麻豆果冻传媒影音

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An experimental myosin activator drug improved cardiac function in patients with chronic stable systolic heart failure, according to a phase II study.

In 45 patients, the drug, omecamtiv mecarbil, increased systolic ejection time, stroke volume, and fractional shortening in a dose-dependent manner compared with placebo, John G.F. Cleland, MD, from the University of Hull in East Yorkshire, England, and colleagues reported online in The Lancet.

Plasma concentrations of the drug greater than 100, 200, 300, and 500 ng/mL were, respectively, associated with increased systolic ejection time and fractional shortening, increased stroke volume, increased left ventricular ejection fraction, and decreased left ventricular end­-systolic and end­-diastolic volumes.

Conventional inotropic drugs increase contractility without prolonging systole and at the expense of oxygen consumption, which exacerbates myocardial ischemia, and can cause atrial and ventricular arrhythmias. The hemodynamic benefits are "inextricably linked" to the drugs' recognized adverse effects, investigators noted.

Myosin activators, however, have been shown in preclinical studies to "increase the duration of systole without changing the rate of left ventricular pressure development, thereby increasing stroke volume and cardiac output."

The resulting "cardiac efficiency" could be clinically beneficial for patients, Cleland and colleagues said.

In a complementary study, John R. Teerlink, MD, from the San Francisco Veterans Affairs Medical Center, and colleagues determined in 34 healthy male volunteers that the maximum tolerated dose of omecamtiv mecarbil is a six-hour infusion at 0.5 mg/kg per hour.

That study, also published online Aug. 18 in The Lancet, found similar dose-dependent increases in cardiac function that were highly correlated with drug concentration (P<0.001 for all cardiac functions).

Success with the volunteers led to the phase II trial, a double-blind, placebo-controlled, crossover, dose-escalation study where 45 heart failure patients received 151 infusions of the drug or placebo at various time points.

Only three patients from the U.S. were enrolled. Most of the others were from the U.K. (29), followed by Russia (11) and Georgia (2). The median age was 51, and 87% were men.

Investigators divided patients into five sequential cohorts comprising eight to 10 patients. Cohorts one through four were randomly assigned to one of four treatment sequences comprising three escalating doses and placebo. Patients in cohort five had only two treatment sequences where they were randomly administered the drug or placebo.

Because the drug distributes well and has a 19-hour half-life, patients received a high loading dose followed by a lower maintenance rate, which researchers posited would help achieve target plasma concentrations.

Patients received echocardiograms at baseline and then following infusion at 1.5 hours and 24 hours for all cohorts, 48 hours for cohort four, and 72 and 96 hours for cohort five.

In the study of the healthy volunteers, researchers had determined that left ventricular systolic ejection time was the most sensitive measure of the drug's effect.

One of the more positive results seen in all heart failure cohorts was a consistent relationship between a rise in systolic ejection time and plasma drug concentration (up to 600 ng/mL) from 1.5 hours to 24 hours post infusion, which was maintained in the fewer number of patients with plasma concentrations between 600 and 900 ng/mL.

Two of three patients who had plasma concentration greater than 1,200 ng/mL did not tolerate it well.

Teerlink and colleagues in the study of healthy volunteers had observed that plasma concentration in excess of 1,200 ng/mL led to "signs and symptoms of myocardial ischemia."

In fact, Teerlink et al. noted that future research should closely monitor patients for "prolongation of systolic ejection time, which might result in compromised diastolic coronary filling and myocardial ischemia."

However, in the phase II trial, Cleland and colleagues observed that along with the increase in the duration of left ventricular systole, there was a decrease in heart rate, which attenuated the decrease in the duration of diastole.

"Conversely, the duration of left atrial systole increased, possibly because of an increase in atrial contractility, emptying of the left ventricle improved, and ventricular end-­systolic and end-­diastolic volumes decreased," they wrote.

"This study suggests that omecamtiv mecarbil is generally well tolerated in patients with stable heart failure over a broad range of plasma concentrations," they concluded.

The authors cautioned, however, that they have not correlated improvements in cardiac function with improved outcomes. They also noted that the results do not apply to patients with severe heart failure who might have an inadequate cardiac output at rest, or those with mild ­to­ moderate heart failure who might not have an adequate cardiac output during exercise.

In an accompanying editorial, Kenneth Dickstein, MD, from Stavanger University Hospital in Stavanger, Norway, wrote that the mechanism of cardiac myosin activation is novel and intuitively attractive.

And while the data from these two studies are encouraging and warrant further study, "very few new agents have survived the most rigorous test: the randomized clinical trial assessing clinical outcomes," Dickstein said.

He suggested that the need for IV infusion would limit the target population, but also noted that research has begun into an oral preparation.