Prostaglandin analogues for the treatment of glaucoma and ocular hypertension: a systematic review of economic evidence

We conducted a systematic review of economic studies of prostaglandin analogues for the treatment of glaucoma to assess the scope of current cost-effectiveness evidence and its relevance to decision-makers. The literature search retrieved 102 studies published before July 2005; after additional hand searching of conference proceedings, 13 full-text articles and 13 abstracts met the inclusion criteria. The reviewers extracted the key characteristics of each of the economic evaluations, and all studies received a grade in five categories to summarise the quality of the study: methodology, transparency, sensitivity, relevance and overall score.The current economic literature is predominantly focused on identifying the short-term direct cost of glaucoma treatment, particularly the precise quantification of glaucoma drug costs. Using the European and US treatment guidelines as a benchmark, it is evident that the current body of literature does not satisfy the needs of decision-makers, although certain studies provide some valuable information, which is a step towards reaching this goal.The main methodological issue in the economic models is an absence of a clinically relevant long-term effectiveness measure, or where this measure is produced, there is a lack of transparency and validation of the methods used. More attention needs to be given to modelling the consequences of treatment, and those consequences should include patient compliance, control of intraocular pressure and progression of visual field deficit, since these drive both the costs and the overall outcomes.We recognise that constructing the 'ideal' clinical outcome measure represents a major challenge to researchers. As such, we have outlined a modelling framework that could be used to produce the required level of economic evidence, and ongoing clinical research (such as the Early Manifest Glaucoma Trial) could provide the validated link between intraocular pressure and disease progression, which forms an essential part of such models.     

The problem of protocol driven costs in pharmacoeconomic analysis.

The increasing number of economic evaluations of healthcare interventions and of drug therapies in particular has been well documented. Surveys of the quality of studies have demonstrated that standards of conduct of such studies have not similarly increased. Concerns over the standards have led to increased calls that economic analyses be more closely linked to randomised controlled clinical trials (RCT). Seven potential threats to the external validity of results limit the generalisability of studies based on RCTs. One such threat is the existence of protocol driven costs. There are two main types of protocol driven costs. Protocol prescribed costs arise as a result of resource use mandated by the clinical trial design. Protocol derived costs occur when increased clinical investigations mandated by trial protocols lead to atypical disease management. Methods to control for protocol driven costs within pharmacoeconomic study designs are available. Modelling studies can be based on data within clinical trials combined with observational data representing more typical resource use. The adoption of pragmatic clinical trial designs provide greater external validity though reduced internal validity. Refinements to explanatory clinical trials can also lead to reduced protocol driven costs. The extent that current studies control for such costs is unclear due to the lack of transparency in the reporting of study methods. A review of published studies found little consideration of protocol driven costs although in several studies there was evidence of their existence. Future studies conducted alongside RCTs should explicitly address how the issue of protocol driven costs was handled within the study framework.     

A review of limited lists and formularies: are they cost-effective?

The 'limited list' or 'formulary' concept has been used to promote rational use of drugs and to set standards for drug use. Recently the concept has been aimed more toward containment of drug costs. Effective hospital formulary systems assist in purchasing and inventory management. Application of the formulary concept has resulted in savings within specific classes of drugs and in total hospital drug costs. Key features which promote effectiveness are development of policies by prescriber consensus and continued education along with feedback on drug usage. The formulary concept also provides a foundation for appropriate use of drugs in hospitals. In the community setting, limited lists can achieve cost savings and can assist in the rational use of drugs. National limited lists have been less successful in controlling overall drug costs, probably because they have focused on economic effects, rather than education, feedback or user participation. Properly organised drug rationalisation policies embracing the limited list concept can improve health outcomes by promoting rational drug use. They can also contain or reduce drug costs.     

What's in a cost? Comparing economic and public health measures of alcohol's social costs

Studies based on a cost of illness method frequently assert large social costs from a variety of risky activities, the harms from which most typically fall upon the risk-taker himself. Many of these costs are inadmissible in a standard economic framework; consequently, figures derived by the cost of illness method are not comparable with other economic notions of cost and are of very limited policy use.     

Retrospective economic and outcomes analyses using non-US databases: a review

Retrospective database analyses pose a series of methodological challenges, some of which are unique to their data sources, particularly in countries outside the US. This study aimed to qualitatively review the methodological challenges of using non-US databases to conduct retrospective economic and outcomes research studies. We conducted a MEDLINE search to obtain a sample of literature published after the year 2000 on retrospective analyses using non-US databases. We reviewed all relevant components of the selected articles in accordance with the checklist proposed for retrospective database studies by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force and identified issues found in the data sources, methods, study designs, statistics and sources of possible threats to internal and external validity. We found a wide variation in the quality of studies in terms of outcome definitions, patient selection criteria, data collection methods, sample sizes, risk adjustment methods, potential measurement errors and external validity of the studies. Few economic studies included information on indirect cost components because of a lack of relevant data. The quality of non-US retrospective database analyses varied. Future such analyses may be improved if researchers implement the checklist developed by the ISPOR Task Force on Retrospective Database Studies.     

Treatment costs to prevent or treat upper gastrointestinal adverse events associated with NSAIDs.

The widespread use of nonselective NSAIDs and cyclo-oxygenase (COX)-2 inhibitors has a substantial impact on healthcare budgets worldwide. The cost of their gastrointestinal (GI) adverse effects is a major component of their direct cost and has received much attention in the literature. Published studies have often differed in their methodologies and results. It is important for decision makers to understand the reasons for these differences in order to make informed decisions.We conducted a literature review to summarise data that evaluate the direct costs of NSAID-related GI adverse effects worldwide. This resulted in 789 articles from which 29 studies met the inclusion criteria and were fully reviewed. Of these 29, the 9 studies that assessed the cost of COX-2 inhibitors were all based on decision economic models, compared with only 7 of the remaining 20 studies, which assessed the cost of nonselective NSAIDs. In most studies, the perspective was that of the healthcare payer and the costs assessed were reimbursement costs. Costs of GI events almost doubled between regular users and non-users of nonselective NSAIDs and were much higher in high-dose versus low-dose users. The ratio of the total cost of nonselective NSAIDs to their acquisition cost reported in all studies varied from 1.36 to 2.12. Both of these numbers were reported in one single study assessing several different NSAIDs in France. Thus, the GI adverse events attributable to nonselective NSAIDs are substantial, and their costs often exceed the cost of the nonselective NSAID itself.The acquisition cost of the COX-2 inhibitors was the main driver of their total cost. The GI adverse effects with the COX-2 inhibitors added 10-20% to their acquisition cost in North America, while this increase was about 50% in some European countries. Decision analysis models showed that the direct costs of COX-2 inhibitors were lower than those of nonselective NSAIDs in patients at risk of NSAID gastropathy but higher in patients at no to low risk of gastropathy. Thus, from an economic perspective, the healthcare system would benefit from treating patients at risk of NSAID gastropathy with COX-2 inhibitors, but not those at no to low risk.     

Unrelated medical costs in life-years gained: should they be included in economic evaluations of healthcare interventions?

Which costs and benefits to consider in economic evaluations of healthcare interventions remains an area of much controversy. Unrelated medical costs in life-years gained is an important cost category that is normally ignored in economic evaluations, irrespective of the perspective chosen for the analysis. National guidelines for pharmacoeconomic research largely endorse this practice, either by explicitly requiring researchers to exclude these costs from the analysis or by leaving inclusion or exclusion up to the discretion of the analyst. However, the inclusion of unrelated medical costs in life-years gained appears to be gaining support in the literature.This article provides an overview of the discussions to date. The inclusion of unrelated medical costs in life-years gained seems warranted, in terms of both optimality and internal and external consistency. We use an example of a smoking-cessation intervention to highlight the consequences of different practices of accounting for costs and effects in economic evaluations. Only inclusion of all costs and effects of unrelated medical care in life-years gained can be considered both internally and externally consistent. Including or excluding unrelated future medical costs may have important distributional consequences, especially for interventions that substantially increase length of life. Regarding practical objections against inclusion of future costs, it is important to note that it is becoming increasingly possible to accurately estimate unrelated medical costs in life-years gained. We therefore conclude that the inclusion of unrelated medical costs should become the new standard.     

A Markov process analysis comparing the cost effectiveness of maintenance therapy with citalopram versus standard therapy in major depression

The objective of this study was to demonstrate the cost effectiveness of long term maintenance treatment with citalopram versus standard therapy (defined as short term antidepressant treatment) in patients with major depression in Germany. We chose doxepin, amitriptyline and trimipramine as standard therapy because these drugs are the leading antidepressants in that country. A Markov process analysis was used to model health status and economic outcomes as they accrued over a 1-year follow-up period. The main outcome measures were time without depression, direct costs and indirect costs (work days lost). All costs were in 1993 Deutsche marks. The clinical data were obtained from the published literature and US clinical practice guidelines; the associated unit costs of the medical resources used were derived from official German tariff lists. The results show that, compared with standard therapy, long-term maintenance treatment with citalopram is associated with a mean increase in time without depression of 7.9% (8.2 vs 7.6 months). The total costs of maintenance treatment with citalopram were substantially lower than with standard therapy (DM7985 vs DM11,948 per patient per year. In addition, both the direct and indirect costs of maintenance treatment with citalopram (DM3764 vs DM4221 per patient, respectively) were lower than with standard therapy (DM4577 vs DM7371 per patient, respectively). In conclusion, the study demonstrates that one year's maintenance treatment with citalopram is both more effective and less costly than standard therapy in the treatment of patients with major depression.     

Direct costs of hip fractures in patients over 60 years of age in Belgium.

OBJECTIVE: Osteoporosis-related costs are now considered a major burden for health authorities in most developed countries. An accurate and exhaustive evaluation of these costs would be a major contribution to health economic studies evaluating the efficiency of screening and prevention strategies. Osteoporosis is the most frequent underlying cause of femoral neck fractures in the elderly; these fractures weigh heavily on healthcare budgets. However, in Belgium, very few data on the financial burden of hip fractures are available and no updated estimates have been made. The goal of this paper is to estimate the direct medical expenditures associated with hip fractures in Belgium in 1996. DESIGN AND SETTING: This 1-year population-based cross-sectional study is conducted from the social security perspective. The target population in this study are men and women aged 60 years and over. PATIENTS AND PARTICIPANTS: We selected patients who had been hospitalised for a hip fracture during the year 1996 who were also affiliated with a registered social security organisation (covering 25% of the Belgian population). The sample constituted 2374 patients. INTERVENTIONS: For each of these patients, we collected an exhaustive and detailed list of healthcare resource use as well as nursing home admissions following the hip fracture event. Cost items investigated in the analysis were inpatient hospital costs and outpatient costs. Mean annual costs per case recorded in the sample were then extrapolated to the whole country on the basis of an exhaustive list of diagnoses having lead to all countrywide hospitalisations (1,700,000 hospital stays/year). MAIN OUTCOME MEASURES AND RESULTS: The mean hospital inpatient costs for hip fracture were evaluated at 332,148 Belgian francs (BeF) [$US8977] per case and BeF4,367,746,200 ($US118,047,194) for the whole country (10 million inhabitants). Patients with a hip fracture experienced an annual BeF27,825 ($US752) extra outpatient cost during the year following this fracture event, after correcting for costs related to additional comorbidity already present before the hip fracture. Finally, after a proximal femoral neck fracture, the rate of nursing home admission was higher, both for men and women at any age compared with age- and gender-matched population. CONCLUSIONS: With a total cost (acute hospital and outpatient costs) of BeF4,667,894,950 ($US126,159,323) per year in Belgium, proximal femoral neck fracture should be considered a major health economic problem and appropriate measures to prevent this disease should be rapidly undertaken.     

Economic evaluations in rheumatoid arthritis: a critical review of measures used to define health States

We reviewed the clinical measures used in rheumatoid arthritis (RA) economic evaluations with respect to their relevance and sensitivity to changes in survival, health-related quality of life (HR-QOL) and costs. We compared the measures from the economic perspective and discussed the validity of methods used to extrapolate beyond the trial data. Cost-effectiveness evaluations of disease-modifying antirheumatic drugs in RA were identified by searching MEDLINE, EMBASE, Econlit and NHS EED databases. Studies were retained if they extrapolated beyond randomized controlled trial evidence using relationships between clinical measures, costs and utilities.In the 22 studies identified, clinical severity was measured using the Health Assessment Questionnaire (HAQ) Disability Index, the American College of Rheumatology (ACR) response criteria, the Disease Activity Score (DAS) or a combination of the HAQ and DAS. The HAQ is correlated with mortality, costs and HR-QOL instruments, and several studies used linear relationships to model these associations. However, a polynomial relationship or discrete states may be more appropriate for patients at the extremes of the disease spectrum, and numerous HAQ health states may be required to capture differences in mortality risk. While the ACR response criteria is a more comprehensive measure than the HAQ, it is a relative measure, which creates difficulties when estimating absolute changes in HR-QOL, costs and mortality risk. The evidence base linking DAS scores with HR-QOL instruments, costs and mortality is less robust, possibly due to the comparatively recent development of the measure and the limited number of possible scores (mild/moderate/severe). While there is some evidence of a relationship between DAS scores and costs, the DAS does not capture all aspects of HR-QOL, and no significant relationship has been established with mortality risk.Evidence suggests the HAQ to be the primary clinical measure for use in economic evaluations as it is measured in almost all clinical studies, and is closely correlated to health utilities, mortality and costs. While new developments suggest the sensitivity of health states may be improved by combining the HAQ with measures such as the DAS, further research is required in this area. Further research is also required to explore the advantages in using either continuous or discrete health states.     

Cyclosporin microemulsion (Neoral). A pharmacoeconomic review of its use compared with standard cyclosporin in renal and hepatic transplantation.

Cyclosporin microemulsion (Neoral) is a self-emulsifying preconcentrate of cyclosporin which is more rapidly and consistently absorbed than the original oil-based formulation of cyclosporin (standard formulation; Sandimmun, Sandimmune). This superior pharmacokinetic profile suggests that cyclosporin microemulsion may be associated with improved therapeutic and economic outcomes compared with the standard formulation. Clinical studies comparing the 2 formulations of cyclosporin (using the recommended 1:1 dosage conversion factor) in de novo or stable renal and de novo liver transplant patients have demonstrated that cyclosporin microemulsion is as efficacious as the standard formulation. Rates of acute and chronic graft rejection are generally unaffected by the formulation of cyclosporin, although a trend toward fewer rejection episodes in cyclosporin microemulsion recipients was noted in several randomised studies (reaching statistical significance in 4 studies). Most transplant recipients experience adverse events during cyclosporin therapy, and with higher and more reliable maximum blood concentrations achieved by cyclosporin microemulsion, there is a potential risk of more drug-related adverse events. However, most studies have suggested that the frequency of drug-related adverse events (including nephrotoxicity) is not affected by the formulation of cyclosporin. Analyses of healthcare resource utilisation and associated costs in renal and liver transplant patients in Canadian and European studies have suggested that the cost of using cyclosporin microemulsion may be lower than the cost of using the standard formulation. Lower resource consumption among cyclosporin microemulsion recipients in several studies led to slightly (but not statistically significantly) lower overall healthcare costs in this group. The cost of cyclosporin itself was not included in most of these analyses; however, because the 2 formulations of cyclosporin are used in similar dosages and have similar acquisition costs, this was probably not an important factor in determining relative costs. A single cost analysis comparing cyclosporin microemulsion and tacrolimus suggested that the 2 drugs were associated with similar overall costs. The available economic data on the use of cyclosporin microemulsion are subject to a number of important limitations. In particular, only partial results and study methodology have been reported for most analyses. Several studies were based on small patient groups (< 25) and short periods of follow-up (3 months), although some economic studies included larger patient groups receiving treatment for up to 1 year. Moreover, all of the analyses published to date were 'protocol driven' studies, and hence may not reflect resource use in usual clinical practice. CONCLUSION: In de novo and stable renal and de novo liver transplant recipients, cyclosporin microemulsion is as effective and well tolerated as the standard formulation of cyclosporin. Economic analyses comparing the 2 formulations indicate a consistent, although small and not statistically significant, reduction in overall healthcare costs associated with use of cyclosporin microemulsion.     

The cost of urinary incontinence in Italian women. A cross-sectional study. Gruppo di Studio Incontinenza

OBJECTIVE: To offer cost estimates of urinary incontinence (UI) in the general population based on prospectively collected data. DESIGN: We analyzed individual costs in a sample of women with UI who were identified in the framework of a cross-sectional study on the prevalence of UI in women aged > 40 years. SETTING: Six areas in Italy. INTERVENTION: Home interview. PATIENTS AND PARTICIPANTS: Women were identified among the patients registered with a network of general practitioners operating in each area using computer-generated random number lists. RESULTS: A total of 2767 women were identified. Of these, 408 (14.7%) reported UI during the year before the interview and 229 underwent a detailed interview on UI-related costs. On the basis of this information, we estimated the direct costs associated with UI from the perspective of the Italian National Health Service (INHS). The lifetime cost per patient of diagnosis was 80,131 Italian lire (L) (exchange rate: $US1 = L1618). Consultations accounted for only 20% of the diagnostic cost, diagnostic tests for 36% and hospital admissions for diagnostic procedures accounted for 44%. The diagnosis cost estimate seems low, partly because several women did not request either consultations or diagnostic tests (the overall rate per patient was 0.76 for consultations and 0.39 for diagnostic tests). The only appreciable treatment cost, according to the INHS perspective, was for diapers. The annual cost per patient for diapers was L255,519. The prevalence of UI in women aged > 40 years in Italy is estimated in the study at 9.3%. Thus, combining this information with the cost estimates, the annual treatment cost of UI in Italian women aged > 40 years is L351,800 billion, considering diapers and drugs only. CONCLUSION: This study has estimated the individual cost of UI in the general population. These figures may be useful when designing economic evaluations of UI.     

Interpretation of "cost-effective" and soundness of economic evaluations in the pharmacy literature.

The varied interpretations of the term "cost-effective" in the pharmacy literature are discussed and the soundness of pharmacoeconomic analyses is assessed. Sixty-five studies concerning cost issues, which were published by six pharmacy journals from January 1985 to December 1990, were evaluated according to 10 methodological criteria. Two investigators independently reviewed each study and completed a data collection form; differences were discussed and resolved to ensure consistency of evaluation. In 36 (55%) of 65 articles, cost-effectiveness was misinterpreted as cost saving. Only 3 of the 10 criteria were fulfilled by 50% or more of the studies evaluated. Problem areas included the following: (1) identification of relevant costs and consequences of each strategy, (2) discounting--adjusting data to reflect the differential timing of costs and consequences, (3) incremental analysis--examining extra costs of a program relative to additional effects provided, and (4) sensitivity analysis. Many pharmacoeconomic studies inappropriately used the term "cost-effective" and inadequately addressed basic methodological components of an economic evaluation.     

Pharmacoeconomics of a pharmacist-managed program for automatically converting levofloxacin route from i.v. to oral.

The economic and clinical outcomes of a pharmacist-managed proactive program that used predetermined clinical criteria for converting levofloxacin therapy from i.v. to oral without physician approval were examined. A prospective observational study (POS) assessing the standard of care was conducted over two months and was compared with a proactive conversion program (PCP). A cost-minimization analysis was performed from the provider's perspective. The analysis was divided into cost levels 1, 2, and 3. During the POS and PCP, 49 and 82 patients were evaluated, respectively. The percentage of patients meeting conversion criteria in each group was similar (61% POS versus 65% PCP) (p = 0.827). Candidates met criteria for conversion on day 2 in both groups. The average days that conversion occurred during the POS and PCP were days 7 and 3, respectively (p = 0.010). In those patients, the length of stay was significantly shorter for the PCP (6 versus 9.5 days) (p = 0.031). Level-1, level-2, and level-3 costs were significantly less during the PCP than during the POS for patients who met conversion criteria ($77 versus $133, $91 versus $151, and $13,931 versus $17,198, respectively). Two patients in the PCP were switched back to i.v. levofloxacin due to noninfection-related complications. The overall clinical success rate for evaluable conversion candidates was 100% during the PCP. A pharmacist-managed proactive program that used predetermined clinical criteria for converting levofloxacin therapy from i.v. to p.o. without physician approval reduced length of stay and institutional health care costs without compromising clinical outcomes.