Despite missing primary efficacy endpoint, ATOMIC-AHF identifies positive trends

September 3, 2013

Omecamtiv mecarbil, a cardiac myosin-activator, did not achieve its primary efficacy endpoint in reducing dyspnoea (shortness of breath) in patients with acute heart failure, according to the results of the phase II ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) study.

However, a cohort which received the highest dose of the drug showed greater dyspnoea relief compared with placebo, and there were also other favourable dose and concentration-related trends, noted lead investigator John R. Teerlink, MD, Professor of Clinical Medicine at the University of California San Francisco and Director of Heart Failure at the San Francisco Veterans Affairs Medical Center, USA.

"The study was a real success for its purpose, as a dose-finding, safety and tolerability study," he said. "The main objective of ATOMIC-AHF was to investigate the pharmacokinetics and tolerability of intravenous omecamtiv mecarbil in the (AHF) population, and like most Phase II studies, it was not powered or designed around the efficacy endpoint," he explained.

"We are pleased to see as much efficacy signal as was apparent, and the study provides essential data to inform the dosing regimen for future Phase 3 trials of the intravenous formulation."

ATOMIC-AHF enrolled 613 patients with left ventricular systolic dysfunction who were acutely hospitalised with dyspnoea at rest or minimal exertion.

The subjects, from 106 sites in North America, Europe and Australia, were randomly assigned to receive 48 hours of intravenous placebo or omecamtiv mecarbil (OM) in 3 ascending dose cohorts designed to achieve plasma concentrations of 115, 230, and 310 ng/mL.

The primary efficacy endpoint was the effect on dyspnoea at 6, 24 and 48 hours, with secondary endpoints of safety, tolerability, pharmacokinetics, and echocardiographic indices of .

Compared to the pooled placebo groups the OM groups showed no statistically significant difference in dyspnoea symptoms (P = 0.33) - therefore, the primary endpoint was not met, said Prof. Teerlink,

However, in the cohort with the highest OM dose there was a trend towards greater response compared to its paired placebo group (51% vs 37%, P = 0.03), along with significant dose-related and plasma concentration-related trends in response (P = 0.025 and P = 0.007, respectively).

Additionally, there were significant (P < 0.001) concentration-related increases in systolic ejection time, which is the echocardiographic signature of OM, said Prof. Teerlink.

"Unlike prior agents that increased intracellular cAMP and calcium and decrease ejection time, omecamtiv mecarbil's unique mechanism of action prolongs ejection time, allowing for increased stroke volume without significantly increased myocardial oxygen consumption," he said. "This effect has been remarkably reproducible from healthy dogs, dogs with heart failure, healthy human volunteers, and patients with both chronic, and now in ATOMIC-AHF, acute heart failure."

As seen in previous studies, OM produced significant reductions in heart rate (P < 0.001) without decreasing systolic blood pressure, said Prof. Teerlink.

There were also trends toward reductions in worsening , reduced incidence of supraventricular arrhythmias, and no increase in ventricular arrhythmias.

"None of these outcomes should be considered confirmed, since that was not the intent of the study, but the trends are very encouraging, especially for a trial of its size and scope," he said, adding that adverse events, including adjudicated deaths and rehospitalisations were "indistinguishable" from placebo.

There were 7 post-randomization myocardial infarctions in the omecamtiv mecarbil treated groups compared with 3 in placebo treated groups (2.3% vs 1.0% respectively). There was a modest increase in cardiac troponin I in OM-treated patients, but no evidence to suggest this was linked to increasing OM concentrations, "however, we will be vigilant about studying the ATOMIC-AHF data for possible explanations."

"One of the greatest challenges of the ATOMIC-AHF trial has been managing expectations, explained Prof. Teerlink. "Omecamtiv mecarbil is probably one of the most interesting new chemical entities in cardiovascular medicine now and consequently, expectations are very high in the scientific and lay communities. Physicians have struggled for decades to develop agents that improve cardiac function without increasing arrhythmias or mortality; omecamtiv mecarbil has the potential to be such an agent."

Explore further: RELAX-AHF shows first positive findings in HFpEF patients

Related Stories

RELAX-AHF shows first positive findings in HFpEF patients

May 26, 2013
Serelaxin may be more effective for relieving dyspnea in heart failure with preserved ejection fraction (HFpEF) than reduced (HFrEF) during the first 24 hours, according to results from RELAX-AHF presented in today's late ...

Study finds new drug may hold promise for hospitalized heart failure patients

November 7, 2012
Hospitalized heart failure patients given an investigational drug had improved symptoms and other clinical benefits including fewer deaths, than those given standard of care plus a placebo, according to late-breaking clinical ...

Drug may improve outcomes after heart attack

March 12, 2013
The prescription drug eplerenone appears to reduce the risk of cardiovascular mortality and heart failure after a heart attack by more than one-third, according to research presented today at the American College of Cardiology's ...

Not faster, but longer -- new drug changes beat in treating heart failure

August 19, 2011
A new drug which offers a radically different approach to treating certain types of heart failure has been shown to improve cardiac function in heart failure patients in its first clinical trials.

Hot Line IV: Late-breaking trials on heart failure and acute coronary syndrome

September 3, 2013
The blood pressure lowering drug aliskiren did not improve coronary artery disease when given to patients who had prehypertension, results of the Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound ...

Recommended for you

New molecule may hold the key to triggering the regeneration and repair of damaged heart cells

August 21, 2017
New research has discovered a potential means to trigger damaged heart cells to self-heal. The discovery could lead to groundbreaking forms of treatment for heart diseases. For the first time, researchers have identified ...

Researchers investigate the potential of spider silk protein for engineering artificial heart

August 18, 2017
Ever more people are suffering from cardiac insufficiency, despite significant advances in preventing and minimising damage to the heart. The main cause of reduced cardiac functionality lies in the irreversible loss of cardiac ...

Lasers used to detect risk of heart attack and stroke

August 18, 2017
Patients at risk of heart attacks and strokes may be spotted earlier thanks to a diagnosis tool that uses near-infrared light to identify high-risk arterial plaques, according to research carried out at WMG, University of ...

Cholesterol crystals are sure sign a heart attack may loom

August 17, 2017
A new Michigan State University study on 240 emergency room patients shows just how much of a role a person's cholesterol plays, when in a crystallized state, during a heart attack.

How Gata4 helps mend a broken heart

August 15, 2017
During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts ...

Injectable tissue patch could help repair damaged organs

August 14, 2017
A team of U of T Engineering researchers is mending broken hearts with an expanding tissue bandage a little smaller than a postage stamp.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.