Heart's discontent: Studies of promising heart failure treatments bring one disappointment after another


The much-anticipated results of recently completed studies on new drugs to treat heart failure (HF) have somewhat dampened the prospects of extending patients' lives

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The much-anticipated results of recently completed studies on new drugs to treat heart failure (HF) have somewhat dampened the prospects of extending patients' lives.

One of the most disappointing studies has been the Efficacy of Vasopressin Antagonism in Heart Failure (EVEREST) trial, which evaluated the once-promising investigational vasopressin antagonist tolvaptan (Otsuka Inc.). The agent was being examined as a possible alternative to loop diuretics, which are associated with neurohormonal activation and electrolyte abnormalities. Tolvaptan has been purported to be a neurohormonal antagonist that promotes aquaresis, the excretion of electrolyte-free water, as opposed to natriuresis, the excretion of fluid and sodium.

On the other hand, significantly more tolvaptan-treated patients than those on placebo showed improvements in dyspnea, orthopnea, jugular venous distension, rales, edema, and hyponatremia over the first several days after presenting with acute decompensated heart failure (ADHF).

In an editorial, published recently in the Journal of the American Medical Association, author Clyde W. Yancy of Baylor University Medical Center criticized tolvaptan for its "modest" symptom-related benefits. But he also acknowledged that "no other therapeutic intervention has been demonstrated in well-controlled studies to positively influence symptoms in ADHF without generating a question of harm."

In fact, the study appears to have broken a trend of failures in ADHF trials, in which cardiac-contracting inotropic agents (e.g., milrinone, dobutamine) improved patients' symptoms but at the cost of ventricular arrhythmias and increased mortality. At one point, the inotropic agent levosimendan, available in Europe, was reported to have promise in chronic HF without promoting arrhythmias, but those hopes were dashed when the agent failed to improve clinical outcomes in a phase II study of patients with severe chronic HF.

FUSION-2 trial

Even Natrecor (nesiritide, Scios), a non-inotropic vasodilator/natriuretic, has been surrounded by considerable controversy regarding its potential to worsen renal function and increase mortality. It appears that the recently released results of the Second Follow-up Serial Infusions of Nesiritide in Advanced Heart Failure (FUSION-2) trial have laid most of these fears to rest, but they haven't brought much positive news either.

Also presented at the recent ACC meeting, the FUSION-2 trial randomized just over 900 patients with NYHA class 3 or 4 HF with an LVEF less than 40% and a history of at least two prior hospitalizations within the past year to receive a nesiritide infusion or placebo for four to six hours, once or twice a week for 12 weeks.

At the end of the trial, there were no significant differences in all-cause mortality or cardiovascular/ cardiorenal hospitalization. But perhaps more important in this case are findings indicating that the drug does not appear to be harmful overall or to renal function in particular.

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