Stroke and Bleeding Risks in Patients with Atrial Fibrillation Treated with Reduced Apixaban Dose: A Real-Life Study.

The purpose of this study was to assess the association between reduced apixaban dose and two outcomes: ischemic stroke/systemic embolism (SE) and major bleeding. We performed a retrospective cohort study within the database of the largest healthcare provider in Israel. We identified all patients diagnosed with atrial fibrillation, who started apixaban treatment between 2013 and 2017. Apixaban users were classified into three dosing regimen groups based on their renal function, age, and weight: standard dose (5 mg b.i.d.), adjusted reduced dose (2.5 mg b.i.d.), and underdosing (2.5 mg b.i.d.). Patients were followed through 2018 for the occurrence of stroke/SE and major bleeding. Of the 27,765 included patients, 13,141 (47%) adequately received standard apixaban dose, 4,739 patients (17%) received adjusted reduced dose, and 9,885 patients (36%) were classified as underdosed. The CHA2DS2-VASc score adjusted hazard ratio for ischemic stroke/SE was 1.1 (95% confidence interval (CI), 0.83-1.43) in the adjusted reduced dose group, and 1.04 (95% CI, 0.83-1.35) in the underdosing group, compared with the standard apixaban dose group. The HAS-BLED score adjusted hazard ratio for any major bleeding was 1.66 (95% CI, 1.32-2.09) in the adjusted reduced dose group, and 1.51 (95% CI, 1.24-1.83) in the underdosing group, compared with apixaban in the standard dose group. Results were similar for major gastrointestinal bleeding and intracranial hemorrhage separately. We conclude that underdosing with apixaban is very common, and may not disproportionately elevate the risk of ischemic stroke. However, albeit halving the dose, patients treated with reduced apixaban dose (adjusted or underdosing) seem to be at higher risk for major bleeding.

Tetrahydrobiopterin (BH4 ): Targeting endothelial nitric oxide synthase as a potential therapy for pulmonary hypertension.

PURPOSE: Pulmonary Hypertension (PH) is complex disease which is associated with endothelial and cardiac dysfunction. Tetrahydrobiopterin (BH4 ) regulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide rather than superoxide which maintains normal endothelial and cardiac function. This study explores the therapeutic potential of BH4 in experimental PH. METHODS: Monocrotaline-induced PH in rats and Hph-1 deficiency in mice were used for animal experiments. Hemodynamic measurements using pressure transducers were conducted for pulmonary and cardiac pressures, and Langendorff apparatus was used for isolated heart experiments; preventive as well as rescue treatment protocols were conducted; tissues were collected for histological and biochemical studies. RESULTS: In vivo acute BH4 administration reduced pulmonary artery pressure (PAP) only in the MCT rat. In a Langendorff preparation, BH4 increased right ventricular systolic pressure (RVSP) in right ventricular hypertrophy (RVH) but not in control. In "prevention" therapy, BH4 (10 and 100 mg/kg) attenuated the development of PH in rat MCT model. eNOS protein levels in lung homogenates were maintained and cGMP levels were increased. In "rescue" therapy, BH4 (10 and 100 mg/kg) ameliorated pulmonary vascular muscularization in a dose-dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH4 at 10 mg/kg reduced RV myocyte diameter while BH4 at 100 mg/kg reversed it to control level. BH4 restored normal levels of eNOS protein and in a dose of 100 mg/kg enhanced lung tissue levels of BH4 , cGMP, and NO compared to placebo. CONCLUSION: The current study provides scientific evidence for a therapeutic potential of BH4 in PH and invites further investigation.

Laboratory and clinical acute effects of active and passive indoor group water-pipe (narghile) smoking.

BACKGROUND: Indoor group water-pipe tobacco smoking, commonly referred to as water-pipe smoking (WPS), especially in coffee shops, has gained worldwide popularity. We performed a comprehensive laboratory and clinical evaluation of the acute effects of active and passive indoor group WPS. METHODS: This comparative study evaluated pre- and post-30-min active and passive indoor group WPS. The outcome parameters were carboxyhemoglobin (COHb), nicotine, and cotinine levels; CBC count; and cardiorespiratory parameters. Exhaled breath condensate (EBC) cytokines and endothelial function (using the EndoPat device [Itamar Medical Ltd]) were measured only in active smokers. Statistical methods used were Student t test, Wilcoxon signed rank test, Fisher exact test, analysis of variance, and Newman-Keuls post hoc test where relevant. RESULTS: Sixty-two volunteers aged 24.9±6.2 years were included; 47 were active smokers, and 15 were passive smokers. COHb level increased postactive WPS (active smokers, 2.0%±2.9% vs 17.6%±8.8%; P<.00001); six subjects (12.7%) had a >25% increase, and two subjects (4.2%) had a >40% increase. Plasma nicotine level increased postactive WPS (active smokers, 1.2±4.3 ng/mL vs 18.8±13.9 ng/mL; P<.0001); plasma cotinine and urinary nicotine and cotinine levels also increased significantly. EBC IL-4, IL-5, IL-10, IL-17, and γ-interferon decreased significantly with postactive smoking; endothelial function did not change. WPS was associated with adverse cardiorespiratory changes. In passive smokers, COHb level increased (0.8%±0.25% vs 1.2%±0.8%, respectively, P=.003) as did respiratory rate. CONCLUSIONS: One session of active indoor group WPS resulted in significant increases in COHb and serum nicotine levels (eightfold and 18-fold, respectively) and was associated with adverse cardiorespiratory health effects. The minor effects found in passive smokers suggest that they too may be affected adversely by exposure to WPS. The results call for action to limit the continuing global spread of WPS in coffee shops. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT1237548; URL: www.clinicaltrials.gov.