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

Effects of the lercanidipine - Enalapril combination vs. The corresponding monotherapies on home blood pressure in hypertension: Evidence from a large database

103siObjective: To compare a combination of a dihydropyridine calcium-channel blocker with an angiotensin converting enzyme inhibitor vs. monotherapy with one or the other drug and placebo for their effects on home blood pressure (HBP). Methods: After a 2-week placebo wash-out, patients with an elevated office blood pressure (BP) (diastolic 100–109 and systolic <180 mmHg) and HBP (diastolic 85 mmHg) were randomized double-blind to a 10-week treatment with placebo, lercanidipine, 10 or 20mg daily, enalapril, 10 or 20mg daily, or the four possible combinations. In addition to office BP, HBP was self-measured via a validated semiautomatic device twice in the morning and twice in the evening during the 7 days before randomization and at the end of treatment. Baseline and treatment HBP values were separately averaged for each day, morning, evening or the whole monitoring period, excluding the first day. Day-by-day HBP variability was defined as the SD or the variation coefficient of the daily BP averages. Results: Eight hundred and fifty-four patients with valid HBP recordings at baseline and at the end of treatment were analyzed (intention-to-treat population). From the baseline value (147.011.6 mmHg) systolic/diastolic HBP showed a small reduction (average baseline-adjusted change: –1.8/–1.6 mmHg) with placebo, a more marked significant fall with monotherapies (8.8/5.9 mmHg, P<0.001/<0.001 vs. placebo) and even more with combination treatment (11.6/7.6 mmHg, P<0.001/ <0.001 vs. placebo and P<0.01/<0.05 vs. monotherapy). A similar pattern was observed for each of the days of the BP self-monitoring period as well as for either morning or evening values, although the difference between mono and combination treatment appeared to be consistently significant for the morning values only. Dayby- day systolic BP-SD was unaffected by placebo and slightly reduced by drug treatments, with no, however, significant changes in SBP-variation coefficient. Baseline and end of treatment HBP values showed a limited correlation with office BP values, this being particularly the case for treatment-induced changes (correlation coefficients: 0.37 for systolic and 0.45 for diastolic BP). Conclusion: This large HBP database shows that the lercanidipine–enalapril combination lowers HBP more effectively than the corresponding monotherapies and placebo, and that this greater effect is consistent between days.reservedmixedMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek-Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza-Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka-Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk-Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, ValeriiMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, Valeri

Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND: Type 1 diabetes is characterised by progressive loss of functional beta-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve beta-cell function) could enable beta-cell survival with a reduced risk of complications compared with traditional immunomodulation.METHODS: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual beta-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155.FINDINGS: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (&lt;10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema).INTERPRETATION: The combination of anti-IL-21 and liraglutide could preserve beta-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme.FUNDING: Novo Nordisk

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.)