T Moxham

Home based versus centre based cardiac rehabilitation: Cochrane systematic review and meta-analysis.

Objective To compare the effect of home based and supervised centre based cardiac rehabilitation on mortality and morbidity, health related quality of life, and modifiable cardiac risk factors in patients with coronary heart disease. Design Systematic review. Data sources Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, CINAHL, and PsycINFO, without language restriction, searched from 2001 to January 2008. Review methods Reference lists checked and advice sought from authors. Included randomised controlled trials that compared centre based cardiac rehabilitation with home based programmes in adults with acute myocardial infarction, angina, or heart failure or who had undergone coronary revascularisation. Two reviewers independently assessed the eligibility of the identified trials and extracted data independently. Authors were contacted when possible to obtain missing information. Results 12 studies (1938 participants) were included. Most studies recruited patients with a low risk of further events after myocardial infarction or revascularisation. No difference was seen between home based and centre based cardiac rehabilitation in terms of mortality (relative risk 1.31, 95% confidence interval 0.65 to 2.66), cardiac events, exercise capacity (standardised mean difference −0.11, −0.35 to 0.13), modifiable risk factors (weighted mean difference systolic blood pressure (0.58 mm Hg, −3.29 mm Hg to 4.44 mm Hg), total cholesterol (−0.13 mmol/l, −0.31 mmol/l to 0.05 mmol/l), low density lipoprotein cholesterol (−0.15 mmol/l, −0.31 mmol/l to 0.01 mmol/l), or relative risk for proportion of smokers at follow-up (0.98, 0.73 to 1.31)), or health related quality of life, with the exception of high density lipoprotein cholesterol (−0.06, −0.11 to −0.02) mmol/l). In the home based participants, there was evidence of superior adherence. No consistent difference was seen in the healthcare costs of the two forms of cardiac rehabilitation. Conclusions Home and centre based forms of cardiac rehabilitation seem to be equally effective in improving clinical and health related quality of life outcomes in patients with a low risk of further events after myocardial infarction or revascularisation. This finding, together with the absence of evidence of differences in patients’ adherence and healthcare costs between the two approaches, supports the further provision of evidence based, home based cardiac rehabilitation programmes such as the “Heart Manual.” The choice of participating in a more traditional supervised centre based or evidence based home based programme should reflect the preference of the individual patient.

Exercise training for systolic heart failure: Cochrane systematic review and meta‐analysis

To determine the effect of exercise training on clinical events and health‐related quality of life (HRQoL) of patients with systolic heart failure.

Reduced Dietary Salt for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials (Cochrane Review)

BACKGROUND Although meta-analyses of randomized controlled trials (RCTs) of salt reduction report a reduction in the level of blood pressure (BP), the effect of reduced dietary salt on cardiovascular disease (CVD) events remains unclear. METHODS We searched for RCTs with follow-up of at least 6 months that compared dietary salt reduction (restricted salt dietary intervention or advice to reduce salt intake) to control/no intervention in adults, and reported mortality or CVD morbidity data. Outcomes were pooled at end of trial or longest follow-up point. RESULTS Seven studies were identified: three in normotensives, two in hypertensives, one in a mixed population of normo- and hypertensives and one in heart failure. Salt reduction was associated with reductions in urinary salt excretion of between 27 and 39 mmol/24 h and reductions in systolic BP between 1 and 4 mm Hg. Relative risks (RRs) for all-cause mortality in normotensives (longest follow-up-RR: 0.90, 95% confidence interval (CI): 0.58-1.40, 79 deaths) and hypertensives (longest follow-up RR 0.96, 0.83-1.11, 565 deaths) showed no strong evidence of any effect of salt reduction CVD morbidity in people with normal BP (longest follow-up: RR 0.71, 0.42-1.20, 200 events) and raised BP at baseline (end of trial: RR 0.84, 0.57-1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause mortality in those with heart failure (end of trial RR 2.59, 1.04-6.44, 21 deaths).We found no information on participants health-related quality of life. CONCLUSIONS Despite collating more event data than previous systematic reviews of RCTs (665 deaths in some 6,250 participants) there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or CVD morbidity. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved.

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.

Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems

BACKGROUND Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations. OBJECTIVES To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS. DATA SOURCES A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion. REVIEW METHODS CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated. RESULTS Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (639 euros) in each of the intervention clinics compared with a 2% (208 euros) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from 41.8 euros per patient per annum to 47.2 euros after implementation of the system. LIMITATIONS The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA. CONCLUSIONS If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs. STUDY REGISTRATION Study registration 61.

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.

Levels and predictors of exercise referral scheme uptake and adherence: a systematic review

Background The effectiveness of exercise referral schemes (ERS) is influenced by uptake and adherence to the scheme. The identification of factors influencing low uptake and adherence could lead to the refinement of schemes to optimise investment. Objectives To quantify the levels of ERS uptake and adherence and to identify factors predictive of uptake and adherence. Methods A systematic review and meta-analysis was undertaken. MEDLINE, EMBASE, PsycINFO, Cochrane Library, ISI WOS, SPORTDiscus and ongoing trial registries were searched (to October 2009) and included study references were checked. Included studies were required to report at least one of the following: (1) a numerical measure of ERS uptake or adherence and (2) an estimate of the statistical association between participant demographic or psychosocial factors (eg, level of motivation, self-efficacy) or programme factors and uptake or adherence to ERS. Results Twenty studies met the inclusion criteria, six randomised controlled trials (RCTs) and 14 observational studies. The pooled level of uptake in ERS was 66% (95% CI 57% to 75%) across the observational studies and 81% (95% CI 68% to 94%) across the RCTs. The pooled level of ERS adherence was 49% (95% CI 40% to 59%) across the observational studies and 43% (95% CI 32% to 54%) across the RCTs. Few studies considered anything other than gender and age. Women were more likely to begin an ERS but were less likely to adhere to it than men. Older people were more likely to begin and adhere to an ERS. Limitations Substantial heterogeneity was evident across the ERS studies. Without standardised definitions, the heterogeneity may have been reflective of differences in methods of defining uptake and adherence across studies. Conclusions To enhance our understanding of the variation in uptake and adherence across ERS and how these variations might affect physical activity outcomes, future trials need to use quantitative and qualitative methods.

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.

The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model

OBJECTIVE To review the evidence for the effectiveness and cost-effectiveness of storing kidneys from deceased donors prior to transplantation, using cold static storage solutions or pulsatile hypothermic machine perfusion. DATA SOURCES Electronic databases were searched in January 2008 and updated in May 2008 for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs), other study designs and ongoing research. Sources included: Cochrane Library, MEDLINE, EMBASE, CINAHL, ISI Web of Knowledge, DARE, NRR, ReFeR, Current Controlled Trials, and (NHS) HTA. Bibliographies of articles were searched for further relevant studies, and the Food and Drugs Administration (FDA) and European Regulatory Agency Medical Device Safety Service websites were searched. Only English language papers were sought. REVIEW METHODS The perfusion machines identified were the LifePort Kidney Transporter (Organ Recovery Systems) and the RM3 Renal Preservation System (Waters Medical Systems). The cold storage solutions reviewed were: University of Wisconsin, ViaSpan; Marshalls hypertonic citrate, Soltran; and Genzyme, Celsior. Each intervention was compared with the others as data permitted. The population was recipients of kidneys from deceased donors. The main outcomes were measures of graft survival, patient survival, delayed graft function (DGF), primary non-function (PNF), discard rates of non-viable kidneys, health-related quality of life and cost-effectiveness. Where data permitted the results of studies were pooled using meta-analysis. A Markov (state transition) model was developed to simulate the main post-transplantation outcomes of kidney graft recipients. RESULTS Eleven studies were included: three full journal published RCTs, two ongoing RCTs [European Machine Preservation Trial (MPT) and UK Pulsatile Perfusion in Asystolic donor Renal Transplantation (PPART) study], one cohort study, three full journal published retrospective record reviews and two retrospective record reviews published as posters or abstracts only. For LifePort versus ViaSpan, no significant differences were found for DGF, PNF, acute rejection, duration of DGF, creatinine clearance or toxicity, patient survival or graft survival at 6 months, but graft survival was better at 12 months post transplant with machine perfusion (LifePort = 98%, ViaSpan = 94%, p < 0.03). For LifePort versus RM3, all outcomes favoured RM3, although the results may be unreliable. For ViaSpan versus Soltran, there were no significant differences in graft survival for cold ischaemic times up to 36 hours. For ViaSpan versus Celsior, no significant differences were found on any outcome measure. In terms of cost-effectiveness, data from the MPT suggested that machine preservation was cheaper and generated more quality-adjusted life-years (QALYs), while the PPART study data suggested that cold storage was preferable on both counts. The less reliable deterministic outputs of the cohort study suggested that LifePort would be cheaper and would generate more QALYs than Soltran. Sensitivity analyses found that changes to the differential kidney storage costs between comparators have a very low impact on overall net benefit estimates; where differences in effectiveness exist, dialysis costs are important in determining overall net benefit; DGF levels become important only when differences in graft survival are apparent between patients experiencing immediate graft function (IGF) versus DGF; relative impact of differential changes to graft survival for patients experiencing IGF as opposed to DGF depends on the relative proportion of patients experiencing each of these two outcomes. CONCLUSIONS The conclusions drawn for the comparison of machine perfusion with cold storage depend on which trial data are used in the model. Owing to the lack of good research evidence that either ViaSpan or Soltran is better than the other, the cheaper, Soltran, may be preferable. In the absence of a cost-utility analysis, the results of our meta-analysis of the RCTs comparing ViaSpan with Celsior indicate that these cold storage solutions are equivalent. Further RCTs of comparators of interest to allow for appropriate analysis of subgroups and to determine whether either of the two machines under consideration produces better outcomes may be useful. In addition, research is required to: establish the strength and reliability of the presumed causal association between DGF and graft, and patient survival; investigate the utility impacts of renal replacement therapy; determine what the additional cost, survival and QALY impacts are of decreased or increased non-viable kidneys when discarded pre transplantation; and identify a reliable measure for predicting kidney viability from machine perfusion.

Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

The submissions evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progression-free survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a three-state Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was 27,365 pounds per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case ICER of 32,636 pounds per QALY. Pfizers sensitivity analysis produced a range of ICERs from 15,536 pounds per QALY to 59,002 pounds per QALY. Weaknesses of the manufacturers submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural failure time (RPSFT) analysis to correct for possible bias; and that a number of errors and omissions were made in the probabilistic sensitivity analysis, meaning that it is not possible to come to firm conclusions about the cost-effectiveness of sunitinib for GIST in this patient population. In conclusion, during the blinded phase of the RCT, overall survival was significantly longer in the sunitinib arm than in the placebo arm (hazard ratio 0.491, 95% CI 0.290 to 0.831, p <0.007). However, intention-to-treat analysis of the entire study showed no statistically significant difference in overall survival for those who received sunitinib (73 weeks) versus those who received placebo (65 weeks) (hazard ratio 0.876, 95% CI 0.679 to 1.129, p = 0.306).