Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Chapter 5: Guideline Recommendations: Which AAD and for Whom?

This chapter discusses the American College of Cardiology/American Heart Association/ Heart Rhythm Society (AHA/ACC/HRS) and European Society of Cardiology (ESC) guidelines for atrial fibrillation (AF) management with particular focus on antiarrhythmic drug (AAD) selection and the identification of individuals for whom AAD treatment is appropriate. Discussion includes AAD indications, when to start an AAD, choosing among AADs, how to minimize proarrhythmic risk, how to determine efficacy, and the use of adjuvant interventions. The indications for all AADs are based on safety; the current AHA/ACC/HRS and ESC guidelines state that the choice of AAD is based on the presence or absence of structural heart disease (SHD), coronary artery disease, or heart failure (HF), with further recommendations in the ESC guidelines based on HF type (e.g., HF with reduced ejection fraction [HFrEF] versus HF with preserved ejection fraction [HFpEF]). The chapter closes with a discussion of the lack of consistent use of guideline-directed care, with a review of supportive data from the recently reported AIM-AF survey-a multinational survey on AF management that involved both cardiologists and electrophysiologists. In AIM-AF, inappropriate drug selection in terms of suitable candidate selection and drug choice occurred with all types of drugs and in most patient groups. Most notable was the overuse of amiodarone in patients without SHD, and the widespread use of sotalol, including its use in patients with HFrEF. Chapter 5 is summarized as follows

Chapter 3: Evidence for the Use of Early Rhythm Control to Prevent Atrial Fibrillation Progression

This chapter reviews atrial fibrillation (AF) progression and its associated mechanisms, including comorbidities and AF as contributors to atrial myopathy, and atrial myopathy as a contributing factor to AF progression. In addition, the chapter discusses the concept of comorbidities and atrial myopathy as synergistic contributors to adverse outcomes, the notion of AF begets AF, and the consequences of AF burden if left untreated. Clinical trials evaluating outcomes with antiarrhythmic drugs (AADs) compared with placebo have demonstrated efficacy, but also reveal a possible proarrhythmic and mortality risk if AAD selection is not appropriate and patients are not correctly identified based on risk factors and comorbidities. Data from ATHENA, the first and only trial to demonstrate that an AAD (dronedarone) can reduce cardiovascular (CV) hospitalizations in people with AF, are reviewed, along with studies reporting on the use of catheter ablation versus AADs for AF rhythm control. Finally, recent data showing a reduction in major adverse outcomes if rhythm control is initiated early are summarized, including results from the EAST-AFNET 4 trial, as well as confirmatory results from several large real-world trials. Chapter 3 is summarized as follows

Introduction: Early Diagnosis and Appropriate Treatment of Atrial Fibrillation

Atrial fibrillation (AF), the most common sustained arrhythmia, represents a significant burden to patients and healthcare systems. Many patients with AF are asymptomatic and often undiagnosed. Improved detection methods and surveillance have resulted in recognition of asymptomatic and subclinical AF, providing earlier diagnosis. The recent EAST-AFNET 4 and Korean studies have demonstrated early rhythm control (ERC) with antiarrhythmic drugs (AADs) or ablation in patients with AF improves outcomes. The EARLY AF and STOP AF First studies have shown that ERC using ablation can slow AF progression. In the following videos, the authors discuss the evolving AF landscape, with an emphasis on the benefits of early diagnosis and treatment. Historic rate versus rhythm control studies and their limitations are reviewed, followed by recent studies that support the use of ERC alongside usual care including rate control. Discussion of ERC treatment includes the selection of appropriate AADs based on safety, when to choose ablation as first-line therapy, and the complementary use of ablation and AADs. The authors summarize the current guidelines for the use of AADs to treat AF, highlighting the importance of concordance with those guidelines. Patient cases are used to relate the contents of the videos to clinical practice and are supplemented with discussion of the importance of shared decision-making involving the patient in treatment decisions. It is anticipated that this digital publication will enable cardiologists and primary care providers to recognize when early treatment of AF will improve patient outcomes, and to empower them to initiate that treatment accordingly

Chapter 2: Rate Versus Rhythm Control

Atrial fibrillation (AF) is a potentially serious health risk, both because of its symptoms and because of its association with an increased risk for heart failure, hospitalization, thromboembolism, and death. Chapter 2 discusses selection of appropriate treatments and when to initiate these therapies. Older trials focused on comparing rate versus rhythm control treatment options for AF. It is now recognized that both rate and rhythm control are important and can be used together. This chapter reviews the historical, pivotal rate versus rhythm control trials that failed to show any overall survival benefit of rhythm over rate control, as well as the trials\u27 now-recognized limitations with respect to modern therapy. In addition, an in-depth discussion of the more recent trials of antiarrhythmic drugs (AAD) and ablation techniques (which have become available since the original rate versus rhythm trials were performed) is included. These updated trials show that when applied to patient- and disease-specific situations, rhythm control can reduce the risk for mortality and hospitalization. The chapter also reviews the guidelines that have been developed to achieve these goals. Chapter 2 is summarized as follows: (1) Rate control is needed (at rest and during exertion) to reduce rate-related symptoms when rhythm control is ineffective or incomplete and to prevent a tachycardia-induced cardiomyopathy. (2) Previous trials with pharmacological therapy alone comparing rate versus rhythm control using the AADs available at that time failed to show any overall survival benefit of rhythm control over rate control. (3) These earlier trials had many methodological limitations and enrolled participants who did not have access to modern therapies. (4) Newer therapies, including those for stroke prevention, dronedarone (the latest approved AAD), and AF ablation, have improved the safety and efficacy of rhythm control strategies

Chapter 1: The Evolving Atrial Fibrillation Landscape: Importance of Early Diagnosis and Treatment

Chapter 1 begins with data that show the rising prevalence of atrial fibrillation (AF), which is increasing in tandem with the growing number of older adults, increased survival of people who have cardiovascular (CV) disorders, and the expanding use of wearable and insertable/implantable devices capable of detection. Together, these increases will result in healthcare providers seeing more patients with AF who present at earlier stages of the disease. The panel discussion covers information regarding symptoms that are common to patients with AF as well as information about the important adverse outcomes that may occur in patients with AF, including heart failure, hospitalization, thromboembolism, and death. Notably, these events may reflect either the comorbidities commonly underlying AF, AF itself, or a combination of these conditions. The chapter also introduces the four pillars of therapy- upstream therapy, rate control, rhythm control, and embolic prevention-with an emphasis on early rhythm control as being optimal. Chapter 1 is summarized as follows

Chapter 4: Evidence for the Early Use of Ablation and AADs Post-Ablation

Both catheter ablation and antiarrhythmic drugs (AADs) are effective treatments for atrial fibrillation (AF) and can be used individually or as complementary treatments. This chapter discusses the use of ablation for early rhythm control in AF, and the use of AADs post-ablation. Decisions on which therapeutic approach to pursue should be based on shared decision-making with the patient. The chapter reviews data from the CABANA trial, in which the intent-to-treat (ITT) analysis failed to show superiority for ablation versus AADs. Statistical significance was achieved, however, when using the pre-specified per-protocol and pre-treatment analyses. The discussion addresses the fact that data analysis was complicated by several factors: (1) not all members of the group assigned to ablation actually received ablation; (2) the AAD arm included rate control treatment without the use of AADs; (3) there were a large number of crossovers from the AAD arm to the ablation arm; and (4) many ablation-treated participants also used AADs. Results from the CABANA trial showed that ablation was better at preventing AF recurrence than AADs alone. Data from the STOP AF and EARLY AF trials that support the observation of ablation being superior to AADs alone for the reduction of recurrent AF are also reviewed. Many patients who undergo catheter ablation for AF either continue to use or need to restart AADs following ablation. This combination therapy is used by up to 40-50% of people at 1-year post ablation, as is clearly demonstrated by the results from the trials discussed above, in addition to those from the 5A trial, the POWDER AF trial, the AMIO-CAT trial, and a substantial meta-analysis. All these trials are reviewed in this chapter, noting that a variety of differences exist between the randomized clinical trials, including in ablation procedures, follow-up periods, physician experience, and AADs. Chapter 4 is summarized as follows

Chapter 6: AAD Use in Different Patient Populations, and a Patient-Centric Approach to Optimal Patient Management

Associated with longer life expectancy, greater survival of patients with cardiovascular disorders, and increased use of wearable and insertable/implantable devices capable of detection, the frequency of atrial fibrillation (AF) diagnosis is increasing. This chapter describes two representative patient cases that were used to enable a discussion of the evaluation and management of AF in different scenarios. One patient is young and healthy with paroxysmal AF but no major comorbidities (though there is a family history of AF). The other is older with multiple complicating comorbidities. These cases sparked an active discussion among the panelists that demonstrated not only the multitude of considerations when choosing the optimal therapy for each individual, but also the individualistic differences in biases and styles that can exist between experts in the field. The results of these discussions revealed agreement that

International Transmission of Bank and Corporate Distress

The paper evaluates how increases in banks’ and nonfinancial corporates’ default risk are transmitted in the global economy, using in a vector autoregression model for 30 advanced and emerging economies for the period from January 1996 to December 2008. The results point to two-way causality between bank and corporate distress and to significant global macroeconomic and financial spillovers from either type of distress when it originates in a systemic economy. Corporate distress in advanced economies has a larger impact on economic growth in emerging economies than bank distress in advanced economies has. In contrast, activity in advanced economies is more vulnerable to bank distress than to corporate distress.Spillovers;Banking sector;Corporate sector;Credit risk;Developed countries;Economic models;Emerging markets;Financial risk;probability, bank distress, probabilities, bank default, logarithm, banking, probability of default, bank default probability, kurtosis, skewness, statistics, correlations, equations, equation, vector autoregression, bank capital, present value, descriptive statistics, banks ? balance sheets, banks ? loan, probability distribution, banking sectors, missing data, significance level, banks loan, statistical tests, bank lending relationship, standard deviations, var model, financial statistics, bank balance sheets, normal distribution, calibration, correlation, time series, bank borrowing, bank liquidity, econometrics, bank lending, banks ? assets, standard deviation, bank credit, number of parameters, forecasting, bank portfolio