Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

BACKGROUND: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. METHODS: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. RESULTS: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. CONCLUSIONS: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Trial-based cost-effectiveness analysis of toric versus monofocal intraocular lenses in cataract patients with bilateral corneal astigmatism in the Netherlands.

PURPOSE: To evaluate the cost-effectiveness of toric versus monofocal intraocular lens (IOL) implantation in cataract patients with bilateral corneal astigmatism. SETTING: Two ophthalmology clinics in the Netherlands. DESIGN: Prospective cost-effectiveness analysis. METHODS: Resource-use data were collected over a 6-month postoperative period. Consecutive patients with bilateral age-related cataract and 1.25 diopters or more of corneal astigmatism were included in the economic evaluation. Patients were randomized to phacoemulsification with bilateral toric or monofocal IOL implantation. All relevant resources were included in the cost analysis. The base-case analysis was performed from a societal perspective based on quality-adjusted life years (QALYs). The main outcome was the incremental cost-effectiveness ratio. RESULTS: The analysis comprised 77 consecutive patients (33 toric IOL; 44 monofocal IOL). Societal costs were higher in the toric IOL group (€3203 [$3864]) than in the monofocal IOL group (€2796 [US$3373]). QALYs were slightly lower in the toric IOL group (0.30 versus 0.31; P = .75). Toric IOLs were therefore inferior to monofocal IOLs from a cost-effectiveness perspective. The cost-effectiveness probability ranged from 1% to 15%, assuming a ceiling ratio for the incremental cost-effectiveness ratio of €2500 to €20 000 per QALY. CONCLUSIONS: From a societal perspective, bilateral toric IOL implantation in cataract patients with corneal astigmatism was not cost-effective compared with monofocal IOL implantation. Copayment by patients should therefore be considered.

A systematic review on the quality, validity and usefulness of current cost-effectiveness studies for treatments of neovascular age-related macular degeneration.

PURPOSE: Ophthalmologists increasingly depend on new drugs to advance their treatment options. These options are limited by restraints on reimbursements for new and expensive drugs. These restraints are put in place through health policy decisions based on cost-effectiveness analyses (CEA). Cost-effectiveness analyses need to be valid and of good quality to support correct decisions to create new treatment opportunities. In this study, we report the quality, validity and usefulness of CEAs for therapies for nAMD. METHODS: A systematic review in PubMed, EMBASE and Cochrane was performed to include CEAs. Quality and validity assessment was based on current general quality criteria and on elements that are specific to the field of ophthalmology. RESULTS: Forty-eight CEAs were included in the review. Forty-four CEAs did not meet four basic model quality and validity criteria specific to CEAs in the field of ophthalmology (both eyes analysed instead of one; a time horizon extending beyond 4 years; extrapolating VA and treatment intervals beyond trial data realistically; and including the costs of low-vision). Four CEAs aligned with the quality and validity criteria. In two of these CEAs bevacizumab as-needed (PRN) was more cost-effective than bevacizumab monthly; aflibercept (VIEW); or ranibizumab monthly or PRN. In two CEAs, ranibizumab (PRN or treat and extent) was dominant over aflibercept. In two other CEAs, aflibercept was either more cost-effective or dominant over ranibizumab monthly or PRN. CONCLUSION: Two of the CEAs of sufficient quality and validity show that bevacizumab PRN is the most cost-effective treatment. Comparing ranibizumab and aflibercept, either treatment can be more cost-effective depending on the assumptions used for drug prices and treatment frequencies. The majority of the published CEAs are of insufficient quality and validity. They wrongly inform decision-makers at the cost of opportunities for ophthalmologists to treat patients. As such, they may negatively influence overall patient outcomes and societal costs. For future ophthalmic treatments, CEAs need to be improved and only published when they are of sufficient quality and validity.

Ocular hypertension and the risk of blindness.

PURPOSE: To estimate the risk of blindness in patients with ocular hypertension (OHT) using an appropriate model and current empirical data. DESIGN: A Markov model with data from a systematic literature review. METHODS: A Markov model with 3 health states was built: OHT, primary open-angle glaucoma (POAG), and unilateral blindness. Literature was searched for reports on conversion from OHT to POAG and progression from POAG to blindness, to estimate a range of annual conversion and progression probabilities. The model had a cycle length of 1 year. RESULTS: The 15-year risk estimates ranged from 3.1% to 9.4% in untreated, and from 0.9% to 8.6% in treated patients with OHT. The ranges were the result of differences in patient populations, treatments, and outcome definitions in currently available empirical data. CONCLUSIONS: The best estimates of the 15-year risk of unilateral blindness in patients with OHT, based on the currently available empirical data and an appropriate model, show that the risk is <10%.

The cost-utility of aflibercept for the treatment of age-related macular degeneration compared to bevacizumab and ranibizumab and the influence of model parameters.

BACKGROUND: Age-related macular degeneration (AMD) is a blinding disease placing considerable burden on society due to blindness-associated costs. Intravitreal anti-vascular endothelial growth factors (anti-VEGFs) are effective in reducing the incidence of blindness, but at potentially high costs, depending on the cost of the drug used. Aflibercept has been introduced as an anti-VEGF equally effective to ranibizumab, but less costly. For this new drug, new cost-effectiveness analyses are needed, and AMD models used today give biased results. We investigated the cost-effectiveness of aflibercept compared to bevacizumab, ranibizumab, and no treatment and studied the influence of commonly used model parameters. METHODS: A patient-level, visual acuity-based, 2-eye model was developed. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of aflibercept, bevacizumab, and ranibizumab. Utility and resource utilization were assessed in interviews with AMD patients. Costs were based on standard health care cost prices. Time horizons were two and five years. A societal perspective was employed. RESULTS: Over five years, costs associated with aflibercept treatment were 36,030, with 2.15 QALYs. Costs associated with the bevacizumab regimens, ABC study as-needed (PRN); CATT study PRN; and CATT study 1×/month, were 19,367; 26,746; and 30,520, with 2.16; 2.17; and 2.15 QALYs, respectively. Costs associated with ranibizumab PRN and 1×/month were 45,491 and 74,837 with 2.16 and 2.15 QALYs, respectively. 'No treatment' was associated with 9530 and 1.96 QALYs. The incremental cost-effectiveness ratios versus 'no treatment' were: aflibercept-140,274; bevacizumab-51,062 (ABC PRN), 83,256 (CATT PRN) and 110,361 (1×/month); ranibizumab-181,667 (PRN) and 349,773 (1×/month). Results were highly dependent on whether only one or both eyes were included, length of time horizon, and whether the costs of blindness and low-vision were included in the analysis. CONCLUSIONS: Aflibercept is a cost-effective treatment for AMD over ranibizumab. However, aflibercept is not a cost-effective treatment when compared to bevacizumab. Application of inappropriate model assumptions leads to a biased cost-saving estimate of the cost-effectiveness of aflibercept. Therefore, cost-effectiveness analyses should be conducted with appropriate models.

The long term effectiveness and cost-effectiveness of initiating treatment for ocular hypertension.

PURPOSE: To investigate the long-term health and economic consequences of direct treatment initiation in ocular hypertension patients. METHODS: A cost-effectiveness analysis with a societal perspective and a lifelong horizon was performed. The primary outcomes were the incremental quality-adjusted life years (QALYs) and costs of direct pressure-lowering treatment for ocular hypertension, compared to a strategy where treatment is postponed until conversion to glaucoma has been observed. We used a decision analytic model based on individual patient simulation to forecast disease progression and treatment decisions in both strategies in a representative heterogeneous patient population and in 18 patient subgroups stratified by initial intraocular pressure and additional risk factors for conversion. RESULTS: The incremental discounted health gain of direct treatment was 0.27 QALYs, whereas the incremental discounted costs were -€ 649 during an average lifetime of 26 years. In the simulations of patient subgroups, the model outcomes moved towards higher health gains and lower incremental costs with increasing risk of conversion in the patient population. The incremental cost-effectiveness ratio of direct treatment ranged from € 15,425 per QALY gained in the lowest-risk subgroup to dominance in the highest-risk subgroup. Probabilistic sensitivity analysis indicated that uncertainty surrounding the model input parameters did not affect the conclusions. CONCLUSION: Direct, early, pressure-lowering treatment is a dominant cost-effective treatment strategy over a strategy to start the same treatment approach later, after glaucoma has occurred for patients with ocular hypertension. Its implementation and consequences should be discussed with ophthalmologists and individual patients.

The influence of the assessment method on the incidence of visual field progression in glaucoma: a network meta-analysis.

PURPOSE: To study and quantify the difference in incidence of progression between methods for the assessment of glaucomatous visual field progression. METHODS: We identified 2450 articles published up to April 2009 in the following data sources: PubMed, EMBASE, and Cochrane. Ten studies covering 30 methods were included. All studies aimed to compare different methods for the assessment of glaucomatous visual field progression in the same study population. A network meta-analysis using a mixed-effects model was performed to combine within-study between-method comparisons with indirect comparisons from other studies. The summarized incidence of progression was calculated for every method, and methods were ranked according to this incidence. RESULTS: In total, methods were compared in 1040 eyes of 948 patients with glaucoma. On average, 21% of the eyes progressed. When all 30 methods were ranked, the incidence ranged from 2% to 62%. These incidences are corrected for a baseline mean deviation (MD) value of -7 decibels and a mean follow-up time of 6 years. Besides the assessment method, the incidence was only determined by the follow-up period and baseline MD value, leaving no unexplained variance in the incidence of progression. CONCLUSION: The incidence of progression varies considerably between different studies. This is mainly caused by the variety of methods used to assess progression but also by differences in follow-up time and baseline visual field loss.

Latanoprost versus timolol as first choice therapy in patients with ocular hypertension. A cost-effectiveness analysis.

PURPOSE: To determine the cost-effectiveness of ocular hypertension (OH) treatment initiated with latanoprost compared to timolol. METHODS: Two strategies for OH therapy are modelled, (1) 'starting with timolol' and (2) 'starting with latanoprost'. Therapy can be maintained or changed dependent on the achieved intraocular pressure (IOP) and side-effects. Adjustments of therapy to reach a target pressure involve monotherapy, combination therapy and laser. Four drugs are used: latanoprost, timolol, brimonidine and dorzolamide. Once the adjustments of therapy are completed, lifelong follow-up with IOP-dependent conversion to glaucoma and progression to blindness are modelled. Direct medical costs are assigned. The IOP-lowering effect of drugs is based on meta-analyses and applied by Monte Carlo simulation to a hypothetical cohort of patients with OH. The characteristics of the cohort, including the initial IOP distribution, are based on data of 1000 patients. RESULTS: The IOP decreased from 25,4 mm Hg (mean) to 16.7 (±0.017) mm Hg (strategy 1) and to 16.5 (±0.013) mm Hg (strategy 2). Costs per patient within 15 months of therapy were € 367 and € 469, respectively. Lifetime blindness and costs were 0.0334 years and € 3,514 (strategy 1) and 0.0318 years and € 4,397 (strategy 2). Incremental costs per year of vision saved for strategy (2) in comparison with strategy (1) amount to, given the uncertainties in the model, approximately € 537,000. CONCLUSION: For saving 1 year of vision, high costs are needed when OH therapy is initiated with latanoprost compared to timolol, when the cost price of latanoprost remains high.

The clinical impact of 2 different strategies for initiating therapy in patients with ocular hypertension.

PURPOSE: To assess the impact of 2 strategies for initiating therapy in ocular hypertension (OH) on drug use, intraocular pressure (IOP), and blindness caused by glaucoma. METHODS: Using a simulation model, initiating therapy with timolol (strategy 1) and with latanoprost (strategy 2) was simulated for a hypothetic cohort of ocular hypertension patients with an initial IOP distribution (data of 1000 patients). Adjustment of therapy within 15 months and a subsequent lifelong follow-up, with an IOP dependent conversion to glaucoma, were modeled. The IOP lowering effect of medication (based on a meta-analysis) was applied by Monte Carlo simulation. Therapy could be maintained or changed, depending on the achieved IOP and side effects. Four drugs (latanoprost, timolol, brimonidine, dorzolamide) were used as monotherapy or in combination. Glaucoma conversion rate was based on literature. RESULTS: Treatment goal was achieved in both strategies in 90% by monotherapy. This was 60% for patients with initial IOP's of 30 mm Hg. The originally prescribed medication was maintained in 66% (1) and in 77% (2). IOP decreased with approximately 34%, from 25.4 mm Hg (mean) to 16.7 mm Hg (1) and to 16.5 mm Hg (2) Blindness per person within 18.7 years of life expectancy was 0.0923 years (1) and 0.0870 years (2), which corresponds to approximately 1 month. The difference between strategies was 2 days spent in blindness per patient. CONCLUSIONS: The difference in clinical effects of the strategies is small. This is largely owing to the key concept of a target pressure, which underlies both strategies.

Modeling complex treatment strategies: construction and validation of a discrete event simulation model for glaucoma.

OBJECTIVE: Discrete event simulation (DES) modeling has several advantages over simpler modeling techniques in health economics, such as increased flexibility and the ability to model complex systems. Nevertheless, these benefits may come at the cost of reduced transparency, which may compromise the model's face validity and credibility. We aimed to produce a transparent report on the construction and validation of a DES model using a recently developed model of ocular hypertension and glaucoma. METHODS: Current evidence of associations between prognostic factors and disease progression in ocular hypertension and glaucoma was translated into DES model elements. The model was extended to simulate treatment decisions and effects. Utility and costs were linked to disease status and treatment, and clinical and health economic outcomes were defined. The model was validated at several levels. The soundness of design and the plausibility of input estimates were evaluated in interdisciplinary meetings (face validity). Individual patients were traced throughout the simulation under a multitude of model settings to debug the model, and the model was run with a variety of extreme scenarios to compare the outcomes with prior expectations (internal validity). Finally, several intermediate (clinical) outcomes of the model were compared with those observed in experimental or observational studies (external validity) and the feasibility of evaluating hypothetical treatment strategies was tested. RESULTS: The model performed well in all validity tests. Analyses of hypothetical treatment strategies took about 30 minutes per cohort and lead to plausible health-economic outcomes. CONCLUSION: There is added value of DES models in complex treatment strategies such as glaucoma. Achieving transparency in model structure and outcomes may require some effort in reporting and validating the model, but it is feasible.

Prevalence and determinants of non-adherence to topical hypotensive treatment in Dutch glaucoma patients.

BACKGROUND: To assess the prevalence and determinants of non-adherence to topical hypotensive treatment in glaucoma patients in order to support interventions targeting enhancement of patient adherence. METHODS: One-hundred and sixty-six glaucoma patients, recruited by nationwide multi-stage sampling, filled in an extensive and carefully developed questionnaire covering various theoretically relevant determinants of patient adherence which were categorized as psychosocial aspects, barriers and skills. RESULTS: Prevalence of self-reported non-adherence was 27.3%. Younger patients (<55 years of age) had a higher risk of being non-adherent. Forgetfulness, unavailability of eye drops and difficulties with holding the bottle above the eye when applying the eye drops were the most cited reasons for non-adherence. Fifty percent of the patients indicated that they required more information on the correct administration of eye drops. There was no association between non-adherence and sex, level of education, type of insurance, duration of disease or family history of glaucoma. CONCLUSIONS: Non-adherence to topical glaucoma medication is fairly common. Aids that minimize forgetfulness and delivery systems facilitating the delivery of medications to the eye could be considered to enhance patient adherence before advancing to other therapies with additional risks and costs.

Socioeconomic differences in glaucoma patients' knowledge, need for information and expectations of treatments.

PURPOSE: To study the specific items for which socioeconomic differences in glaucoma patients' knowledge, need for information and expectations of treatments exist, with the aim of developing a patient education programme. METHODS: A total of 44 randomly selected ophthalmologists assigned 166 consecutive outpatient glaucoma patients to complete a questionnaire that had been systematically developed based on focus group interviews, suggestions from several experts and a pilot test. Topics included knowledge about glaucoma and its treatment, need for information and expectations of treatment. Educational level was used as a measure for socioeconomic status. Logistic regression analysis was conducted to adjust for age, sex and duration of glaucoma. RESULTS: After adjusting for age, sex and duration of glaucoma, knowledge of glaucoma and its treatment was found to be positively correlated with socioeconomic status. Items on knowledge with socioeconomic differences concerned risk factors, pathophysiology and consequences of glaucoma, as well as effects and adverse effects of treatments. The lowest socioeconomic group demonstrated more need for information on public assistance and practical aspects of glaucoma and more often expected that glaucoma damage could be repaired. CONCLUSION: Important socioeconomic differences in knowledge, need for information and expectations of treatment exist in glaucoma patients. Patient education should focus on every glaucoma patient, but better information for the lower socioeconomic groups about specific items mentioned in this study might reduce the negative effects of low socioeconomic status on visual impairment.