Intraocular Pressure and Medication Changes Associated with Xen Gel Stent: A Systematic Review of the Literature.

The Xen gel stent (Allergan Inc, an AbbVie company; Dublin, Ireland) was conceived as an option for patients requiring modest IOP reduction but for whom trabeculectomy was not yet indicated. As with any glaucoma surgery, establishing criteria for patient selection and identifying factors that contribute to a high likelihood of success are important. To help guide clinical decision-making, a systematic review of published studies on the gel stent was performed, with the goal of understanding postoperative outcomes based on clinical and patient factors. Results were organized around a series of pertinent clinical questions based on scenarios encountered in clinical practice. Criteria for including studies were intentionally broad, with the objective of simulating the diverse population of glaucoma patients encountered in real-world practice. Outcomes for IOP and medication reduction postoperatively were assessed in various analyses, including in eyes with various glaucoma types and severity; in eyes naïve to surgery as well as those with a history of prior incisional glaucoma surgery; and when surgery was performed as a standalone procedure or at the time of cataract surgery. The results of each of the various analyses were consistent in demonstrating that successful gel stent surgery achieved a postoperative IOP of approximately 14.0 mm Hg and reduction to fewer than 1 glaucoma medication. Additional data are shown on outcomes by method of implant (ab interno vs ab externo); intraoperative use of antifibrotics; and rates of needling in published studies.

The Effect of an Educational Intervention on Adherence to Intraocular Pressure-Lowering Medications in a Large Cohort of Older Adults with Glaucoma.

BACKGROUND: Glaucoma is a progressive, irreversible disease that can lead to vision loss and lower quality of life if treatment is not optimized. Effective glaucoma therapies are available to lower intraocular pressure (IOP) and minimize or delay disease progression. Nonetheless, adherence to treatment remains suboptimal for many patients. OBJECTIVE: To identify potentially nonadherent patients and evaluate the effect of patient- and physician-centric educational interventions on adherence by using a validated predictive model of nonadherence to glaucoma medication. METHODS: This prospective, randomized, controlled, and interventional study included Humana Medicare Advantage Prescription Drug plan patients with a glaucoma diagnosis between May and October 2014, ≥ 1 pharmacy claim for glaucoma medication, and ≥ 50% likelihood of nonadherence. Patients and physicians were randomized to cohorts A (no interventions), B (physician intervention), or C (patient and physician interventions). Physicians in cohorts B and C received information on the model, adherence, and patient profiles at baseline and months 3, 6, and 9. Patients in cohort C received educational materials on glaucoma and adherence (same schedule). The primary outcome was the proportion of days covered (PDC) with medication over 12 months. Adherence was defined as PDC ≥ 0.80. RESULTS: Overall, 23,306 patients and 2,955 physicians were eligible. After excluding physicians with < 3 nonadherent patients, each cohort included 200 physicians and 600 patients. Mean PDC was 0.54-0.56 across cohorts. At 12 months, ≥ 90.5% of physicians and ≥ 75.5% of patients remained in the study; mean PDC was 0.53-0.54 across cohorts. No statistically significant between-cohort differences in PDC and adherence were observed. CONCLUSIONS: Intensive educational mailings to patients and their physicians did not improve PDC or adherence in this large population of potentially nonadherent patients with glaucoma. Findings highlight the difficulty of improving adherence in a disease that requires lifelong therapy despite being largely asymptomatic and can inform development of future interventions aimed at improving adherence to glaucoma therapy. DISCLOSURES: This study was sponsored by Allergan plc (Dublin, Ireland). Fiscella and Chandwani are employees of Allergan plc. Caplan, Kamble, Bunniran, and Uribe are employees of Comprehensive Health Insights, a Humana company. The authors did not receive honoraria or other payments for authorship.

Predictors of Nonadherence to Topical Intraocular Pressure Reduction Medications Among Medicare Members: A Claims-Based Retrospective Cohort Study.

BACKGROUND: Reported adherence rates with ocular hypotensive medications typically range from 51% to 56% over the first year of therapy. As intraocular pressure (IOP) reduction slows the progression of vision loss from glaucoma, early identification of nonadherent members is crucial to effective disease management. OBJECTIVES: To (a) identify member characteristics and other factors related to nonadherence with topical IOP-lowering medications available in administrative claims data and (b) create a predictive model incorporating these variables. METHODS: This retrospective cohort study analyzed data from Humana's administrative claims database. The study cohort included members aged 65-89 years enrolled in a Medicare Advantage Prescription Drug plan (MAPD; medical and pharmacy benefits), with > 1 topical IOP-lowering medication claims between January 2011 and September 2012 and a minimum of 24 months of continuous enrollment-12 months before and 12 months after the initial (index) prescription claim for a topical IOP-lowering medication. Adherence was defined as the proportion of days covered (PDC) with drug supply (calculated from the number of drops per bottle and dose) over the first year after the index prescription. Members with PDC > 0.80 were considered adherent, while members with PDC < 0.80 were considered nonadherent. Multivariable stepwise logistic regression with backward elimination was used to construct a predictive model for the likelihood of nonadherence (PDC < 0.80). The model was developed using 28 input variables*#x2013;10 variables were retained in the final model. RESULTS: 73,256 MAPD members were included in this study; most (69%) of these members were continuing topical IOP-lowering medication users. The proportion of patients adherent (PDC > 0.80) to IOP-lowering medications was 51%. The study sample was split, using a 2:1 ratio, into a development sample (n = 48,840 members) and a validation sample (n=24,416 members). The model performed equally well in the development sample and the validation sample (area under the curve = 0.71 for development and validation sets), making it appear robust in this Medicare population. In the final predictive model, characteristics increasing the likelihood (P < 0.01) of nonadherence to IOP-lowering medication within the MAPD population included index IOP prescription filled through mail order, higher medical costs during the pre-index period, being a new IOP-lowering medication user, and being male. Characteristics that lowered the likelihood of nonadherence included advanced age, higher pharmacy costs during the pre-index period, receiving a low-income subsidy, residing in the South, and a previous diagnosis of open-angle glaucoma or history of glaucoma surgery. CONCLUSIONS: Nonadherence to topical IOP-lowering medication can be predicted with 10 commonly available demographic, clinical, and treatment-related variables generally available in administrative claims data for an MAPD population. Given that this predictive model was constructed using these generally available data, it could potentially be replicated by other health plans for use in predicting nonadherence to topical IOP-lowering medications among MAPD plan members. This predictive model can be used to identify members that are likely to be nonadherent in order to target interventions intended to improve ocular hypotensive medication adherence. DISCLOSURES: Funding for this study was contributed by Allergan. Comprehensive Health Insights was contracted by Allergan to conduct this study. Sheer, Bunniran, and Uribe are employed by Comprehensive Health Insights/Humana and own stock in Humana. Fiscella, Chandwani, and Patel are employed by Allergan. Study concept and design were contributed by Sheer, Fiscella, and Patel, along with Bunniran and Uribe. Sheer and Bunniran took the lead in data collection, and data interpretation was performed by Bunniran and Uribe, along with the other authors. The manuscript was written and revised by Sheer, Bunniran, Chandwani, and Uribe, with assistance from Fiscella and Patel.

Cost-offset analysis: bimatoprost versus other prostaglandin analogues in open-angle glaucoma.

OBJECTIVES: To develop a cost-offset model from a US payer perspective comparing glaucomatous progression and costs among primary open-angle glaucoma (POAG) patients using bimatoprost, latanoprost, or travoprost. STUDY DESIGN: Cost-offset model. METHODS: A Markov cohort model was used to estimate glaucomatous progression for POAG patients over 7 years. The model assumed bimatoprost-treated patients had lower resulting intraocular pressure (IOP) (by 1 mm Hg) for all presenting IOP categories than latanoprost- or travoprost-treated patients. Patients with lower IOP were assumed to have lower probability of progression. Those that progressed were assumed to do so at a rate of -0.6 dB per year. Direct costs associated with mean deviation score categories were applied to each treatment cohort to calculate the expected 7-year costs of treating patients with each prostaglandin analogue (PGA). Literature was used to support assumptions. A budget impact analysis was conducted where all travoprost patients switched to generic latanoprost and where all bimatoprost patients switched to generic latanoprost. The base case market share was 22% bimatoprost, 23% travoprost, and 55% latanoprost. RESULTS: Model results demonstrate that for a managed care plan with 9500 PGA-treated glaucoma patients, exclusive bimatoprost use would prevent progression in 136 additional individuals compared with exclusive travoprost or latanoprost treatment. Model results demonstrate that greater IOP reduction from bimatoprost is associated with increased cost savings compared with latanoprost or travoprost treatments. CONCLUSIONS: Model results demonstrate that greater IOP reduction from bimatoprost could reduce managed care spending.

Understanding dry eye disease: a managed care perspective.

Dry eye disease (DED) is a multifactorial disorder that results in eye discomfort, visual disturbance, and often ocular surface damage. This supplement to The American Journal of Managed Care discusses the prevalence of DED and the economic burden associated with DED. The etiology and pathophysiology of DED will also be discussed, including disease progression and impact on the patient's quality of life. With greater understanding of the pathophysiology of DED, there are numerous available therapies/strategies for the management of the disorder, ranging from artificial tear substitutes, anti-inflammatory agents, secretagogues, punctal plugs, and systemic immunosuppressives, to surgery. This activity will aim to provide managed healthcare professionals with an understanding of when and how to use these different strategies to reduce morbidity and prevent complications.

Aqueous and vitreous penetration of linezolid and levofloxacin after oral administration.

PURPOSE: To evaluate the time course of drug concentrations achieved in aqueous (AQ), vitreous (V), and serum (S) compartments after oral administration of linezolid and levofloxacin. DESIGN: Randomized, clinical trial. SETTINGS: Clinical practice. PATIENT POPULATION: Sixteen patients (16 eyes) undergoing vitrectomy who had not had a prior pars plana vitrectomy in the study eye were randomly assigned to one of 4 groups. INTERVENTION: AQ, V, and S samples were obtained from all subjects after single concomitant doses of linezolid 600 mg and levofloxacin 750 mg between 1 and 12 h before the procedure: group A = 1-3 h; group B = 3-6 h; group C = 6-9 h; group D = 9-12 h. MAIN OUTCOME MEASURES: AQ, V, and S concentrations of linezolid and levofloxacin. RESULTS: Overall mean concentrations ± standard deviation (µg/mL) achieved by linezolid in AQ, V, and S compartments were 3.32 ± 2.06, 2.98 ± 1.87, and 7.91 ± 3.94, respectively. Overall mean concentrations ±standard deviation (µg/mL) achieved by levofloxacin in AQ, V, and S compartments were 2.19 ± 1.92, 1.95 ± 1.27, and 7.38 ± 3.47, respectively. CONCLUSIONS: Single concomitant doses of linezolid and levofloxacin achieved AQ and V concentrations above the minimum inhibitory concentration for 90% of common ocular gram-positive and gram-negative pathogens up to 12 h after administration. The combination of linezolid and levofloxacin represents a viable option for the prophylaxis and management of endophthalmitis.

An adaptable HPLC method for the analysis of frequently used antibiotics in ocular samples.

Four different antibiotics, delivered individually to rabbit eyes via hydrophilic intraocular lenses soaked in the drug solution prior to implantation, were measured in aqueous and vitreous humor samples from the eyes. To meet this analytical need, we developed a sensitive, high performance liquid chromatographic (HPLC) method for measuring the concentrations of moxifloxacin, gatifloxacin, linezolid, and cefuroxime in the ocular tissue. Separations were carried out on a LichroSpher RP-18 column, maintained at room temperature. The fluoroquinolones were eluted with a mobile phase consisting of 20% acetonitrile, in 0.1% trifluoroacetic acid (pH 3.0) with 30 mM tetrabutylammonium chloride. Linezolid and cefuroxime were eluted with 25% acetonitrile in 25 mM Na acetate buffer, pH 5.0. All elutions were isocratic. With ultraviolet detection, the lower limit of quantitation (LLOQ) for these compounds approached 1 ng (on-column injection). By using fluorescence detection, the LLOQ for the fluoroquinolones improved to 200 pg. The overall accuracy of the method was >or=90%. With minor modifications, the method was optimized for each of the agents, and the resulting analytical sensitivity made the method suitable for clinical investigations of the ocular penetration of these drugs.

Interaction of intravitreal combination drugs and the effect on the targeted site.

BACKGROUND: After evaluating experimentally the diffusion processes in the retina using peroxidase as a tracer material (previously published work), we found that junctional complexes of the retinal pigment epithelium and retinal capillaries were the major impediment to free diffusion between the retina and choroidal-retinal blood vessels. These experiments indicated that to achieve high therapeutic concentrations of medications inside the eye, it was necessary to administer them by intravitreal injection. Soon after initial experimental work the necessity of combining antibiotics or antibiotics with steroids became obvious. As the use of intravitreal injection grew over the last 2 decades, so did the concept of combination therapy. METHODS: This review describes potential causes of drug-drug interaction and the rationale for combination therapy when injected into the vitreous cavity, encompassing publications between 1971 and 2008. RESULTS: We describe the conditions that can cause physical-chemical interactions between the medications and the need for combination therapy for treatment of various intraocular disease processes. CONCLUSIONS: The intravitreal injection of medication and their combinations has become a part of standard care for many diseases of the retina and choroid. This article reviews the potential interaction of nontoxic doses of medications when injected simultaneously in the vitreous cavity, and disease processes that are now treated with these combination therapies.

Combination angiostatic therapies: current status.

One of the most important obstacles to combining pharmaceutical agents to treat ocular diseases is the risk of physiochemical reactions. In intraocular administration, these reactions may produce incompatibility, instability, or both. They may change the nature of drug activity, and they may threaten normal cellular function, resulting in lens opacities, corneal toxicity, retinal cell damage, or other adverse outcomes. Although many medications have demonstrated efficacy or have shown promise when administered intravitreally, including antifungals, nonsteroidal antiinflammatory drugs, anti-tumor necrosis factor-alpha agents, mammalian target of rapamycin inhibitors, metalloproteinase inhibitors, antiviral agents, antineoplastic compounds, and antivascular endothelial growth factor therapies, these have been typically tested as single agents. The potential for these agents to be combined will be largely determined by their physiochemical compatibility.

Cost of illness of glaucoma: a critical and systematic review.

Cost-of-illness studies determine the total financial burden of a disease by considering direct and indirect costs, including medication, diagnostics and surgery. Studies of resource use and costs associated with primary open-angle glaucoma have used varying methodologies. Most have focused on consumption of healthcare resources at various stages of disease to anticipate costs. The direct costs associated with the disease often continue to increase as glaucoma progresses from the earliest to most advanced stages. Determinations of the costs associated with glaucoma progression and prevention should also incorporate the chance of patient non-compliance with treatment. Since glaucoma severity most often correlates with increased costs, minimizing or halting visual field loss and increasing patient treatment compliance may all contribute to a reduction in the overall economic burden of glaucoma.

Third- and fourth-generation fluoroquinolones: retrospective comparison of endophthalmitis after cataract surgery performed over 10 years.

PURPOSE: To determine differences in endophthalmitis rates with prophylactic use of third- versus fourth-generation fluoroquinolones in cataract surgery. SETTING: University hospitals. METHODS: This retrospective cross-sectional (prevalence) study looked at patients who had phacoemulsification at a university eye center over a 10-year period. A nosocomial infectious reporting database was used to report endophthalmitis occurrences. The following were performed: a retrospective analysis of prospectively collected data to establish endophthalmitis rates, a prevalence analysis of the postoperative quinolone antibiotic prescribed, and a comparative analysis of endophthalmitis rate versus postoperative quinolone prescribed for all reported endophthalmitis cases. The main outcome measure was occurrence of endophthalmitis after cataract surgery. RESULTS: From January 1997 to December 2007, 29276 patients had phacoemulsification cataract surgery. Forty cases of postoperative bacterial endophthalmitis were reported. The endophthalmitis rate from January 1997 to August 2003 associated with use of third-generation fluoroquinolones (ciprofloxacin, ofloxacin) was 0.197% (33/16710). The rate from September 2003 to December 2007 associated with fourth-generation fluoroquinolones (gatifloxacin, moxifloxacin) was 0.056% (7/12566). The difference between third- and fourth-generation drugs was statistically significant (P = .0011). Of fourth-generation fluoroquinolone infections, 0.015% (1/6651) and 0.1% (6/5915) were associated with gatifloxacin and moxifloxacin, respectively. The difference between drugs was statistically significant (P = .040). CONCLUSIONS: The differences in the pharmacokinetic and pharmacodynamic properties of quinolone antibiotics may affect the endophthalmitis incidence after cataract surgery. The significant difference in endophthalmitis rates between gatifloxacin and moxifloxacin requires further study.

Utilization characteristics of topical cycolsporine and punctal plugs in a managed care database.

A retrospective administrative claims analysis of treatment options for dry eye disease (DED) evaluated treatment patterns and utilization characteristics of patients receiving cyclosporine, punctal plugs, or a combination of cyclosporine and punctal plugs, and examined differences in health plan costs with the 2 treatments. A total of 23,821 commercial health plan enrollees that initiated treatment with cyclosporine or punctal plugs between January 1, 2004, and December 31, 2005, were reviewed. There were 9065 subjects in the cyclosporine group, with a mean of 3.93 (median of 3) prescription fills reported in the 365-day follow-up period per subject. The mean health plan cost per patient was $336 (median $228), with total health plan costs of $3.05 million. In the punctal plugs cohort of 8758 subjects, there was a mean of 2.85 punctal plugs procedures per patient in the follow-up period. Total health plan costs for punctal plugs procedures were $3.28 million (mean cost per patient $375). During the follow-up period, 21.1% of punctal plugs patients subsequently received cyclosporine, whereas only 11.4% of topical cyclosporine patients subsequently received punctal plugs. Our results suggest that use of topical cyclosporine before punctal plugs insertion may be of benefit to patients with DED and could result in a savings in overall treatment costs.

Refill rates and budget impact of glaucoma lipid therapy: a retrospective database analysis.

BACKGROUND AND OBJECTIVE: Drugs in the lipid class of glaucoma medications, including bimatoprost, travoprost and latanoprost, are effective at lowering intraocular pressure. In addition to clinical efficacy, the budget impact of long-term therapy with each medication is important for patients, physicians and managed-care decision makers to differentiate between the products and make informed decisions regarding the choice of therapy. This study aimed to determine the average number of days between refills for latanoprost, travoprost and bimatoprost, and to estimate the potential effect of differences in refill rates on pharmacy budgets. METHODS: In this retrospective database analysis of pharmacy records, the dispensing patterns of patients with glaucoma lipid therapies were obtained. Patients with a pharmacy prescription for the 2.5 mL bottle of latanoprost, travoprost or bimatoprost between September 2002 and December 2002, and receiving continuous treatment defined as having at least one prescription for the same lipid agent and bottle size 1 year later between September 2003 and December 2003, were included in this study. The main outcome measures were mean number of days between refills, mean number of refills, cost per patient per year (based on the average wholesale price [AWP]), and annual refill cost differences between cohorts. RESULTS: The mean number of days between refills was 46.74 days, 53.65 days and 51.98 days for latanoprost, travoprost and bimatoprost, respectively (p < 0.0001, ANOVA). The mean number of refills per year was 7.1, 6.2 and 6.4 for latanoprost, travoprost and bimatoprost, respectively. Based on this and the AWP, the average cost per patient per year was $US435.16 for latanoprost, $US385.58 for travoprost and $US397.44 for bimatoprost. The cost savings per year if the population of patients using latanoprost (n = 79,820) used bimatoprost or travoprost instead would be approximately $US3.0-$US3.9 million. CONCLUSION: A statistically significant difference in mean days between refills was found among the three studied drugs. Latanoprost presented the highest annual cost followed by bimatoprost and travoprost.

Topical ophthalmic fourth-generation fluoroquinolones: Appropriate use and cost considerations.

PURPOSE: The utilization and refill rates of topical ophthalmic fourth-generation fluoroquinolones among physicians, as well as the associated costs, were studied. METHODS: A large data set of retrospective pharmacy prescription claims was obtained from multiple plans, including commercial managed care organizations, Medicaid, and Medicare. The data included the number and cost of all new and refill prescriptions for six months for gatifloxacin 0.3% and moxifloxacin 0.5% by physician specialty. New prescription and refill data were also analyzed from a state Medicaid plan to determine if similar trends existed. RESULTS: Primary care physicians wrote approximately 7,000 (7.7%) gatifloxacin and 84,000 (92.3%) moxifloxacin prescriptions, with pediatricians accounting for 4,000 (5.1%) gatifloxacin and 75,000 (94.9%) moxifloxacin prescriptions. Eye care physicians accounted for a similar amount of prescriptions for each antibiotic during the same period. The total cost of prescriptions for all primary care practitioners was approximately $170,000 for gatifloxacin and $2.5 million for moxifloxacin; prescriptions written by pediatricians accounted for $110,000 for gatifloxacin and $2.2 million for moxifloxacin. CONCLUSION: Prescription drug claims from payers using pharmacy benefit management companies during a six-month period indicated that the numbers of prescriptions written for gatifloxacin and moxifloxacin were similar among eye care physicians, but primary care physicians wrote a greater number of prescriptions for moxifloxacin. Analysis of claims to a Medicaid database revealed an increase in the prescriptions written by primary care physicians for moxifloxacin after its addition to the drug formulary.

The effect of temperature on the antimicrobial activity of Optisol-GS.

PURPOSE: To determine the survival of different bacteria inoculated in Optisol-GS at refrigerated storage temperature (6 degrees C) and after subsequent warming to room temperature (19-22 degrees C). METHODS: Staphylococcus aureus, Enterococcus faecium, Streptococcus pneumoniae, and Pseudomonas aeruginosa were chosen from stock clinical isolates for inclusion in the study. The first group consisted of 12 Optisol-GS vials. The second group consisted of 12 Optisol-GS vials containing corneas inappropriate for transplantation according to the Eye Bank Association of America (EBAA) protocols. Each group was inoculated with 3 concentrations of approximately 10, 10, and 10 colony-forming units (CFU)/mL of each bacterial species and then refrigerated per EBAA protocol. After 48 hours of refrigeration, all vials were placed at room temperature (RT) and counts were performed at 48, 50 (2 hour RT), 54 (6 hour RT), 60 (12 hour RT), 72 (24 hour RT), and 96 (48 hour RT) hours. At 96 hours, the corneal tissue from 10 and 10 inocula were cultured. All samples underwent serial dilution, spiral plating on blood agar plates, and incubation at 35 degrees C. Viable colony counts were determined at 24 hours. RESULTS: Except for the 10 CFU/mL inocula of P. aeruginosa, all isolates were viable after 48 hours of refrigeration. Rapid bactericidal activity was observed against P. aeruginosa after 2 hours at RT, with complete sterilization by 6 hours. The rate and extent of killing against S. aureus were influenced by the initial inoculum. Bactericidal activity was achieved after 2 hours at RT with 10 CFU/mL of S. aureus versus 24 hours with the 10 inoculum. Of note, bactericidal activity was not observed against S. pneumoniae and E. faecium following 24 hours of storage at RT. The presence of corneal tissue did not affect viable counts, with counts from corneal tissue cultures reflecting the counts seen from Optisol-GS after 48 hours at RT. CONCLUSIONS: The antimicrobial activity of Optisol-GS was reduced at refrigerated temperature and enhanced at RT. Bactericidal activity was not observed against E. faecium at either refrigerated temperature or RT.