Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Les hémorragies graves sous antivitamines K (étude observationnelle et descriptive de prescription de PPSB portant sur 267 cas admis et pris en charge au sein du service d'accueil urgence du CHU de Clermont-Ferrand de janvier 2010 à décembre 2011)

En 2008, l'HAS publie des recommandations sur la prise en charge des accidents hémorragiques graves sous AVK. L'objectif de l'étude était de vérifier si le traitement de ces hémorragies était conforme à ces recommandations. Une analyse rétrospective a été réalisée sur l'ensemble des patients ayant reçu des CCP en 2010 et 2011 aux urgences adultes du CHU DE Clermont-Ferrand. Les caractéristiques recueillies sont : type d'AVK, INR, localisation de l'hémorragie grave, prise en charge et évolution. Durant la période 2010-2011, au SAU du CHU de Clermont-Ferrand, 264 patients ont reçu des complexes prothrombiniques pour hémorragies graves sous AVK dont 24,3% présentaient un INR au de-là de la valeur supérieure de l'intervalle cible. L'âge moyen était de 78 ans. Les deux principales localisations hémorragiques étaient intracrânienne (25,1%) et digestive (33%). Sur les 264 patients, 240 ont reçu de la vitamine K1 dont 195 à la dose préconisée, et 169 ont reçu la posologie recommandée de PPSB ; 46,1% des patients ont eu une prise en charge conforme aux recommandations en termes de posologie de vitamine K1 et de PPSB. Le délai médian d'administration de la vitamine K1 est de 15 minutes et celui des PPSB de 55 minutes. Le taux d'hospitalisation est de 97,7% pour une durée moyenne de 15,1 jours. A J7,29 patients sont décédés et 169 restent hospitalisés. La prise en charge des hémorragies graves sous AVK est très satisfaisante, en amélioration par rapport à l'étude menée en 2009.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Predictive factors of intracranial bleeding in head trauma patients receiving antiplatelet therapy admitted to an emergency department

Abstract Background In head trauma cases involving antiplatelet agent treatment, the French Society of Emergency Medicine recommends performing computed tomography (CT) scans to detect brain lesions, 90% of which are normal. The value of CT is still debatable given the scarce number of studies and controversial results. Methods We used the RATED registry (Registry of patient with Antithrombotic agents admitted to an Emergency Department, NCT02706080) to assess factors of cerebral bleeding related to antiplatelet agents following head trauma. Results From January 2014 to December 2015, 993 patients receiving antiplatelet agents were recruited, 293 (29.5%) of whom underwent CT scans for brain trauma. Intracranial bleeding was found in 26 (8.9%). Multivariate analysis revealed these patients more likely to have a history of severe hemorrhage (odds ratio [OR]: 8.47, 95% confidence interval [CI]: 1.56–45.82), dual antiplatelet therapy (OR: 6.46, 95%CI:1.46–28.44), headache or vomiting (OR: 4.27, 95%CI: 1.44–2.60), and abnormal Glasgow coma scale (OR: 8.60; 95%CI: 2.85–25.99) compared to those without intracranial bleeding. The predictive model derived from these variables achieved 98.9% specificity and a negative predictive value of 92%. The area under the ROC curve (AUROC) was 0.85 (95%CI: 0.77–0.93). Conclusions Our study demonstrated that the absence of history of severe hemorrhage, dual antiplatelet therapy, headache or vomiting, and abnormal Glasgow coma scale score appears to predict normal CT scan following traumatic brain injury in patients taking antiplatelets. This finding requires confirmation by prospective studies. Trial registration ClinicalTrials.gov number: NCT02706080

Characteristics and outcomes of reversed patients admitted to an emergency department for VKA-related intramuscular hematoma

Background According to the International Society on Thrombosis and Haemostasis (ISTH), intramuscular hematoma without other severity criteria is not considered a major bleeding. Objectives: In a large cohort of reversed vitamin K antagonist (VKA) patients admitted to the emergency unit for muscular hematoma, we assess frequency, severity, and anticoagulation management based on whether ISTH criteria were met or not. Materials and methods We performed a retrospective single-center study involving patients admitted to an emergency unit for VKA-induced intramuscular hematoma whose bleeding was reversed with prothrombin complex concentrates. Results During the study period, 631 VKA-induced bleeding events occurred in our emergency unit, of which 73 (11.6%) were intramuscular hematomas and half met ISTH criteria. The mean age was 75.5 years (95% CI = 72.6–78.3). Admission blood tests showed that patients with ISTH criteria had higher international normalized ratio (7.0 ± 4.6 vs. 4.1 ± 3.0, p = 0.002) and lower hemoglobin (8.1 ± 1.8 vs. 11.9 ± 2.2, p < 0.001) than those without. Patients with ISTH criteria were more likely to have intramuscular hematoma in the iliopsoas, gluteal, and pectoral muscles than those without. Interestingly, two-thirds of rectus sheath hematomas involved patients without ISTH criteria. However, patients with or without ISTH criteria exhibited a similar hospitalization duration and rate of re-bleeding. Conclusion We showed that half of the patients admitted with intramuscular hematoma could not be qualified as having ISTH-criteria major bleeding. Interestingly, these patients displayed a similar hospitalization duration and rate of re-bleeding to those with ISTH-criteria major bleeding

Assessment of the impact of L-Thyroxine therapy on bleeding risk in patients receiving Vitamin K antagonists

Background: Several studies have suggested a link exists between L-thyroxine and the coagulation system, and, according to some drug interaction studies, L-thyroxine can potentiate the effect of warfarin. This study sought to assess whether thyroid hormone therapy could impact the risk of bleeding in patients receiving vitamin K antagonists (VKAs). Methods: We conducted a monocentric, retrospective study on prospectively collected data from consecutive patients enrolled in the Registry of patient with AntiThrombotic agents admitted to an Emergency Department (RATED) database, and compared the hemorrhage rates (both major and nonmajor) of patients receiving treatment with and without L-thyroxine. Propensity score matching analysis was performed to reduce the differences between patients receiving L-thyroxine and those not receiving L-thyroxine in order to reassess bleeding outcomes in patients receiving VKAs. Results: From January 2014 to June 2015, 1454 patients receiving VKAs were recruited into the RATED database. Overall, 187 patients (12.8%) received L-thyroxine. Patients receiving L-thyroxine were more likely to be female than those not receiving L-thyroxine (78.1 vs. 55%) and more likely to exhibit hypertension (65.5 vs. 55.7%; p = 0.015), but less likely to have history of myocardial infarction (9.6 vs. 16.6%; p = 0.022) or higher creatinine levels (96.1 vs. 112.1 μmol/L; p = 0.04). After propensity score matching, bleeding outcomes were not significantly different between patients receiving L-thyroxine and those not receiving L-thyroxine. Conclusions: Our study revealed no evidence that L-thyroxine could increase bleeding risk in patients receiving VKAs. However, physicians must be aware that patients with thyroid disease receiving VKA therapy could have other drug interactions, particularly with amiodarone therapy. ClinicalTrials.gov number: NCT02706080