Candesartan as a tentative treatment for COVID-19: A prospective non-randomized open-label study.

Background: This study aimed to investigate whether the addition of candesartan to the standard care regimen improved the outcome in patients with coronavirus 2019 (COVID-19).

Methods: A prospective non-randomized open-label study was undertaken from May to August 2020 on 75 subjects (aged 18-70 years) hospitalized in Siloam Kelapa Dua Hospital. Uni- and multi-variable Cox regression analyses were performed to obtain hazard ratios (HRs).

Reducing recombinant protein expression during CHO pool selection enhances frequency of high-producing cells.

Chinese hamster ovary (CHO) cells are the most widely used mammalian host for industrial-scale production of monoclonal antibodies (mAbs) and other protein biologics. Isolation of rare high-producing CHO cell lines from heterogeneous populations of stable transfectants is a daunting task and delays the process of manufacturing of novel biologics. A variety of factors that contribute to the low frequency of high-producing clones have been described; however, the impact of metabolic burden and other stresses (eg.

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin.

Rapid protein production from stable CHO cell pools using plasmid vector and the cumate gene-switch.

To rapidly produce large amounts of recombinant proteins, the generation of stable Chinese Hamster Ovary (CHO) cell pools represents a useful alternative to large-scale transient gene expression (TGE). We have developed a cell line (CHO) allowing the inducible expression of recombinant proteins, based on the cumate gene switch. After the identification of optimal plasmid DNA topology (supercoiled vs linearized plasmid) for PEIpro™ mediated transfection and of optimal conditions for methionine sulfoximine (MSX) selection, we were able to generate CHO pools producing high levels of recombinant proteins.

Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials.

Objectives: The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure.

Background: Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking.

Abnormal liver function tests in acute heart failure: relationship with clinical characteristics and outcome in the PROTECT study.

Aims: Episodes of acute heart failure (AHF) unfavourably affect multiple organs, which may have an adverse impact on the outcomes. We investigated the prevalence and clinical consequences of abnormal liver function tests (LFTs) in AHF patients enrolled in the PROTECT study.

Methods And Results: The LFTs comprised serial assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin at baseline and during follow-up (daily until discharge, on days 7 and 14).

Patient journey after admission for acute heart failure: length of stay, 30-day readmission and 90-day mortality.

Aims: The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study.

Methods And Results: PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment.

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.

Background: Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.

Methods: After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy).

The Aliskiren Trial to Minimize OutcomeS in Patients with HEart failure trial (ATMOSPHERE): revised statistical analysis plan and baseline characteristics.

Aims And Methods: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.

Results: A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men.

Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response.

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups.

Facilitation of a Multihospital Community of Practice to Increase Enrollment in the Hospital to Home National Quality Improvement Initiative.

Background: Hospital to Home (H2H) is a national quality improvement (QI) initiative composed of three recommended hospital interventions to improve the transition of care for hospitalized patients with heart disease. A study was conducted to determine if enrollment of Department of Veterans Affairs (VA) hospitals in H2H and adoption of the recommended interventions would both increase following facilitation of an existing Heart Failure (HF) provider-based community of practice (COP) within the VA health care system. The VA HF COP includes more than 800 VA providers and other VA staff from VA inpatient medical centers.

The Hospitalization Burden and Post-Hospitalization Mortality Risk in Heart Failure With Preserved Ejection Fraction: Results From the I-PRESERVE Trial (Irbesartan in Heart Failure and Preserved Ejection Fraction).

Objectives: The aim of this study was to investigate prognosis in patients with heart failure (HF) with preserved ejection fraction and the causes of hospitalization and post-hospitalization mortality.

Background: Although hospitalizations in patients with HF with preserved ejection fraction are common, there are limited data from clinical trials on the causes of admission and the influence of hospitalizations on subsequent mortality risk.

Methods: Patients (n = 4,128) with New York Heart Association functional class II to IV HF and left ventricular ejection fractions >45% were enrolled in I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction).

Worsening Heart Failure Following Admission for Acute Heart Failure: A Pooled Analysis of the PROTECT and RELAX-AHF Studies.

Objectives: These studies conducted analyses to examine patient characteristics and outcomes associated with worsening heart failure (WHF).

Background: WHF during an admission for acute heart failure (AHF) represents treatment failure and is a potential therapeutic target for clinical trials of AHF.

Methods: Individual patient data from the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) and RELAX-AHF (Relaxin in Acute Heart Failure) phase II and III studies were pooled for analysis.

The IGF-Trap: Novel Inhibitor of Carcinoma Growth and Metastasis.

The IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, and the compensatory function of, the insulin receptor system. Here, we report on the production, characterization, and biologic activity of a novel, IGF-targeting protein (the IGF-Trap) comprising a soluble form of hIGFIR and the Fc portion of hIgG1.

Comparative assessment of short-term adverse events in acute heart failure with cystatin C and other estimates of renal function: results from the ASCEND-HF trial.

Objectives: The purpose of this study was to investigate the predictive values of baseline and changes in cystatin C (CysC) and its derived equations for short-term adverse outcomes and the effect of nesiritide therapy on CysC in acute decompensated heart failure (ADHF).

Background: Newer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure.

Methods: CysC levels were measured in sequential plasma samples from 811 subjects with ADHF who were enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) biomarker sub-study (randomized to nesiritide therapy vs.

Improving care for patients with acute heart failure: before, during and after hospitalization.

Acute heart failure (AHF) is a common and serious condition that contributes to about 5% of all emergency hospital admissions in Europe and the USA. Here, we present the recommendations from structured discussions among an author group of AHF experts in 2013. The epidemiology of AHF and current practices in diagnosis, treatment, and long-term care for patients with AHF in Europe and the USA are examined.

Acute heart failure in elderly patients: worse outcomes and differential utility of standard prognostic variables. Insights from the PROTECT trial.

Aims: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear.

Methods And Results: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo.

A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction.

Aims: Sudden cardiac death (SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed.

Methods And Results: We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial.

History of atrial fibrillation as a risk factor in patients with heart failure and preserved ejection fraction.

Background: Atrial fibrillation (AFib) is common in heart failure (HF) with preserved ejection fraction (HFpEF). Current AFib stroke risk prediction models include the presence of HF but do not specifically include HFpEF as a risk factor. Whether a history of AFib should be used to identify patients with HFpEF who are at risk has not been established.

Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment.

Background: Worsening renal function (WRF) associated with renin-angiotensin-aldosterone system (RAAS) inhibition does not confer excess risk in heart failure patients with reduced ejection fraction (HFrEF).

Objectives: The goal of this study was to investigate the relationship between WRF and outcomes in heart failure patients with preserved ejection fraction (HFpEF) and the interaction with RAAS blockade.

Methods: In 3,595 patients included in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, change in estimated glomerular filtration rate (eGFR) and development of WRF after initiation of irbesartan or placebo were examined.

Establishment and validation of new complementing cells for production of E1-deleted adenovirus vectors in serum-free suspension culture.

E1-deleted adenovirus vectors (AdV) are important gene transfer vehicles for gene therapy and vaccination. Amplification of AdV must take place in cells that express the adenovirus E1A and E1B genes. Sequence homology between AdV and the E1 genes integrated within the complementing cells should be minimal to reduce the odds of generating replication-competent adenovirus (RCA).

Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve).

Background: Higher heart rate is associated with poorer outcomes in patients with heart failure and reduced ejection fraction (HF-REF). Less is known about the association between heart rate and outcomes in patients with heart failure and preserved ejection fraction (HF-PEF). Therefore, we examined the relationship between heart rate and outcomes in the irbesartan in patients with heart failure and preserved systolic function trial (I-Preserve) in patients with an ejection fraction >45% aged >60 years.

International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial.

Aims: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial.

Methods And Results: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo.

Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure.

Background: This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF).

Methods: We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment.

Diuretic response in acute heart failure: clinical characteristics and prognostic significance.

Aim: Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for diuretic response, examine associated patient characteristics and relationships with outcome.

Methods And Results: We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial.