Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial

AIM Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

[1]  Akshay S. Desai,et al.  Factors Associated With Noncompletion During the Run-In Period Before Randomization and Influence on the Estimated Benefit of LCZ696 in the PARADIGM-HF Trial , 2016, Circulation. Heart failure.

[2]  D. Mozaffarian,et al.  The Seattle Heart Failure Model: Prediction of Survival in Heart Failure , 2006, Circulation.

[3]  P. Ponikowski,et al.  Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long‐Term Registry , 2013, European journal of heart failure.

[4]  Jose H. Flores-Arredondo,et al.  Effect of Ejection Fraction on Clinical Outcomes in Patients treated with Omecamtiv Mecarbil in GALACTIC-HF. , 2021, Journal of the American College of Cardiology.

[5]  K. Anstrom,et al.  Clinical factors related to morbidity and mortality in high‐risk heart failure patients: the GUIDE‐IT predictive model and risk score , 2019, European journal of heart failure.

[6]  D. DeMets,et al.  Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF) , 2020, European heart journal.

[7]  M. Metra,et al.  Medical treatment of heart failure with reduced ejection fraction: the dawn of a new era of personalized treatment? , 2021, European heart journal. Cardiovascular pharmacotherapy.

[8]  P. Ponikowski,et al.  Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC‐HF baseline characteristics and comparison with contemporary clinical trials , 2020, European journal of heart failure.

[9]  Karl Swedberg,et al.  Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. , 2013, European heart journal.

[10]  P. Ponikowski,et al.  Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. , 2020, The New England journal of medicine.

[11]  D. Cox,et al.  Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure , 2011, Science.

[12]  A. Cohen-Solal,et al.  Management of low blood pressure in ambulatory heart failure with reduced ejection fraction patients , 2020, European journal of heart failure.

[13]  J. Ferreira Omecamtiv Mecarbil: a Personalized Treatment for Patients with Severely Impaired Ejection Fraction. , 2021, Journal of the American College of Cardiology.

[14]  J. Rouleau,et al.  Care Gaps in Adherence to Heart Failure Guidelines: Clinical Inertia or Physiological Limitations? , 2020, JACC. Heart failure.

[15]  Akshay S. Desai,et al.  Angiotensin-neprilysin inhibition versus enalapril in heart failure. , 2014, The New England journal of medicine.

[16]  J. Rouleau,et al.  Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. , 2004, Journal of the American College of Cardiology.

[17]  Roberto Ferrari,et al.  Epidemiology and one‐year outcomes in patients with chronic heart failure and preserved, mid‐range and reduced ejection fraction: an analysis of the ESC Heart Failure Long‐Term Registry , 2017, European journal of heart failure.

[18]  V. J. Planelles-Herrero,et al.  Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil , 2017, Nature Communications.

[19]  R. McKelvie,et al.  CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction. , 2021, The Canadian journal of cardiology.

[20]  S. Solomon,et al.  Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF , 2017, European heart journal.

[21]  S. Solomon,et al.  Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF. , 2020, JACC. Heart failure.

[22]  G. Parati,et al.  Multiparametric prognostic scores in chronic heart failure with reduced ejection fraction: a long‐term comparison , 2017, European journal of heart failure.

[23]  S. Solomon,et al.  Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE‐MI): design and baseline characteristics , 2021, European journal of heart failure.

[24]  J. H. Patterson,et al.  Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. , 2018, Journal of the American College of Cardiology.

[25]  R. Wachter,et al.  Impact of systolic blood pressure on the safety and tolerability of initiating and up‐titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study , 2018, European journal of heart failure.

[26]  G. Fonarow,et al.  2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. , 2021, Journal of the American College of Cardiology.

[27]  J. Teerlink,et al.  Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction. , 2017, Handbook of experimental pharmacology.