Comparison of two techniques used in routine care for the treatment of inflammatory macular oedema, subconjunctival triamcinolone injection and intravitreal dexamethasone implant: medical and economic importance of this randomized controlled trial.

BACKGROUND: Whether they are injected peri- or intraocularly, corticosteroids are still essential tools in the therapeutic arsenal for treating inflammatory macular oedema. A few years ago, however, only triamcinolone acetonide was available to ophthalmologists. While this compound was initially developed for rheumatological or dermatological use, it has been increasingly deployed in ophthalmology, despite still being off-label. In 2011, the system for delivery of dexamethasone from a biodegradable, injectable implant into the vitreous cavity obtained approval for use in inflammatory macular oedema. While the efficacy and safety of triamcinolone in macular oedema, including inflammatory oedema, have already been studied, there are currently no publications on subconjunctival triamcinolone injections, which are simple, effective and well tolerated. To date, the dexamethasone 700 µg implant has been authorized for the treatment of noninfectious intermediate and posterior uveitis, but there have been no studies to evaluate the efficacy and safety of the different peri- and intraocular strategies, including the treatment of inflammatory macular oedema. METHODS: This protocol is therefore designed to compare the efficacy and safety of peri- and intraocular corticosteroid injections in the treatment of inflammatory macular oedema. In this ongoing study, 142 patients will be included, and the oedematous eye will be randomised to treatment with either subconjunctival triamcinolone injection or an intravitreal implant containing 700 µg dexamethasone. Follow-up is planned for 6 months with monthly visits. Each visit will include visual acuity measurement, a slit lamp examination, fundoscopy, intraocular pressure measurement, laser flare measurement (if available) and spectral domain optical coherence tomography. DISCUSSION: The results of this trial will have a real impact on public health if it is shown that a Kenacort retard® (i.e. triamcinolone) injection costing just €2.84 and performed in the physician's office (with no additional overhead costs) is at least as effective as the dexamethasone 700 µg implant (Ozurdex®; costing approximately €960 with the injection performed in a dedicated room), with no increased side effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02556424. Registered on 22 September 2015.

A randomised controlled trial of the clinical and cost-effectiveness of ultrasound-guided intra-articular corticosteroid and local anaesthetic injections: the hip injection trial (HIT) protocol.

BACKGROUND: Evidence on the effectiveness of intra-articular corticosteroid injection for hip osteoarthritis is limited and conflicting. The primary objective of the Hip Injection Trial (HIT) is to compare pain intensity over 6 months, in people with hip OA between those receiving an ultrasound-guided intra-articular hip injection of corticosteroid with 1% lidocaine hydrochloride plus best current treatment with those receiving best current treatment alone. Secondary objectives are to determine specified comparative clinical and cost-effectiveness outcomes, and to explore, in a linked qualitative study, the lived experiences of patients with hip OA and experiences and impact of, ultrasound-guided intra-articular hip injection. METHODS: The HIT trial is a pragmatic, three-parallel group, single-blind, superiority, randomised controlled trial in patients with painful hip OA with a linked qualitative study. The current protocol is described, in addition to details and rationale for amendments since trial registration. 204 patients with moderate-to-severe hip OA will be recruited. Participants are randomised on an equal basis (1:1:1 ratio) to one of three interventions: (1) best current treatment, (2) best current treatment plus ultrasound-guided intra-articular hip injection of corticosteroid (triamcinolone acetonide 40 mg) with 1% lidocaine hydrochloride, or (3) best current treatment plus an ultrasound-guided intra-articular hip injection of 1% lidocaine hydrochloride alone. The primary endpoint is patient-reported hip pain intensity across 2 weeks, 2 months, 4 months and 6 months post-randomisation. Recruitment is over 29 months with a 6-month follow-up period. To address the primary objective, the analysis will compare participants' 'average' follow-up pain NRS scores, based on a random effects linear repeated-measures model. Data on adverse events are collected and reported in accordance with national guidance and reviewed by external monitoring committees. Individual semi-structured interviews are being conducted with up to 30 trial participants across all three arms of the trial. DISCUSSION: To ensure healthcare services improve outcomes for patients, we need to ensure there is a robust and appropriate evidence-base to support clinical decision making. The HIT trial will answer important questions regarding the clinical and cost-effectiveness of intra-articular corticosteroid injections. TRIAL REGISTRATION: ISRCTN: 50550256 , 28th July 2015.

Adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): study protocol for a phase III, multi-centre, double-masked randomised controlled trial.

BACKGROUND: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Ocular injuries which result in visual loss invariably affect the posterior segment of the eye, and prevention of visual loss involves posterior segment (vitreoretinal) surgery. Despite improvements in vitreoretinal surgical techniques, outcomes in these patients remain unsatisfactory, and development of the intraocular scarring response proliferative vitreoretinopathy is the leading cause. Proliferative vitreoretinopathy is the most common cause of recurrent retinal detachment in these eyes; it is reported to occur in up to 45 % of cases. METHODS/DESIGN: The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a multi-centre, double-masked, parallel-arm randomised controlled trial with an internal pilot designed to investigate the effectiveness and cost-effectiveness of using intravitreal and sub-Tenon's triamcinolone acetonide peri-operatively in patients undergoing vitrectomy following open globe trauma. In total, 300 eyes of 300 patients will be recruited and randomly allocated to one of two treatment groups. Both groups will receive standard surgical treatment and routine pre-operative and post-operative treatment and care. The treatment group will receive an adjunctive peri-operative steroid combination (triamcinolone acetonide) consisting of 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml into the sub-Tenon's space. The trial incorporates a two-stage internal pilot to examine projected recruitment and retention rates. Progression criteria from the internal pilot study will enable us to determine whether to undertake the main trial. Patients and primary outcome assessors will be masked to treatment allocation. The primary outcome will be an improvement from baseline to 6 months of at least 10 on the corrected visual acuity as measured by ETDRS letter score. Secondary outcomes will be development of scarring, retinal detachment, intraocular pressure abnormalities, quality of life and public sector service use. DISCUSSION: This is the first powered, controlled clinical trial to investigate the use of adjunctive triamcinolone in patients undergoing vitrectomy following open globe trauma. TRIAL REGISTRATION: EudraCT2014-002193-37 . Registered on 5 September 2014. ISRCTN30012492 . Registered on 5 September 2014.

THE OMAR STUDY: Comparison of Ozurdex and Triamcinolone Acetonide for Refractory Cystoid Macular Edema in Retinal Vein Occlusion.

PURPOSE: To compare the risks and benefits of adding either intravitreal dexamethasone implant (DEX) or preservative-free triamcinolone acetonide (TA) to bevacizumab monotherapy in refractory cystoid macular edema due to retinal vein occlusion. METHODS: This is a multicenter, comparative, interventional, retrospective study that included 74 patients who were initially treated with intravitreal bevacizumab and later received either DEX or TA for the treatment of recalcitrant cystoid macular edema due to retinal vein occlusion. Main outcomes were best-corrected visual acuity, central macular thickness, cost of therapy, frequency of intravitreal injections, and side effects. RESULTS: Thirty-nine patients received TA and 35 patients received DEX injections. Groups were similar in age and gender distribution. Although the mean central macular thickness improved significantly for all groups (P < 0.0001), logMAR best-corrected visual acuity did not change significantly after steroid introduction (P = 0.06). Frequency of any intravitreal injection decreased significantly from 0.66 ± 0.18 to 0.26 ± 0.08 injections per month after initiation of steroids (P < 0.0001). This effect was greater in the DEX groups (P < 0.0001). Monthly cost decreased with TA but increased with DEX. CONCLUSION: Adding steroids improved anatomical outcome but did not affect final vision. Injection frequency decreased significantly after adding steroids, more so with DEX. There was no difference between TA and DEX regarding anatomical or functional outcomes or the incidence of side effects.

[A cost-effectiveness study of dexamethasone implants in macular edema]. / Resultados coste-efectividad del implante de dexametasona en edema macular.

OBJECTIVE: To analyze the cost-effectiveness and benefits of a dexamethasone intravitreal implant (Ozurdex®, Allergan, Irvine, CA, USA.) in its clinically relevant applications. MATERIAL AND METHODS: A total of 88 eyes of 86 patients with macular edema of > 300 µm measured by optical coherence tomography (Cirrus Zeiss, Dublin, CA, USA) were included in this two-year retrospective study, with a minimum of 6 months follow-up. The patients were divide into 3 groups: group 1 with macular edema in retinal vein occlusion, group 2 with non-infectious posterior uveitis, and group 3 with diabetic macular edema. The treatment was off-label but supported by the literature. Before implantation, and on days 1, 30, 60, 90 and 180, corrected visual acuity (Snellen), central retinal thickness, intraocular pressure and biomicroscopy were evaluated. The cost-benefit analysis was tabulated by line of visual acuity gained, comparing the main therapeutic alternatives and assessment of the safety profile of the dexamethasone intravitreal implant (Ozurdex®, Allergan, Irvine, CA, USA). RESULTS: The results of this study did not differ from the published studies, in terms of visual acuity improvement in 63.3% of cases, and with central macular thickness improvement in 97% of cases. There were relapses, which occurred after 120 days on average, and the need for retreatment was 40.9%. Increased intraocular pressure >23 mm Hg was among the side effects in 29.54%, and was controlled with topical treatment, except in 1.13% requiring surgical treatment. The development of cataract was 44.7%, and 10.6% required surgery. Treatment results showed less frequent use of Ozurdex® than other treatments for disease control, being a cost saving option. DISCUSSION: Cost-effectiveness analyses are clinically relevant when applying treatment strategies in patients with macular edema. Dexamethasone intravitreal implant appears to be a safe and efficient therapy.

Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema.

OBJECTIVE: Anti-vascular endothelial growth factor therapies have revolutionized the treatment of clinically significant diabetic macular edema (CSDME); yet these agents are expensive, and whether they are cost-effective is unclear. The purpose of this study is to determine the most cost-effective treatment option for patients with newly diagnosed CSDME: focal laser photocoagulation alone (L), focal laser plus intravitreal ranibizumab (L+R), focal laser plus intravitreal bevacizumab (L+B), or focal laser plus intravitreal triamcinolone (L+T) injections. DESIGN: Cost-effectiveness analysis. PARTICIPANTS: Hypothetical cohort of 57-year-old patients with newly diagnosed CSDME. METHODS: By using a Markov model with a 25-year time horizon, we compared the incremental cost-effectiveness of treating patients with newly diagnosed CSDME using L, L+R, L+B, or L+T. Data came from the DRCRnet randomized controlled trial, the Medicare fee schedule, and the medical literature. MAIN OUTCOME MEASURES: Costs, quality-adjusted life years (QALYs), and incremental costs per QALY gained. RESULTS: Compared with L, the incremental cost-effectiveness of L+R and L+B was $89903/QALY and $11138/QALY, respectively. L+T was dominated by L. A probabilistic sensitivity analysis demonstrated that, at a willingness to pay (WTP) of $50000/QALY, L was approximately 70% likely to be the preferred therapy over L+R and L+T. However, at a WTP of $100000/QALY, more than 90% of the time, L+R therapy was the preferred therapy compared with L and L+T. In the probabilistic sensitivity analysis, L+B was found to be the preferred therapy over L and L+T for any WTP value >$10000/QALY. Sensitivity analyses revealed that the annual risk of cerebrovascular accident would have to be at least 1.5% higher with L+B than with L+R for L+R to be the preferred treatment. In another sensitivity analysis, if patients require <8 injections per year over the remainder of the 25-year time horizon, L+B would cost <$100000/QALY, whereas L+R would be cost-effective at a WTP of $100000/QALY if patients require fewer than 0.45 injections per year after year 2. CONCLUSIONS: With bevacizumab and ranibizumab assumed to have equivalent effectiveness and similar safety profiles when used in the management of CSDME, bevacizumab therapy confers the greatest value among the different treatment options for CSDME. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Clinical applications of cost analysis of diabetic macular edema treatments.

OBJECTIVE: To apply cost-benefit analyses in specific circumstances in which the results of multiple modalities of treating diabetic macular edema (DME) are similar, as a basis for considering economic ramifications in clinically relevant applications. DESIGN: A model of resource use, outcomes, and cost-effectiveness and utility. PARTICIPANTS: There were no participants. METHODS: Results from published clinical trials (index studies) of laser, intravitreal corticosteroids, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and vitrectomy trials were used to ascertain visual benefit and clinical protocols of patients with DME. Calculations followed from the costs of 1 year of treatment for each modality and the visual benefits as ascertained. MAIN OUTCOME MEASURES: Visual acuity (VA) saved, cost of therapy, cost per line saved, cost per line-year saved, and costs per quality-adjusted life years (QALYs) saved. RESULTS: Four specific situations were observed or analyzed: (1) Treatment results for DME causing VA loss <20/200 show at least as much visual benefit for intravitreal triamcinolone (IVTA) versus laser; (2) a subgroup analysis of pseudophakic DME eyes shows equivalent visual results with anti-VEGF treatment versus laser combined with IVTA; (3) eyes with VA of ≥ 20/32 have been studied only by laser; and (4) less frequent use of aflibercept yields equivalent visual results as more frequent treatment. When the results are equivalent, opting for the less-expensive treatment option could yield cost savings of 40% to 88%. CONCLUSIONS: Cost-effectiveness analyses can be clinically relevant and may be considered when formulating and applying treatment strategies for some subsets of patients with DME. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Cost-effectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.

OBJECTIVE: Perform a cost-effectiveness analysis of the treatment of diabetic macular edema (DME) with ranibizumab plus prompt or deferred laser versus triamcinolone plus prompt laser. Data for the analysis were drawn from reports of the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I. DESIGN: Computer simulation based on Protocol I data. Analyses were conducted from the payor perspective. PARTICIPANTS: Simulated participants assigned characteristics reflecting those seen in Protocol I. METHODS: Markov models were constructed to replicate Protocol I's 104-week outcomes using a microsimulation approach to estimation. Baseline characteristics, visual acuity (VA), treatments, and complications were based on Protocol I data. Costs were identified by literature search. One-way sensitivity analysis was performed, and the results were validated against Protocol I data. MAIN OUTCOME MEASURES: Direct cost of care for 2 years, change in VA from baseline, and incremental cost-effectiveness ratio (ICER) measured as cost per additional letter gained from baseline (Early Treatment of Diabetic Retinopathy Study). RESULTS: For sham plus laser (S+L), ranibizumab plus prompt laser (R+pL), ranibizumab plus deferred laser (R+dL), and triamcinolone plus laser (T+L), effectiveness through 104 weeks was predicted to be 3.46, 7.07, 8.63, and 2.40 letters correct, respectively. The ICER values in terms of dollars per VA letter were $393 (S+L vs. T+L), $5943 (R+pL vs. S+L), and $20 (R+dL vs. R+pL). For pseudophakics, the ICER value for comparison triamcinolone with laser versus ranibizumab with deferred laser was $14 690 per letter gained. No clinically relevant changes in model variables altered outcomes. Internal validation demonstrated good similarity to Protocol I treatment patterns. CONCLUSIONS: In treatment of phakic patients with DME, ranibizumab with deferred laser provided an additional 6 letters correct compared with triamcinolone with laser at an additional cost of $19 216 over 2 years. That would indicate that if the gain in VA seen at 2 years is maintained in subsequent years, then the treatment of phakic patients with DME using ranibizumab may meet accepted standards of cost-effectiveness. For pseudophakic patients, first-line treatment with triamcinolone seems to be the most cost-effective option.

Economic implications of current age-related macular degeneration treatments.

PURPOSE: To measure the cost versus benefit of age-related macular degeneration (AMD) treatment strategies, existing and proposed, in the postranibizumab era. DESIGN: Cost-effectiveness model. PARTICIPANTS: None. METHODS: University with hospital-based practice modeling of clinical examination, imaging, and treatment schedules were constructed considering published protocols where available, or by estimating usual practices. Medicare-allowable reimbursement schedules for a hospital-based, south Florida practice in 2007 were used to calculate costs of treatment. The lines of vision saved were deduced from published reports or using identified assumptions. This information was used to calculate cost per lines saved and, using actuarial tables data, costs per line-year saved were calculated. MAIN OUTCOME MEASURE: Cost ($US) per line-year. RESULTS: Consensus control values of expected lines loss if untreated (natural history) were established from published reports (2.5 lines at 1 year; 3.5 at 2 years) and photodynamic therapy (2.0 lines at 1 year; 3.0 at 2 years) for use in calculating lines of vision saved in studies without untreated control groups. The cost per line-year for 1 year of treatment ranged from a low of $84 with as-needed bevacizumab to $766 for protocol-style use of ranibizumab. Combination treatment regimens yielded a range of $71 to $269. The pharmaceutical proportion of treatment costs is higher than professional or facility costs, ranging to 83% for protocol-style ranibizumab. CONCLUSIONS: Pharmaceutical-based treatments of AMD have markedly improved visual outcomes, but also have escalated costs markedly. Treatment regimens involving as-needed dosing, alternate medications, and combination therapy may preserve benefit for substantially lower costs. Disparate safety profiles would require consideration in choosing treatment regimens. Cost-benefit issues must be considered in AMD treatment regimens.

Triamcinolone-assisted internal limiting membrane peeling.

PURPOSE: To review our experience with triamcinolone-assisted pars plana vitrectomy for internal limiting membrane (ILM) peeling for various retinal diseases. METHODS: Twenty-one patients underwent surgery in which intraoperative triamcinolone acetonide (TA) was used. Indications for surgery included epiretinal membrane (3 patients), branch retinal vein occlusion associated with macular edema (2), traction retinal detachment (3), diabetic macular edema (4), vitreous hemorrhage with diabetic macular edema (4), macular hole (4), and cystoid macular edema (1). RESULTS: TA was useful in the removal of the ILM in all cases. There were no intraoperative complications or toxicity. The mean follow-up was 22 weeks (range, 9-30 weeks). Eleven patients improved by >or=2 Snellen lines, 1 lost >or=2 Snellen lines, and 9 were within 2 Snellen lines of preoperative vision at the last follow-up. CONCLUSIONS: The intraoperative use of TA improves visualization of ILMs associated with a variety of conditions. No intraoperative or postoperative complications were observed. TA-assisted removal of the ILM appears to be safe and cost effective. TA-assisted ILM peeling should be considered as an alternative to the use of intraoperative dyes.

Cost-effectiveness and safety of epidural steroids in the management of sciatica.

OBJECTIVES: To investigate the clinical effectiveness of epidural steroid injections (ESIs) in the treatment of sciatica with an adequately powered study and to identify potential predictors of response to ESIs. Also, to investigate the safety and cost-effectiveness of lumbar ESIs in patients with sciatica. DESIGN: A pragmatic, prospective, multicentre, double-blind, randomised, placebo-controlled trial with 12-month follow-up was performed. Patients were stratified according to acute (<4 months since onset) versus chronic (4-18 months) presentation. All analyses were performed on an intention-to-treat basis with last observation carried forward used to impute missing data. SETTING: Rheumatology, orthopaedic and pain clinics in four participating centres: three district hospitals and one teaching hospital in the south of England. PARTICIPANTS: Total of 228 patients listed for ESI with clinically diagnosed unilateral sciatica, aged between 18 and 70 years, who had a duration of symptoms between 4 weeks and 18 months. INTERVENTIONS: Patients received up to three injections of epidural steroid and local anaesthetic (active), or an injection of normal saline into the interspinous ligament (placebo). MAIN OUTCOME MEASURES: The primary outcome measure was the Oswestry Disability Questionnaire (ODQ); measures of pain relief and psychological and physical function were collected. Health economic data on return to work, analgesia use and other interventions were also measured. Quality-adjusted life-years (QALYs) were calculated using the SF-6D, calculated from the Short Form (SF-36). Costs per patient were derived from figures supplied by the centres' finance departments and a costings exercise performed as part of the study. A cost-utility analysis was performed using the SF-36 to calculate costs per QALY. RESULTS: ESI led to a transient benefit in ODQ and pain relief, compared with placebo at 3 weeks (p = 0.017, number needed to treat = 11.4). There was no benefit over placebo between weeks 6 and 52. Using incremental QALYs, this equates to and additional 2.2 days of full health. Acute sciatica seemed to respond no differently to chronic sciatica. There were no significant differences in any other indices, including objective tests of function, return to work or need for surgery at any time-points. There were no clinical predictors of response, although the trial lacked sufficient power to be confident of this. Adverse events were uncommon, with no difference between groups. Costs per QALY to providers under the trial protocol were 44,701 pounds sterling. Costs to the purchaser per QALY were 354,171 pounds sterling. If only one ESI was provided then costs per QALY fell to 25,745 pounds sterling to the provider and 167,145 pounds sterling to the purchaser. ESIs thus failed the QALY threshold recommended by the National Institute for Health and Clinical Excellence (NICE). CONCLUSIONS: Although ESIs appear relatively safe, it was found that they confer only transient benefit in symptoms and self-reported function in a small group of patients with sciatica at substantial costs. ESIs do not provide good value for money if NICE recommendations are followed. Additional research is suggested into the epidemiology of radicular pain, producing a register of all ESIs, possible subgroups who may benefit from ESIs, the use of radiological imaging, optimal early interventions, analgesic agents and nerve root injections, the use of cognitive behavioural therapy in rehabilitation, improved methods of assessment, a comparative cost-utility analysis between various treatment strategies, and methods to reduce the effect of scarring and inflammation.

Asthma treatment costs using inhaled corticosteroids.

Asthma is a chronic inflammatory disorder of the airways that affects 10 to 17.5 million people and leads to more than $5 billion in treatment costs in the Unites States annually. This retrospective study is an initial step in understanding the beneficial economic outcomes of inhaled corticosteroid therapy by determining whether differences exist in healthcare utilization expenditures for three inhaled corticosteroids available for use in the United States: (1) beclomethasone dipropionate (Vanceril/Schering and Beclovent/Allan & Hanburys); (2) flunisolide (Aerobid/Forest); and (3) and triamcinolone acetonide (Azmacort/Rhône-Poulenc Rorer). This study was based on an analysis of 4,441 patients with at least one pharmaceutical claim for one of the study drugs, using inpatient, outpatient, and prescription drug claims data obtained from The MEDSTAT Group's MarketScan database for calendar years 1990 through 1993. We tested a null hypothesis for no differences in total asthma treatment costs, when drugs were excluded, using multivariate linear regression modeling controlling for patient demographic and clinical characteristics that might affect the study outcome. We found that, after excluding study drug payments and controlling for other contributing factors, total asthma healthcare expenditures to triamcinolone acetonide (Azmacort) users were higher than those for beclomethasone dipropionate (Vanceril and Beclovent) and flunisolide (Aerobid) users. When study drug costs were included in the expenditure measure, both triamcinolone acetonide (Azmacort) and flunisolide (Aerobid) users had higher expenditures than did beclomethasone dipropionate (Vanceril and Beclovent) users. No significant differences in expenditures were detected between Vanceril and Beclovent patients, a finding consistent with the fact that these drugs are the same type of inhaled corticosteroid. Other factors contributing to differences in total asthma healthcare costs included patient age, patterns of switching among and continuing with study drugs, prestudy asthma utilization or drug proxy severity, and comorbidities of precipitating illnesses.