I Tumur

The University of Sheffield, Sheffield, ENG, United Kingdom

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Publications (10)36.38 Total impact

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    ABSTRACT: To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. Systematic review and meta-analysis of randomized controlled trials (RCTs). Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of -18.58%, (95% CI: -19.67 to -17.48, P < 0.00001) compared with placebo. Significant (P < 0.00001) changes were also found in total cholesterol (-13.46%, 95% CI: -14.22 to -12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (-8.06%, 95% CI: -10.92 to -5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo. In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.
    Journal of Internal Medicine 12/2008; 265(5):568-80. · 6.46 Impact Factor
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    ABSTRACT: Ezetimibe has been reported to improve lipid control in patients with established cardiovascular disease (CVD). The aim of this study was to estimate the potential long-term impact on health status of prescribing ezetimibe in combination with statin therapy in patients with established CVD and evaluate its cost-effectiveness in a health economic model. A Markov model was used to compare ezetimibe and statin combination therapy with statin monotherapy. A published relationship linking changes in low-density lipoprotein cholesterol and cardiovascular events was used to estimate the cardiovascular events avoided through lipid-lowering therapies. The model was populated using results of extensive literature searches and a meta-analysis of clinical evidence. An adjustment was applied to model second-line lipid-lowering benefits. Conservative assumptions were used to extend the patient pathway beyond the clinical evidence. The analysis took the perspective of the UK Department of Health; therefore, only direct costs were included. Costs were calculated as year-2006 British pounds. For a cohort of 1,000 hypothetical male patients aged 55 years, ezetimibe coadministered with current statin therapy was estimated to prevent a mean of 43 nonfatal myocardial infarctions, 7 nonfatal strokes, and 26 cardiovascular deaths over a lifetime, compared with doubling the current statin dose. The events avoided would provide a mean of 134 additional quality-adjusted life-years (QALYs). With a mean incremental cost of pound 3,693,000, the lifetime discounted cost per QALY gained would be pound 27,475 (95% CI, pound 27,331- pound 27,620) and would rise to pound 32,000 for men aged 75 years. The results suggest that, in some instances, ezetimibe coadministration may be cost-effective compared with statin monotherapy, but there are several limitations with this model. The economic effects of ezetimibe must be revisited when long-term effectiveness and safety data become available.
    Clinical Therapeutics 09/2008; 30(8):1508-23. · 2.23 Impact Factor
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    ABSTRACT: To evaluate three technologies for the management of advanced colorectal cancer: (1) first-line irinotecan combination [with 5-fluorouracil (5-FU)] or second-line monotherapy; (2) first- or second-line oxaliplatin combination (again, with 5-FU); and (3) raltitrexed, where 5-FU is inappropriate. To examine the role of irinotecan and oxaliplatin in reducing the extent of incurable disease before curative surgery (downstaging). Ten electronic bibliographic databases covering the period up to August 2004. Searches identified existing studies of the effectiveness and economics of the technologies and any studies that evaluated any of the indications outlined above were included. Data were extracted and assessed generic components of methodological quality. Survival outcomes were meta-analysed. Seventeen trials were found, of varying methodological quality. Compared with 5-FU, first-line irinotecan improved overall survival (OS) by 2-4 months (p=0.0007), progression-free survival (PFS) by 2-3 months (p<0.00001) and response rates (p<0.001). It offered a different toxicity profile and no quality of life (QoL) advantage. However, second-line irinotecan compared with 5-FU improved OS by 2 months (p=0.035) and PFS by 1 month (p=0.03), and provided a better partial response rate, but with more toxicities and no QoL advantage. Compared with second-line best supportive care, irinotecan improved OS by 2 months (p=0.0001), had a different toxicity profile and maintained baseline QoL longer, but with no overall difference. The addition of oxaliplatin to second-line 5-FU is associated with a borderline significant improvement in overall survival (p<0.07); a significantly higher response rate (<0.0001); and more serious toxicities. There is no evidence for a significant difference in QoL. Schedules with treatment breaks may not reduce clinical effectiveness but reduce toxicity. The addition of oxaliplatin to second-line 5-FU also saw no improvement in OS (p<0.07), better PFS (by 2.1 months, p=0.0001), an 8.9% higher response rate (p<0.0001), more toxicities and no QoL advantage. There was no significant difference in OS or PFS between first-line irinotecan and oxaliplatin combinations except when 5-FU was delivered by bolus injection, when oxaliplatin provided better OS (p=0.032) and response rates (p=0.032), but not PFS (p=0.169). The regimens had different toxicity profiles and neither conferred a QoL advantage. When compared to 5-FU, raltitrexed is associated with no significant difference in overall or progression-free survival; no significant difference in response rates; more vomiting and nausea, but less diarrhoea and mucositis; no significant difference in, or worse QoL. Raltitrexed treatment was cut short in two out of four included trials due to excess toxic deaths. 5-FU followed by irinotecan was inferior to any other sequence. First-line irinotecan/5-FU combination improved OS and PFS, although further unplanned therapy exaggerated the OS effect size. Staged combination therapy (combination oxaliplatin followed by combination irinotecan or vice versa) provided the best OS and PFS, although there was no head-to-head comparison against other treatment plans. In the only trial to use three active chemotherapies in any staged combination, median OS was over 20 months. In another study, the longest median OS from a treatment plan using two active agents was 16.2 months. Where irinotecan or oxaliplatin were used with 5-FU to downstage people with unresectable liver metastases, studies consistently showed response rates of around 50%. Resection rates ranged from 9 to 35% with irinotecan and from 7 to 51% with oxaliplatin. In the one study that compared the regimens, oxaliplatin enabled more resections (p=0.02). Five-year OS rates of 5-26% and disease-free survival rates of 3-11% were reported in studies using oxaliplatin. Alone or in combination, 5-FU was more effective and less toxic when delivered by continuous infusion. Existing economic models were weak because of the use of unplanned second-line therapies in their trial data: the survival benefits in patients on such trials cannot be uniquely attributed to the allocated therapy. Consequently, the economic analyses are either limited to the use of PES (at best, a surrogate outcome) or are subject to confounding. Weaknesses in cost components, the absence of direct in-trial utility estimates and the limited use of sensitivity analysis were identified. Improvements to the methodologies used in existing economic studies are presented. Using data from two trials that planned treatment sequences, an independent economic evaluation of six plans compared with first-line 5-FU followed on progression by second-line irinotecan monotherapy (NHS standard treatment) is presented. 5-FU followed on progression by irinotecan combination cost 13,174 pounds per life-year gained (LYG) and 10,338 pounds per quality-adjusted life-year (QALY) gained. Irinotecan combination followed on progression by additional second-line therapies was estimated to cost 12,418 pounds per LYG and 13,630 pounds per QALY gained. 5-FU followed on progression by oxaliplatin combination was estimated to cost 23,786 pounds per LYG and 31,556 pounds per QALY gained. Oxaliplatin combination followed on progression by additional second-line therapies was estimated to cost 43,531 pounds per LYG and 67,662 pounds per QALY gained. Evaluations presented in this paragraph should be interpreted with caution owing to missing information on the costs of salvage therapies in the trial from which data were drawn. Irinotecan combination followed on progression by oxaliplatin combination cost 12,761 pounds per LYG and 16,663 pounds per QALY gained. Oxaliplatin combination followed on progression by irinotecan combination cost 16,776 pounds per LYG and 21,845 pounds per QALY gained. The evaluation suggests that these two sequences have a cost-effectiveness profile that is favourable in comparison to other therapies currently funded by the NHS. However, the differences in OS observed between the two trials from which data were taken may be a result of heterogeneous patient populations, unbalanced protocol-driven intensity biases or other differences between underlying health service delivery systems. Treatment with three active therapies appears most clinically effective and cost-effective. NHS routine data could be used to validate downstaging findings and a meta-analysis using individual patient-level data is suggested to validate the optimal treatment sequence.
    Health technology assessment (Winchester, England) 06/2008; 12(15):iii-ix, xi-162. · 4.03 Impact Factor
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    ABSTRACT: To review the clinical and cost-effectiveness of ezetimibe as a combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK. Twelve electronic databases were searched from inception to June 2006. Searches were supplemented by hand-searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings. A systematic review and meta-analysis (where appropriate) of the clinical efficacy evidence was undertaken following recommended guidelines. A Markov model was developed to explore the costs and health outcomes associated with ezetimibe treatment. No published clinical outcome trials (> 12 weeks) were identified. In the absence of clinical end-point data from trials, 13 (of which five were multi-arm) phase III multi-centre randomised controlled trials (RCTs) (of varying methodological quality) of short-term duration (12-48 weeks) with surrogate end-point data were included. For patients not adequately controlled with a statin alone, a meta-analysis of six studies showed that a fixed-dose combination of ezetimibe and statin treatment was associated with a statistically significant reduction in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (Total-c) compared with statin alone (p < 0.00001). Four studies (not eligible for meta-analysis) that titrated (either forced or stepwise) the statin doses to LDL-c targets generally showed that the co-administration of ezetimibe and statin was significantly more effective in reducing plasma LDL-c concentrations than statin monotherapy (p < 0.05 for all studies). For patients where a statin is not considered appropriate, a meta-analysis of seven studies demonstrated that ezetimibe monotherapy significantly reduced LDL-c levels compared with placebo (p < 0.00001). There were no statistically significant differences in LDL-c-lowering effects across different subgroups. Ezetimibe therapy (either in combination with a statin or monotherapy) appeared to be well tolerated compared to statin monotherapy or placebo, respectively. No ezetimibe studies reported data on health-related quality of life (HRQoL). There was a wide range in the economic results depending on the treatment strategies evaluated. When comparing ezetimibe monotherapy with no treatment in individuals with baseline LDL-c values of 3.0-4.0 mmol/l, the results range from 21,000 pounds to 50,000 pounds per quality-adjusted life-year (QALY). Results for individuals with baseline LDL-c values over 5.0 mmol/l are below 30,000 pounds per QALY. When comparing the costs and benefits of adding ezetimibe to ongoing statin treatment compared with maintaining statin treatment at the current dose, the majority of results are above values generally considered to be cost-effective (range 19,000 pounds to 48,000 pounds per QALY). Based on the evidence available, when comparing the costs and benefits associated with adding ezetimibe to ongoing statin treatment compared with a switch to a more potent statin, the results are governed by the difference in the cost of the treatment regimens compared and results range from 1500 pounds to 116,000 pounds per QALY. The short-term RCT clinical evidence demonstrated that ezetimibe was effective in reducing LDL-c when administered as monotherapy or in combination with a statin. However, when used as a monotherapy, ezetimibe is less effective than statins in lowering LDL-c. Given the limitations in the effectiveness data, there is great uncertainty in the economic results. These suggest that ezetimibe could be a cost-effective treatment for individuals with high baseline LDL-c values, for patients with diabetes and for individuals with heterozygous familial hypercholesterolaemia. Long-term clinical outcome studies are needed to allow more precise cost-effectiveness estimates to be calculated.
    Health technology assessment (Winchester, England) 06/2008; 12(21):iii, xi-xiii, 1-212. · 4.03 Impact Factor
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    ABSTRACT: To evaluate the cost effectiveness of long-term ezetimibe monotherapy in patients with established cardiovascular disease (CVD) who do not tolerate statins or in whom they are contraindicated. A Markov model was used to estimate the potential costs and benefits associated with ezetimibe monotherapy compared with no treatment. The benefits associated with ezetimibe treatment were informed by a systematic review of clinical evidence and a published relationship linking changes in low-density lipoprotein cholesterol (LDL-C) levels to cardiovascular events. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid levels were used as indicators of clinical outcomes. A meta-analysis of seven placebo-controlled trials included in the review showed that ezetimibe was associated with a statistically significant mean reduction (from baseline to endpoint) in LDL-C of 18.56% (95% CI -19.68, -17.44; p < 0.00001) compared with placebo. Using 10,000 Monte Carlo simulations, it is estimated that ezetimibe monotherapy would prevent an average of 49 nonfatal myocardial infarctions, 11 nonfatal strokes, and 37 cardiovascular deaths in a cohort of 1,000 patients aged 55 years with a baseline LDL-C concentration of 4.0 mmol/L. Events avoided provide an additional 211 quality-adjusted life-years (QALYs) over the 45 years modeled. With a mean incremental cost of pound 4,861,000 (year 2006 value), the discounted cost per QALY is pound 23,026 (Jackknife CI 22 979, 23 074). The model is reasonably robust to variations in key parameters. Incremental cost-effectiveness ratios fall below pound 20,000 per QALY for cohorts with baseline LDL-C values >4.5 mmol/L. Ezetimibe monotherapy compared with no treatment is a cost-effective alternative for individuals with a history of CVD and high LDL-C levels, who do not tolerate statins or in whom they are contraindicated.
    American Journal of Cardiovascular Drugs 01/2008; 8(6):419-27. · 2.20 Impact Factor
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    ABSTRACT: Computer-guided therapy is an innovative treatment strategy that could have an important role in the future of psychological treatment. This paper summarises the available published evidence that assesses the effectiveness of a computerised cognitive behaviour therapy (CCBT) for obsessive-compulsive disorder (OCD). Fifteen electronic bibliographic databases including Medline, Embase, the Cochrane Library, Cinahl, PsycINFO, Biological Abstracts, HMIC and NHS CRD databases were comprehensively searched in March 2004: ['obsessive compulsive disorder' (text and indexed terms)] AND ['cognitive therapy' (text and indexed terms)] AND ['computer' (text and indexed terms)]. Reference lists of included studies, guidelines, generic research, trials registers and specialist mental health sites were hand-searched. The search produced 149 citations from which we identified two RCTs and two single-arm studies with relevant data. All four studies used one software programme - BTSteps. In the large RCT, YBOCS effect sizes for BTSteps, therapist-led cognitive behaviour therapy (TCBT) and relaxation (RLX) were 0.84, 1.22, and 0.35, respectively. The smaller RCT found significantly better outcomes with brief scheduled support compared to brief on-demand phone support. BTSteps was as good as TCBT for reducing time spent in rituals and obsessions and for improving the Work and Social Adjustment Scale (WSA), and was superior to RLX treatment. The available evidence also showed that improvement of OCD persisted beyond the end of CCBT. TCBT was more effective than CCBT for all patients overall though not in those who went on to start self-exposure. Such a system has the potential to widen the access to CBT in general and considerably shorten clinician-guided care.
    Psychotherapy and Psychosomatics 02/2007; 76(4):196-202. · 9.38 Impact Factor
  • Journal of Mental Health Policy. 01/2007; 10:S5-S6.
  • Journal of Mental Health Policy. 01/2007; 10:S18-19.
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    ABSTRACT: To summarise the available evidence on the clinical effectiveness and cost-effectiveness of psychological therapies including dialectical behaviour therapy (DBT) for borderline personality disorder (BPD). Electronic databases were searched up to March 2005. Relevant studies were assessed using standard checklists and data were abstracted by two reviewers using standardised forms. Separate economic evaluations were undertaken for six selected randomised controlled trials (RCTs). Cost-effectiveness was assessed in terms of cost per parasuicide event avoided in all six trials and cost per quality-adjusted life-year (QALY) in four of them. All results are at 2003-4 prices and for 12 months follow-up. Nine RCTs and one non-RCT of moderate to poor quality were identified in the clinical effectiveness review. They provided some evidence that DBT is more effective than treatment as usual (TAU) for the treatment of chronically parasuicidal and drug-dependent borderline women; that DBT-orientated therapy is more effective than client-centred therapy (CCT) for the treatment of BPD; and that DBT is as effective as comprehensive validation therapy plus 12-Step for the treatment of opioid-dependent borderline women. There was also some evidence that partial hospitalisation is more effective than TAU in the treatment of BPD, good evidence that manual-assisted cognitive behavioural therapy (MACT) is no more effective than TAU in the treatment of BPD and some evidence that interpersonal group therapy is no more effective than individual mentalisation-based partial hospitalisation (MBT) for the treatment of BPD. However, these results should be interpreted with caution as not all studies were primarily targeted to borderline symptoms and there were considerable differences between the studies. The assessment of cost-effectiveness found a mix of results in the four trials of DBT, along with the high levels of uncertainty and the limitations in the analyses. The findings do not support the cost-effectiveness of DBT though they suggest it has the potential to be cost-effective. The results for MBT are promising, though again surrounded by a high degree of uncertainty and for MACT, the analysis suggests that the intervention is unlikely to be cost-effective. The overall efficacy of psychological therapies is promising; however, at this stage the evidence is inconclusive. The cost-effectiveness of the intervention in six RCTs examined, however, does not support the cost-effectiveness of DBT although potential is suggested. There is a need for considerable research in this area. This research should involve appropriately powered head-to-head RCTs of psychological therapies; a survey of current practice and the use of the full range of services by people with BPD to inform future economic analyses; full resource-use data collected in the context of pragmatic clinical trials; psychometric assessment of the validity of the EQ-5D or other generic and condition-specific preference-based measures in BPD, and the development of a more formal cost-effectiveness model using the above data.
    Health technology assessment (Winchester, England) 10/2006; 10(35):iii, ix-xii, 1-117. · 4.03 Impact Factor
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    ABSTRACT: To evaluate computerised cognitive behaviour therapy (CCBT) for the treatment of anxiety, depression, phobias, panic and obsessive-compulsive behaviour (OCD). The software packages to be considered include Beating the Blues (BtB), Overcoming Depression: a five areas approach, FearFighter (FF), Cope and BT Steps. Other packages or programmes incorporating CCBT were also considered. Electronic databases from 1966 to March 2004. Evidence submitted by sponsors for CCBT products. A systematic review was a review of the literature and the evidence submitted by sponsors for each of the products. A series of cost-effectiveness models was developed and run by the project team for the five CCBT products across the three mental health conditions. Twenty studies were identified in the clinical effectiveness review. The analysis of these results showed some evidence that CCBT is as effective as therapist-led cognitive behaviour therapy (TCBT) for the treatment of depression/anxiety and phobia/panic and is more effective than treatment as usual (TAU) in the treatment of depression/anxiety. CCBT also appears to reduce therapist time compared with TCBT. When reviewing cost-effectiveness studies, only one published economic evaluation of CCBT was found. This was an economic evaluation of the depression software BtB alongside a randomised controlled trial (RCT), which found that BtB was cost-effective against TAU in terms of cost per quality-adjusted life-year (QALY) (less than 2000 pounds), however it contained weaknesses that were then addressed in the cost-effectiveness model developed for the study. The results of the model for the depression software packages in terms of incremental cost per QALY compared with TAU and the chance of being cost-effective at 30,000 pounds per QALY were for BtB 1801 pounds and 86.8%, for Cope 7139 pounds and 62.6% and for Overcoming Depression 5391 pounds and 54.4%. The strength of the BtB software being that it has been evaluated in the context of an RCT with a control group. The subgroup analysis found no differences across the severity groupings. For phobia/panic software, the model showed an incremental cost per QALY of FF over relaxation was 2380 pounds. Its position compared with TCBT is less clear. When modelling OCD packages, using the practice-level licence cost meant that BT Steps was dominated by TCBT, which had significantly better outcomes and was cheaper. However, the cheaper PCT licence resulted in the incremental cost-effectiveness of BT Steps over relaxation being 15,581 pounds and TCBT over BT Steps being 22,484 pounds. The study findings are subject to substantial uncertainties around the organisational level for purchasing these products and the likely throughput. This is in addition to concerns with the quality of evidence on response to therapy, longer term outcomes and quality of life. The position of CCBT within a stepped care programme needs to be identified, as well as its relationship to other efforts to increase access to CBT and psychological therapies. Research is needed to compare CCBT with other therapies that reduce therapist time, in particular bibliotherapy and to explore the use of CCBT via the Internet. Independent research is needed, particularly RCTs, that examine areas such as patient preference and therapist involvement within primary care.
    Health technology assessment (Winchester, England) 10/2006; 10(33):iii, xi-xiv, 1-168. · 4.03 Impact Factor