Systematic Literature Review and Network Meta-analysis of the Efficacy and Acceptability of Interventions in Actinic Keratoses.

A systematic literature review was conducted to identify and qualitatively assess randomized controlled trials in immunocompetent patients ≥ 18 years with head- region lesions of actinic keratoses who were treated with field-directed, lesion-directed and other therapies. Network meta-analysis was used to quantitatively evaluate field-directed therapies (5-fluorouracil formulations, diclofenac sodium, imiquimod, ingenol mebutate, 5-aminolevulinic acid or methyl aminolevulinate plus photodynamic therapy) using complete clearance or partial clearance of actinic keratoses lesions, and adverse event-related withdrawals as a proxy of acceptability. Of 2,863 references identified, 75 trials reported in 151 publications were included. In summary, comparative network meta-analysis evaluation showed that 5-fluorouracil formulations were the most efficacious interventions examined. 5-fluorouracil 4%, which was recently approved, showed a comparable efficacy profile to 5-fluorouracil 5%, and had satisfactory acceptability outcomes.

Use of complete clearance for assessing treatment efficacy for 5-fluorouracil interventions in actinic keratoses: how baseline lesion count can impact this outcome.

Background: Many trials in actinic keratoses (AK) use complete clearance rate (100% reduction in number of lesions) as the primary endpoint. We explore limitations (predominantly baseline factors) associated with this outcome. Objective: This analysis assessed the effect of baseline lesion count on complete clearance rate using randomized controlled trials (RCTs) that evaluated 5-fluorouracil (5-FU) formulations, alone or with 10% salicylic acid solution, in patients with AK. Methodology: Correlation between baseline lesion count and complete clearance rate at week 8 was assessed using Pearson's coefficient. Results: Five RCTs assessing 5-FU (4%, 5%, or 0.5% in 10% salicylic acid solution) in 1,080 patients with AK were included. Mean lesion count at baseline ranged from 8.1 to 21.2 lesions per patient. Complete clearance rate was negatively associated with number of lesions at baseline. Correlation between mean number of lesions at baseline and complete clearance rate was strong (r2 = 0.94) and statistically significant (p < 0.001). Conclusion: This analysis showed that, in a homogenous set of trials, complete clearance rates achieved with 5-FU interventions are inversely related to number of lesions at baseline. These findings highlight the limits of restricting treatment evaluation to complete clearance rate and the relevance of alternative measures.

Efficacy and tolerability of switching therapy to vortioxetine versus other antidepressants in patients with major depressive disorder.

OBJECTIVES: To assess the relative efficacy and tolerability of vortioxetine against different antidepressant monotherapies in patients with major depressive disorder (MDD) with inadequate response to selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) therapy. METHODS: A systematic search was conducted for monotherapy studies in patients with MDD with inadequate response to first-line therapy. Treatments included SSRIs, SNRIs, and other antidepressants. Identified studies underwent a three-stage screening/data extraction process and critical appraisal. Adjusted indirect treatment comparisons (ITCs) on systematic literature review outputs were made using Bucher's method, comparing remission rates and withdrawal rates due to adverse events (AEs). RESULTS: Of 27 studies meeting the inclusion criteria, a few studies were of high quality according to the National Institute of Health and Care Excellence checklist. Three studies contributed to an evidence network for quantitative assessment comparing vortioxetine with agomelatine, sertraline, venlafaxine XR, and bupropion SR. Vortioxetine had a statistically significantly higher remission rate than agomelatine (risk difference [RD]: -11.0% [95% CI: -19.4; -2.6]), and numerically higher remission rates than sertraline (RD: -14.4% [95% CI: -29.9; 1.1]), venlafaxine (RD: -7.20% [95% CI: -24.3; 9.9]), and bupropion (RD: -10.70% [95% CI: -27.8; 6.4]). Withdrawal rates due to AEs were statistically significantly lower for vortioxetine than sertraline (RD: 12.1% [95% CI: 3.1; 21.1]), venlafaxine XR (RD: 12.3% [95% CI: 0.8; 23.8]), and bupropion SR (RD: 18.3% [95% CI: 6.4; 30.1]). CONCLUSIONS: The current systematic literature review found a few high quality switch studies assessing monotherapies in patients with MDD with inadequate response to SSRI/SNRIs. ITCs indicated that switching to vortioxetine leads to numerically higher remission rates compared with other antidepressants. Vortioxetine is a well tolerated treatment, showing statistically lower withdrawal rates due to AEs compared with other antidepressants. Vortioxetine is a relevant therapeutic alternative in patients experiencing inadequate response to prior SSRI or SNRI therapy.

Can we well assess the relative efficacy and tolerability of a new drug versus others at the time of marketing authorization using mixed treatment comparisons? A detailed illustration with escitalopram.

OBJECTIVE: To assess the variation of relative efficacy and tolerability of an antidepressant versus others based on both pre-marketing (registration studies) and post-marketing studies versus pre-marketing studies only in patients with major depressive disorder. METHODS: The relative efficacy and tolerability of antidepressants was assessed by mixed treatment comparisons (MTCs) using data acquired over two time periods: before registration of the reference drug escitalopram (1989-2002) and up to 5 years later (1989-2007). Ranking probability outputs were presented for efficacy, using change from baseline to 8 weeks on Montgomery-Åsberg Depression Rating Scale total score, and tolerability, using withdrawals due to adverse events. RESULTS: The relative efficacy and tolerability of some selected antidepressants, including escitalopram, varied considerably over the two time periods. The improved relative efficacy and tolerability of escitalopram over time, compared with citalopram, was demonstrated by greater separation of ranking probability curves for efficacy and tolerability. In 2002, escitalopram ranked low with 13.9% and 5.1% probability of being in the top four antidepressants' relative efficacy and tolerability, respectively. In 2007, ranking probabilities for relative efficacy and tolerability of escitalopram increased to 52.5% and 82.1%, respectively. CONCLUSIONS: Time of marketing authorization may not be the most appropriate time to evaluate the relative efficacy and tolerability of a new antidepressant based on MTC approach due to the asymmetry of information between new and older compounds. However, the first evaluation of relative effect of a new drug for health technology assessment recommendations is commonly done at this time. Re-evaluation of a drug several years after its launch is likely to provide a more accurate indication of its relative efficacy and tolerability.