Nowadays, heart failure therapy is based on some pharmacological pillars, represented by ACE inhibitors, angiotensin receptor antagonists, beta blockers and diuretics. These treatments have largely replaced the use of an historic inotropic drug, digitalis, thus leaving this type of approach to the disease uncovered.
However, in the last years new inotropic drugs, capable of activating cardiac myosin, improving the function of sarcomeres, and increasing myocardial function, have been developed and tested.
The best known of these new drugs is omecamtiv mecarbil. By selectively binding to cardiac myosin, this molecule increases the number of sites that can bind to the actin filament, thus increasing the contraction force of myocardium in systole.
Current inotropic therapies work by increasing cardiac contraction force through a modulation of cellular calcium, such as digoxin, or a stimulation of adrenergic receptors.
However, these mechanisms are associated with adverse effects, such as an increase in myocardial oxygen consumption and desensitization of the adrenergic receptors.
As we said, omecamtiv mecarbil acts in a completely different way. This new drug works by activating myocardial ATPase, improving the formation and durability of actin and myosin bridges.
More precisely, this molecule increases the rate of release of phosphate from myosin, thereby accelerating the speed of the transition of the actin-myosin complex from the weakly bound state to the strongly bound state.
Furthermore, omecamtiv mecarbil causes myosin to remain bound to actin considerably longer.
These processes lead to an increase in myocardial contraction force, which can be objectified in an increase in the ventricular systolic ejection time and in the ejection fraction.
At the same time, omecamtiv mecarbil does not increase myocardial oxygen consumption.
Several clinical studies have shown that this drug, administered intravenously, is able to improve cardiac performance in the short term.
Once the effectiveness of omecamtiv mecarbil had been defined from the point of view of cardiac performance, it remained to be clarified whether this drug was also able to reduce mortality and cardiovascular events in patients with heart failure.
The GALACTIC-HF study tried to answer these questions. Its results were presented during the virtual congress 2020 of the American Heart Association, and simultaneously published in the New England journal of Medicine.
In the GALACTIC-HF study, 8,256 patients with symptomatic chronic heart failure and an ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo.
The dosage of the active drug was modulated based on pharmacokinetics, varying in doses from 25 mg, 37.5 mg or 50 mg twice daily. In addition to the experimental treatment, all patients also received the best usual therapy for heart failure.
The primary endpoint of the study was a composite of a first event of heart failure or death from cardiovascular causes. A heart failure event was defined as an urgent clinical visit, emergency room visit, or hospitalization for subjective and objective worsening of heart failure, with intensification of treatment plus a change in oral diuretic therapy.
Secondary endpoints were cardiovascular death, change in Kansas City Cardiomyopathy Questionnaire Total Score, from baseline to week 24, first hospitalization for heart failure, and death from any cause.
The median follow-up of the study was 21.8 months. In this time interval, the primary endpoint occurred in 37% of patients treated with omecamtiv mecarbil and in 39.1% of those assigned to placebo.
Deaths from cardiovascular causes occurred in similar proportions in the two groups, affecting 19.6% and 19.4% of patients, respectively.
No significant difference in the changes in scores obtained on the Kansas City cardiomyopathy questionnaire was showed.
At week 24, compared to the baseline assessment, NT-proBNP was reduced by 10% more in the group of patients on active treatment, compared to the placebo group. Heart rate was slightly lower in the omecamtiv mecarbil group compared to the placebo group at the two time points analyzed.
This new study, therefore, seems to complete the picture of the advantages offered by omecamtiv mecarbil in a positive way. The improvement in cardiac function is also associated with a reduction in a particularly relevant composite endpoint such as the one evaluated in this study.
Even if from the point of view of symptoms, the treatment does not seem to provide significant improvements, the reduction of important events such as worsening of heart failure and cardiovascular mortality are objectives of great importance.
Already in May of this year, the Food and Drug Administration granted a fast-track designation for omecamtiv mecarbil. Therefore, we can expect that this new treatment will be available very soon to be used in the treatment of patients with heart failure and reduced ejection fraction.
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