Permutation criteria to evaluate multiple clinical endpoints in a proof-of-concept study: lessons from Pre-RELAX-AHF

Clinically relevant endpoints cannot be routinely targeted with reasonable power in a small study. Hence, proof-of-concept studies are often powered to a primary surrogate endpoint. However, in acute heart failure (AHF) effects on surrogates have not translated into clinical benefit in confirmatory studies. Although observing an effect on one of many endpoints due to chance is likely, observing concurrent positive trends across several outcomes by chance is usually unlikely. Pre-RELAX-AHF, which compared 4 relaxin doses with placebo in AHF, has shown favourable trends versus placebo (one-sided P <0.10) on six of nine clinical endpoints in the 30 mu g/kg/day group. To illustrate evaluation of multiple, correlated clinical endpoints for evidence of efficacy and for dose selection, a permutation method was applied retrospectively. By randomly re-assigning the treatment group to the actual data for each of the 229 subjects, 20,000 permutation samples were constructed. The permutation P value for at least six favourable trends among nine endpoints in any dose groups was 0.0073 (99.9% CI 0.0053-0.0093). This is higher than would be expected if the endpoints were uncorrelated (0.00026), but much lower than the probability of observing one of nine comparisons significant at the traditional two-sided P <0.05 (0.74). Thus, the result was unlikely due to correlated endpoints or to chance. Examining consistency of effect across multiple clinical endpoints in a proof-of-concept study may identify efficacious therapies and enable dose selection for confirmatory trials. The merit of the approach described requires confirmation through prospective application in designing future studies

Effects of omecamtiv mecarbil on symptoms and health-related quality of life in patients with chronic heart failure: results from the COSMIC-HF study

Background: Chronic HF with reduced ejection fraction (HFrEF) impairs health related quality of life (HRQL). Omecamtiv mecarbil, a novel activator of cardiac myosin, improves left ventricular systolic function and remodeling and reduces natriuretic peptides. We sought to evaluate the effect of omecamtiv mecarbil on symptoms and HRQL in patients with chronic HFrEF and elevated natriuretic peptides enrolled in the COSMIC-HF trial. Methods: Patients (n = 448) were randomized 1:1:1 to placebo, 25 mg of omecamtiv mecarbil twice daily (OM 25 mg), or to pharmacokinetically-guided dose titration (OM-PK) for 20 weeks. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered to assess HRQL at baseline, 16 weeks, and 20 weeks. The primary scores of interest were the Total Symptom Score (TSS), Physical Limitation Scale (PLS), and Clinical Summary Score (CSS). Results: Mean change in score from baseline to 20 weeks for the TSS was 5.0 (95%CI: 1.8-8.1) for placebo, 6.6(95%CI: 3.4-9.8) for OM 25 mg (p = 0.32 vs placebo), and 9.9 (95%CI: 6.7-13.0) for OM-PK (p = 0.03 vs placebo); for the PLS, it was 3.1 for placebo (95%CI: -0.3-6.6), 6.0 (95%CI: 3.1-8.9) for OM 25 mg (p=0.12), and 4.3 (95%CI: 0.7-7.9) for OM-PK (p=0.42); for the CSS, it was 4.1 (95%CI: 1.4-6.9) for placebo, 6.3 (95%CI: 3.6-9.0) for OM 25 mg (p=0.19), and 7.0 (95%CI: 4.1-10.0) for OM-PK (p=0.14). Differences between omecamtiv mecarbil and placebo were greater in patients who were more symptomatic at baseline. Conclusions: HRQL as measured by the TSS improved in patients with HFrEF assigned to omecamtiv mecarbil (OM-PK group) relative to placebo. Ongoing trials are prospectively testing whether omecamtiv mecarbil improves symptoms and HRQL in HFrEF

Decision making in advanced heart failure: A scientific statement from the american heart association

Shared decision making for advanced heart failure has become both more challenging and more crucial as duration of disease and treatment options have increased. High-quality decisions are chosen from medically reasonable options and are aligned with values, goals, and preferences of an informed patient. The top 10 things to know about decision making in advanced heart failure care are listed in Table 1

Decision Making in Advanced Heart Failure: A Scientific Statement From the American Heart Association

Shared decision making for advanced heart failure has become both more challenging and more crucial as duration of disease and treatment options have increased. High-quality decisions are chosen from medically reasonable options and are aligned with values, goals, and preferences of an informed patient

Omecamtiv mecarbil in Black patients with heart failure and reduced ejection fraction: insights from GALACTIC-HF

Background: Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug benefit across race is a key public health topic. Objectives: The purpose of this study was to evaluate the effect of omecamtiv mecarbil among self-identified Black patients. Methods: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) patients with symptomatic HF, elevated natriuretic peptides, and left ventricular ejection fraction (LVEF) ≤35% were randomized to omecamtiv mecarbil or placebo. The primary outcome was a composite of time to first event of HF or cardiovascular death. The authors analyzed treatment effects in Black vs White patients in countries contributing at least 10 Black participants. Results: Black patients accounted for 6.8% (n = 562) of overall enrollment and 29% of U.S. enrollment. Most Black patients enrolled in the United States, South Africa, and Brazil (n = 535, 95%). Compared with White patients enrolled from these countries (n = 1,129), Black patients differed in demographics, comorbid conditions, received higher rates of medical therapy and lower rates of device therapies, and experienced higher overall event rates. The effect of omecamtiv mecarbil was consistent in Black vs White patients, with no difference in the primary endpoint (HR = 0.83 vs 0.88, P-interaction = 0.66), similar improvements in heart rate and N-terminal pro–B-type natriuretic peptide, and no significant safety signals. Among endpoints, the only nominally significant treatment-by-race interaction was the placebo-corrected change in blood pressure from baseline in Black vs White patients (+3.4 vs −0.7 mm Hg, P-interaction = 0.02). Conclusions: GALACTIC-HF enrolled more Black patients than other recent HF trials. Black patients treated with omecamtiv mecarbil had similar benefit and safety compared with White counterparts

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 &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 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

Effects of Omecamtiv Mecarbil on Symptoms and Health-Related Quality of Life in Patients With Chronic Heart Failure

Background: Chronic HF with reduced ejection fraction (HFrEF) impairs health related quality of life (HRQL). Omecamtiv mecarbil, a novel activator of cardiac myosin, improves left ventricular systolic function and remodeling and reduces natriuretic peptides. We sought to evaluate the effect of omecamtiv mecarbil on symptoms and HRQL in patients with chronic HFrEF and elevated natriuretic peptides enrolled in the COSMIC-HF trial. Methods: Patients (n = 448) were randomized 1:1:1 to placebo, 25 mg of omecamtiv mecarbil twice daily (OM 25 mg), or to pharmacokinetically-guided dose titration (OM-PK) for 20 weeks. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered to assess HRQL at baseline, 16 weeks, and 20 weeks. The primary scores of interest were the Total Symptom Score (TSS), Physical Limitation Scale (PLS), and Clinical Summary Score (CSS). Results: Mean change in score from baseline to 20 weeks for the TSS was 5.0 (95%CI: 1.8-8.1) for placebo, 6.6(95%CI: 3.4-9.8) for OM 25 mg (p = 0.32 vs placebo), and 9.9 (95%CI: 6.7-13.0) for OM-PK (p = 0.03 vs placebo); for the PLS, it was 3.1 for placebo (95%CI: -0.3-6.6), 6.0 (95%CI: 3.1-8.9) for OM 25 mg (p=0.12), and 4.3 (95%CI: 0.7-7.9) for OM-PK (p=0.42); for the CSS, it was 4.1 (95%CI: 1.4-6.9) for placebo, 6.3 (95%CI: 3.6-9.0) for OM 25 mg (p=0.19), and 7.0 (95%CI: 4.1-10.0) for OM-PK (p=0.14). Differences between omecamtiv mecarbil and placebo were greater in patients who were more symptomatic at baseline. Conclusions: HRQL as measured by the TSS improved in patients with HFrEF assigned to omecamtiv mecarbil (OM-PK group) relative to placebo. Ongoing trials are prospectively testing whether omecamtiv mecarbil improves symptoms and HRQL in HFrEF

Eligibility of sodium-glucose co-transporter-2 inhibitors among patients with diabetes mellitus admitted for heart failure.

AimsSodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown.Methods and resultsUsing data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities.ConclusionsThe majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies