Roxane Gaïsset

Background C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway.We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.Methods APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression).Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries.Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <085 lower limit of the central laboratory normal range]) at screening, urine proteincreatinine ratio (UPCR) of 10 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 173 m or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae.All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no).During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily.The primary endpoint was relative reduction in proteinuria (measured by logtransformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months.The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis.This trial was registered with ClinicalTrials.gov(NCT04817618) and the adult cohort has been completed.Findings Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36).One participant in the placebo group discontinued treatment during the open-label period.The 24-h UPCR percentage change relative to baseline at 6 months was -302% (95% CI -428 to -148) in the iptacopan group and 76% (-119 to 313) in the placebo group.In the iptacopan group, the geometric mean of 24-h UPCR was 333 g/g (95% CI 279 to 397) at baseline and 217 g/g (162 to 291) at 6 months; in the placebo group, this was 258 g/g (218 to 305) at baseline and 280 g/g (237 to 330) at 6 months.The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 351% (138 to 511; p=00014).30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity.There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group.Interpretation Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months.Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy.

OBJECTIVE: In patients with critical limb ischemia (CLI), blood pressure (BP) impact on mortality is unknown. We analyzed the predictive value of SBP, DBP and pulse pressure (PP) at hospital admission on 3-month mortality in patients with CLI undergoing revascularization procedure. METHODS: From November 2013 to December 2018, 297 consecutive patients were retrospectively included. Admission BP was recorded using automated brachial sphygmomanometer, before revascularization procedure. A median of seven (IQR3-13) separate readings were recorded for each patient and the average represented patient's mean BP (mBP). Clinical and biological parameters were recorded at baseline. RESULTS: The cohort included 163 men (55%) and 134 women (45%) with a mean age of 77.7 ± 11.9 years. Treated hypertension and diabetes were present in, respectively, 62 and 48% of patients. Mean SBP, DBP and PP were 132 ± 18, 70 ± 8 and 62 ± 16 mmHg. Thirty-four patients (11.4%) died during 3-month follow-up, mostly from cardiovascular causes. In univariate analysis, age, female sex, brain natriuretic peptide and C-reactive protein were positively correlated with mortality. BMI, mSBP, mDBP, mPP, hemoglobin, serum albumin and statin treatment were negatively correlated with mortality. In single-pressure multivariate analyses, mSBP (P = 0.024) and mPP (P = 0.030) were negatively correlated with mortality. Association between mSBP and mortality had an asymptotic curve pattern and SBP level 135 mmHg or less was significantly correlated with mortality. CONCLUSION: In patients undergoing revascularization for CLI, admission SBP is an independent predictor for short-term mortality with a negative relationship. SBP level 135 mmHg or less represents a warning sign to explore and correct associated comorbidities.

Objective: Patients with critical limb ischemia (CLI) present a high-risk of cardiovascular events and death. Hypertension is one of the most prevalent risk factors in this population. This study investigated the association between blood pressure (BP) level at hospital admission, major cardiovascular events (MACE) and one-year mortality in patients undergoing percutaneous revascularization for CLI. Design and method: This retrospective analysis of an ongoing cohort study included 285 consecutive patients ospitalised from November 2013 to December 2018. Major cardiovascular events, defined as heart failure, acute coronary syndrome, ischemic stroke and sudden death, were collected during the first year following revascularization. Multivariate analysis identified factors independently associated with MACE occurrence and one-year mortality. A p &lt; = 0.05 was considered statistically significant. Results: The study included 157 men (55%) and 128 women (45%), mean age of 77.8 ± 12 years. Treated hypertension was present in 222 (78%) patients (admission systolic BP 132 (±18.2) mmHg, diastolic BP 69.9 (±7.79) mmHg, pulse pressure 62.3 (±15.8) mmHg and mean BP 90.7 (±9.77) mmHg); diabetes was present in 137 (48%) patients; 112 (39%) patients had known coronary heart disease (CHD) and 20 (7%) patients were dialysis dependent. During one-year follow-up after revascularization, 75 (26.3%) patients presented a MACE. Peri-operative mortality rate was 4% (12 patients, of whom 6 patients died from MACE). At one-year, cumulative mortality rate was 26.7% (76 patients) mostly from MACE. Twenty-three patients (8%) experienced major limb amputation. In multivariate analysis, the occurrence of MACE was associated with an increased mortality risk (HR 7.06 (2.99–17.51), p&lt;0.001). Of the four BP indexes, systolic BP (p = 0.01), mean BP (p = 0.02), pulse pressure (p = 0.02), but not diastolic BP, were significantly and inversely correlated with 1-year mortality. Decompensated heart failure and CHD were both associated with incident MACE in multivariate analysis, independently of confounders. Conclusions: Incident MACE were prevalent in the year following endovascular procedure in patients with CLI and were associated with an increased risk of mortality. There is an inverse association between admission BP and one-year mortality, independently of the occurrence of MACE. Decompensated heart failure and CHD are important contributors for the occurrence of MACE.