Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Which Strategy of Immunoablative Therapy with Autologous Stem Cell Transplantation (ASCT) Is Preferable in Multiple Sclerosis (MS) Patients?.

Abstract During the last decade immunoablative therapy with ASCT (IT+ASCT) has been used with increasing frequency as a therapeutic option for MS patients. Among a number of unanswered questions is the timing of IT+ASCT. We have identified 3 strategies of IT+ASCT depending on the stage in disease process: early, conventional and salvage/late. The goal of our research was to study clinical and patient-reported outcomes in MS patients after early, conventional and salvage/late transplantation. 54 patients with MS (secondary progressive - 26 patients, primary progressive -10, progressive-relapsing - 1, and relapsing-remitting - 17) from 6 medical centers were included in this study (mean age - 32.0, range: 17–51; male/female - 21/33). 13 patients underwent early, 37 patients - conventional, and 4 patients - salvage/late transplantation. Median EDSS at base-line was 6.0 (range 1.5 – 8.0). The median follow-up duration was 18 months (range 6 – 84 months). Neurological and quality of life (QoL) evaluation was performed at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter following IT+ASCT. MRI examinations were conducted at baseline, at 6, 12 months, and at the end of follow-up. FACT-BMT and FAMS were used for QoL evaluation. Notably, no transplant-related deaths or unpredictable severe adverse events were observed. All 42 patients (6 - early transplantation; 32 - conventional transplantation; 4 - salvage/late transplantation) with the follow-up of longer than 9 months experienced clinical stabilization or improvement. More than half of them (27 patients) improved: 8 patients showed significant improvement in EDSS, 9 patients improved by 1.0 point, and 10 - by 0.5 points on EDSS. Notably, all of the patients after early transplantation (mean age - 28.0) improved at least by 0.5 points on EDSS. 15 patients achieved stabilization. 2 patients deteriorated to a worse score after 18 months of stabilization; 2 others progressed after 12 and 30 months of improvement, respectively. All of the patients with clinical stabilization and improvement had negative MRI scans. Out of 24 patients included in QoL analysis 22 exhibited improved QoL 6 months post-transplantation. In conclusion, IT+ASCT appears to be an effective treatment for MS both in terms of clinical and patient-reported outcomes. The data obtained point to feasibility of early, conventional and salvage/late transplantation in MS patients. Our data support the hypothesis that transplantation is more effective in young patients at early stages of rapidly progressing disease. Further studies should be done to establish the best timing for transplantation and to validate IT+ASCT regimens in patients receiving early, conventional and salvage transplantation.</jats:p

Four Strategies of Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis Treatment

Abstract Conventional therapies do not provide satisfactory control of multiple sclerosis (MS) due to their inability to eradicate self-specific T cell clones. During the last decade high-dose immunosuppressive therapy (HDIT) with autologous haematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients. We have identified 4 strategies of HDIT+AHSCT depending on the stage in disease process: early, conventional, late, and salvage. In the current study we aimed to study clinical and patient-reported outcomes in MS patients after different strategies of HDIT+AHSCT. One hundred and twenty patients with MS (secondary progressive – 53 patients, primary progressive –21, progressive-relapsing – 9, relapsing-remitting – 37) were included in this study (mean age - 33.0, range: 17–54; male/female – 53/67). Thirty seven patients underwent early transplantation (EDSS 1.0–3.0), 72 patients – conventional transplantation (EDSS 3.5–6.0), 6 patients – late transplantation (EDSS 6.5–7.0), and 5 patients – salvage transplantation (EDSS 7.5–8.5). Median EDSS at baseline was 5.0 (range 1.5 – 8.0). The mean follow-up duration was 18 months (range 6 – 108 months). Neurological and quality of life (QoL) evaluation was performed at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter following AHSCT; MRI examinations - at baseline, at 6, 12 months, and at the end of follow-up. Notably, transplantation procedure was well tolerated by the patients with no transplant-related deaths. The efficacy analysis was performed in 79 patients. At 6 months post transplant the following distribution of patients according to clinical response was observed: 42 patients (53%) achieved an objective improvement of neurological symptoms; 37 patients (47%) had disease stabilization. At long-term follow-up clinical response was classified as improvement in 40 patients (50.6%); stabilization in 34 patients (43.1%); progression in 5 patients (1 patient after early transplantation, 3 patients after conventional transplantation, and 1 patient after late transplantation). No active, new or enlarging lesions were registered in patients without disease progression. Furthermore, out of 44 patients included in QoL analysis 39 exhibited improved QoL 6 months post-transplantation. Further QoL improvement was observed at longer follow-up in patients without disease progression. All the patients without disease progression were off therapy throughout the post-transplant period. Thus, AHSCT appears to be an effective treatment for MS both in terms of clinical and patient-reported outcomes. Further studies should be done to establish the best timing for transplantation and to validate high-dose immunosuppressive therapy with ASCT regimens in patients receiving early, conventional, late and salvage transplantation.</jats:p

Multicenter Experience of High Dose Chemotherapy (HDCT)+Autologous Stem Cell Transplantation (ASCT) in Multiple Sclerosis (MS) Patients.

Abstract During the last decade HDCT+ASCT is more often used as a therapeutic option for MS patients. The major treatment outcomes for MS patients are disease-progressive free period and improvement of patient’s quality of life (QoL). We aimed to study treatment outcomes in MS patients after early, conventional and salvage HDCT+ASCT. Thirty two patients with MS (secondary progressive - 16 patients, primary progressive - 8, progressive-relapsing - 1, relapsing-remitting - 7) from 6 medical centers were included in this study (mean age - 32.0, range: 19–49; male/female - 12/20). Two patients underwent early HDCT +ASCT, 27 patients - conventional HDCT+ASCT and 3 patients - salvage HDCT+ASCT. Median EDSS at base-line was 6.0 (range 2.0 – 8.0). The median follow-up duration was 18 months (range 6 – 78 months). All of the patients had previously undergone conventional treatment. Neurological and QoL evaluation was provided at baseline, at discharge, 3, 6, 9, 12 months, and then every 6 months after HDCT+ASCT. MRI was conducted at baseline, at 6, 12 months, and at the end of follow-up. FACT-BMT and FAMS were used for QoL evaluation. QoL response was evaluated using Integral QoL index. All 27 patients with the follow-up longer than 1 year, included in the analysis, experienced a clinical stabilization or improvement. More than half of them improved: 6 patients showed significant improvement in EDSS (by more than 1.0 point), 4 patients improved by 1.0 point, and 5 patients - by 0.5 points on EDSS. Twelve patients achieved stabilization. Two patients deteriorated to a worse score after 18 months of stabilization; 2 other patients progressed after 12 and 30 months of improvement, respectively. All the patients with clinical stabilization and improvement exhibited negative MRI scans. Out of 21 patients included in the analysis of QoL response 19 exhibited improved QoL 6 months post-transplantation. At one year after HDCT+ASCT 1 patient exhibited excellent QoL response; 3 patients - good QoL response; 7 patients - moderate QoL response and 8 patients - minimal QoL response. At 2.5 years post-transplantation 3 more patients had excellent QoL response. Further QoL improvement was observed at longer follow-up. One of the patients who experienced progression after stabilization had no QoL response; another patient who progressed after stabilization had stable QoL during 6 months post-transplant and significantly worsened at 9 months. In conclusion, clinical response was observed in 100% of MS patients after early, conventional and salvages HDCT+ASCT. The majority of patients with clinical response had a good or moderate QoL response. Further studies should be done to investigate the clinical and patient-reported outcomes of HDCT+ASCT in MS patients to better define treatment success.</jats:p

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)