Blood pressure management and long-term outcomes in kidney transplantation: a holistic view over a 35-year period.

INTRODUCTION: Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. METHODS: In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). RESULTS: Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving ≥ 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs ≥ 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. CONCLUSIONS: Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer.

Immune checkpoint inhibitors (ICI) have high efficacy in metastatic colorectal cancer (mCRC) with microsatellite instability (MSI) but not in microsatellite stable (MSS) tumour due to the low tumour mutational burden. Selective internal radiation therapy (SIRT) could enhance neoantigen production thus triggering systemic anti-tumoral immune response (abscopal effect). In addition, Oxalipatin can induce immunogenic cell death and Bevacizumab can decrease the exhaustion of tumour infiltrating lymphocyte. In combination, these treatments could act synergistically to sensitize MSS mCRCs to ICI SIRTCI is a prospective, multicentre, open-label, phase II, non-comparative single-arm study evaluating the efficacy and safety of SIRT plus Xelox, Bevacizumab and Atezolizumab (anti-programmed death-ligand 1) in patients with liver-dominant MSS mCRC. The primary objective is progression-free survival at 9 months. The main inclusion criteria are patients with MSS mCRC with liver-dominant disease, initially unresectable disease and with no prior oncologic treatment for metastatic disease. The trial started in November 2020 and has included 10 out of the 52 planned patients.

Is CD25 blockade optimal in kidney transplant patients treated with basiliximab? A target-mediated drug disposition model.

AIMS: Basiliximab, an anti-CD25 chimeric monoclonal antibody, is approved in prevention of acute kidney transplant rejection. This study aims at investigating target-mediated pharmacokinetics of basiliximab. METHODS: Data from the IDEALE study, where 16 kidney transplant patients were treated with 2 40- or 80-mg basiliximab injections, were reanalysed. Basiliximab pharmacokinetics was described using a population 2-compartment target-mediated drug disposition model with the quasi-steady-state approximation. RESULTS: Volume of distribution was significantly higher in males (P = .029). Estimated baseline target antigen (CD25) level was lower is patients cotreated with cyclosporine (P = .026). CONCLUSION: This analysis allows the first description of the target-mediated nonlinear elimination of basiliximab. Our results suggest that cyclosporine cotreatment is associated with decreased target level and that an optimized dosing regimen may improve basiliximab effects.

Infliximab Treatment Does Not Lead to Full TNF-α Inhibition: A Target-Mediated Drug Disposition Model.

BACKGROUND AND OBJECTIVE: Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. METHODS: In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. RESULTS: The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day-1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. CONCLUSIONS: The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment-A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model.

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day-1 and kPint = 0.0079 day-1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

Predictors of response to TNF inhibitors in rheumatoid arthritis: an individual patient data pooled analysis of randomised controlled trials.

OBJECTIVE: To identify patient characteristics associated with responsiveness to tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). MATERIALS AND METHODS: Individual patient data from 29 randomised controlled trials (RCTs) evaluating the efficacy of a TNFi versus placebo or conventional therapy were obtained. Response to treatment was assessed in subgroups according to the following baseline characteristics: smoking status, physical activity, sex, age, body mass index, autoantibody profile, disease duration, high initial disease activity defined by Disease Activity Score on 28 joints (DAS28)(C reactive protein (CRP)) >5.1. The primary outcome was the between-treatment group difference in DAS28(CRP) change from baseline to 6 months. The secondary endpoints were the between-treatment group difference in final DAS28(CRP) measured until 6 months and EULAR response criteria until 6 months. Data from each RCT were then pooled by the Mantel-Haenszel method using a random effects model. A linear metaregression was also carried out on two data-sharing platforms separately to support the results. RESULTS: Individual data of 11 617 patients from 29 RCTs were analysed. Until 6 months, a significantly higher EULAR non-response rate was observed in obese patients (OR 0.52 vs 0.36 for non-obese, p=0.01). A multivariable regression model performed on 7457 patients indicated that patients treated by TNFi had a final DAS28(CRP) decreased by 0.02 for each year of disease duration (p<0.001), and a 0.21 decreased for patients with a baseline DAS28(CRP) >5.1 (p<0.001). CONCLUSIONS: In RA, patients who are more responsive to TNFi are those who are non-obese, have a long disease duration and have a high initial disease activity.

Cardiovascular Adverse Events With Intravitreal Anti-Vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

IMPORTANCE: Systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary. OBJECTIVE: To evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments in patients with ocular diseases. DATA SOURCES: Electronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020. STUDY SELECTION: Randomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs. DATA EXTRACTION AND SYNTHESIS: Studies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated. MAIN OUTCOMES AND MEASURES: Main outcomes were major cardiovascular events (MACEs) and total mortality. Secondary outcomes included nonocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious SAEs, and all SAEs. RESULTS: A total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14 190 patients with age-related macular degeneration (AMD), 24 (32%) included 5424 patients with diabetic retinopathy (diabetic macular edema or proliferative diabetic retinopathy), 17 trials (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Anti-VEGF drug administration did not increase MACEs compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). There was an interaction (subgroup difference, P = .04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P = .04) in the risk of death in patients with diabetic retinopathy; however, no increase was observed in patients with AMD or retinal vein occlusion. Administration of anti-VEGF drugs increased the risk of nonocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD. CONCLUSIONS AND RELEVANCE: Intravitreal anti-VEGF was not associated with an increase in MACEs in the trials examined herein. Increased mortality in patients with diabetes and nonocular hemorrhages, especially in those with AMD, could represent a safety signal, but the evidence was not strong. However, continued surveillance of SAEs remains warranted.

Is There a Role for Vitamin D in Amyotrophic Lateral Sclerosis? A Systematic Review and Meta-Analysis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive loss of motor neurons. Patients usually die 3-5 years after diagnosis from respiratory failure. Several studies investigated the role of vitamin D as a biomarker or a therapeutic option for ALS patients. To clarify the scientific evidence, we performed a systematic review and different meta-analyses regarding the potential role of vitamin D in ALS. Methods: We performed a systematic review of clinical trials, cohorts, and case-control studies retrieved from PubMed, EMBASE, and Cochrane databases reporting vitamin D levels as a putative biomarker for ALS diagnosis or prognosis or the effect of vitamin D supplementation in ALS patients. Whenever possible, data were pooled using a random-effects model, with an assessment of heterogeneity. Results: Out of 2,996 articles retrieved, we finally included 13 research articles, 12 observational studies (50% prospective), and 1 clinical trial. We found that ALS patients had slightly lower levels of vitamin D than controls (mean difference -6 ng/ml, 95% CI [-10.8; -1.3]), but important confounding factors were not considered in the studies analyzed. We found no relationship between vitamin D levels and ALS functional rate score-revised (ALSFRS-R), with highly heterogeneous results. Discordant results were reported in three studies regarding survival. Finally, five studies reported the effects of vitamin D supplementation with discordant results. Two of them showed a small improvement, whereas two others showed a deleterious effect on ALSFRS-R. One very small clinical trial with important methodological limitations showed some improvement in ALSFRS-R with high doses of vitamin D compared with normal doses. Conclusions: Our review did not find evidence to support the role of vitamin D on ALS diagnosis, prognosis, or treatment. Most studies had important limitations, mostly regarding the risk of bias for not considering confounding factors. Vitamin D supplementation should be offered to ALS patients to avoid other health issues related to vitamin D deficiency, but there is not enough evidence to support the use of vitamin D as a therapy for ALS.

Kinetic modelling of myocardial necrosis biomarkers offers an easier, reliable and more acceptable assessment of infarct size.

Infarct size is a major prognostic factor in ST-segment elevation myocardial infarction (STEMI). It is often assessed using repeated blood sampling and the estimation of biomarker area under the concentration versus time curve (AUC) in translational research. We aimed at developing limited sampling strategies (LSS) to accurately estimate biomarker AUC using only a limited number of blood samples in STEMI patients. This retrospective study was carried out on pooled data from five clinical trials of STEMI patients (TIMI blood flow 0/1) studies where repeated blood samples were collected within 72 h after admission to assess creatine kinase (CK), cardiac troponin I (cTnI) and muscle-brain CK (CK-MB). Biomarker kinetics was assessed using previously described biomarker kinetic models. A number of LSS models including combinations of 1 to 3 samples were developed to identify sampling times leading to the best estimation of AUC. Patients were randomly assigned to either learning (2/3) or validation (1/3) subsets. Descriptive and predictive performances of LSS models were compared using learning and validation subsets, respectively. An external validation cohort was used to validate the model and its applicability to different cTnI assays, including high-sensitive (hs) cTnI. 132 patients had full CK and cTnI dataset, 49 patients had CK-MB. For each biomarker, 180 LSS models were tested. Best LSS models were obtained for the following sampling times: T4-16 for CK, T8-T20 for cTnI and T8-T16 for CK-MB for 2-sample LSS; and T4-T16-T24 for CK, T4-T12-T20 for cTnI and T8-T16-T20 for CK-MB for 3-sample LSS. External validation was achieved on 103 anterior STEMI patients (TIMI flow 0/1), and the cTnI model applicability to recommended hs cTnI confirmed. Biomarker kinetics can be assessed with a limited number of samples using kinetic modelling. This opens the way for substantial simplification of future cardioprotection studies, more acceptable for the patients.

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature. METHODS: The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis. RESULTS: Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p = 0.03). CONCLUSION: This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.

Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.

BACKGROUND: The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. AIM: To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. METHODS: We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. RESULTS: MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. CONCLUSIONS: In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.

[Endogenous and exogenous estrogens]. / Hormones endogènes et exogènes.

Before menopause, women are protected from the risk of hypertension and atherosclerosis by endogenous estrogens. Estrogens have a vasoprotective role, while progesterone seems to have a neutral effect. Exogenous estrogens used in menopausal treatment have vascular effects. These effects depend of type, dose and administration type, and with age and atherosclerosis stages. Synthetic progestins have varying clinical effects. Each drug must be evaluated separately.

Effects of Mineralocorticoid Receptor Antagonists on Atrial Fibrillation Occurrence: A Systematic Review, Meta-Analysis, and Meta-Regression to Identify Modifying Factors.

Background Mineralocorticoid receptor antagonists (MRAs) have emerged as potential atrial fibrillation (AF) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRAs on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRAs on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta-analyses to compute odds ratios with 95% CIs. Meta-regression was then applied to explore the sources of between-study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow-up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta-analyses showed a significant overall reduction in AF occurrence in the MRA-treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI, 0.44-0.70 [P<0.00001]), with the greatest benefit regarding recurrent AF episodes (odds ratio, 0.42; 95% CI, 0.31-0.59 [P<0.00001]) and with significant heterogeneity among the included studies (I2=54%; P=0.0008). Meta-regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRAs seem to be effective in AF prevention, especially regarding recurrent AF episodes.

GLUcose COntrol Safety & Efficacy in type 2 DIabetes, a systematic review and NETwork meta-analysis.

BACKGROUND: The last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality. METHODS AND FINDINGS: We conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level. CONCLUSIONS: SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention. TRIAL REGISTRATION: PROSPERO CRD42016043823.

Plasma creatinine and amyotrophic lateral sclerosis prognosis: a systematic review and meta-analysis.

Background: Plasma creatinine has been described as a prognostic biomarker for Amyotrophic Lateral Sclerosis (ALS), but with conflicting results in the literature. We performed a systematic review followed by a meta-analysis to address this question. Methods: We performed a systematic review of Pubmed, Embase and Cochrane databases and retrieved 14 distinct cohorts (19 studies) reporting results regarding the relationship between plasma creatinine and a clinical marker for ALS progression, notably ALSFRS (ALS Functional Rating Scale) and survival. Results: For baseline plasma creatinine, mortality risk was 28% lower when creatinine was higher than 88.4 µmol/L (hazard ratio (HR): 0.72; 95% confidence interval (CI): 0.58 to 0.88; p = 0.0003) and was 25% lower if creatinine was above versus below the median (HR: 0.75; 95% CI: 0.63 to 0.89; p = 0.0008). We found a significant positive correlation between plasma creatinine at baseline and functional score, and between creatinine decline and functional score decline (p < 0.0001 for both); but a negative correlation between plasma creatinine and functional score decline (p = 0.033). The overall quality of the studies was low mainly due to potential attrition bias, and several studies did not report analyzable results raising concern regarding a potential reporting bias. Conclusions: Plasma creatinine seems to be a promising prognostic biomarker for ALS. However, new studies with sound methodology and standardized criteria for the evaluation of ALS progression should be conducted to validate plasma creatinine as a clinical biomarker for ALS prognosis.

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans.

Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably owing to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to non-linear elimination decay in 50 publications, which was described using target-mediated drug disposition or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as a covariate of pharmacokinetic parameters. If some reported covariates, such as the circulating antigen level or tumour size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at the cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximise therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibodies in all patients. If necessary, antigen mass should be taken into account in routine clinical practice.

Efficacy and Safety of Anti-D Immunoglobulins versus Intravenous Immunoglobulins for Immune Thrombocytopenia in Children: Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulins (IVIG) and anti-D immunoglobulin (anti-D) in pediatric immune thrombocytopenia (ITP). STUDY DESIGN: We conducted a systematic review and meta-analysis following PRISMA guidelines, including all randomized controlled trials that have assessed the efficacy and safety of anti-D and IVIG in children with ITP. We searched Medline, Embase, and Cochrane databases. Primary outcomes were the proportion of children achieving platelet count responses as defined in each study and bleeding response. Other safety outcomes included infusion reactions and hemolysis. RESULTS: Eleven studies with 558 children were included. Anti-D was significantly inferior to IVIG at increasing platelet counts, both for thresholds of >20 × 109/L at 24-72 hours (response rate ratio for anti-D vs IVIG: 0.85, 95% CI 0.78-0.94) and >50 × 109/L at 24-72 hours (response rate ratio for anti-D vs IVIG: 0.75, 95% CI 0.61-0.92). Bleeding response was assessed in 4 studies, but some heterogeneity in reporting leads to unclear conclusion. General symptoms after anti-D infusion were less frequent than after IVIG (Peto OR 0.39, 95% CI 0.25-0.62). Hemolysis was more frequent after anti-D. The overall quality of the studies was low. CONCLUSIONS: Compared with anti-D, IVIG led to a better response in terms of platelet count and may be preferred as a first-line treatment of ITP in children with acute hemorrhagic symptoms. However, the clinical significance of IVIG superiority on platelet count remains unclear.