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HFSA: Novel IV Drug No Help in Acute HF

By Todd Neale, Senior Staff Writer, September 22, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Note that the use of intravenous cinaciguat, an activator of soluble guanylate cyclase, in patients with acutely decompensated heart failure, was not associated with improved clinical outcome and was associated with significant hypotension as an adverse event.
Review
BOSTON -- An investigational IV agent for acute decompensated heart failure does not appear to reduce dyspnea, although some questions remain about whether development should continue, researchers found.

In a series of three phase IIb trials, cinaciguat -- an activator of soluble guanylate cyclase -- failed to show substantial benefits over placebo, and resulted in a higher rate of severe hypotension, according to Mihai Gheorghiade, MD, of Northwestern University School of Medicine in Chicago.

That risk resulted in the premature termination of two of the three trials -- COMPOSE 1 and COMPOSE EARLY -- after only 74 patients were enrolled, he reported at the Heart Failure Society of America meeting here.


The third trial -- COMPOSE 2 -- was stopped early after only four patients enrolled because of indications that the trial could not be completed in a reasonable amount of time.

"Short-term treatment with intravenous cinaciguat in heart failure should no longer be investigated given its hypotensive effects at relatively low doses without a substantial benefit in terms of dyspnea, wedge pressure, or cardiac output," Gheorghiade concluded.

But in comments following Gheorghiade's presentation, John Burnett Jr., MD, of the Mayo Clinic in Rochester, Minn., said that the potential benefits of lower doses of cinaciguat could not be determined because that trial -- COMPOSE 2 -- only enrolled four patients before stopping.

He called for further research, perhaps in a chronic heart failure population instead of an acute population.

"I think we're premature in calling an end at this point with this small number of patients in a trial that's been terminated early," Burnett said.

But Gheorghiade stuck with his conclusion that it would be futile to continue looking at the short-term use of cinaciguat, and that there have to be options to stop investigating agents early in the process of development when they fail to show any signs of benefit.

"In the future, given the fact that we have so many molecules now in heart failure, we need to develop methods where we can stop early," he said.

"We cannot afford another ASCEND trial," he added, referring to the ASCEND-HF trial that showed nesiritide (Natrecor) -- widely used for acute decompensated heart failure at one time -- was no help or harm in that population.

The COMPOSE program included three randomized, placebo-controlled, phase IIb trials of cinaciguat in patients with chronic heart failure who were hospitalized with dyspnea and congestion.

The program was started based on preclinical studies that showed cardiorenal protective effects from the agent, independent of its powerful vasodilatory effects.

COMPOSE 1 (12 patients) and COMPOSE 2 (four patients) evaluated the hemodynamic effects of five IV doses of cinaciguat administered over 24 to 48 hours -- 10 and 25 µg/h (COMPOSE 1) and 50, 100, and 150 µg/h (COMPOSE 2). All of the patients in these two trials required invasive hemodynamic monitoring, and the primary outcome was an effect on pulmonary capillary wedge pressure at eight hours.

COMPOSE EARLY (62 patients) evaluated the three higher doses in patients hospitalized with worsening heart failure who were randomized within 12 hours of presentation. The primary outcome was an effect on dyspnea at eight hours.

Because of the low patient numbers, Gheorghiade presented descriptive analyses for COMPOSE 1 and COMPOSE EARLY only.

In COMPOSE 1, the hemodynamic study, each of the three doses of cinaciguat was associated with a greater reduction in systolic and diastolic blood pressure at eight, 24, and 48 hours, compared with placebo. There were no major changes in heart rate, cardiac index, right atrial pressure, or pulmonary capillary wedge pressure, Gheorghiade said.

In COMPOSE EARLY, there was also a substantial drop in blood pressure with each dose of cinaciguat, with no major changes in heart rate, renal function, creatinine, B-type natriuretic peptide (BNP), or N-terminal pro-BNP.

Dyspnea was not affected, although Gheorghiade noted that even though the average time to randomization was well within the 12-hour limit (5 hours 36 minutes), most patients did not have severe dyspnea when the infusions started.

Most of the treatment-emergent adverse events were related to severe hypotension, which was more frequent with cinaciguat than with placebo both in COMPOSE 1 (22% versus 0%) and COMPOSE EARLY (28% versus 5%).

Although Gheorghiade said cinaciguat should no longer be investigated, he said chronic cyclic guanosine monophosphate modulation with available oral soluble guanylate cyclase activators and stimulators should continue because of the cardiorenal protective effects seen in preclinical studies that were separate from their vasodilatory effects.