Treatment Of Systolic Heart Failure Research Articles

Beneficial effects of ivabradine in patients with heart failure, low ejection fraction, and heart rate above 77 b.p.m.

AimsIvabradine has been approved in heart failure with reduced ejection fraction (HFrEF) and elevated heart rate despite guideline‐directed medical therapy (GDMT) to reduce cardiovascular (CV) death and hospitalization for worsening HF. The median value of 77 b.p.m. is the lower bound selected for the regulatory approval in Canada, South Africa, and Australia. Patient‐reported outcomes (PROs) including symptoms, quality of life, and global assessment are considered of major interest in the global plan of care of patients with HF. However, the specific impact of GDMT, and specifically ivabradine, on PRO remains poorly studied. In the subgroup of patients from the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) who had heart rate above the median of 77 b.p.m. (pre‐specified analysis) and for whom the potential for improvement was expected to be larger, we aimed (i) to evaluate the effects of ivabradine on PRO (symptoms, quality of life, and global assessment); (ii) to consolidate the effects of ivabradine on the primary composite endpoint of CV death and hospitalization for HF; and (iii) to reassess the effects of ivabradine on left ventricular (LV) remodelling.Methods and resultsComparisons were made according to therapy, and proportional hazards models (adjusted for baseline beta‐blocker therapy) were used to estimate the association between ivabradine and various outcomes. In SHIFT, n = 3357 (51.6%) patients had a baseline heart rate > 77 b.p.m. After a median follow‐up of 22.9 months (inter‐quartile range 18–28 months), ivabradine on top of GDMT improved symptoms (28% vs. 23% improvement in New York Heart Association functional class, P = 0.0003), quality of life (5.3 vs. 2.2 improvement in Kansas City Cardiomyopathy Questionnaire overall summary score, P = 0.005), and global assessment [from both patient (improved in 72.3%) and physician (improved in 61.0%) perspectives] significantly more than did placebo (both P < 0.0001). Ivabradine induced a 25% reduction in the combined endpoint of CV death and hospitalization for HF (hazard ratio 0.75; P < 0.0001), which translates into a number of patients needed to be treated for 1 year of 17. Patients under ivabradine treatment demonstrated a significant reduction in LV dimensions when reassessed at 8 months (P < 0.05).ConclusionsIn patients with chronic HFrEF, sinus rhythm, and a heart rate > 77 b.p.m. while on GDMT, the present analysis brings novel insights into the role of ivabradine in improving the management of HFrEF, particularly with regard to PRO (ISRCTN70429960).

TCT-338 Electrical Microcurrent Therapy for Treatment of Chronic Systolic Heart Failure: Animal and First-in-Man Data

Given the growing burden of systolic heart failure (HF), there is an immense need for novel treatment strategies, which aim at myocardial recovery. Direct application of an electrical microcurrent to the myocardium triggers reverse remodeling and modifies myocardial inflammation. The aim of the

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator

The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.

Sacubitril/Valsartan and Ivabradine: Two Compounds for Heart Failure with Low Ejection Fraction (EFrEF), Acting by Innovative Mechanisms

The role of two new compounds - Sacubitril/valsartan and Ivabradine in treatment of systolic heart failure (HFrEF) was evaluated. Sacubitril/valsartan (also called as Entresto), together the remaining optimal medical therapy, antagonize HFrEF both strengthening the beneficial effects of natriuretic peptides (NP) and acting against angiotensin II by angiotensin receptor blocker (ARB), valsartan. PARADIGM-HF study has demonstrated that Sacubitril/valsartan is superior to angiotensin-converting-enzyme (ACE) alone in reducing the risks of death and hospitalization for HFrEF. On the contrary Ivabradine, a selective inhibitor of the “funny” channel current present in the sino-atrial node, acts against HFrEF inducing a reduction of heart rate in sinus rhythm patients. This reduction yields an improvement in stroke volume due to the increased of LV diastolic filling, improving the HFrEF symptoms. The results reported in the SHIFT Trial support the importance of heart rate reduction obtained with Ivabradine for improvement of clinical outcomes in HFrEF and confirm the important role of heart rate in the pathophysiology of this disorder. Two drugs act with two diverse and innovative mechanisms and, together the remaining optimal medical therapy, represent an effective improvement in HFrEF therapy.

Sex differences in the central and peripheral manifestations of ischemia-induced heart failure in rats.

Sex differences in the presentation, outcome, and responses to treatment of systolic heart failure (HF) have been reported. In the present study, we examined the effect of sex on central neural mechanisms contributing to neurohumoral excitation and its peripheral manifestations in rats with HF. Male and female Sprague-Dawley rats underwent coronary artery ligation (CL) to induce HF. Age-matched rats served as controls. Ischemic zone and left ventricular function were similar 24 h and 4 wk after CL. Female rats with HF had a lower mortality rate and less hemodynamic compromise, pulmonary congestion, and right ventricular remodeling 4 wk after CL. Plasma angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine levels were increased in HF rats in both sexes, but AVP and norepinephrine levels increased less in female rats. In the hypothalamic paraventricular nucleus, a key cardiovascular-related nucleus contributing to neurohumoral excitation in HF, mRNA levels for the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β as well as cyclooxygenase-2 and the ANG II type 1a receptor were increased in HF rats of both sexes, but less so in female rats. Angiotensin-converting enzyme 2 protein levels increased in female HF rats but decreased in male HF rats. mRNA levels of AVP were lower in female rats in both control and HF groups compared with the respective male groups. Activation of extracellular signal-regulated protein kinases 1 and 2 increased similarly in both sexes in HF. The results suggest that female HF rats have less central neural excitation and less associated hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. NEW & NOTEWORTHY Sex differences in the presentation and responses to treatment of heart failure (HF) are widely recognized, but the underlying mechanisms are poorly understood. The present study describes sex differences in the central nervous system mechanisms that drive neurohumoral excitation in ischemia-induced HF. Female rats had a less intense central neurochemical response to HF and experienced less hemodynamic compromise. Sex hormones may contribute to these differences in the central and peripheral adaptations to HF.

Pacing electrode modeling and simulation of cardiac contractility modulation

Abstract Cardiac contractility modulation (CCM) is a device-based therapy for the treatment of systolic left ventricular chronic heart failure. Unlike other devicebased therapies for heart failure, CCM delivers nonexcitatory pacing signals to the myocardium. This leads to an extension of the action potential and to an improved contractility of the heart. The modeling and simulation was done with the electromagnetic simulation software CST. Three CCM electrodes were inserted into the Offenburg heart rhythm model and subsequently simulated the electric field propagation in CCM therapy. In addition, simulations of CCM have been performed with electrodes from other device-based therapies, such as cardiac resynchronization therapy (CRT) and implantable cardioverter./.defibrillator (ICD) therapy. At the same distance to the simulation electrode, the electric field is slightly stronger in CCM therapy than in CCM therapy with additionally implanted CRT or ICD electrodes. In addition, there is a change in the electric field propagation at the electrodes of the CRT and the shock electrode of the ICD. By simulating several different therapy procedures on the heart, it is possible to check how they affect their behavior during normal operation. CCM heart rhythm model simulation allows the evaluation the individual electrical pacing and sensing field during CCM.

Abstract 164: Evaluation of Clinical and Social Factors for Patients Taking Very Low Dose of Beta Blockers for Systolic Heart Failure

Background: All guidelines agree that beta-blockers (BBs) should be used for patients with systolic heart failure (SHF) to improve survival. BBs are a class Ia indication for treatment of SHF based on 3 landmark clinical trials (CIBIS-II, COPERNICUS, and MERIT-HF). Despite recommendations, the doses of BBs prescribed are commonly less than target dose (TD). Underdosing of BBs is suggested by doses less than 50% of TD and/or sinus rate (SR) above 70 bpm whereas a very low dose of BB is 25% or less of the TD. Clinical and social factors including depression, dizziness, ability to walk without assistance, Morse Fall Scale score and living status, whether independently or in a care facility, could be likely reasons for patients receiving a very low dose of BB. Failure to achieve SR below 70 bpm might lead physicians to use ivabradine which is a relatively new and expensive medication and is a class IIa indication for SHF. The objective is to evaluate the clinical and social factors affecting underdosing of BBs between the two patient groups with ≤25% of TD vs &gt;25% of TD. Methods: A retrospective chart review was completed for SHF patients admitted to Charleston Area Medical Center from 2007 to 2016. Doses of BB, SR, and clinical/social factors were recorded. Patients over the age of 18 years with diagnosed SHF (EF&lt;40%) and on BB treatment for more than 8 weeks prior to admission were included. Results: An initial sample size of 254 patients with SHF was obtained. 65% (164 of 254) were on approved BBs. Of the patients on approved BBs, 71% (117 of 164) were receiving ≤ 25% of the TD and 29% (47 of 164) were receiving &gt;25% of the TD. Mean SR on admission EKG was 85±19.5 in the ≤ 25% TD group, and 83±21.4 in the &gt;25% TD group. Of the 164 patients on approved BB therapy, SR could only be recorded in 105 patients due to atrial pacing or atrial arrhythmias; and 82% (86 of 105) had a SR &gt;70 bpm on their initial EKG. No statistically significant differences were identified between the two groups when reviewing the clinical and social factors. Conclusions: This study will help enable cardiovascular clinicians to realize that although the use of BBs for SHF has improved dramatically since Get With The Guidelines; there is still marked underdosing of approved BB and inappropriate use of non-approved BB. We are unable to explain this practice based on the clinical and social factors that may have led to underdosing of BB. We found the mean dose of BBs to be 25% or less of TD in 71% (117 of 164) patients on approved BBs and only 18% (19 of 105) of these patients had SR &lt;70bpm. Inappropriate dosing of BBs could potentially be responsible for worsening outcomes and possible overutilization of ivabradine.

Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ.

The development of calcium sensitizers for the treatment of systolic heart failure presents difficulties, including judging the optimal efficacy and the specificity to target cardiac muscle. The thin filament is an attractive target because cardiac troponin C (cTnC) is the site of calcium binding and the trigger for subsequent contraction. One widely studied calcium sensitizer is levosimendan. We have recently shown that when a covalent cTnC-levosimendan analogue is exchanged into cardiac muscle cells, they become constitutively active, demonstrating the potency of a covalent complex. We have also demonstrated that levosimendan reacts in vitro to form a reversible covalent thioimidate bond specifically with cysteine 84, unique to cTnC. In this study, we use mass spectrometry to show that the in vitro mechanism of action of levosimendan is consistent with an allosteric, reversible covalent inhibitor; to determine whether the presence of the cTnI switch peptide or changes in either Ca2+ concentration or pH modify the reaction kinetics; and to determine whether the reaction can occur with cTnC in situ in cardiac myofibrils. Using the derived kinetic rate constants, we predict the degree of covalently modified cTnC in vivo under the conditions studied. We observe thatcovalent bond formation would be highest under the acidotic conditions resulting from ischemia and discuss whether the predicted level could be sufficient to have therapeutic value. Irrespective of the in vivo mechanism of action for levosimendan, our results provide a rationale and basis for the development of reversible covalent drugs to target the failing heart.

Cost-Effectiveness of Ivabradine in the Treatment of Chronic Heart Failure

In the Systolic Heart failure treatment with the If inhibitor Trial (SHIFT) randomised placebo-controlled trial, ivabradine was shown to reduce hospital admissions for worsening heart failure (HF) and deaths due to HF in patients with symptomatic systolic HF and an elevated resting heart rate (HR). This analysis evaluates the cost effectiveness of adding ivabradine to optimal standard HF treatment in patients with a HR≥77 bpm. A Markov model was developed to assess the impact of ivabradine on mean survival and quality of life over a patient's lifetime (10 years). The hospitalisation and death rates were calculated using patient-level data from SHIFT. The reduction in quality of life due to HF hospitalisations was estimated directly from EQ-5D data collected in SHIFT. Australian costs were applied to the resource use from SHIFT. The modelled mean increase in survival with ivabradine was 0.115 years. The mean increase in quality-adjusted survival was 0.108 years. The average cost of ivabradine was A$2,957 and the cost savings associated with a reduction in HF hospitalisations was A$1,344. The cost per quality adjusted life year gained (QALYG) was A$14,905. The conservative approach to the modelled evaluation, as well as results of the sensitivity analysis, demonstrates that ivabradine is likely to be cost-effective in this indication. The conservative approach to the modelled evaluation, as well as results of the sensitivity analysis, demonstrates that ivabradine is a cost-effective treatment in the Australian setting for HF patients with a HR≥77 bpm on optimal standard therapy with a cost per QALYG similar or lower than that for other publicly funded treatments.

Design and synthesis of sulfonamidophenylethylureas as novel cardiac myosin activator

To optimize the lead urea scaffold 1 and 2 as selective cardiac myosin ATPase activator, a series of urea derivatives have been synthesized to explore its structure activity relationship. Among them N,N-dimethyl-4-(2-(3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (13, CMA = 91.6%, FS = 17.62%; EF = 11.55%), N,N-dimethyl-4-(2-(1-methyl-3-(3-phenylpropyl)ureido)ethyl)benzene sulfonamide (40, CMA = 52.3%, FS = 38.96%; EF = 24.19%) and N,N-dimethyl-4-(2-(3-methyl-3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (41, CMA = 47.6%, FS = 23.19%; EF = 15.47%) proved to be efficient to activate the cardiac myosin in vitro and in vivo. Further the % change in ventricular cell contractility at 5 μM of 13 (47.9 ± 3.2), 40 (45.5 ± 2.4) and 41 (63.5 ± 2.2) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13, 40, 41 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, thus proving them these new urea derivatives is a novel scaffold for discovery of cardiac myosin activators for the treatment of systolic heart failure.

GW28-e1153 Study of Intrinsic QRS Complex Duration Changes 6 Months After Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is one of the important advances in the treatment of ventricular systolic heart failure (HF) in recent years. It can reduce the mortality and improve the quality of life of patients. Patients who had response to CRT were often accompanied with a reversal of

Heart rate and its reduction in chronic heart failure and beyond.

Heart rate (HR) is associated with cardiovascular outcomes in all the stages of the cardiovascular continuum as well as in patients with pulmonary, cerebrovascular, and renal disease, sepsis, cancer, and erectile dysfunction. In patients with cardiovascular disease, but also in the general population, increased HR represents an important indicator of mortality with each acceleration of HR over 70 b.p.m. increasing the risk. In patients in sinus rhythm with chronic heart failure with reduced ejection fraction (HFrEF), a HR >70 b.p.m. increased the risk of hospitalization, and >75 b.p.m. the risk of cardiovascular death as shown in the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT). Reducing HR with ivabradine by 11 b.p.m. (placebo-controlled) reduced the primary composite endpoint (cardiovascular death and hospitalization for worsening heart failure). Ivabradine was well tolerated showing benefit irrespective of age or diabetes status, and also in the presence of low systolic blood pressure and severe heart failure (SHIFT trial). Therefore, HR qualifies as a modifiable risk factor in heart failure. In patients with stable coronary disease, HR is a risk marker but HR reduction with ivabradine does not improve outcomes. The role of selective HR lowering remains unclear in patients with pulmonary, renal, cerebrovascular, and other diseases, as the potential benefit of interventions on HR has not been explored in these conditions. Future studies should scrutinize if HR reduction improves outcomes, defining HR as a potential risk factor and therapeutic target in other conditions beyond heart failure.

Device Therapy for Rate Control: Pacing, Resynchronisation and AV Node Ablation.

Atrioventricular node ablation (AVNA) is generally reserved for patients whose atrial fibrillation (AF) is refractory all other therapeutic options, since the recipients will often become pacemaker dependent. In such patients, this approach may prove particularly useful, especially if a tachycardia-induced cardiomyopathy is suspected. Historically, an "ablate and pace" approach has involved AVNA and right ventricular pacing, with or without an atrial lead. There is also an evolving role for atrioventricular node ablation in patients with AF who require cardiac resynchronisation therapy for treatment of systolic heart failure. A mortality benefit over pharmacotherapy has been demonstrated in observational studies and this concept is being further investigated in multi-centre randomised control trials.

Is There a Role for Ivabradine in the Contemporary Management of Patients with Chronic Heart Failure in Academic and Community Heart Failure Clinics in Canada?

In patients with heart failure (HF) and reduced ejection fraction, increased heart rate (HR) is an independent risk factor for adverse outcomes. In systolic HF treatment with the If inhibitor ivabradine trial (SHIFT), Ivabradine improved survival when added to conventional treatment including β-blockers. However, the extent of benefit in the real world is unclear. We examined the characteristics of patients on guideline-directed therapy and determined who had SHIFT-like characteristics. A total of 1096 patients with chronic HF were reviewed from June 2014 to April 2015 in two HF clinics in Toronto: an academic institution (AI), and a community hospital (CH) clinic. SHIFT-like characteristics [left ventricular ejection fraction (LVEF) ≤35%; sinus rhythm; and HR≥70bpm] were described. For all patients, mean age was 75±13years, overall LVEF was 44±15%, AI less than CH (41.9±14.0% vs. 45.7±15.0%; p<0.0001). More than two-thirds of patients in both groups were on β-blockers; with less than one-third at target dose. The proportion of patients with SHIFT-like characteristics was 8.4% AI and 11.7% CH, respectively (p=0.0658). In HF clinics from both academic and community hospitals in Toronto, up-titration in the dose of β-blockers and other guideline therapy can be improved on. A small proportion of patients with HF and SHIFT-like characteristics may potentially benefit from the addition of Ivabradine, just approved in Canada; this number will be further reduced if target dosage for β-blockers is achieved. Servier Inc.

Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure

A series of flexible urea derivatives have been synthesized and demonstrated as selective cardiac myosin ATPase activator. Among them 1-phenethyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation at 10 μM = 51.1%; FS = 18.90; EF = 12.15) and 1-benzyl-3-(3-phenylpropyl)urea (9, cardiac myosin ATPase activation = 53.3%; FS = 30.04; EF = 18.27) showed significant activity in vitro and in vivo. The change of phenyl ring with tetrahydropyran-4-yl moiety viz., 1-(3-phenylpropyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)urea (14, cardiac myosin ATPase activation = 81.4%; FS = 20.50; EF = 13.10), and morpholine moiety viz., 1-(2-morpholinoethyl)-3-(3-phenylpropyl)urea (21, cardiac myosin ATPase activation = 44.0%; FS = 24.79; EF = 15.65), proved to be efficient to activate the cardiac myosin. The potent compounds 1, 9, 14 and 21 were found to be selective for cardiac myosin over skeletal and smooth myosins. Thus, these urea derivatives are potent scaffold to develop as a newer cardiac myosin activator for the treatment of systolic heart failure.

Efficacy and safety analysis of ivabradine hydrochloride treatment of Chinese patients with chronic heart failure: subgroup analysis of Chinese patients in the SHIFT study

Objective: To evaluate the efficacy and safety of ivabradine for the treatment of Chinese patients with chronic heart failure based on the Chinese subgroup data of the systolic heart failure treatment with the I(f) inhibitor ivabradine trial (SHIFT). Method: A total of 6 558 stable outpatients who presented symptoms of heart failure, with a left ventricular ejection fraction (LVEF) ≤35%, sinus rhythms with a heart rate ≥70 bpm participated in the randomized, double-blind, placebo-controlled, international multicenter clinical study.The subset of Chinese patients with heart rate ≥75 bpm was enrolled in the post-hoc subgroup analyses.Patients were randomly allocated by computer-generated assignment through a telephone interactive voice response system to ivabradine group (starting dose 5 mg bid, which was then uptitrated to the maximum 7.5 mg bid) or matched placebo group.The clinical baseline characteristics of participants were obtained and analyzed.The primary outcome endpoint was a composite endpoint of cardiovascular death or hospitalization resulting from worsening HF.The primary safety endpoint included total incidence of adverse events during the study, bradycardia, and adverse visual reaction (phosphenes). Results: A total of 49 Chinese centers enrolled a total of 225 patients with chronic heart failure, of whom, 106 patients were randomized to the ivabradine group and the other 119 patients to the placebo group, and the mean follow-up time was (15.6±5.1) months.By the end of the study, mean heart rate (71.0 bpm vs. 80.3 bpm, P<0.05) and incidence of the primary endpoint events (18.9% (20/106) vs. 31.9%(38/119), HR=0.56, 95%CI 0.33-0.97, P=0.039) were significantly lower, while the percentage of patients with improvement in heart functional class NYHA (53.8% (56/106) vs. 34.5% (41/119), P=0.006 1) was significantly higher in the ivabradine group than in the placebo group.The total number of adverse events (129 events, 49.6% PY) in the ivabradine group was lower than that in the placebo group (203 events, 50.8% PY). In the ivabradine group and the placebo group, there were respectively 2 patients (1.9%) and 0 patients experienced bradycardia, 3 patients (2.9%) and 1 patient (0.8%) experienced adverse visual reaction (phosphenes). Conclusions: Ivabradine significantly reduced heart rate and improved the clinical outcomes and NYHA function class in Chinese patients with chronic heart failure, these beneficial effects are achieved without inducing remarkable adverse reactions.The results of Chinese subgroup analysis were thus consistent with the overall results of the SHIFT study. Clinical Trial Registry: International standard randomized controlled trials registry, ISRCTN 70429960.

Potential Expanded Indications for Neprilysin Inhibitors.

The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease. Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Neprilysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprilysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II-III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications.

Analyzing Health-Related Quality of Life Data to Estimate Parameters for Cost-Effectiveness Models: An Example Using Longitudinal EQ-5D Data from the SHIFT Randomized Controlled Trial.

IntroductionThe aim of this article is to discuss methods used to analyze health-related quality of life (HRQoL) data from randomized controlled trials (RCTs) for decision analytic models. The analysis presented in this paper was used to provide HRQoL data for the ivabradine health technology assessment (HTA) submission in chronic heart failure.MethodsWe have used a large, longitudinal EuroQol five-dimension questionnaire (EQ-5D) dataset from the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) (clinicaltrials.gov: NCT02441218) to illustrate issues and methods. HRQoL weights (utility values) were estimated from a mixed regression model developed using SHIFT EQ-5D data (n = 5313 patients). The regression model was used to predict HRQoL outcomes according to treatment, patient characteristics, and key clinical outcomes for patients with a heart rate ≥75 bpm.ResultsIvabradine was associated with an HRQoL weight gain of 0.01. HRQoL weights differed according to New York Heart Association (NYHA) class (NYHA I–IV, no hospitalization: standard care 0.82–0.46; ivabradine 0.84–0.47). A reduction in HRQoL weight was associated with hospitalizations within 30 days of an HRQoL assessment visit, with this reduction varying by NYHA class [−0.07 (NYHA I) to −0.21 (NYHA IV)].ConclusionThe mixed model explained variation in EQ-5D data according to key clinical outcomes and patient characteristics, providing essential information for long-term predictions of patient HRQoL in the cost-effectiveness model. This model was also used to estimate the loss in HRQoL associated with hospitalizations. In SHIFT many hospitalizations did not occur close to EQ-5D visits; hence, any temporary changes in HRQoL associated with such events would not be captured fully in observed RCT evidence, but could be predicted in our cost-effectiveness analysis using the mixed model. Given the large reduction in hospitalizations associated with ivabradine this was an important feature of the analysis. Funding: The Servier Research Group.

Myosin Activator Omecamtiv Mecarbil Differentially Impacts the Contractile Properties of Skinned Myocardium from Failing and Donor Human Hearts

Omecamtiv mecarbil (OM) is a compound that selectively targets the cardiac sarcomere and enhances myosin crossbridge (XB) activation and force generation. Because of these properties OM has been proposed as a treatment for systolic heart failure in humans, however, there are no studies that have directly examined the functional effects of OM, at XB level, in remodeled human failing myocardium. Thus, we tested whether OM differentially impacts contractile properties in failing and donor human myocardium. Isometric force, myofilament Ca2+-sensitivity (pCa50), rates of XB detachment (krel), recruitment (kdf), and magnitude of XB recruitment (Pdf) were measured both before and after OM incubation in chemically-skinned myocardial preparations isolated from failing and donor hearts. Because the failing myocardium exhibited an enhanced pCa50, dynamic XB parameters were measured at pCa's 6.6 and 6.3, respectively for failing and donor groups in order to achieve equivalent levels of activation (∼22% and ∼35% of maximal force, respectively for pre- and post-OM incubations). OM incubation did not alter the pCa50 but significantly enhanced the sub-maximal force production at forces lower than 50%, an affect that was less pronounced as Ca2+ levels increased. Furthermore, OM differentially impacted the contractile properties of failing and donor myocardium. Specifically, OM-induced force increases were more pronounced in the failing myocardium (∼79% increase vs. ∼28% in donor myocardium). Additionally, the OM-induced slowing of krel and kdf, and increase in Pdf were also more pronounced in the failing myocardium. Our results suggest that OM is effective in increasing force generation in myocardium isolated from failing hearts by increasing XB on-time and enhancing cooperative XB recruitment.

Ivabradine in the treatment of systolic heart failure - A systematic review and meta-analysis.

AIMTo perform a systematic-review and meta-analysis to compare outcomes of ivabradine combined with beta-blocker to beta-blocker alone in heart failure with reduced ejection fraction (HFrEF).METHODSWe searched PubMed, Cochrane, EMBASE, CINAHL and Web of Science for trials comparing ivabradine + beta-blocker to beta-blocker alone in HFrEF. We performed a systematic-review and meta-analysis of published literature. Primary end-point was combined end point of cardiac death and hospitalization for heart failure.RESULTSSix studies with 17671 patients were included. Mean follow-up was 8.7 ± 7.9 mo. Combined end-point of heart failure readmission and cardiovascular death was better in ivabradine + beta-blocker group compared to beta-blocker alone (RR: 0.93, 95%CI: 0.79-1.09, P = 0.354). Mean difference (MD) in heart rate was higher in the ivabradine + beta-blocker group (MD: 6.14, 95%CI: 3.80-8.48, P < 0.001). There was no difference in all cause mortality (RR: 0.98, 95%CI: 0.89-1.07, P = 0.609), cardiovascular mortality (RR: 0.99, 95%CI: 0.86-1.15, P = 0.908) or heart failure hospitalization (RR: 0.87, 95%CI: 0.68-1.11, P = 0.271).CONCLUSIONFrom the available clinical trials, ivabradine + beta-blocker resulted in a significantly greater reduction in HR coupled with improvement in combined end-point of heart failure readmission and cardiovascular death but with no improvement in all cause or cardiovascular mortality. Given the limited evidence, further randomized controlled trials are essential before widespread clinical application of ivabradine + beta-blocker is advocated for HFrEF.