A randomized clinical trial to evaluate the efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valve and atrial fibrillation or flutter: Rationale and design of the RIVER trial.

The efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valves and atrial fibrillation or flutter remain uncertain. DESIGN: RIVER was an academic-led, multicenter, open-label, randomized, non-inferiority trial with blinded outcome adjudication that enrolled 1005 patients from 49 sites in Brazil. Patients with a bioprosthetic mitral valve and atrial fibrillation or flutter were randomly assigned (1:1) to rivaroxaban 20 mg once daily (15 mg in those with creatinine clearance <50 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-30.); the follow-up period was 12 months. The primary outcome was a composite of all-cause mortality, stroke, transient ischemic attack, major bleeding, valve thrombosis, systemic embolism, or hospitalization for heart failure. Secondary outcomes included individual components of the primary composite outcome, bleeding events, and venous thromboembolism. SUMMARY: RIVER represents the largest trial specifically designed to assess the efficacy and safety of a direct oral anticoagulant in patients with bioprosthetic mitral valves and atrial fibrillation or flutter. The results of this trial can inform clinical practice and international guidelines.

Efficacy of bupropion and varenicline genetic markers in choosing pharmacological treatment for smoking cessation, and implications for combining drugs: A randomized controlled trial - GENTSMOKING.

INTRODUCTION: Smoking cessation is the best strategy for reducing tobacco-related morbimortality. The goal of this randomized controlled trial was to test whether using the genetically favorable markers to choose a smoking cessation drug treatment (precision medicine) was superior to using the most effective drug (varenicline) in terms of abstinence rates. Additionally, combination therapy was tested when monotherapy failed. METHODS: This partially blind, single-center study randomized (1:1) 361 participants into two major groups. In the genetic group (n=184), CYP2B6 rs2279343 (genotype AA) participants started treatment with bupropion, and CHRNA4 rs1044396 (genotype CT or TT) participants started treatment with varenicline; when genetic favorable to both, participants started treatment with bupropion, and when favorable to neither, on both drugs. In the control group (n=177), participants started treatment with varenicline, regardless of genetic markers. Drug treatment lasted 12 weeks. Efficacy endpoints were abstinence rates at Weeks 4, and Weeks 8-12, biochemically validated by carbon monoxide in exhaled air. Participants who did not achieve complete abstinence at Week 4, regardless of group, were given the choice to receive combination therapy. RESULTS: Abstinence rates were 42.9% (95% CI: 36-64) in the control group versus 30.4% (95% CI: 23-37) in the genetic group at Week 4 (p=0.01); and 74% (95% CI: 67-80) versus 52% (95% CI: 49-64) at Week 12 (p<0.001), respectively. The strategy of combining drugs after Week 4 increased abstinence rates in both groups and the significant difference between genetic and control groups was maintained. CONCLUSIONS: Results show that using these selected genetic markers was inferior to starting treatment with varenicline (control group), which is currently the most effective smoking cessation drug; moreover, the addition of bupropion in cases of varenicline monotherapy failure improves the efficacy rate until the end of treatment. CLINICAL TRIAL IDENTIFIER: NCT03362099.

Cue restricted smoking increases quit rates with varenicline.

INTRODUCTION: Varenicline effectively helps smokers quit by reducing withdrawal symptoms and blocking the reward of smoking. However, most quitters return to smoking within one year. 'Cue Restricted Smoking' is a behavioral technique designed to increase quit rates by asking smokers attempting to quit to restrict smoking to the standing position, while alone, in an isolated area facing a wall, with the cigarette as the only stimulus. METHODS: Using retrospective clinic records we compared quit rates in 281 smokers (50% males) instructed in the cue restricted smoking cessation method during 2016-2018 to quit rates in 324 smokers (46% males) advised to completely stop smoking on the target quit date which we previously used during 2011-2014. All were prescribed varenicline for 12 weeks alone, with the addition of bupropion if needed after 4 weeks. Follow-up consisted of behavioral support at 4-6 visits during active drug treatment and telephone counselling at 24 and 52 weeks. The smoking cessation rate was confirmed with exhaled carbon monoxide at the clinic visit at 12 weeks and only by telephone at 52 weeks. RESULTS: The mean age of smokers was 49 years in both groups and the number of cigarettes smoked daily was similar (18/day in the cue restricted vs 19/day in the target quit day group). The smoking cessation rate at 12 weeks was 75% in the cue restricted versus 45% in the target quit day group (relative risk, RR=1.8; 95% CI: 1.4-2.2, p<0.001). At 52 weeks the quit rate was 65% vs 34%, respectively (RR=1.9; 95% CI: 1.5-2.4, p<0.001). CONCLUSIONS: Cue restricted smoking was associated with a substantially increased chance of quitting compared with standard advice during treatment with varenicline. These results should be further studied in a randomized controlled trial.

Early IFN-gamma production after YF 17D vaccine virus immunization in mice and its association with adaptive immune responses.

Yellow Fever vaccine is one of the most efficacious human vaccines ever made. The vaccine (YF 17D) virus induces polyvalent immune responses, with a mixed TH1/TH2 CD4(+) cell profile, which results in robust T CD8(+) responses and high titers of neutralizing antibody. In recent years, it has been suggested that early events after yellow fever vaccination are crucial to the development of adequate acquired immunity. We have previously shown that primary immunization of humans and monkeys with YF 17D virus vaccine resulted in the early synthesis of IFN-γ. Herein we have demonstrated, for the first time that early IFN-γ production after yellow fever vaccination is a feature also of murine infection and is much more pronounced in the C57BL/6 strain compared to the BALB/c strain. Likewise, in C57BL/6 strain, we have observed the highest CD8(+) T cells responses as well as higher titers of neutralizing antibodies and total anti-YF IgG. Regardless of this intense IFN-γ response in mice, it was not possible to see higher titers of IgG2a in relation to IgG1 in both mice lineages. However, IgG2a titers were positively correlated to neutralizing antibodies levels, pointing to an important role of IFN-γ in eliciting high quality responses against YF 17D, therefore influencing the immunogenicity of this vaccine.