Cardiac Myosin Activation for the Treatment of Systolic Heart Failure

Abstract

Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. Additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

Introduction

Left ventricular systolic dysfunction is the hallmark pathology of heart failure with reduced ejection fraction.¹ Beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, and levosimendan, an inodilator with calcium-sensitizing and phosphodiesterase-3-inhibitory effects, have all previously been studied as potential therapies to increasing left ventricular contractility in heart failure with reduce ejection fraction.² Broadly, agents in this family either increase the risk of adverse clinical outcomes or have neutral effects in patients with chronic heart failure.³ While altered calcium handling has been proposed as the mechanism underlying life-threatening arrhythmias associated with these agents, the increased mortality observed with inotropes such as vesnarinone, a weak phosphodiesterase-3 inhibitor, and flosequinan, which lacks effect on beta-adrenergic signaling and phosephodiesterase-3, indicate that current understanding of cardiac inotropy and clinical outcomes remains incomplete and suggests that avoidance of alterations in calcium handling per se does not indicate safety. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors remain an important option not only for patients with acute cardiogenic shock but also for those with Stage D advanced chronic heart failure either as definitive palliative therapy or as a bridge to transplantation or mechanical circulatory support.

A new class of therapeutics, cardiac myotropes, directly target the sarcomere to enhance left ventricular systolic performance.² Two agents from this broad class, omecamtiv mecarbil and danicamtiv, have begun to demonstrate promising efficacy and safety in pre-clinical and early stage clinical studies.^4,5 Omecamtiv mecarbil and danicamtiv promote cardiac myosin activation without modulating cardiomyocyte calcium handling and potentially without adverse effects on myocardial energetic efficiency. Herein, we review the pharmacology of omecamtiv mecarbil and danicamtiv, their proposed effects on human cardiac structure and function and their potential role in the treatment of heart failure with reduced ejection fraction.

Pharmacology of Cardiac Myosin Activators

Omecamtiv mecarbil (AMG-423, CK-1827452) increases cardiomyocyte contractility by enhancing cardiac myosin ATP hydrolysis (Figure 1).^6–9 Omecamtiv mecarbil binds to the base of the lever arm of cardiac myosin, which stabilizes the myosin head in the pre-powerstroke state and lowers the energy barrier for release of phosphate from the ADP-myosin-actin complex. Omecamtiv mecarbil thus increases the proportion of myosin heads primed for the force-generating powerstroke. Danicamtiv exerts similar effects on cardiac myosin.⁵

Figure 1. Mechanism of Action of Cardiac Myosin Activators.

(1) Omecamtiv mecarbil (data shown) and danicamtiv (data not shown) selectively increase ATP hydrolysis in cardiomyocytes. (2) Cardiac myosin activators increase the number of myosin-actin interactions. (3) Myosin cycles through a series of unbound (Step 1), weakly bound (Steps 2 and 3) and strongly bound (Steps 4 and 5) interactions with actin. Beginning with Step 1, unbound myosin hydrolyzes ATP to ADP+P, which enables weak binding to actin (Step 2). Subsequent release of phosphate from the myosin-ADP-P complex (Step 3) initiates a strong bond between myosin and actin (Step 4). Phosphate release also induces a conformational change in myosin that produces a 10-nm stroke (Step 5). ATP binding to myosin causes dissociation from the strongly bound state (Step 6). Cardiac myosin activators stabilize actin-myosin cross-bridge formation. As a result, a greater number of myosin heads are capable of strong bonding to actin (increased duty ratio). Cardiac myosin activators thus overcome the rate-limiting step of actin-myosin cross-bridge formation, which is the conversion of the weakly bound cross-bridge to a strongly bound cross-bridge through release of phosphate from the myosin-ADP-P complex (Step 4).

Omecamtiv mecarbil possesses good oral bioavailability, minimal extravascular distribution and low potential for clinically relevant drug-drug interactions. After intravenous infusion, the max plasma concentration of omecamtiv mecarbil increases in a dose-proportional manner with a half-life of 17 to 21 hours and a volume of distribution of 3.7 to 5.2 L/kg, consistent with minimal extravascular distribution.¹⁰ A modified release formulation provides oral bioavailability of at least 75% while allowing consistent steady state concentrations with twice daily dosing.¹¹ Ketoconazole, a strong inhibitor of CYP3A4, increased omecamtiv mecarbil area-under-the-curve by 30% to 50% in healthy volunteers with varying CYP3A4 phenotypes.¹² Diltiazem, a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, had no effect on omecamtiv mecarbil exposure or max concentration. There are no published studies on the effects of renal or hepatic dysfunction on omecamtiv mecarbil pharmacokinetics.

Omecamtiv mecarbil clinical trials have studied both intravenous and oral routes of administration as well as fixed-dose and dose-adjusted regimens. The therapeutic range of omecamtiv mecarbil plasma concentration appears to be 200–1000 ng/mL.

Little has been reported about danicamtiv pharmacokinetics. In a phase 2 dose-ranging clinical trial, escalating doses of danicamtiv 50 mg twice daily, 75 mg twice daily and 100 mg twice daily for 9 days led to mean trough concentrations of 2096 ng/mL, 2930 ng/mL and 4694 ng/mL, respectively, and mean maximal concentrations of 2735 ng/mL, 3862 ng/mL and 5560 ng/mL, respectively. Pharmacokinetic data on oral bioavailability, volume of distribution, metabolism and excretion of danicamtiv remain unpublished.

Cardiovascular Effects of Cardiac Myosin Activators in Heart Failure with Reduced Ejection Fraction

Omecamtiv mecarbil and danicamtiv each prolong left ventricular systolic ejection time (Supplementary Table 1). Compared to placebo, omecamtiv mecarbil significantly increased left ventricular systolic ejection time by 11 ms for a fixed dose 25 mg twice daily regimen and by 25 ms for a dose-adjusted regimen targeting at least plasma drug concentrations of at least 200 ng/mL at 20-weeks in stable patients with heart failure with reduced ejection fraction.¹² Additionally, omecamtiv mecarbil significantly increased left ventricular stroke volume, fractional shortening and ejection fraction (Figure 2).

Figure 2. Effect of Omecamtiv Mecarbil on Left Ventricular Structure and Function in Patients with Heart Failure with Reduced Ejection Fraction.

Omecamtiv mecarbil improves left ventricular systolic function and promotes reverse remodeling in patients with heart failure with reduced ejection fraction.

In a phase 2 dose-ranging clinical trial, danicamtiv increased placebo-corrected left ventricular systolic ejection time by 15 ms for < 2000 ng/mL, 36 ms for 2000 to < 3500 ng/mL and 48 ms for ≥ 3500 ng/mL.⁵ Although danicamtiv did not have a statistically significant effect on left ventricular ejection fraction, it increased left ventricular stroke volume, global longitudinal strain and global circumferential strain (Supplemental Figure 1).

Cardiac myosin activators also may affect left atrial function. Danicamtiv increased left atrial emptying fraction, left atrial minimum volume index and left atrial functional index in patients with heart failure with reduced ejection fraction in a dose-dependent manner (Figure 3).⁵ By contrast, a 72-hour infusion of omecamtiv mecarbil had no significant effects on left atrial functional index or emptying fraction in healthy male volunteers.¹⁰

Figure 3. Effect of Danicamtiv on Left Atrial Structure and Function in Patients with Heart Failure with Reduced Ejection Fraction.

Patients with heart failure with reduced ejection fraction were randomized in a 3:1 ratio to receive danicamtiv (50 mg, 75 mg or 100 mg twice daily) or placebo for 7 days. Placebo-corrected differences in left atrial structure and function are depicted for the pooled danicamtiv group according to mean danicamtiv plasma concentration (< 2000 ng/mL, 2000 to <3500 ng/mL, ≥3500 ng/mL).

Excessive prolongation of systolic ejection time may decrease diastolic filling time or impair diastolic function. At concentrations less than 3500 ng/mL, danicamtiv had no effect on lateral E/e’ ratio, lateral e’, peak mitral inflow velocity during early diastole (E-wave) or isovolumetric relaxation time.⁵ At concentrations greater than 3500 ng/mL, danicamtiv significantly increased isovolumetric relaxation time, lateral e’, decreased peak mitral inflow velocity during early diastole and prolonged the isovolumetric relaxation time (Supplemental Figure 2). In patients with heart failure with reduced ejection fraction, intravenous infusion of omecamtiv mecarbil decreased peak mitral inflow velocity during early diastole, increased peak mitral inflow velocity during late diastole, prolonged late diastole (as measured by A wave duration) and increased e’, with a trend towards increased E/e’ ratio in a dose-dependent manner.¹³

Omecamtiv mecarbil decreased NT-proBNP concentration compared to placebo in patients with stable chronic heart failure (fixed-dose: −822 [−1516 to −127] pg/mL, P=0.02; dose-adjusted: −970 [−1672 to −268] pg/mL, P=0.007), but not in decompensated, heart failure with reduced ejection fraction.^12,14

Omecamtiv mecarbil decreases heart rate at plasma concentrations greater than 200 ng/mL (−2 [−3.6 to −4] beats per minute for concentrations of >200 to 300 ng/mL and −2.3 [−3.9 to −0.6] beats per minute for concentrations of >300 to 787 ng/mL) and increases systolic blood pressure at concentrations greater than 300 ng/mL (+2.4 [0.6 to 4.2] mm Hg).¹⁴ By contrast, danicamtiv is reported to decrease systolic blood pressure and have no effect on diastolic blood pressure or heart rate.⁵

Omecamtiv mecarbil has been studied in patients with chronic heart failure as well as those with decompensated heart failure. Although the intravenous formulation of omecamtiv mecarbil is not under active phase 3 investigation, the ongoing GALACTIC-HF study of oral omecamtiv mecarbil enrolled both stable outpatients and patients hospitalized for heart failure.

Cardiac Myosin Activators, Myocardial Ischemia and Elevated Serum Troponin Concentrations

Omecamtiv mecarbil was associated with dose-dependent myocardial ischemia in phase 2 clinical trials, including ST segment depression, chest pain and elevated cardiac enzymes.^10,13 Omecamtiv mecarbil plasma concentrations generally exceeded 1250 ng/mL in patients with evidence of treatment-related myocardial ischemia.

In the ATOMIC-AHF trial of patients with decompensated heart failure with reduced ejection fraction, asymptomatic ST segment and/or T wave changes occurred in 2 patients who received the 48-hour omecamtiv mecarbil infusion (maximal omecamtiv mecarbil plasma concentration of 273 ng/mL in one patient and unavailable in the other). Two patients with a history of angina experienced nitrate-responsive exertional angina while walking to the bathroom (maximal omecamtiv mecarbil plasma concentrations of 450 ng/mL and 709 ng/mL). Two patients were hospitalized for myocardial infarction on days 11 and day 22, respectively. One of these patients underwent routine coronary angiography to evaluate heart failure etiology, which revealed severe 3-vessel coronary artery disease. This patient suffered a percutaneous coronary intervention-related myocardial infarction during this procedure.

The median changes in cardiac troponin I for the omecamtiv mecarbil and placebo arms in ATOMIC-AHF were 0.000 ng/mL (−0.017 to 0.12) ng/mL and −0.004 ng/mL (interquartile range, −0.17 to 0.001 ng/mL), respectively, at 48-hours. Cardiac troponin I change did not differ between high-dose omecamtiv mecarbil and placebo patients and did not correlate with omecamtiv mecarbil maximal plasma concentration, plasma concentration at 48-hours or changes in systolic ejection time. Maximum change in left ventricular systolic ejection time within 48 hours of baseline did not associate with maximum change in in cardiac troponin I within 48 hours of baseline (R = 0.03; P=0.88).

By contrast, cardiac troponin I concentration increased modestly in each omecamtiv mecarbil arm of the 20-week COSMIC-HF trial (fixed-dose: 0.001 [0 to 0.012] ng/mL; dose-adjusted: 0.006 [0 to 0.024] ng/mL), but remained unchanged in the placebo arm. Myocardial infarction occurred in one patient in the dose-adjusted omecamtiv mecarbil arm and one patient in the placebo arm. One patient in the fixed dose omecamtiv mecarbil arm experienced unstable angina and non-myocardial infarction, anginal chest pain occurred in one, two and two patients in the placebo, fixed-dose omecamtiv mecarbil and dose-adjusted omecamtiv mecarbil arms, respectively.

A study of 94 patients with ischemic cardiomyopathy and stable angina who received a 20-hour infusion of omecamtiv mecarbil supports the short-term tolerability of this agent in high-risk patients, provided therapeutic concentrations can be maintained.¹⁵ The number patients who stopped exercise for angina or for any reason at a stage earlier than baseline was not significantly different between low-dose intravenous omecamtiv mecarbil (C_max target of 295 ng/mL), high-dose intravenous omecamtiv mecarbil (C_max target of 550 ng/mL) or placebo. A 1-mm ST-segment depression during exercise occurred in 2 of 7 evaluable placebo patients as compared to 1 of 22 evaluable omecamtiv mecarbil patients.

The danicamtiv clinical development program has contributed additional information about cardiac myosin activators and myocardial ischemia. Among 30 patients with heart failure with reduced ejection fraction who received danicamtiv for 7 days, asymptomatic cardiac troponin I elevation occurred in 7 (23%).⁵ One patient enrolled in a single-dose trial of danicamtiv reported dyspnea and chest discomfort and had a troponin I increase from less than 0.03 ng/mL to 0.12 ng/mL at 24-hours in the absence of ischemic electrocardiographic changes.

The mechanisms of cardiac myosin activator-related myocardial ischemia remain incompletely understood. Changes in systolic ejection time do not correlate with cardiac troponin concentrations in omecamtiv mecarbil-treated patients, which argues against decreased diastolic filling time as a potential mechanism. Interpretation of isolated cardiac troponin elevations without clinical signs or symptoms of ischemia remains a challenge. The subgroup of GALACTIC-HF participants with coronary artery disease (60% of participants) will provide important insight into the long-term safety of omecamtiv mecarbil in patients at high risk for drug-induced myocardial ischemia.

Omecamtiv Mecarbil and Therapeutic Drug Monitoring

The cardiovascular effects of omecamtiv mecarbil, as well as the risk of myocardial ischemia, link closely to plasma concentrations. Omecamtiv mecarbil plasma concentration and dose correlate significantly with left ventricular systolic ejection time in patients with decompensated heart failure with reduced ejection fraction and healthy volunteers.^10,13 Significant increases in left ventricular systolic ejection time, stroke volume and ejection fraction, as well as reductions in end-systolic and end-diastolic volumes, were not observed until omecamtiv plasma concentrations exceeded 100–200 ng/mL in patients with heart failure with reduced ejection fraction, although such effects were apparent at lower concentrations in health volunteers.¹³

Therapeutic drug monitoring appears to improve the probability of achieving therapeutic omecamtiv mecarbil drug concentrations in patients. COSMIC-HF compared achievement of omecamtiv mecarbil plasma concentrations greater than 200 ng/mL between a fixed-dose regimen of 25 mg orally twice daily and a dose-adjusted regimen. The omecamtiv mecarbil dose was increased to 50 mg twice daily at week 8 if plasma drug concentration was less than 200 ng/mL at week 2. While only 46% of patients in the fixed-dose arm achieved a plasma drug concentration greater than 200 ng/mL, 87% in the pharmacokinetic-guided arm achieved a therapeutic drug concentration. The highest plasma omecamtiv mecarbil concentration in the pharmacokinetic-guided arm was 831 ng/mL and no other patients had a concentration greater than 750 ng/mL. Thus, therapeutic drug monitoring of omecamtiv mecarbil may ensure both efficacy and safety.

GALACTIC-HF modified the COSMIC-HF dose adjustment algorithm to include a 37.5 mg twice daily dose, drug discontinuation for plasma concentrations greater than or equal to 1,000 ng/mL and a second plasma drug concentration measurement to verify and/or decrease the dose (Figure 4). Most important, GALACTIC-HF will provide the opportunity to assess the relationship between plasma drug concentration and clinical outcomes, such as cardiovascular death, heart failure hospitalization and myocardial infarction.

Figure 4. Pharmacokinetic-Guided Omecamtiv Mecarbil Titration in GALACTIC HF.

The randomized, double-blind, placebo-controlled, phase 3 GALACTIC HF clinical trial uses a pharmacokinetic-guided dosing algorithm to achieve omecamtiv mecarbil plasma concentrations within the purported therapeutic range.

The potential Food and Drug Administration assessment of therapeutic drug monitoring with omecamtiv mecarbil remains uncertain. Clinics and hospitals will need to implement in-house assays or collaborate with outside commercial or non-profit entities to ensure access to omecamtiv mecarbil drug concentration monitoring.

Omecamtiv Mecarbil and Clinical Outcomes: GALACTIC-HF in Context

GALACTIC-HF is a randomized, double-blind, placebo-controlled, event-driven clinical trial that will compare the effect of oral omecamtiv mecarbil and placebo on the primary composite endpoint of cardiovascular death and heart failure hospitalization.^4,16 Patients (N=8,256) with heart failure with reduced ejection fraction (≤35%) were eligible if they were currently hospitalized for heart failure or had a heart failure decompensation requiring hospitalization or urgent emergency department visit within the prior 1 year. In the omecamtiv arm, dose adjustments were made to achieve a trough plasma concentration of 200 to 1,000 ng/mL (Figure 4). Although the primary endpoint of GALACTIC-HF will be the composite of cardiovascular death or heart failure hospitalization, this event-driven study continued enrollment until 1,590 cardiovascular deaths accumulated, thus providing 90% power to detect a hazard ratio of 0.80 for cardiovascular death and >99% to detect a hazard ratio of 0.80 for the primary composite endpoint.

GALACTIC-HF implemented several unique clinical trial approaches that not only represent important advances in the field of heart failure clinical trials but also will inform the potential clinical use of this therapy (Table). First, both currently (25% or 2,100 participants) and recently hospitalized (75% or 6,156 participants) patients were eligible for participation. Initiation of medical therapies during hospitalization improves adherences and provides the opportunity for close monitoring of high-risk patients.^17–20 Omecamtiv mecarbil lacks the hemodynamic adverse effects of other guideline-directed medical therapies and may be more amenable to inpatient initiation. GALACTIC-HF will allow comparison of in-hospital and ambulatory initiation of omecamtiv mecarbil.

Table.

Comparison of Landmark Heart Failure Clinical Trials in the 21^st Century

	PARADIGM-HF		DAPA-HF		VICTORIA		GALACTIC-HF
	Enalapril (n= 4212)	Sacubitril-Valsartan (n=4187)	Placebo (n= 2371)	Dapagliflozin (n= 2373)	Placebo (n= 2524)	Vericiguat (n= 2526)	All Participants (N=8256)
LVEF requirement	≤35%*	≤35%*	≤40%	≤40%	≤45%	≤45%	≤35%
Mean LVEF	29%	30%	31%	31%	29%	29%	27 (6)
Prior HF hospitalization	63%	62%)	48%	47%	84%	84%	Currently hospitalized: 2100
Prior IV diuretics for HF	Not reported	Not reported	Not reported	Not reported	16%	16%	Recently hospitalized: 6156
NT-proBNP threshold	≥ 400 –600 pg/mL		≥ 400 – 900 pg/mL		≥ 1,000 –1,600 pg/mL		≥ 400–1,200 pg/mL
Median NT-proBNP	1594 pg/mL	1631 pg/mL	1446 pg/mL	1428 pg/mL	2816 pg/mL	2816 pg/mL	2134 pg/mL
BNP threshold	≥ 100–150 pg/mL		Not reported		≥ 300 –500 pg/mL		≥ 125 – 375 pg/mL
Median BNP	251 pg/mL	255 pg/mL	Not reported	Not reported	Not reported	Not Reported	Not Reported
NYHA Class	II, III, IV		II, III, IV		II, III, IV		II, III, IV
eGFR cutoff	< 30 mL/min per 1.73 m2		< 30 mL/min per 1.73 m2		< 15 mL/min per 1.73 m2		< 20 mL/min per 1.73 m2
Mean eGFR	SCr = 1.12 mg/dL	SCr = 1.13 mg/dL	66 mL/min per 1.73 m2	64 mL/min per 1.73 m2	61	62	59
Mean or median follow-up	27 months	27 months	18.2 months	18.2 months	10.8 months	10.8 months	TBD
CV death or HF hospitalization	1117 (26.5%)	914 (21.8%)	495 (20.9%%)	382 (16.1%)	972 (38.5%)	897 (35.5%)	TBD
HF hospitalization	835 (15.6%)	537 (12.8%)	318 (13.4%)	231 (9.7%)	747 (29.6%	691 (27.4%)	TBD
CV death	693 (16.5%)	558 (13.3%)	273 (11.5%)	227 (9.6%)	225 (8.9%)	206 (8.2%)	TBD
Any death	835 (19.8%)	711 (17.0%)	329 (13.9%)	276 (11.6%)	285 (11.3%)	266 (10.5%)	TBD

BNP = B-type natriuretic peptide; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; IV = intravenous; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal B-type natriuretic peptide

Second, GALACTIC-HF targeted a high-risk population by requiring elevated natriuretic peptide levels and either a current or prior worsening heart failure event. Event rates in the VICTORIA trial, which enrolled patients with elevated natriuretic peptide levels and a worsening heart failure event within the prior 6 months, were significantly higher than those observed in PARADIGM-HF or DAPA-HF, which required an elevation in natriuretic peptide level but not a recent worsening heart failure event.^21–23 Additionally, the upper limit of left ventricular ejection fraction of 35% in GALACTIC-HF is lower than VICTORIA (45%), DAPA-HF (40%) and the original PARADIGM threshold (40%, lowered to 35% after an amendment). The mean left ventricular ejection fraction in GALACTIC-HF of 27% is lower than PARADIGM-HF (30%), DAPA-HF (31%) and VICTORIA (29%). The median NT-proBNP concentration in non-hospitalized GALACTIC-HF patients (1958 [1027–3959] pg/mL) exceeds that in PARADIGM-HF (approxiately 1,600 pg/mL) and DAPA-HF (approximately 1,400 pg/mL), which enrolled stable outpatients. The median NT-proBNP of the hospitalized subgroup in GALACTIC-HF is similar to that in VICTORIA (2799 [1381–5609] pg/mL vs. 2816 pg/mL).

Third, GALACTIC-HF implemented therapeutic drug monitoring of omecamtiv mecarbil using trough plasma concentrations, a practice developed in earlier phase 2 clinical trials. By contrast, VICTORIA titrated vericiguat to the maximally tolerated dose using systolic blood pressure and clinical symptoms, DAPA-HF used a fixed dose of dapagliflozin (with dose reduction if needed for tolerability) and PARADIGM-HF used a run-in period to ensure tolerability. Digoxin is the only heart failure therapy that requires drug concentration monitoring, albeit for safety considerations alone.

Last, GALACTIC-HF will test the addition of omecamtiv mecarbil to background therapy with an ACE inhibitor, angiotensin receptor blocker or sacubitril-valsartan (87% of all participants), beta-blocker (95% of all participants), mineralocorticoid receptor antagonist (78% of all participants) and an implantable cardioverter defibrillator or cardiac resynchronization therapy (34%). As omecamtiv mecarbil lacks effect on blood pressure, serum potassium and renal function, it could be well-tolerated and complementary to neurohormonal blockers. While SGLT2 inhibitors also lack effect on potassium excretion, they have modest blood-pressure lowering effects and may induce short-term renal hemodynamic alterations that decrease glomerular filtration rate (although they exert reno-protective effects in the long-term).^24,25 Vericiguat and sacubitril-valsartan increase intracellular cyclic guanosine monophosphate through separate mechanisms (soluble guanylate cyclase activation and natriuretic peptide receptor activation, respectively). The efficacy of vericiguat did not differ according to background sacubitril-valsartan use in VICTORIA, although the number within the sacubitril-valsartan subgroup was small (n=287).

Conclusions

Phase 2 clinical trials have demonstrated that omecamtiv mecarbil and danicamtiv improve left ventricular systolic function in patients with heart failure with reduced ejection fraction. An ongoing phase 3 clinical trial, GALACTIC-HF, will determine the potential role of cardiac myosin activation in the therapeutic armamentarium for chronic heart failure with reduced ejection fraction. Further studies are warranted in patients with advanced heart failure refractory to guideline-directed heart failure therapies and those with cardiogenic shock.