Paul Tappenden

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus

BACKGROUND Pioglitazone is a member of a recently developed class of glucose-lowering agents, the thiazolidinediones, used in the treatment of type 2 diabetes mellitus. In the United States, it is approved for use both as monotherapy and in combination with metformin, a sulfonylurea, or insulin; in Europe, it is approved for use in combination with metformin or a sulfonylurea but not insulin. OBJECTIVE This article presents a systematic review of the published literature on the effectiveness of pioglitazone in the treatment of type 2 diabetes, both as monotherapy and in combination with other antidiabetic agents. METHODS The peer-reviewed English- and foreign-language literature was searched using MEDLINE, PubMED, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the UK National Health Service Centre for Reviews and Dissemination databases, and the Office of Health Economics Health Economic Evaluations Database. Searches were not limited to specific publication types, study designs, dates, or languages. The latest search was performed in March 2001. For a trial to be included in the review, at least 1 outcome measure had to involve the effects of pioglitazone on glycemic control or cardiovascular risk factors, or its side effects. Because of the heterogeneity of studies, no formal meta-analysis was performed. RESULTS Eleven studies met the inclusion criteria, 6 involving pioglitazone monotherapy and 5 involving combination therapy. Full reports were available for only 6 of the 11 studies. No studies directly compared pioglitazone with other antidiabetic drugs. Both as monotherapy and in combination therapy, pioglitazone produced decreases in blood glucose levels (up to 95 mg/dL) and glycosylated hemoglobin (up to 2.6%). At doses of > or = 30 mg/d, pioglitazone was associated with reductions in triglyceride levels (-30-70 mg/dL) and increases in high-density lipoprotein cholesterol (HDL-C) levels (-4-5 mg/dL). Pioglitazone treatment was associated with significant weight gain (up to 4 kg over 16 weeks). Adverse effects included mild edema (in up to 11.7% of patients) and a clinically nonsignificant decrease in hemoglobin concentrations. Abnormal results on liver function testing were no more common in treated patients than in control groups. CONCLUSIONS Pioglitazone has been shown to reduce blood glucose levels in patients with type 2 diabetes. Although the observed decreases in triglyceride levels and increases in HDL-C levels could be expected to lead to a reduction in cardiovascular risk, the effects of weight gain may counteract this benefit. The evidence suggests that the preferred role for pioglitazone may be as an adjunct to metformin or a sulfonylurea in patients whose condition is not well controlled with monotherapy and for whom a metformin-sulfonylurea combination is contraindicated. There is a need for large-scale, long-term studies comparing the effectiveness of combination therapy that includes pioglitazone with that of other combinations of antidiabetic drugs.

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis.

Abstract Objective: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. Design: Modelling cost effectiveness. Setting: UK NHS. Participants: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. Main outcome measures: Cost per quality adjusted life year gained. Results: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from £42 000 (

Option appraisal of population-based colorectal cancer screening programmes in England

66 469; €61 630) to £98 000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than £20 000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. Conclusions: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments. What is already known on this topic Interferon beta and glatiramer acetate are the only disease modifying therapies used to treat multiple sclerosis Economic evaluations of these drugs have had flaws in the specification of the course of the disease, efficacy, duration of treatment, mortality, and the analysis of uncertainty None of the existing estimates of cost effectiveness can be viewed as robust What this study adds The cost per quality adjusted life year gained is unlikely to be less than £40 000 for interferon beta or glatiramer acetate Experience after stopping treatment is a key determinant of the cost effectiveness of these therapies Key factors affecting point estimates of cost effectiveness are the cost of interferon beta and glatiramer acetate, the effect of these therapies on disease progression, and the time horizon evaluated

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis

Objectives: To estimate the effectiveness, cost-effectiveness and resource impact of faecal occult blood testing (FOBT) and flexible sigmoidoscopy (FSIG) screening options for colorectal cancer to inform the Department of Health’s policy on bowel cancer screening in England. Methods: We developed a state transition model to simulate the life experience of a cohort of individuals without polyps or cancer through to the development of adenomatous polyps and malignant carcinoma and subsequent death in the general population of England. The costs, effects and resource impact of five screening options were evaluated: (a) FOBT for individuals aged 50–69 (biennial screening); (b) FOBT for individuals aged 60–69 (biennial screening); (c) once-only FSIG for individuals aged 55; (d) once-only FSIG for individuals aged 60; and (e) once-only FSIG for individuals aged 60, followed by FOBT for individuals aged 61–70 (biennial screening). Results: The model suggests that screening using FSIG with or without FOBT may be cost-saving and may produce additional benefits compared with a policy of no screening. The marginal cost-effectiveness of FOBT options compared to a policy of no screening is estimated to be below £3000 per quality adjusted life year gained. Conclusions: Screening using FOBT and/or FSIG is potentially a cost-effective strategy for the early detection of colorectal cancer. However, the practical feasibility of alternative screening programmes is inevitably limited by current pressures on endoscopy services.

The Multiple Sclerosis Risk Sharing Scheme Monitoring Study--early results and lessons for the future.

Abstract Objective: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. Design: Modelling cost effectiveness. Setting: UK NHS. Participants: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. Main outcome measures: Cost per quality adjusted life year gained. Results: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from £42 000 (

Supplemental calcium in the chemoprevention of colorectal cancer: a systematic review and meta-analysis

66 469; €61 630) to £98 000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than £20 000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. Conclusions: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments. What is already known on this topic Interferon beta and glatiramer acetate are the only disease modifying therapies used to treat multiple sclerosis Economic evaluations of these drugs have had flaws in the specification of the course of the disease, efficacy, duration of treatment, mortality, and the analysis of uncertainty None of the existing estimates of cost effectiveness can be viewed as robust What this study adds The cost per quality adjusted life year gained is unlikely to be less than £40 000 for interferon beta or glatiramer acetate Experience after stopping treatment is a key determinant of the cost effectiveness of these therapies Key factors affecting point estimates of cost effectiveness are the cost of interferon beta and glatiramer acetate, the effect of these therapies on disease progression, and the time horizon evaluated

The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No. 150 and part review of technology appraisal No. 118): a systematic review and economic model

BackgroundRisk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS.MethodsThis case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments.ResultsCentres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies.ConclusionSuccessful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.

A Stated Preference Binary Choice Experiment to Explore NICE Decision Making

OBJECTIVE The aim of the review was to assess the evidence for the effectiveness of calcium in reducing the recurrence of adenomas and the occurrence of colorectal cancer among populations at high, intermediate, and low risk of the disease. METHODS A systematic review of randomized controlled trials (RCTs) was performed to compare calcium alone, and with other agents, versus placebo. Nine databases (Cochrane Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE, Web of Science, Biological Abstracts, the National Research Register, and Current Controlled Trials) were searched for published and unpublished trials. Searches were not restricted by either language or date of publication. All searches were completed in January 2010. Database thesaurus and free text terms for calcium and adenomas or colorectal cancer were used to search for trial reports; additional terms were used to search for other agents of interest, such as NSAIDs and folic acid. Search terms consisted of a combination of terms for colorectal cancer (eg, colon or colorectal and neoplasm or cancer or adenoma) and terms for calcium and RCTs. The initial searches were conducted in June 2008, with update searches in January 2010 to identify more recent studies. The reference lists of relevant studies were also searched for additional papers not identified by the search of electronic databases. Studies had to satisfy the following criteria to be included: RCTs about calcium, with or without other chemopreventive agents, in adults with familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer, or a history of colorectal adenomas, or with no increased baseline risk of colorectal cancer. Meta-analysis was performed. For discrete and numerical outcomes, relative risks (RRs) and risk differences were reported with 95% CIs. The random-effects model was used to account for clinical and methodologic variations between trials. RESULTS The original and update searches of electronic databases produced 3835 citations, of which 6 studies (8 papers) met the inclusion criteria. Supplemental calcium had no effect on the number of adenomas in 1 small trial of patients with FAP. Meta-analysis of 3 trials in individuals with a history of adenomas showed a statistically significant reduction in the RR for adenoma recurrence (RR = 0.80 [95% CI, 0.69-0.94], P = 0.006) for those receiving calcium 1200 to 2000 mg/d, but no effect was seen in advanced adenoma (RR = 0.77 [95% CI, 0.501.17], P = NS). Meta-analysis of 2 trials in populations with no increased baseline risk for colorectal cancer suggested that calcium, with or without vitamin D, had no effect on the RR for colorectal cancer (RR = 0.62 [95% CI, 0.11-3.40], P = NS). CONCLUSION Published reports indicated that supplemental calcium was effective for the prevention of adenoma recurrence in populations with a history of adenomas, but no similar effect was apparent in populations at higher or lower risk.

A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS)

BACKGROUND Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab. OBJECTIVE To investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy. DATA SOURCES The assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010. REVIEW METHODS Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS The searches identified 7745 titles and abstracts. Two clinical trials (reported in 12 papers) were included. No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients. Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups. Third-line treatment with cetuximab plus best supportive care or panitumumab plus best supportive care appears to have statistically significant advantages over treatment with best supportive care alone in patients with KRAS WT status. For the economic evaluation, five studies met the inclusion criteria. The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with best supportive care is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with best supportive care is £150,000 per QALY and for cetuximab plus irinotecan compared with best supportive care is £88,000 per QALY. All ICERs are sensitive to treatment duration. LIMITATIONS In the specific populations of interest, there is a lack of evidence on bevacizumab, cetuximab and cetuximab plus irinotecan used second line and on bevacizumab and cetuximab plus irinotecan used third line. For cetuximab plus irinotecan treatment for KRAS WT people, there is no direct evidence on progression-free survival, overall survival and duration of treatment. CONCLUSIONS Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT for patients with KRAS WT status receiving cetuximab plus irinotecan. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of population-based screening for colorectal cancer: a comparison of guaiac-based faecal occult blood testing, faecal immunochemical testing and flexible sigmoidoscopy

AbstractObjective: To explore whether the National Institute for Health and Clinical Excellence (NICE) takes account of concerns other than just incremental cost effectiveness in commissioning healthcare services. Method: A stated preference binary choice experiment was used to explore the preferences of members of NICE’s Appraisal Committees for incremental cost effectiveness, the degree of uncertainty surrounding incremental costs and health outcomes, the age of beneficiaries, baseline health-related quality of life (HR-QOL) and the availability of alternative therapies when considering whether to recommend health technologies. Results: A logit modelling analysis of Committee members’ stated preferences suggested that increases in the incremental cost-effectiveness ratio and economic uncertainty, and the availability of other therapies was associated with statistically significant reductions in the odds of a positive recommendation (p < 0.01). The transition from a very low to a comparatively high level of baseline HR-QOL was also associated with a statistically significant reduction in the odds of a positive recommendation (p = 0.003). The age of beneficiaries did not significantly affect decisions concerning whether to recommend technologies. Conclusion: The results of the choice experiment support the notion of a probabilistic adoption/rejection approach rather than the operation of a single cost-effectiveness threshold.