Tracing the natural course of visual acuity and quality of life in neovascular age-related macular degeneration: a systematic review and quality of life study.

BACKGROUND: Describing the natural course of neovascular age-related macular degeneration (nAMD) is essential in discussing prognosis and treatment options with patients and to support cost-effectiveness studies. METHODS: First, we performed a literature search in PubMed, Embase, and Cochrane. We included randomized clinical trials and prospective observational studies reporting visual acuity (VA) in non-treated patients, 24 studies in total. We integrated VA data using best fit on Lineweaver-Burke plots and modelled with non-linear regression using reciprocal terms. Second, we performed a quality-of-life (QoL) study in nAMD patients. We measured VA with Radner reading charts and QoL with the Health Utilities Index issue 3 (HUI-3) questionnaire in 184 participants. We studied the relation VA-QoL with linear regression. Third, with Monte Carlo simulation, we integrated the VA model from the literature review and the relation VA-QoL from the QoL study. RESULTS: Visual acuity was 0.4 and 0.07 after 5 years in the better-seeing, and worse-seeing eye, respectively. After 4.3 years, VA was <0.5 in the better-seeing eye; <0.3 after 7 years; 0.05 after 17 years. QoL score decreased from 0.6 to 0.45 after 10 years. CONCLUSIONS: The natural course of nAMD in both eyes needs to be considered when informing patients. Visual acuity in the best eye decreases to below 0.5 in 4.3 years. This affects QoL significantly.

Distinguishing between Better and Worse Visual Acuity by Studying the Correlation with Quality of Life in Neovascular Age-Related Macular Degeneration.

PURPOSE: To determine whether there is a level of visual acuity (VA) in neovascular age-related macular degeneration (nAMD) above which the correlation of VA with disease-related quality of life (QoL) is significantly greater than below this level. DESIGN: An observational, cross-sectional study. PARTICIPANTS: A total of 184 patients with nAMD aged at least 50 years were included in the study. METHODS: In face-to-face interviews, we assessed QoL with the Macular Disease-Dependent Quality of Life (MacDQoL) questionnaire. We measured VA with standardized Radner reading charts. We used regression splines analysis with a single hinge point, with the MacDQoL score as the dependent variable and VA as the independent variable. The x-coordinate (VA) of the hinge point was varied and tested with each iteration. A second method of regression splines analysis was also performed, without a preset hinge point. MAIN OUTCOME MEASURES: The primary outcome measure is the cutoff point at or below which VA is associated with significantly less change in QoL than above this cutoff. The linear coefficients below and above the cutoff are defined as change in MacDQoL score per logarithm of the minimum angle of resolution (logMAR) unit of change in VA. RESULTS: With Snellen equivalent VA 0.05 (1.3 logMAR) or worse, the linear coefficient was 0.15. With VA better than 0.05, the linear coefficient was 2.40 (P value of the difference: 0.009). CONCLUSIONS: When VA is above 0.05, there is a stronger and significant relation between VA and QoL. At or below this level, the relation between VA and QoL approaches zero. With better VA, a difference in VA implies a significant difference in QoL. With poorer VA, a difference in VA is unlikely to imply a difference in QoL. Therefore, in treating nAMD, the aim should be to keep Snellen VA above 0.05 to have an impact on QoL. If it is certain that the best-corrected VA below 0.05 is permanent, these findings imply there may be less, if any, benefit to continue further treatment. This is to be evaluated on a case-by-case basis.

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.

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.

A new epidemiological aid in deciding whether to continue or stop a treatment.

PURPOSE: To present a new epidemiological method relying on randomized controlled clinical trial (RCT) data to assess whether a treatment was effective, aiding in the decision to continue or stop the treatment in clinical patients. METHODS: A cutoff point is calculated in the change of a continuous outcome for which a proportion of treated patients clearly achieved a change better than this cutoff point as a result of the treatment. This cutoff point can then be applied to individual patients during routine therapy. The method was applied to reports of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, which included patients with AMD treated with monthly intravitreal injections of ranibizumab, and to reports of trials involving patients with high IOP, macular edema, and convergence insufficiency. RESULTS: The cutoff point in the change in visual acuity (number of letters), above which a proportion of patients clearly benefited due to ranibizumab treatment, was -5.0 at 24 months follow-up. The proportion of treated patients who ended above this cutoff point due to the treatment was 60%. The cutoff point varies with time of follow-up and by subgroup. CONCLUSIONS: Contrary to common interpretation, no change, or a limited decline, in the outcome (visual acuity) can still imply that the patients are better off with the treatment than with no treatment. Stopping the treatment above the cutoff point may not be appropriate since it was effective in at least a proportion of patients. This method applies to a broad range of scales and conditions. (ClinicalTrials.gov number, NCT00056836.).

Detection of Raman spectra in ocular drugs for potential in vivo application of Raman spectroscopy.

PURPOSE: Raman spectroscopy holds potential for the assessment of intraocular pharmacokinetics. Raman spectra of ocular drugs were acquired, to determine the drug-specific Raman signature. The ability of the Raman technique to quantify drug concentrations was also investigated. METHODS: The experimental setup was based on a High Performance Raman Module 2500 Raman module, designed for 180° "backscatter" signal detection in the wavenumber range of 400-1,800 cm(-1). Excitation source was a diode laser emitting a beam with a wavelength of 785 nm and a power of 10 mW. Laser light was focused in the sample with a long-working-distance microscope objective (25×/0.50). Samples were measured in quartz cuvettes in 10 sequential measurements, with exposure time 30 s. The total number of measured drugs was 49. To determine whether signal intensity and drug concentration correlate, 2 drugs were diluted in water and measured with 120 s exposure time at different concentrations. RESULTS: An active ingredient-specific Raman signature was detected in 4 glaucoma drugs, 6 mydriatics, 5 antibiotics, 4 anesthetics, 3 anti-inflammatory drugs, 2 types of artificial tears, and 5 other drugs. In 20 drugs, no specific Raman signature was detected. Linear correlation of drug concentration with signal intensity was high (R(2)≥0.94). CONCLUSIONS: Using low laser powers, Raman signatures for 29 commonly used ocular drugs were detected. Correlation of drug concentration with signal intensity is high, which is essential for monitoring drug concentration in ocular media. The presented results encourage the use of Raman spectroscopy to acquire detailed information on the pharmacokinetics of these ocular drugs.