Assessing the Quality and Coherence of Network Meta-Analyses of Biologics in Plaque Psoriasis: What Does All This Evidence Synthesis Tell Us?

INTRODUCTION: A range of treatments are available for moderate-to-severe psoriasis; however, there remains a paucity of direct comparisons of these in head-to-head trials. Network meta-analyses (NMA) allow comparisons of these to support clinical decision making. This systematic literature review assesses the methodological quality of NMAs available for moderate-to-severe psoriasis and compares their methods and results. Their validity and applicability for current practice is also assessed. METHODS: A systematic review of published NMAs of at least two biologics for moderate-to-severe psoriasis was undertaken. Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Library were last searched on 19 February 2020. The quality of NMAs was assessed using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) criteria. NMA methodology, funding, and results were compared and differences in results explored. RESULTS: Twenty-five analyses evaluating up to 19 different treatments at 8-24 weeks, and two analyses at 1 year, were included. Psoriasis Area Severity Index (PASI) response was assessed in 23, facilitating comparisons between NMAs. All NMAs met at least half of the ISPOR criteria. The major limitations were explaining the rationale for methodology, exploring effect modifiers, and consistency between direct and indirect estimates. The analyses differed in model type (Bayesian or frequentist), analysis of PASI response (binomial or multinomial), and analysis of different treatment doses (separate or pooled). PASI results were broadly similar, except for the Cochrane Collaboration NMA which provided lower estimates of treatment efficacy versus placebo. This analysis differed methodologically from others, including pooling data for different doses. CONCLUSIONS: Based on PASI 90 at induction, the majority of recent NMAs came to similar conclusions: interleukin (IL) 17 inhibitors (brodalumab, ixekizumab, secukinumab), IL-23 inhibitors (guselkumab and risankizumab) and infliximab were most efficacious, supporting the validity of NMAs in this clinical area. Decisions should be made using high-quality, up-to-date NMAs with assumptions relevant to clinical practice.

Comparability of compressed sensing-based gradient echo perfusion sequence SPARSE and conventional gradient echo sequence in assessment of myocardial ischemia.

PURPOSE: Stress perfusion imaging plays a major role in non-invasive detection of coronary artery disease. We compared a compressed sensing-based and a conventional gradient echo perfusion sequence with regard to image quality and diagnostic performance. METHOD: Patients sent for coronary angiography due to pathologic stress perfusion CMR were recruited. All patients underwent two adenosine stress CMR using conventional TurboFLASH and prototype SPARSE sequence as well as quantitative coronary angiography with fractional flow reserve (FFR) within 6 weeks. Coronary angiography was considered gold standard with FFR < 0.75 or visual stenosis >90 % for identification of myocardial ischemia. Diagnostic performance of perfusion imaging was assessed in basal, mid-ventricular and apical slices by quantification of myocardial perfusion reserve (MPR) analysis utilizing the signal upslope method and a deconvolution technique using the fermi function model. RESULTS: 23 patients with mean age of 69.6 ± 8.9 years were enrolled. 46 % were female. Image quality was similar in conventional TurboFLASH sequence and SPARSE sequence (2.9 ± 0.5 vs 3.1 ± 0.7, p = 0,06). SPARSE sequence showed higher contrast-to-noise ratio (52.1 ± 27.4 vs 40.5 ± 17.6, p < 0.01) and signal-to-noise ratio (15.6 ± 6.2 vs 13.2 ± 4.2, p < 0.01) than TurboFLASH sequence. Dark-rim artifacts occurred less often with SPARSE (9 % of segments) than with TurboFLASH (23 %). In visual assessment of perfusion defects, SPARSE sequence detected less false-positive perfusion defects (n = 1) than TurboFLASH sequence (n = 3). Quantitative perfusion analysis on segment basis showed equal detection of perfusion defects for TurboFLASH and SPARSE with both upslope MPR analysis (TurboFLASH 0.88 ± 0.18; SPARSE 0.77 ± 0.26; p = 0.06) and fermi function model (TurboFLASH 0.85 ± 0.24; SPARSE 0.76 ± 0.30; p = 0.13). CONCLUSIONS: Compressed sensing perfusion imaging using SPARSE sequence allows reliable detection of myocardial ischemia.

Comparing the EQ-5D-5L utility index based on value sets of different countries: impact on the interpretation of clinical study results.

OBJECTIVE: To compare the country-specific value sets of the EQ-5D-5L utility index and to evaluate the impact on the interpretation of clinical study results. Six country value sets from Canada, England, Japan, Korea, Netherlands and Uruguay were obtained from literature. In addition, ten crosswalk value sets were downloaded from the EuroQol.org website. RESULTS: For each of the 3125 possible health states the difference between the country with the highest index and the country with the lowest index was calculated. The median difference was 0.417 across the health states. When analyzing multinational clinical studies, country-specific value sets should be used to evaluate treatment effects. Additional country-specific analyses are needed.

On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.

Inflammation assessment in patients with arthritis using a novel in vivo fluorescence optical imaging technology.

BACKGROUND: Indocyanine green (ICG)-enhanced fluorescence optical imaging (FOI) is an established technology for imaging of inflammation in animal models. In experimental models of arthritis, FOI findings corresponded to histologically proven synovitis. This is the first comparative study of FOI with other imaging modalities in humans with arthritis. METHODS: 252 FOI examinations (Xiralite system, mivenion GmbH, Berlin, Germany; ICG bolus of 0.1 mg/kg/body weight, sequence of 360 images, one image per second) were compared with clinical examination (CE), ultrasonography (US) and MRI of patients with arthritis of the hands. RESULTS: In an FOI sequence, three phases could be distinguished (P1-P3). With MRI as reference, FOI had a sensitivity of 76% and a specificity of 54%, while the specificity of phase 1 was 94%. FOI had agreement rates up to 88% versus CE, 64% versus greyscale US, 88% versus power Doppler US and 83% versus MRI, depending on the compared phase and parameter. FOI showed a higher rate of positive results compared to CE, US and MRI. In individual patients, FOI correlated significantly (p<0.05) with disease activity (Disease Activity Score 28, r=0.41), US (r=0.40) and RAMRIS (Rheumatoid Arthritis MRI Score) (r=0.56). FOI was normal in 97.8% of joints of controls. CONCLUSION: ICG-enhanced FOI is a new technology offering sensitive imaging detection of inflammatory changes in subjects with arthritis. FOI was more sensitive than CE and had good agreement with CE, US in power Doppler mode and MRI, while showing more positive results than these. An adequate interpretation of an FOI sequence requires a separate evaluation of all phases. For the detection of synovitis and tenosynovitis, FOI appears to be as informative as 1.5 T MRI and US.

Computed tomography for preoperative planning in minimal-invasive total hip arthroplasty: radiation exposure and cost analysis.

Computed tomography (CT) was used for preoperative planning of minimal-invasive total hip arthroplasty (THA). 92 patients (50 males, 42 females, mean age 59.5 years) with a mean body-mass-index (BMI) of 26.5 kg/m(2) underwent 64-slice CT to depict the pelvis, the knee and the ankle in three independent acquisitions using combined x-, y-, and z-axis tube current modulation. Arthroplasty planning was performed using 3D-Hip Plan(®) (Symbios, Switzerland) and patient radiation dose exposure was determined. The effects of BMI, gender, and contralateral THA on the effective dose were evaluated by an analysis-of-variance. A process-cost-analysis from the hospital perspective was done. All CT examinations were of sufficient image quality for 3D-THA planning. A mean effective dose of 4.0 mSv (SD 0.9 mSv) modeled by the BMI (p<0.0001) was calculated. The presence of a contralateral THA (9/92 patients; p=0.15) and the difference between males and females were not significant (p=0.08). Personnel involved were the radiologist (4 min), the surgeon (16 min), the radiographer (12 min), and administrative personnel (4 min). A CT operation time of 11 min and direct per-patient costs of 52.80 € were recorded. Preoperative CT for THA was associated with a slight and justifiable increase of radiation exposure in comparison to conventional radiographs and low per-patient costs.

Whole-body MRI with assessment of hepatic and extraabdominal enhancement after administration of gadoxetic acid for staging of rectal carcinoma.

BACKGROUND: In TNM staging of rectal cancer by MRI, unspecific extracellular contrast agent Gd-DTPA is established for extrahepatic and vascular enhancement whereas liver-specific gadoxetic acid has proven high accurate detection of liver metastasis. PURPOSE: To compare intraindividually the qualification and quantification of enhancement in liver parenchyma, abdominal, pulmonary, and pelvic vessels between gadoxetic acid and Gd-DTPA. MATERIAL AND METHODS: Sixteen patients with histologically proven rectal carcinoma (mean age 62.9 years) were imaged twice by MRI. For pretherapeutic staging 10 mL gadoxetic acid (mean dose 0.032 mmol Gd/kg body weight) and for restaging after neoadjuvant therapy Gd-DTPA (0.1 mmol Gd/kg body weight) were administered. The liver was acquired in arterial-dominant and portal venous phases, the thorax and pelvis were depicted in venous phases using three-dimensional T1-weighted sequences. Contrast enhancement was rated by two independent readers and compared by means of multinomial regression analysis using generalized estimating equations. Signal-to-noise ratios were compared by two-sided paired t-tests. RESULTS: Overall contrast enhancement was rated sufficient for diagnosis in all examinations and both contrast agents. Vascular enhancement was rated comparable with exception of the aorta, the peripheral intrahepatic veins, and the central lung vessels (p = 0.0182, p = 0.0053, p = 0.0083, in favor of Gd-DTPA). Quantitative evaluation revealed no statistically significant differences in parenchymal and vascular signal-to-noise ratios with exception of the aorta, and the central pulmonary artery (67.4 vs. 89.3; p = 0.0421, 44.5 vs. 59.5; p = 0.0446 respectively, in favor of Gd-DTPA). CONCLUSION: The contrast enhancement after gadoxetic acid is comparable to Gd-DTPA and appears suitable for comprehensive TNM-staging by combining high accurate liver-specific phases with efficacious vascular enhancement in the different anatomic regions.