mood, general health and quality of life showed significant steady improvements with reduction of pain in patients with SCD on admission to hospital, before discharge and at 1-week follow-up (p<0.01). Health utility scores derived from the EQ-5D showed a negative association with pain in regression analysis over the three time-points. Conclusion Examining health-related quality of life and health utility in relation to pain during hospital admissions is valuable in terms of targeting appropriate psychological interventions within the context of a multidisciplinary approach to managing sickle cell pain. This has implications for healthcare costs.

Carmustine implants for the treatment of newly diagnosed high-grade gliomas: a cost-utility analysis.

BackgroundHigh-grade gliomas are aggressive brain tumours that are extremely challenging to treat effectively. The intracranial implantation of carmustine wafers (BCNU-W), which delivers chemotherapy directly to the affected area, may prolong survival in this population. However, no attention has yet been paid to the economic implications of BCNU-W in this setting.ObjectiveTo investigate the cost effectiveness of BCNU-W as an adjunct to surgery followed by radiotherapy, compared with surgery plus radiotherapy alone. Newly diagnosed, operable grade III and IV gliomas in a population with a mean age of 55 years were considered.MethodsA Markov cost-utility model was developed in Microsoft® Excel, adopting a UK NHS perspective. Transition probabilities and cost data (year 2004 values) were obtained from published literature or expert opinion. The model incorporated utility values, obtained from members of the public, reflecting the quality of life associated with high-grade glioma. The effects of uncertainty were explored through extensive one-way and probabilistic sensitivity analysis.ResultsSurgery with the implantation of BCNU-W followed by radiotherapy costs £54 500 per additional QALY gained when compared with surgery plus radiotherapy alone. Probabilistic sensitivity analysis shows a <10% probability that BCNU-W would be considered cost effective at a willingness-to-pay threshold of £30 000 per QALY. Although model outputs were sensitive to alterations in several key parameters, the incremental cost effectiveness of the intervention remained above £30 000 per QALY in all analyses.ConclusionCompared with usual care for the treatment of newly diagnosed high-grade gliomas, BCNU-W is unlikely to be considered a cost-effective use of healthcare resources when judged by the standards commonly adopted in England and Wales. However, the dreadful prognosis of the condition and the paucity of alternative therapies are additional issues that healthcare commissioners may choose to take into account when considering an adoption decision.

Diagnosis and management of gallstone disease: summary of NICE guidance

Gallstone disease is common—10-15% of adults in Western populations are thought to have the condition.1 2 Concerns about inappropriate variation in the management of gallstones have led to the development of recommendations on the diagnosis and management of cholelithiasis, cholecystitis, and choledocholithiasis in an attempt to improve patient outcomes and promote effective use of resources. This article summarises the most recent recommendations on the management of gallstone disease from the National Institute for Health and Care Excellence (NICE).3 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Diagnosis ### Treating asymptomatic gallbladder stones

Parkinson’s disease: summary of updated NICE guidance

#### What you need to know Parkinson’s disease is one of the most common neurological conditions, estimated to affect around 250 people per 100 000 in the UK.1 People with Parkinson’s disease classically present with motor symptoms including bradykinesia, rigidity, rest tremor, and postural instability; however, non-motor symptoms may also be prominent, including depression, cognitive impairment, and autonomic disturbances. This article summarises the most recent update to the National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of Parkinson’s disease in adults.2 This NICE guideline provides an update on most aspects of managing Parkinson’s disease, incorporating knowledge generated by a series of recent, large scale, independently funded, randomised trials in Parkinson’s therapy, and replaces guidance published in 2006. The update reflects emerging experience in areas such as impulse control disorders that may coexist with Parkinson’s disease and provides recommendations on the use of treatments that may provide some relief from the distressing symptoms of advanced Parkinson’s disease. The guideline update has not changed the suggested approach to the diagnosis of Parkinson’s disease, communication with people with Parkinson’s disease and their carers, pharmacological neuroprotective therapy, and interventions by Parkinson’s disease nurse specialists. Recommendations, full details of evidence, and the NICE pathway are available via the NICE website (www.nice.org.uk/guidance/ng71). NICE recommendations are …