Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/1/phar2404_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/2/phar2404.pd

A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate, posterior or panuveitis in adults

Background: Non-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biologic drugs. Objectives: To evaluate clinical and cost-effectiveness of subcutaneous adalimumab and dexamethasone intravitreal implant in adults with non-infectious intermediate, posterior or panuveitis. Methods: Nine electronic databases were searched to June 2016. A Markov model was developed to assess cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from an NHS and PSS perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken. Results: Two studies (VISUAL I, active uveitis; and VISUAL II, inactive uveitis) compared adalimumab against placebo, plus limited standard care in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer for adalimumab than placebo, with hazard ratio 0.50 (95% CI 0.36 to 0.70, p<0.001) in VISUAL I and 0.57 (0.39 to 0.84, p=0.004) in VISUAL II. Adalimumab provided significantly greater improvement in VFQ-25 composite score in VISUAL I (mean difference, 4.20; p=0.010) but not VISUAL II (mean difference, 2.12; p=0.16). Some systemic adverse effects occurred more frequently with adalimumab than placebo. One study (HURON, active uveitis) compared single 0.7mg dexamethasone implant against sham, plus limited standard care in both arms. Dexamethasone provided significant benefits over sham at 8 and 26 weeks in percentage of patients with vitreous haze score zero (p<0.014); mean BCVA improvement (p≤0.002); and percentage of patients with ≥5-point improvement in VFQ-25 (p<0.05). Raised intraocular pressure and cataracts occurred more frequently with dexamethasone than sham. The incremental cost-effectiveness ratio (ICER) of one dexamethasone implant in one eye for a combination of patients with unilateral and bilateral uveitis, compared with limited current practice as per the HURON trial, is estimated as £19,509 per quality-adjusted life year (QALY) gained. The ICER of adalimumab for patients with mainly bilateral uveitis, compared with limited current practice as per the VISUAL trials, is estimated as £94,523 and £317,547 per QALY gained in active and inactive uveitis respectively. Sensitivity analyses suggest rate of blindness has the biggest impact upon model results. The interventions may be more cost-effective in populations where there is a greater risk of blindness. Limitations: The clinical trials did not fully reflect clinical practice. Thirteen studies of clinically-relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain due to the limited evidence base. Conclusions: Two RCTs of systemic adalimumab and one RCT of unilateral, single dexamethasone implant showed significant benefits over placebo or sham. The ICERs for adalimumab are estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone is estimated to fall below standard thresholds. However there is substantial uncertainty around the model assumptions. Future work: Primary research should compare dexamethasone and adalimumab with current treatments over the long term, and in important subgroups, and consider how short-term improvements relate to long-term effects on vision. Study registration: PROSPERO CRD42016041799 Funding details: NIHR HTA Programm