GKM Gesellschaft für Therapieforschung mbH

To evaluate progression from nonradiographic (nr‐) to radiographic axial spondyloarthritis (r‐axSpA) over 5 years in patients with recently diagnosed (≤1 year) axSpA fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria.

A prospsective, observational study (Patients with Axial Spondyloarthritis: Multi‐Country Registry of Clinical Characteristics) was conducted in rheumatology practices in 29 countries. Baseline and follow‐up radiographs of sacroiliac joints were centrally evaluated by three readers according to the grading system of the modified New York criteria for patients initially classified as nr‐axSpA. Radiographic progression from nr‐axSpA to r‐axSpA was evaluated by Kaplan‐Meier analysis. Cox proportional regression analyses for progression from nr‐axSpA to r‐axSpA were also conducted.

Among 2,165 patients with axSpA, 1,612 (74%) were classified as having r‐axSpA (1,050 [65%]) or nr‐axSpA (562 [35%]) by central reading. Of 246 patients with nr‐axSpA (mean [SD] symptom duration: 4.4 [6.2] years) who had at least one follow‐up sacroiliac joint radiograph, progression from nr‐axSpA to r‐axSpA at any follow‐up visit was observed in 40 patients (16%) over 5 years. Mean time to radiographic progression was 2.4 years (ranging from 0.9 to 5.1 years). Progression to r‐axSpA was associated with male sex (hazard ratio [HR] 3.16 [95% CI 1.22–8.17]), fulfillment of the imaging arm of the ASAS classification criteria (HR 6.64 [1.37–32.25]), and good response to nonsteroidal anti‐inflammatory drugs (HR 4.66 [1.23–17.71]).

16% of patients with nr‐axSpA progressed to r‐axSpA within 5 years. Male sex, fulfillment of the imaging arm of the ASAS criteria, and good response to nonsteroidal anti‐inflammatory drugs were predictors of radiographic progression in patients with recently diagnosed axSpA.

We tested the hypothesis that initiation versus non-initiation of sacubitril/valsartan is associated with a more favorable subsequent change in left ventricular ejection fraction (LVEF) in a real-world setting.

A prospective, non-randomized, double-arm, open-label, cohort study had been conducted across 687 centers in 17 European countries enrolling HFrEF patients aged ≥18 years with symptoms of HF (New York Heart Association [NYHA] II-IV) and "reduced LVEF". For the current analysis, 2602 patients with LVEF measured at baseline and follow-up were chosen, of which 860 (33%, mean age 67 years, 26% women) were started on sacubitril/valsartan at baseline and 1742 (67%, 68 years, 23% women) were not. Patients started on sacubitril/valsartan had higher NYHA class and lower LVEF.

LVEF increased from mean 32.7% to 38.1% in the sacubitril/valsartan group versus from 35.9% to 38.7% in the non-sacubitril/valsartan group (mean difference in increase 2.6%, p < 0.001). LVEF increased from baseline in 64% versus 53% of patients and increased by ≥5% (absolute %) in 50% versus 35% of patients in the sacubitril/valsartan versus non-sacubitril/valsartan groups, respectively. In the overall cohort, initiation of sacubitril/valsartan was independently associated with any increase in LVEF (adjusted odds ratio [OR] 1.49 [1.26-1.75]) and with increase by ≥5% (OR 1.65 [1.39-1.95]).

Initiating versus not initiating sacubitril/valsartan was independently associated with a greater subsequent increase in LVEF in this real-world setting. Reverse cardiac remodeling may be one mechanism of benefit of sacubitril/valsartan.

The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo.

Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted.

Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (-1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either "good" or "very good".

The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.