scholarly journals Vagal stimulation in heart failure

Herz ◽  
2021 ◽  
Author(s):  
Veronica Dusi ◽  
Gaetano Maria De Ferrari
Keyword(s):  
Heart Failure ◽  
Adaptive Design ◽  
Vagal Stimulation ◽  
Randomized Study ◽  
Pulse Amplitude ◽  
Phase Iii ◽  
Reduced Ejection Fraction ◽  
Electrical Modulation ◽  
Sufficient Degree ◽  
Phase Iii Studies

AbstractVagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials—NECTAR-HF and INOVATE-HF—failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose–response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.

scholarly journals Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction

Heart ◽  
2017 ◽  
Vol 104 (12) ◽  
pp. 1006-1013 ◽  
Author(s):  
John J V McMurray ◽  
David Trueman ◽  
Elizabeth Hancock ◽  
Martin R Cowie ◽  
Andrew Briggs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sensitivity Analysis ◽  
Cost Effectiveness ◽  
Ejection Fraction ◽  
Willingness To Pay ◽  
Cost Effective ◽  
Phase Iii ◽  
Reduced Ejection Fraction ◽  
The Uk ◽  
The Cost

ObjectiveChronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia.MethodsA cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER).ResultsIn the UK, the cost per quality-adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was £17 100 (€20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (€22 600). In Colombia, the ICER was COP$39.5 million (€11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%–94% in the UK, 84% in Denmark and 95% in Colombia.ConclusionsOur analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF.

Combining Proof-of-Concept With Dose-Finding: Utilization of Adaptive Designs in Migraine Clinical Trials

Cephalalgia ◽  
2008 ◽  
Vol 28 (8) ◽  
pp. 805-812 ◽  
Author(s):  
A Sagkriotis ◽  
J Scholpp
Keyword(s):  
Adaptive Design ◽  
Dose Finding ◽  
Phase Iii ◽  
Proof Of Concept ◽  
Trial Duration ◽  
Number Of Patients ◽  
Probability Of Success ◽  
Flexible Designs ◽  
Subsequent Phase ◽  
Phase Iii Studies

There is an obvious need to improve clinical trial designs with respect to efficiency, duration and the number of patients recruited. Adaptive (flexible) designs may be valuable in this respect. We simulated the properties of a two-stage adaptive proof-of-concept and dose-finding trial design in adult migraine patients with moderate to severe headache, with or without aura. We also assessed the usefulness of a combined Bayesian and frequentist approach in the estimation of the probability of success of subsequent Phase III studies. Applying such an innovative approach would result in a reduction of the required sample size by 30 patients and no prolongation of the trial duration. The probability of success in Phase III is > 81%. An innovative adaptive design can facilitate testing of investigational migraine medications by reducing patient numbers and improving predictivity of success in Phase III.

How to treat elderly patients with multiple myeloma: combination of therapy or sequencing

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 566-577 ◽  
Author(s):  
Antonio Palumbo ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Randomized Study ◽  
Proteasome Inhibitors ◽  
Phase Iii ◽  
Novel Agents ◽  
Standards Of Care ◽  
Choice Of Treatment ◽  
Treatment Paradigm ◽  
Phase Iii Studies

AbstractPatients with multiple myeloma aged older than 65 years have traditionally received an oral regimen combining melphalan and prednisone (MP). The introduction of novel agents, such as immunomodulatory drugs and proteasome inhibitors, has substantially changed the treatment paradigm of this disease. Five randomized phase III studies, comparing MP plus thalidomide (MPT) versus MP, have shown that MPT increased time to progression (TTP); however, only two of these five studies showed improvement in overall survival (OS). One randomized study has shown that MP plus bortezomib (MPV) increases both TTP and OS compared with MP. Both MPT and MPV are now regarded as the new standards of care for elderly patients. Other promising results have been reported with MP plus lenalidomide or lenalidomide plus dexamethasone, or the combination of cyclophosphamide, thalidomide, and dexamethasone. Reduced-intensity transplantation can be an option for some patients, especially when novel agents are incorporated into pre-transplant induction and post-transplant consolidation. For patients aged older than 75 years a gentler approach should be used, and doses of standard MPT or MPV should be reduced. An accurate management of treatment-related adverse events with prompt dose-reduction can greatly reduce the rate of early discontinuation and significantly improve treatment efficacy. The choice of treatment should be tailored according to the patient’s biologic age and comorbidities, and the expected toxicity profile of the regimen.

scholarly journals Phase II clinical trial testing the safety of a humanised monoclonal antibody anti-CD20 in patients with heart failure with reduced ejection fraction, ICFEr-RITU2: study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. e022826 ◽  
Author(s):  
Luis Sánchez-Trujillo ◽  
Carlos Jerjes-Sanchez ◽  
David Rodriguez ◽  
Jathniel Panneflek ◽  
Claudia Ortiz-Ledesma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Ejection Fraction ◽  
Phase Ii ◽  
Human Monoclonal Antibody ◽  
Functional Class ◽  
Phase Iii ◽  
Reduced Ejection Fraction ◽  
Transplant Patients

IntroductionChronic heart failure with reduced ejection fraction (HFrEF) treatment targets neurohormonal inhibition; however, our experimental observations and the recent clinical evidence in myocardial infarction and heart transplant patients support the anti-inflammatory pathway as a potential novel therapeutic target. Therefore, we aimed to assess the safety of human monoclonal antibody-CD20 (rituximab) in patients with HFrEF.Methods and analysisWe designed this protocol according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines as a phase II, single-centred, single group and prospective clinical trial. We hypothesise that the use of a monoclonal antibody, rituximab, could be a potentially safe new agent in HFrEF management. We will include patients with EF≤40%, New York Heart Association functional class III/IV and unresponsive to standard treatment. We will use a dosing regimen (1000 mg) previously applied to post-transplant patients and patients with rheumatoid arthritis with favourable results, aiming to provide supplementary evidence of safety in patients with HFrEF. We designed strategies tailored to preserving the integrity of patient safety. The date of study initiation will be 29th of May 2019.Ethics and disseminationThe following protocol was approved by IRB committees, and as a requirement, all patients need to sign an informed consent form before being subjected to any procedure prior to the initiation of the study. We are aware that the trial will be run in patients who due to their cardiovascular functional class, have reserved prognosis, with no known therapy that leads to improvement. Hence, this trial searches to establish the safety of an alternative strategy in ameliorating prognosis. Regardless of the study outcomes, whether favourable or not, they will be published. If a favourable outcome is evidenced, it will prompt performing a phase III, efficacy-based study.Trial registration numberThe trial was approved by the IRB (CONBIOÉTICA-19-CEI-011–20161017 and COFEPRIS-17-CI-19-039-003), and registered at Clinicaltrials.gov (NCT03332888; Pre-Results).

scholarly journals Mechanisms and Models in Heart Failure

2021 ◽  
Vol 128 (10) ◽  
pp. 1435-1450
Author(s):  
Douglas L. Mann ◽  
G. Michael Felker
Keyword(s):  
Heart Failure ◽  
Conceptual Models ◽  
Soluble Guanylate Cyclase ◽  
Clinical Development ◽  
Sglt2 Inhibitors ◽  
Phase Iii ◽  
Development Programs ◽  
Reduced Ejection Fraction ◽  
Therapeutic Class ◽  
Cardiovascular Therapeutics

Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.

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