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Additional analyses from phase III GALACTIC-HF study of AMG 423 showed impact in atrial fibrillation.- Cytokinetics

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Published:2nd Jul 2021
Cytokinetics announced that additional results from the phase III GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) of AMG 423 (omecamtiv mecarbil), including a prespecified subgroup analysis of the influence of atrial fibrillation or flutter (AFF) on the treatment effect of omecamtiv mecarbil in a Late Breaking Clinical Trial Session. Other analyses were presented in the Clinical Trial Updates Session related to which patients in GALACTIC-HF achieved an increased treatment effect with omecamtiv mecarbil.

Researchers presented analyses from GALACTIC-HF assessing how baseline AFF in patients impacted the effectiveness of omecamtiv mecarbil in GALACTIC-HF. Of the 8,256 patients enrolled in GALACTIC-HF, 2,245 patients (27%) had AFF at baseline; these patients were older, more likely to be randomized as inpatients, had a higher New York Heart Association (NYHA) class and had higher NT-proBNP compared to patients without AFF. The effect of treatment with omecamtiv mecarbil on the primary composite endpoint of heart failure events (heart failure hospitalization and other urgent treatment for heart failure) or cardiovascular (CV) death was greater in patients without baseline AFF compared to those patients with AFF at baseline (interaction p=0.012). Importantly, the modification of the treatment effect by AFF was concentrated in patients with AFF using digoxin (n=692) with minimal evidence of effect modification in patients with AFF not using digoxin (n=1553). Digoxin did not modify the treatment effect of omecamtiv mecarbil in patients without AFF. These findings suggest caution should be exercised when treating patients with AFF using both digoxin and omecamtiv mecarbil. Interestingly, given prior observations of the positive impact of omecamtiv mecarbil on left atrial function, an exploratory analysis from GALACTIC-HF indicated fewer serious adverse events of atrial fibrillation in patients without AFF at baseline in patients treated with omecamtiv mecarbil compared to placebo (55 events in 2,974 patients treated with omecamtiv mecarbil vs. 78 events in 3,013 patients treated with placebo, p=0.046).

There was also analyses on the effect of treatment with omecamtiv mecarbil according to baseline NT-proBNP in patients without AFF, as well as in all patients in GALACTIC-HF. NT-proBNP is a biomarker of ventricular wall stress in which higher levels reflect more severe heart failure. Among the 5,971 patients who did not have AFF, the median (Q1, Q3) NT-proBNP level was 1,675 (812-3579 pg/ml). In patients without AFF, the treatment effect of omecamtiv mecarbil on the primary composite endpoint was increased in patients with a baseline NT-proBNP above the median (hazard ratio, 0.81; 95% confidence interval 0.73-0.90) compared to patients with baseline NT-proBNP equal to or below the median (HR, 0.94; 95% CI 0.80-1.09; interaction p=0.095). The same pattern was observed in the overall population in which patients with a baseline NT-proBNP greater than the median experienced an increased treatment effect (HR, 0.88; 95% CI 0.80-0.96) compared to patients with a baseline NT-proBNP equal to or below the median (HR, 1.01; 95% CI 0.90-1.15; interaction p=0.035.) Examined as a continuous variable, there was an interaction between treatment with omecamtiv mecarbil and baseline NT-proBNP that showed an increased treatment effect on the primary outcome in patients as baseline NT-proBNP increased both in those without AFF (interaction p=0.024) and in the overall population (interaction p=0.005). These findings suggest the benefit of treatment with omecamtiv mecarbil increased progressively as baseline NT-proBNP increased consistent with other analyses from GALACTIC-HF that suggest more severe heart failure patients may derive increased benefit from treatment with omecamtiv mecarbil.

Finally there was an analysis of the treatment effect of omecamtiv mecarbil on the primary composite endpoint in patients from GALACTIC-HF classified as having severe heart failure based on modified criteria from the Heart Failure Association of the European Society of Cardiology (ESC-HFA) advanced heart failure position statement. Patients in this subgroup had NYHA class III-IV symptoms, EF at most 30%, and hospitalization for heart failure within the prior six months. Of patients enrolled in GALACTIC-HF, 2,258 (27%) met these criteria for severe heart failure. Patients with severe heart failure had markers of more advanced disease and higher baseline risk, with event rates in patients treated with placebo that were approximately twice those of patients without severe heart failure. In patients with severe heart failure, the treatment effect of omecamtiv mecarbil on the primary composite endpoint was increased (HR, 0.80; 95% CI 0.71-0.90) compared to patients without severe heart failure (HR, 0.99; 95% CI 0.91-1.08; interaction p=0.005). The results for CV death were qualitatively similar; patients with severe heart failure experienced a trend towards treatment benefit from omecamtiv mecarbil (HR, 0.88; 95% CI 0.75-1.03) while patients without severe heart failure did not (HR, 1.10, 95% CI 0.97-1.25; interaction p=0.028). Furthermore, as the severity of heart failure increased, as indicated by the number of the three severity criteria met, both the incidence of the primary composite endpoint and the treatment effect of omecamtiv mecarbil increased. Omecamtiv mecarbil was equally well tolerated in patients with and without severe heart failure, with no significant changes in blood pressure, renal function, or potassium compared to placebo. These results from GALACTIC-HF demonstrate a potentially clinically important treatment effect of omecamtiv mecarbil in patients with severe heart failure. Data were presented at Heart Failure 2021, an International Congress of the European Society of Cardiology.

Condition: Heart Failure
Type: drug

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