Spironolactone for heart failure with preserved ejection fraction

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands)

Low-dose versus High-dose Carfilzomib with Dexamethasone (S1304) in Patients with Relapsed-Refractory Multiple Myeloma

PURPOSE: Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits. PATIENTS AND METHODS: We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m RESULTS: Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms ( CONCLUSIONS: This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/

A Study of the Effect of Kosmotropic and Chaotropic Ions on the Release Characteristics of Lignin Microcapsules under Stimuli-Responsive Conditions

Stimuli-responsive behavior of lignin micro- capsules (LMCs) has been investigated along with the detailed characterization of their stability profiles. The disassembly of LMCs was found to be salt species-dependent, indicating the specific relevance of inherent kosmotropic and chaotropic characteristics. For the first time, a connection between the Hofrneister series and the stability profile of lignin microscale materials is established. LMCs showed excellent stability in water and under high temperature and pressure (autoclaving conditions). Active release is efficiently triggered by pH changes and balancing chaotropic and kosmotropic effects via salinity tuning

Inotersen treatment for patients with hereditary transthyretin amyloidosis

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .)

Diabetes Is Associated with Cerebrovascular but not Alzheimer\u27s Disease Neuropathology

INTRODUCTION: The relationship of diabetes to specific neuropathologic causes of dementia is incompletely understood. METHODS: We used logistic regression to evaluate the association between diabetes and infarcts, Braak neurofibrillary tangle stage, and neuritic plaque score in 2365 autopsied persons. In a subset of \u3e1300 persons with available cognitive data, we examined the association between diabetes and cognition using Poisson regression. RESULTS: Diabetes increased odds of brain infarcts (odds ratio [OR] = 1.57, P \u3c .0001), specifically lacunes (OR = 1.71, P \u3c .0001), but not Alzheimer\u27s disease neuropathology. Diabetes plus infarcts was associated with lower cognitive scores at end of life than infarcts or diabetes alone, and diabetes plus high level of Alzheimer\u27s neuropathologic changes was associated with lower mini-mental state examination scores than the pathology alone. DISCUSSION: This study supports the conclusions that diabetes increases the risk of cerebrovascular but not Alzheimer\u27s disease pathology, and at least some of diabetes\u27 relationship to cognitive impairment may be modified by neuropathology