ATOMIC-AHF: Cautious Optimism for Potential Inotrope Replacement in Acute HF

September 04, 2013

AMSTERDAM — Is it twilight for positive inotropic agents for acute heart failure and their daunting risks? Not necessarily, but an investigational drug that increases stroke volume apparently without upping myocardial oxygen demand or promoting arrhythmias is moving promisingly forward in the clinical-trial process.

In a randomized, placebo-controlled, phase 2 dose-ranging study, patients with acute heart failure infused with the cardiac myosin activator omecamtiv mecarbil (Cytokinetics/Amgen) at the highest of three dosages showed a significant drop in self-assessed dyspnea scores.

However, there was no such dyspnea benefit across the combined dosage cohorts, totaling about 300 patients, which was the prespecified primary end point. Still, while the Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) trial was negative, its researchers and some expert observers are cautiously optimistic about the drug's performance.

"Importantly, omecamtiv mecarbil resulted in greater decreases in the heart rate and less reduction in blood pressure" compared with placebo, observed lead investigator Dr John R Teerlink (University of California San Francisco and San Francisco Veterans Affairs Medical Center) when presenting ATOMIC-AHF here at the European Society of Cardiology (ESC) 2013 Congress. It wasn't associated with excess ventricular arrhythmias, he said. "There was no evidence of proarrhythmia and, if anything, a decrease in supraventricular tachyarrhythmias."

Omecamtiv mecarbil works by potentiating the effects of myosin in myocardial contractions, boosting cardiac output not by strengthening contractile force but by prolonging systole, thereby making contractions more efficient, according to Teerlink. In ATOMIC-AHF and earlier studies of the agent, the effects have been strikingly dose dependent.

"The data at least are positive even if they are not in all instances statistically significant," Dr Kurt Huber (Wilhelminen Hospital, Vienna, Austria), who comoderated a briefing on ATOMIC-AHF for journalists. The trial, he told heartwire , "shows that when you use the right dosage, there is some positive effect. It has to be proven in a bigger study, but now we know the dosage."

Safety Signal or Chance Finding?

One possibly important safety signal emerged; there were seven "myocardial infarctions" after randomization in the active treatment group and only three among controls, for relatively low rates of 2.3% and 1.0%, respectively, but still a noteworthy difference.

Teerlink characterized the MIs as predominantly small, subclinical troponin elevations "that probably wouldn't have been detected by older troponin assays." Most of them, he said to heartwire , were picked up by personnel at the trial's core troponin evaluation center, which appropriately entered them into the record as MIs.

"There was actually no relationship between these mild increases in troponins and omecamtiv mecarbil concentrations, either when evaluated by peak concentrations or the area-under-the-curve total exposure during the 48-hour infusion." Teerlink and his colleagues are reassured by that, he said, "because it makes it likely to be more of a chance finding than mechanistically related, although we didn't show that in the trial."

Teerlink said that he and other ATOMIC-AHF investigators, as well as the study's data safety and monitoring board, are comfortable moving the drug into phase 3 trials.

Huber agrees. "Clearly, just based on what we have been shown, it seems to be safe. We have no clear signs that it's unsafe. I think it's promising, the [myosin activation] principle seems to be working. But we need more data."

As discussant following Teerlink's formal presentation of ATOMIC-AHF at the ESC sessions, Dr Theresa A McDonagh (Kings College Hospital, London, UK) hailed omecamtiv mecarbil as "a truly new inotrope, a drug that acts on the sarcomere itself, and it does seem to be free of the nemesis [represented by] other inotropes, which of course increase heart rate and myocardial oxygen consumption, cause arrhythmias, and raise mortality in heart failure. It appears to be a Holy Grail, maybe capable of replacing dobutamine and milrinone." She called the trial "a very promising start for omecamtiv mecarbil in acute heart failure" but added that "the small increase in troponin should herald some caution among the enthusiasm here."

Also, McDonagh noted, "the trial was conducted in a reasonably tight phenotype of acute heart failure: patients with preserved blood pressure and [estimated glomerular filtration rates] eGFRs. So we don't know how this drug will perform in a broader group of real-world heart-failure patients or those that currently get inotropes in-hospital."

"A Reasonably Tight Phenotype"

ATOMIC-AHF randomized 613 patients with acute heart failure at 106 sites in North America, Europe, and Australia who had an LVEF <40%, elevated natriuretic peptides, and resting dyspnea or dyspnea with minimal exertion, to receive a 48-hour infusion of placebo or omecamtiv mecarbil. Three cohorts received the drug, one at each of three ascending dosage levels designed to achieve plasma concentrations of 115, 230, and 310 ng/mL, respectively. As McDonagh alluded, patients with blood pressure >160/100 mm Hg, a systolic blood pressure <90 mm Hg, a heart rate >110 bpm or <60 bpm, or an eGFR <20 mL/min/1.73m2 were excluded.

Primary Efficacy Outcome of ATOMIC-AHF

End point Pooled placebo cohorts, n=303 (%) Cohort 1, n=103 (%) Cohort 2, n=99 (%) Cohort 3, n=101 (%) p
Primary efficacy* 41 42 47 51 0.331

*Dyspnea response on the seven-point Likert scale corresponding to "minimally, moderately, or markedly better at six hours and moderately or markedly better at both 24 and 48 hours but without worsening HF or death from any cause at 48 hours"

Differences in the primary end point were not significant. But in a prespecified analysis pitting each active-therapy cohort against its respective placebo cohort, Teerlink observed, the highest omecamtiv mecarbil dosage produced a significantly greater rate of the dyspnea-response primary end point: 51% vs 37% for placebo (p=0.03). "If we had only looked at cohort 3, this would have been a positive study," he said to heartwire .

Importantly, he observed, there were significant concentration-related decreases in heart rate and increases in blood pressure and systolic ejection time (SET), "which is the echocardiographic signature of omecamtiv mecarbil." There were also trends toward reduction in risk of worsening heart failure within seven days of treatment, according to Teerlink, as well as a reduced incidence of supraventricular arrhythmias and no increase in ventricular arrhythmias.

Change in Systolic Ejection Time (SET) by Dosage Cohort

End point Cohort 1, n=103 Cohort 2, n=99 Cohort 3, n=101
Change in SET vs control (ms) +23.4 (p=0.005) +33.6 (p<0.0001) +53.2 (p<0.0001)

 

Relative Risk (RR, 95% CI)* for Worsening Heart Failure Within Seven Days by Dosage Cohort

End point Cohort 1, n=103 Cohort 2, n=99 Cohort 3, n=101
Worsening HF 0.68 (0.38–1.21) 0.49 (0.24–0.98) 0.55 (0.28–1.09)
Worsening HF or death 0.67 (0.38–1.18) 0.54 (0.28–1.04) 0.54 (0.27–1.08)

*Reference=pooled placebo groups

The developers of omecamtiv mecarbil aren't stopping with acute heart failure when an oral form of the drug is available. Teerlink briefly described the ongoing phase-2 Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) study, a multicenter, randomized, dose-escalation safety-efficacy trial that will enter an estimated 420 patients with chronic systolic heart failure.

The ATOMIC-AHF study was funded by Amgen. Teerlink has received research grants and/or consulting fees from Amgen, Corthera, Cytokinetics, Merck, Novartis, Sorbent, and Trevena. Huber has previously disclosed being a member of a speaker's bureau for AstraZeneca, Daiichi Sankyo, and Eli Lilly.

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