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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Prof. Theresa McDonagh,
Prof. John R. Teerlink
Presenter abstractDiscussant reportAll the Scientific resources on ESC Congress 365
By John R. TeerlinkOther authors: Prof. John R. Teerlink/ USA; G. Michael Felker/ USA; Prof. John J. V. McMurray/UK; Prof. Piotr Ponikowski/ Poland ; Prof. Marco Metra/ Italy; Prof. Gerasimos S. Filippatos/ Greece; Prof. Kenneth Dickstein/ Norway; Justin A. Ezekowitz/Canada; Prof. John G. Cleland/ UK; Jae B. Kim/ USA; Lei Lei/ USA; Beat Knusel/ USA; Andrew A. Wolff/ USA; Fady I. Malik/USA; Scott M. Wasserman/ USA; on behalf of the ATOMIC-AHF Investigators
Purpose:Currently available inotropic agents can cause myocardial ischemia/damage, arrhythmias, hypotension and increased morbidity and mortality. Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that directly increases cardiac function with no effect on intracellular calcium or cAMP. In healthy volunteers and patients with stable heart failure (HF), OM improves echocardiographic measures of cardiac function. ATOMIC-AHF is the first study of IV OM in patients with acute heart failure (AHF) and was designed to evaluate its efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics in AHF.
Methods:ATOMIC-AHF (ClinicalTrials.gov NCT01300013) is a multi-center, randomized, double-blind, placebo-controlled, dose-escalating study of 3 sequential cohorts (~200 subjects per cohort; median target OM plasma concentration: 115, 230, 310 ng/mL). Patients admitted for AHF with LVEF ≤40% and a history of HF were eligible if they had persisting dyspnea at rest or with minimal exertion despite IV diuretic treatment, and biomarker evidence of congestion (elevated BNP or NTproBNP). Patients were randomized 1:1 to a 48h infusion of placebo or OM within 24h of initial IV diuretic. The primary efficacy hypothesis is that at least 1 dose level of OM will improve dyspnea within 48h. Secondary efficacy endpoints include other symptom/well-being measures, changes in biomarkers, clinical outcomes through 30d, and mortality through 180d; a PK and echocardiogram substudy investigates the relationship of OM plasma concentrations to changes in cardiac function.Results:Enrollment of all 3 dose cohorts is complete and data cleaning underway with results available in mid-June.
Conclusions:This 600-patient study of a novel therapeutic class, cardiac myosin activators, is the first in patients with AHF. OM has the potential to be a safe and effective therapy to improve cardiac performance and patient outcomes. OM is also being studied as an oral formulation in chronic HF.
Theresa McDonaghThis is an important and exciting study extending our knowledge of this new inotrope into the arena of acute heart failure (AHF) and, for the first time looking at a clinical end point.
BackgroundThis is a novel and potentially very exciting inotrope, a drug, that acts on the sarcomere itself. It increases the entry rate of myosin into the tightly bound force- producing state with actin. It increases the duration of systole and stroke volume but does so without causing an increase in intracellular calcium, a change in the rate to peak contraction (dp/dt) or an increase in myocardial oxygen consumption. It seems therefore to be free of the nemesis of other inotropes, acting on cAMP or intracellular calcium handling and which have been plagued by a propensity to increase heart rate (HR) and myocardial oxygen consumption, cause arrhythmia, ischaemia and an excess mortality. It seems to be the Holy Grail, capable of replacing dobutamine and milrinone. So what does this latest study tell us about omercamtiv mecarbil (OM)?
Study SummaryATOMIC-HF evaluated the pharmacokinetics and pharmacodynamics of OM as well as its efficacy on a clinical end point in AHF. It is the first study of OM in AHF. Three different dose infusions of OM were given within 24 hours of iv diuretic treatment for AHF, for 48 hours and compared to placebo. The primary clinical endpoint was of dyspnoea symptom response on the 7-point Likert scale assessed at 4, 24 and 48 hours.
The patients represent a common phenotype of AHF: decompensated systolic HF (HF-REF), with dyspnoea at rest or with minimal exertion after i.v. diuretic, with raised BNP concentrations. Crucially, they did not have ACS, were not receiving inotropes and, indeed, had no requirement of them as the systolic blood pressure (SBP) had to be greater than 90mmHg. The patients enrolled were typical for such a trial. They had well treated HF-REF and had a mean eGFR of around 50 ml/min. The study population represents an area of great unmet need in HF-patients admitted to hospital with AHF have an in-patient mortality of around 10% and a one year mortality of over 30%.
There was no change in the primary efficacy endpoint of dyspnea response on the Likert Scale. There was an improvement in dyspnea in the cohort receiving the highest dose and with higher plasma concentrations achieved. In addition, there was a trend towards a reduction in episodes of WHF with escalating dose.There was the expected dose and plasma concentration dependent increase in systolic ejection time (SET). There was no signal for increased arrhythmic events. Indeed, there was a reduction in HR and a small reduction in SBP at higher doses. On the other hand there was an increase in troponin. No information was given on diastolic dysfunction. However, there was no increase in clinical ischaemic events.
This is concordant with previous work in normal volunteers and patients with chronic stable HF-REF in that it produced a dose and plasma concentration dependent increase in SET. Within the dose range studied here, we did not see the myocardial ischemia reported at higher doses in earlier studies. The reduction in HR in the HF-REF study was replicated in this work.
This trial was conducted in a reasonably tight phenotype of AHF patients with preserved blood pressure and with eGFRs greater than 50mls/min. We do not know how the drug would perform in a broader group of “real world” AHF patients, many of whom have eGFRs <50ml/min or in those who currently get inotropes.
ConclusionsThis first study of omecamtiv mecarbil in AHF is promising. While not having any effect on the primary dyspnea end point, there was a trend towards an improvement in episodes of worsening heart failure. There were no clinical safety issues. However, the small increase in troponin observed should herald some caution amongst the enthusiasm. The mechanism of action of this drug leading to an increase in systolic ejection time always raises concern that diastole may be shortened and coronary perfusion compromised. The reduction in HR seen in this study suggests that there may be an attenuation of that reduction in total diastolic time.Clearly, more studies in AHF will be needed on harder clinical outcomes before we have the replacement for our current inadequate inotropes. However, this is a very promising start for a new class of inotropic agent, with the added promise of an oral formulation in the pipeline, which would broaden its potential use to patients with CHF.
ATOMIC-AHF: Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: Results from ATOMIC-AHF