Omecamtiv Mecarbil use in systolic heart failure- Results of the GALACTIC-HF trial

KEYWORDS:

• Heart failure
• myosin
• Omecamtiv Mecarbil
• GALACTIC-HF Trial

1. Introduction

Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide. It continues to be a significant national and global burden, with a high morbidity rate, mortality rate, and poor quality of life [1]. It has an estimated 30.7 USD billion dollar health-care cost, which includes financial burden of health services, cost of medications to treat HF, and missed work days [2]. About 6.2 million Americans in the United States had HF between 2013 and 2016, and it is anticipated to continue on an upward trajectory as the elderly population continues to increase [3]. Despite significant advances in medicine, the medical treatment of HF in terms of inotropic agents remains limited. The mechanism of heart failure is the impairment of myocardial contractility which consequently leads to poor cardiac output and insufficient oxygenation to remaining organs. Although inotropic agents increase cardiac output, they also accompany considerable complications, including arrhythmia, hypotension, and atrial fibrillation. Omecamtiv Mecarbil (OM) is a cardiac specific myosin activator that has inotropic activity without the consequences of systolic calcium accumulation typically associated with other inotropic agents [4]. OM functions by increasing the proportion of myosin heads which are tightly bound to actin, enhancing cardiac contractility. This novel cardiac drug is currently under investigation for its potential role in the treatment of left ventricular systolic heart failure with reduced ejection fraction (HFrEF). The Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF trial) results have been published and demonstrate the potential significant therapeutic advantage of OM in the clinical treatment and prevention of heart failure.

2. Omecamtiv Mecarbil – unique mechanism of action

Cardiac myocytes contract through a cross bridging cycle between myosin and actin filaments, which is powered by ATP hydrolysis. Myosin binds to ATP, resulting in a weak binding of the complex with actin. Once the ATP is hydrolyzed to ADP, the myosin, actin, and ADP complex becomes tightly bounded. OM is an elective cardiac myosin activator, with no effect on smooth muscle or skeletal muscle myosin. It specifically binds to an allosteric site on the myosin protein leading to conformation changes which hasten the speed of ATP hydrolysis. Consequently, the allosteric binding of OM accelerates the weak binding of actin and myosin to stronger binding, resulting in more myosin bound to actin for a longer period of time. The accumulation of primed myosin heads for a more force generating interaction between myosin and actin during the cardiac cycle results in improved cardiac contraction. Furthermore, there is a noted improvement of systolic function with OM due to prolonged systolic ejection time and stroke volume without an increase in myocyte calcium concentration, velocity of contraction, or heart rate [4,5]. Overall, OM, has a less negative implication on cardiac myocytes when compared to other inotropic agents making OM an advantageous drug of choice for the treatment of HF.

3. GALACTIC-HF trial and results

The future course of treatment and management of HFrEF with OM is greatly influenced by the results of the GALACTIC-HF trial, a large international randomized placebo controlled clinical trial which evaluated the efficacy and safety of the drug. The study enrolled 8,256 patients with symptomatic chronic HFrEF less than <35% or less who were being treated with standard heart-failure therapy [6]. The primary endpoint of the study was a composite of time-to-cardiovascular death or first heart-failure event, whichever was to come first. A heart failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for worsening heart failure that required further treatment beyond a change in oral diuretic therapy. Secondary endpoints include measurement of patient-reported outcomes (Kansas City Cardiomyopathy Questionnaire, KCCQ); cardiovascular death, and all-cause death. The duration of follow up was a median of 21.8 months and mean LVEF of subjects was 27% [6,7]

Results of the trial in terms of primary outcome showed significant reduction in the composite of cardiovascular death or HF event in the OM group when compared to placebo. The primary endpoint occurred in 37.0% of the OM group compared with 39.1% of the placebo group (p = 0.03) [6]. Results further demonstrated that the patients who benefited from OM more significantly were mainly those with LVEF ≤ median. In terms of secondary outcomes, there was not a significant change in any category [5]. The frequency of adverse events, including cardiac ischemic and ventricular arrhythmia was similar in the two groups. There was a decrease in median N-terminal pro–B-type natriuretic peptide level by 10% in the OM group than in the placebo group. A small and asymptomatic increase in troponin was also observed in the OM group, however no clinically evident ischemia was present [6,7].

4. Future prospects of GALACTIC-HF trial

Galactic-HF has served to be a landmark clinical trial, testing the efficacy of increasing cardiac contractility in patients with HFrEF, through a novel mechanism of action. The direct myosin activating mechanism allows it to function as a cardiac inotrope and augment left ventricular systolic function without the complications associated with disturbed calcium homeostasis. Preclinical data have suggested multiple benefits of OM therapy. It can improve cardiac function, increase systolic ejection time, decrease ventricular wall stress, reverse ventricular remodeling, and promote sympathetic withdrawal [8]. The decrease in Pro-BP observed in the GALACTIC-HF trial supports its potential advantageous effects. Vaduganathan M, Claggett B, Packer M, et al. has demonstrated that Pro-BNP decline can be associated with long-term treatment effects on hospitalized patient for HF [9]. In this case, a declining Pro-BNP may very well demonstrate decreased reductions in ventricular wall stress and potential survival benefit. Furthermore, given that OM does not adversely affect blood pressure, heart rate, electrolyte homeostasis, or renal function, it can be readily administered without interfering with the initiation or up-titration of other heart failure medications [10]. This will allow providers to start patients with HFrEF on multiple HF therapies at once, if needed.

A concern that requires further investigation and insight is the elevated troponins observed in the GALACTIC-HF trial. Interestingly, an increase in troponins has also been observed in other OM trials, including the COSMIC trial [4]. As previously noted in the COSMIC trial, increase in troponin occurred among patients taking OM, however, those patients also demonstrated reduced heart rate and improved ventricular volumes. Additionally, no correlation was found between asymptomatic troponin elevation and myocardial ischemia [10]. Similarly, in the GALACTIC-HF trial, the incidences of myocardial ischemia, ventricular arrhythmias, and death were similar in the two trial groups, while the elevation in troponin was asymptomatic [7,10]. Therefore, the small increase of troponin elevation may be a consequent biomarker elevation of OM without clinical adverse effects.

It is important to note that in patients who were tolerating OM, the dose-limiting factor was myocardial ischemia. This was typically seen among patients at plasma concentrations >1,200 ng/ml, and attributed to the prolonged systolic ejection time and reduced systolic filling time, which consequently leads to reduced coronary perfusion and cardiac ischemia [10]. It is anticipated that increased systolic ejection time in the face of coronary artery disease or exercise may cause further worsening of cardiac ischemia among patients taking OM. Smaller studies have shown that OM use during exercise in patients with ischemic cardiomyopathy and angina is safe and well tolerated [11]. Despite evolving research, there is not sufficient evidence to conclusively state that troponin elevation in patients with HF and prolonged systolic ejection fraction is not indicative of cardiac ischemia and is a mere increase in biomarker. In the event that the elevated level of troponin is in fact from cardiac ischemia, OM would be particularly concerning in the outpatient setting. Patients who lack medical literacy or have cognitive decline may accidentally take the incorrect dose of medication in an unsupervised setting which may lead to detrimental outcome. Thus, close follow-up and counseling must be provided to patients taking OM. Furthermore, additional research is imperative to understand the safety profile of OM in high-risk patients.

Overall, the GALATIC HF trial is a large, international, multicenter, placebo-controlled trial with few exclusion criteria. The trial excluded patients with systolic blood pressure <85 mmHg or an estimated glomerular filtration rate <20 ml/min/1.73 m², which ultimately allowed more sick patients to be included in the trial [6]. However, the study excluded patients older than 85 years of age, and those with clinically unstable conditions, including hemodynamic instability requiring mechanical support or intravenous medication [6]. Other limitations were observed in patient population enrolled in the trial. Only 7% of the patients self-reported as black, though this is higher than in any other contemporary international heart failure trial, it is none the less a smaller sample size [12]. Only 21% of the patients were women, and although this is consistent with other heart failure trials, women remain underrepresented. Lastly, while background therapy for most patients was generally excellent, however, only 20% of patients were receiving sacubitril–valsartan at baseline and only 2.5% were receiving a sodium–glucose cotransporter 2 inhibitor [6,12]. Therefore, it is unclear what treatment benefit OM would add in addition to these medications. Parallel studies conducted for a longer period of time modeling the GALACTIC-HF trial and including a wider range of patient population would further clarify the efficacy and side effect profile of OM.

5. Conclusion

With ongoing research and advances in science and technology, myosin activating class of medications may prove to play a pivotal role in the management of heart failure. Thus far, OM has not shown to be a liability. It has not limited the use of current HF therapies, and has shown any negative outcome in terms of hemodynamics and electrolyte imbalance. Furthermore, the changes in ventricular volumes and natriuretic peptides are supportive of a potential survival benefit. However, further insight is still needed to fully understand the scope of treatment offered by OM and its potential adverse effects. Hopefully in the near future, after further research and investigation, the results of the GALACTIC-HF trial will soon be implemented in international guidelines.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. This paper was not funded.