PAPER SPOTLIGHT
Sponsored content
ATOMIC AHF:
A Step Forward; What’s Next?
Sponsored by Amgen
Recent results from the Acute Treatment with
Omecamtiv Mecarbil to Increase Contractility in
Acute Heart Failure (ATOMIC-AHF) suggested that
the drug did not meet the primary study endpoint
of improving dyspnea in patients presenting with
acute heart failure (AHF). The data, however,
provided a great deal of new information on the
drug’s pharmacokinetics, pharmacodynamics,
tolerability, safety, and efficacy.
“In this dose-finding Phase 2b trial, our intent
was to evaluate the potential safety and efficacy
of omecamtiv mecarbil (OM), a novel-mechanism
cardiac myosin activator, in a hospitalized AHF
population, to guide the further development of
this investigational drug candidate,” the authors
said in an interview.
Citing an unmet need in the alleviation of
morbidity and mortality among current AHF
patients using drugs that target myocardial contractility,1 the researchers noted that the lack of
therapeutic options is due in part to the failure of
inotropic agents to demonstrate either adequate
safety or efficacy in a number of studies. Adverse
effects associated with the use of such drugs
includes arrhythmias, hypotension, myocardial
ischemia, and even an increased mortality.2 While
inotropic agents increase myocardial contraction
by working through second messenger signaling
to increase cardiac myocyte calcium, OM works
as a cardiac myosin activator to directly modulate
the cardiac sarcomere in the absence of changes
in cardiac myocyte calcium. Inotropes shorten
systole and increase the velocity of myocardial
contraction; in contrast OM increases the duration
of systole without changing the velocity of the
myocardial contraction.
“Our hope is that this novel mechanism
of action to increase cardiac contractility may
eventually prove beneficial to patients,” they said.
“However, that is still under study.”
The double-blind, prospective, 106-center
ATOMIC-AHF study, sought to evaluate the efficacy of OM by measuring dyspnea relief compared with placebo. The researchers enrolled 606
patients presenting with AHF and LVEF < 40%,
who were randomized at 1:1 to intravenous OM
or matching placebo. There were three sequential
cohorts consisting of ~200 patients each, with
OM plasma 48-hour concentration targets of 115
ng/ml, 230 ng/ml, and 310 ng/ml achieved using
three escalating dose regimens. Patients were
followed-up at 30 days and 6 months.
No Differences, But…
According to the results, there was no statistical difference in the occurrence of the primary
study endpoint of dyspnea relief within 48 hours
(p = 0.316). Despite falling short of the primary
endpoint, which compared the results between the
three dosed groups and a pooled placebo group,
the researchers also performed a pre-specified
supplemental analysis of each of the three dose
groups in comparison to their own respective
placebo groups.
“In the primary analysis of the three dose
groups versus a placebo group pooled together
from all three dose groups, ATOMIC-AHF missed
its primary endpoint of dyspnea improvement,”
the researchers said.
“However, when comparing th e highest
dose group to its own
placebo group, we observed a statistically
significant difference
in dyspnea improvement.”
There was a 41%
relative improvement in dyspnea at
48 hours in the third
cohort (14% absolute
difference: placebo
37%, OM 51%; p =
While the results did not provide
immediate implications for clinical
practice, the researchers noted that
there were several important findings
in the study that cardiologists
should consider.
0.034). An additional post-hoc logistic regression
analysis showed greater dyspnea response rates
with higher dosing across all patient cohorts (1.06
per each 50 mg increase in OM dose, 95% CI: 1.01
to 1.11; p = 0.025 adjusted for important covariates; unadjusted p = 0.035). They also reported
that OM was associated with increased in LV
systolic ejection time and decreased heart rate
(p < 0.0001) No statistically significant differences
in secondary study endpoints were reported (see
TABLE 1).3
The researchers also noted that the lack of
adverse effects on BP and other parameters was
encouraging. Adverse event profiles and tolerability across the OM cohorts were similar to those
seen in the placebo cohort (see Table 2),3 and there
were no increases in ventricular or supraventricular tachyarrhythmias.
They added: “Importantly, heart rate and blood
pressure were not adversely affected, and there
was no observed increase in arrhythmias in this
vulnerable patient population,” they noted. “Given
the high risk nature of the patient population in
ATOMIC-AHF, we were pleased to see that the
serious adverse events and adverse events were
balanced between the OM-treated patients and
those assigned to placebo.”
An increase in plasma troponin concentrations
vs. placebo was reported (median difference at
48 h, 0.004 ng/ml), which they noted would be
closely monitored in future studies involving OM.
Potential Implications?
Despite missing the primary endpoint, the researchers noted that the study results are both
useful and informative. While the results did not
provide immediate implications for clinical practice, the researchers noted that there were several
important findings in the study that cardiologists
should consider.
One of the important takeaways was the drug’s
lack of harmful interactions with other therapies.
“Omecamtiv mecarbil is still an investigational
drug that is under development,” they said. “Based
on the lack of adverse effects on heart rate, blood
pressure, renal function, and potassium concentrations observed, if this agent does advance to practical use, it is not expected to interfere or complicate administration of other standard of care heart
failure therapies, such as ACE inhibitors/ ARBs,