Appropriate use of information in therapeutic decision-making: reflections on indirect comparisons.

Although the statistical strength of direct comparative randomized controlled trials is generally acknowledged, the particular demands of therapeutic decision making will often require indirect comparisons to be made, based on pooled data from multiple trials. As for all post-hoc analyses, the process of indirect comparison runs the risk of introducing significant bias into the results and consequently a robust statistical approach is required, in order to minimise the risk. To address this problem, a range of different methodologies have been developed over the past twenty years, using both frequentist and Bayesian models. It is important to appreciate the strengths and limitations of these techniques: however, the technical complexities tend to make this type of analysis somewhat opaque to the non-specialist reader. In this article, we consider the use of a simple, non-specialist critical appraisal tool developed by ISPOR, which allows methodological and interpretive errors to be identified and flagged as potential sources of bias, even when the detailed statistical methodology is not well understood by the reader.

Optimizing adherence in hypertension: a comparison of outcomes and costs using single tablet regimens vs individual component regimens.

BACKGROUND: Several studies have demonstrated that the use of single tablet regimens (STRs) in hypertension is associated with improved outcomes and reduced healthcare costs compared with individual component regimens. The objective was to carry out a retrospective analysis of a UK general practice population to test these conclusions in a UK context. METHOD: A retrospective cohort study was carried out using a primary care database (The Health Improvement Network; THIN), comparing 9929 hypertensive patients on STRs with 18,665 patients on individual component therapy. Data were collected for prescriptions, significant cardiovascular events, and out-patient referrals over a minimum follow-up period of 5 years after initiation of therapy. Current NHS costings were applied to the data, to arrive at an estimate of comparative resource use. RESULTS: There were significantly more cardiovascular events in the individual component group than those treated with a single tablet regimen. Five year event rates: 8.3% vs 13.6%; Absolute Risk Reduction (ARR) =5.3%; Number needed to treat (NNT) =18.9. After correction for potential confounders, the hazard ratio was 0.74 (95%CI=0.70-0.77), p<0.0001. Hospital admission costs were lower in the STR group, but drug costs were higher. Overall, the mean annual management cost per patient was similar in the two groups (£191.49 vs £189.35). KEY LIMITATIONS: The study was based on a retrospective cohort and the result may therefore be influenced by unidentified confounders. It was not possible to identify the reasons for individual prescriptions, some of which may have been issued for reasons other than hypertension. Costings for some components of the outcome could not be assessed from the dataset and are therefore omitted from the analysis. Finally, no attempt was made to distinguish outcomes associated with individual classes of anti-hypertensives. CONCLUSIONS: This study confirms the association observed by other authors that patients treated with STRs are less likely to experience serious cardiovascular events than those on individual component therapy. In a UK context this analysis has shown that potential hospital savings broadly offset the additional drug acquisition costs associated with STRs. These agents can therefore be considered cost neutral.

Choice of angiotensin receptor blocker in moderate hypertension. A UK-based cost-benefit comparison of olmesartan- and candesartan-based regimens.

INTRODUCTION: Selection of antihypertensive therapy hinges on an appropriate combination of efficacy, tolerability and compatibility with co-morbidities. Within a given class of antihypertensives, the choice of agent is often driven by cost, with the cheapest appropriate agent being chosen. Amongst the angiotensin receptor blockers (ARBs), this choice will often be losartan, as it is available in generic form. However, as the blood pressure lowering efficacy of losartan is modest, some patients will require an alternative ARB. In the UK this choice is often candesartan, although the agent with greatest BP lowering efficacy is olmesartan. The objective of this study was to use a cost-benefit model to compare the costs associated with target achievement using each of these two agents, in order to guide optimum use of prescribing budgets. METHOD: A probabilistic cost-benefit model was constructed for a cohort of patients with moderate hypertension, based on a standardised titration and maintenance algorithm using either olmesartan or candesartan, combined with thiazide and calcium channel blocker where required. Direct treatment costs were recorded, along with the proportion of patients achieving pre-defined treatment targets at each treatment level. Results were expressed as mean treatment cost per patient reaching target. RESULTS: Based on the current QoF target of 150 mmHg systolic, 94.3% of patients on the olmesartan-based regimen reached target of 150 mmHg, compared with 89.0% of those on the candesartan-based regimen. 86% of olmesartan patients reached target on <3 drugs, compared with 74% of candesartan patients. The mean 12-month cost per patient reaching target was £171.36 for olmesartan versus £189.91 for candesartan. Ongoing annual maintenance costs for patients at target were £169.97 and £182.64, respectively. Similar results were obtained when considering alternative treatment targets LIMITATIONS: The study only compared two ARBs - candesartan and olmesartan and the results relate to prescribing costs only and do not include other healthcare costs. Additionally, the chosen outcome was blood pressure target achievement, rather than clinical endpoints. Given the stated objectives of the model, we do not believe these issues will have introduced bias in the direction of either comparator CONCLUSION: Although olmesartan has an apparently higher acquisition cost than candesartan, its superior BP lowering efficacy means that the overall cost per patient treated to target is actually lower. This result could have significant implications for making savings within primary care prescribing budgets in the UK.

Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation.

It is unclear how polyethylene glycol (PEG) laxatives compare with other classes of laxative in terms of efficacy. To assess efficacy of PEG vs. placebo and active comparators in adults with non-organic constipation. Text Word searches were carried out on MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Clinical Trials and Google Scholar databases covering the period January 1970 to October 2009. Search terms were (constipation) AND (randomised OR randomized) AND (PEG OR polyethylene OR macrogol OR movicol OR idrolax OR miralax OR transipeg OR forlax OR colyte OR golytely OR isocolan OR nulytely) NOT colonoscopy. Only published randomised controlled trials, with a parallel-group or cross-over design, comparing oral PEG with placebo or a comparator laxative in adults with a history of non-organic constipation, were included. The frequency of defaecation in each arm, on completion of the protocol-defined treatment duration was extracted. All pooled analyses were based on random effect models. Of the 20 qualifying studies, 10 were vs. placebo, seven were vs. lactulose, and four were vs. other agents. One study compared PEG, placebo and lactulose. PEG treatment resulted in a highly significant increase in defaecations/week over placebo (all studies: additional 1.98 stools/week; p = 0.0003, high-quality studies: additional 2.34 stools/week; p = 0.0001) and over lactulose (all studies: additional 1 stool/week; p = 0.0017, high-quality studies: additional 1.65 stools/week; p = 0.021). This meta analysis is the only quantitative statistical analysis to have been published in the field. PEG was found to be a more effective laxative than lactulose in adult patients with constipation.

Self blood glucose monitoring in type 2 diabetes. A financial impact analysis based on UK primary care.

BACKGROUND: UK consensus guidelines recommend limited use of self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes using diet and exercise, metformin and/or a glitazone. This analysis quantifies the usage of and costs associated with SMBG in type 2 diabetes according to treatment regimen. METHODS: Prevalence data for diabetes were assessed using UK Quality and Outcomes Framework returns for 2006/2007. Data on current SMBG prescribing expenditure were extracted from UK Prescription Pricing Agency Data for 2007. Prescribing data were extracted from the records of 40,651 patients with diabetes on the IMS Disease Analyzer (MediPlus) database. These were combined to arrive at mean usage and expenditure data per patient, broken down by treatment type. The analysis assumes that it is appropriate to use patients' treatment regimen alone to compare the frequency of SMBG in clinical practice with the frequency recommended in treatment guidelines; it does not take into account other valid reasons for SMBG. RESULTS: Mean national expenditure on SMBG was 73.64 pound sterling per patient per year. Estimated mean weekly test strip usage by treatment was 2.5 (diet), 2.6 (glitazone monotherapy), 3.1 (metformin monotherapy) and 3.5 (sulphonylurea monotherapy). Combination oral therapy ranged from 3.3 to 4.1. Mean annual expenditure in patients with an identified treatment type was 62.06 pound sterling per patient, ranging from 9.83 pound sterling for diet-treated patients to 37.87 pound sterling for those on triple therapy, with insulin-treated patients incurring costs 3-5 times higher. CONCLUSIONS: Based on the assumptions that the treatment regimen is the sole factor in determining the appropriate level of SMBG frequency, this study demonstrates that the use of SMBG exceeds current guidelines in certain treatment groups. The study estimates that the potential savings of up to 17 million pound sterling could be made each year if guidelines were followed more closely. There is a need for further research into SMBG use in patients with type 2 diabetes.

Switch strategies in the management of hypertension: a cost minimisation analysis of angiotensin receptor blocker based regimen.

BACKGROUND AND OBJECTIVE: Budgetary pressures within health care systems have led many health care providers to consider the switching of patients on long term anti hypertensive medication to agents with the lowest acquisition price. The long term success of this strategy hinges on price differentials remaining stable, an assumption that may not be valid in drug classes where patent expiry times vary. The treatment of hypertension using angiotensin receptor blockers (ARBs) represents just such a case. The present study, therefore, modelled the 5-year cost consequences of treatment based on losartan, candesartan, valsartan and irbesartan, based on expected patent expiry dates. METHODS: A Markov model was constructed, applying dose-specific blood-pressure lowering and costs to a cohort of uncontrolled mild-moderate hypertensive patients and assessing the anticipated cost of treatment over a 5 year period. A probabilistic approach was adopted to account for between-patient and between-treatment differences. RESULTS: For both undiscounted and discounted models, a losartan-based regimen represents the least costly option of the four agents tested. Median (IQR) discounted expenditure per patient for each agent was: losartan: pound 506 ( pound 441- pound 650), candesartan: pound 610 ( pound 542- pound 766), valsartan: pound 809 ( pound 796- pound 1078), irbesartan pound 696 ( pound 694- pound 934). CONCLUSION: Switching hypertensive patients taking ARBs to the agent with the lowest current acquisition cost may yield only transient budgetary savings. Once patent expiry is taken into account, this model suggests that maintaining or switching patients to losartan would yield considerably greater savings over 5 years.

Non-steroidal anti-inflammatory induced upper gastrointestinal event rates in patients awaiting joint replacement in the United Kingdom. An epidemiologically-based burden of disease model.

OBJECTIVE: To quantify the likely morbidity associated with upper gastrointestinal (GI) ulceration associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients awaiting hip and knee replacement surgery. METHOD: A burden of disease model was constructed, using Hospital Episode Statistics from the Department of Health in England, selected patient cohorts drawn from a pooled anonymised general practice database (MediPlus) and NSAID risk assessments from the published literature. Based on mean derived waiting times from the point of referral to admission for procedure and estimates of both patient exposure to NSAIDs, and the age-specific risk associated with this treatment, the excess risk associated with NSAIDs was then calculated. RESULTS: In 2001-2, there were approximately 109 000 hip and knee replacements carried out in the UK. The mean waiting time for hip and knee replacement, measured from the point of first referral by the GP, was found to be 443 days (95% CI 419-467). 73% (95% CI 72-74) of patients were found to be taking NSAIDs, equating to a total risk exposure of ~96000 patient years. By applying known age-specific bleeding risks it was estimated that there were around 637 upper GI bleeds directly attributable to NSAID treatment in this cohort, with between 51 and 89 deaths resulting. CONCLUSIONS: In order to improve outcomes in this high-risk patient group, action must continue to reduce overall waiting times, while simultaneously adopting treatment regimes that are inherently less likely to cause upper gastrointestinal bleeding.