[Medscape] Reduced stroke with myosin activator in patients with heart failure EF reduced: GALACTIC-HF


Some patients with heart failure with reduced ejection fraction (HFrEF) do not respond well enough to treatment even with “quartet therapy” – a combination of drugs from four separate classes Recommended as a first-line drug to start early after diagnosis. Another class of drugs, considered second-line, or third-line, in such cases, may confer a new side benefit, in addition to the main effect on mortality or on adverse events. HFrEF was seen in a large phase 3 study.

An experimental drug, omecamtiv mecarbil (Cytokinetics), may also reduce the risk of fatal or nonfatal stroke in these patients, suggests a new secondary analysis of the GALACTIC-HF trial. , this trial randomized both inpatients and outpatients with chronic disease.

In part, stroke treatment may be the result of another study finding that reduces the risk of new-onset atrial fibrillation or flutter (AF/AFl) in patients for whom the drug is indicated, described as: a myosin activator.

The results confirm omecamtiv mecarbil as “An exciting and potential new approach to reducing stroke risk in HFrEF patients” – John R. Teerlink, MD, University of California San Francisco and Medical Center The San Francisco VA said it will present the results Nov. 13 during the Virtual American Heart Association (AHA) 2021 Scientific Sessions.

“If there’s one thing I think is the most exciting part, that’s it,” Teerlink told theheart.org/Medscape Cardiology. Patients who develop atrial fibrillation will take oral anticoagulants, “but if there is a way to improve their stroke risk without the need for anticoagulation, that is really exciting to me.” guide.”

These findings are not necessarily conclusive; Although stroke is well defined and declared in the GALACTIC-HF, these findings are not part of the primary endpoint, Teerlink said.

“Omecamtiv mecarbil should not be part of the four drug classes,” he said. It doesn’t save lives” – involves quartet therapy, which includes an angiotensin-neprilysin receptor blocker (ARNI), beta blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor.

But there is enough evidence to say that omecamtiv mecarbil (if it’s approved) “should be added in patients with left ventricular ejection fraction less than 35%, who are on treatment, or are about to take four classes of drugs.” , he said. “I think omecamtiv mecarbil is appropriate for first-line use of second-line drugs.”

Reducing stroke rates makes sense.

As previously reported, patients assigned to the GALACTIC-HF trial showed a small but significant (8%) reduction in the risk of heart failure-related events or cardiovascular death. for a median of 22 months for the primary endpoint of the trial.

In the present analysis, people taking omecamtiv mecarbil also benefited from a 35% reduction in the risk of a fatal or nonfatal first stroke, compared with a control group; The risk of fatal stroke decreased by 44%.

As observed by Stephen J. Greene, MD, Duke Clinical Research Institute, Durham, North Carolina, the findings are “significant” when otherwise clear effects of the drug were observed in its trials. , including new-onset AF/AFl reduction and signs of remodeling reversal.

“I think the jury is still out and more research is needed to back up the issue of stroke mitigation,” he said when interviewed. But at least that sounds like a very good sign.”

Greene, who was not a co-author of the GALACTIC-HF report, said: “Stroke has a very strong association with heart failure, “and is not something that has received much attention in heart failure trials,” said Greene. “. So, for omecamtiv mecarbil, it is at least “proud to be able to say that you can reduce your risk of stroke.”

One major limitation is that the results of the current analysis were not pre-calculated, Martha Gulati, MD, University of Arizona, Phoenix noted with theheart.org/Medscape Cardiology. But “If the findings of GALACTIC HF are confirmed in large, prospective randomized controlled trials, then the drug will make a significant addition to medical therapy according to the HFrEF Guidelines.

Multi-effects can contribute

Stroke treatment was observed to be associated with fewer new-onset AF/AFl in the GALACTIC-HF trial, possibly also due to the reversal of ventricular remodeling with omecamtiv mecarbil demonstrated in the study. and in previous ATOMIC-AHF and COSMIC-HF tests. It has also been suggested that the drug improves ejection fraction, diuretic sodium peptide levels, and sympathetic conduction.

Gulati notes: “The decrease in atrial rate is probably the primary mechanism, but heart failure is a prothrombotic state even in the absence of [rung nhĩ]. Thus, the reduction in stroke risk may also derive independently of the observed structural and physiological changes.

Omecamtiv mecarbil enhances ventricular contractile force by stabilizing myosin to its pre-work state, which increases the amount of myosin primer that can bind to actin filaments, a mechanism distinct from active inotropes through often.

It’s not approved anywhere but is likely under review by US regulators or about to be reviewed after more than a decade of promising phase 2 and 3 clinical trials.

GALACTIC-HF enrolled 8256 patients on standard drug therapy for chronic HFrEF and left ventricular ejection fraction (LVEF), no higher than 35% who had been hospitalized or hospitalized in the past year or had to go to the emergency department. save for heart failure. About 53% in grade 2, 44% in grade 3 and the rest in grade 4 (NYHA).

The benefits seen across the trial were “much better for patients with some other risk factors,” Teeler observed. Testing shows that you’ll get a “great bargain,” for example, in patients with an ejection fraction less than 30%, at least NYHA 3, or with significantly higher diuretic sodium peptides requires input, he noted.

“We need to have as many treatment options as possible, because sometimes patients can’t tolerate other therapies,” Greene said. In GALACTIC-HF, he noted, there was little effect of omecamtiv mecarbil on blood pressure or adverse effects on kidney function. , and the benefits appear to be more pronounced in more severely ill patients.

So it’s likely that the patient needs the most help – the drug appears to be safe, well-tolerated and helpful.

In the present analysis, there were 194 fatal or nonfatal first-time strokes, but the hazard ratio (HR) for that endpoint among users of omecamtiv mecarbil was 0.65 (95% CI, 0). .49 – 0.87, P = 0.004). By itself, it was 0.56 (95% CI, 0.31 – 0.99, P = 0.048) for fatal stroke.

The HR for fatal or nonfatal stroke among the trial’s 754 patients with a history of stroke was 0.23 (95% CI, 0.09–0.56, P = 0.001) and was not significant for the trial. in those with no history of stroke.

The risk of new-onset AF/AFl was reduced with omecamtiv mecarbil, as HR was 0.70 (95% CI, 0.50–0.99, P=0.044) in patients without documented cardiac arrhythmias. at study entry and 0.60 (95% CI, 0.37–1.00, P = 0.048) for those without any history of AF/AFl, Teerlink reported.

Importantly, he said, in the setting, new-onset AF/AFl was recorded as a serious adverse event “so it only included events requiring hospitalization or intervention.”

Given the field’s current focus on the four classes of drugs in the treatment of HFrEF and how to ensure treatment for patients, “we must continue to focus on the residual risk that patients with heart failure have to face. face even with very good treatment,” Greene said.

“I think drugs like omecamtiv mecarbil would be helpful for patients to reduce residual risk,” he added, and for patients who cannot tolerate some of their other heart failure therapies. me, this drug is particularly well tolerated.”

Source: https://www.medscape.com/viewarticle/963392?src=#vp_2

Reference: American Heart Association Scientific Sessions 2021: https://www.abstractsonline.com/pp8/?_ga=2.141042993.2042594723.1635046736-1021258137.1633710264#!/9349/presentation/18177Presented November 13.

The article is edited and translated by ykhoa.org – please do not reup without permission!

Translated by: Gia Minh

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