Tuesday, May 4, 2004

ACTIV-CHF Results May Be Good News for Heart Failure Patients
By Mike Upchurch

A new drug for heart failure could be a safe, effective aid in prolonging the lives of those most at risk, according to the results of a DCRI-led trial. DCRI authors Drs. Chris O’Connor and Wendy Gattis, along with their colleagues on the ACTIV in CHF trial, reported their findings in the April 28 issue of the Journal of the American Medical Association.

There are about 1 million hospitalizations for heart failure each year in the U.S. Heart failure occurs when the heart, through injury or disease, is weakened and cannot pump adequate amounts of blood through the body. The result can be difficulty breathing, leg and ankle swelling, shortness of breath, and dangerous fluid retention in the lungs. Standard drug therapy includes diuretics, which boost urine production to lower fluid volume, but these can cause kidney problems and are often inadequate. Readmission rates for heart failure can be as high as 50% according to the authors.

A new treatment could reduce the reliance on diuretics and those associated risks.

"It would probably not eliminate diuretics but would allow us to reduce their doses," said lead author Dr. Mihai Gheorghiade of Northwestern University.

In this Phase II study, the ACTIV in CHF team tested tolvaptan, a vasopressin blocker, in addition to standard treatment for heart failure. Vasopressin is a hormone that lowers urine volume and promotes the constriction of blood vessels. Tolvaptan is designed to block receptors for vasopressin on cells and so inhibit its action.

The trial enrolled 319 patients with worsening heart failure at sites around the U.S. and Argentina, and randomized them to receive 1 of 3 different doses of tolvaptan or placebo, plus standard therapy. The study used 2 primary endpoints, one in-hospital to measure the medication’s immediate effects and one after discharge to assess it over time. Because this is a Phase II study, it was designed chiefly to ascertain the safety of the medicine and determine if it showed a trend towards benefit in this relatively small number of patients.

The in-hospital endpoint was change in body weight within 24 hours of randomization. Because heart failure patients tend to retain fluid, reducing body weight, and the subsequent strain on the kidneys, lungs, and heart, can be an important factor in treatment.

The outpatient, composite endpoint was a combination of worsening heart failure, defined by the need for rehospitalization or unscheduled ER visit for heart failure or death at 60 days after randomization.

Patients in the tolvaptan groups saw a decrease in body weight after 24 hours ranging from 1.8 kg (about 4 pounds) to 2.1 kg (4.6 pounds). The placebo group’s weight dropped by just 0.6 kg, or roughly 1.3 pounds. Importantly, tolvaptan achieved this without dangerously lowering blood pressure or impairing kidney function, both of which are dangers with diuretics.

Rates of the composite, outpatient endpoint of worsening heart failure or death were similar in patients on tolvaptan and placebo. Though it was not statistically significant, rates of mortality among those patients with systemic congestion did suggest an advantage with tolvaptan.

Systemic congestion is a dangerous accumulation of blood beyond the heart and its surrounding major blood vessels due to inefficient pumping, and it significantly increases a patient’s risk. As treatment for heart failure has improved, the problem of congestion has become more prevalent.

"We're much more effective now at preventing sudden death with defibrillators and beta-blockers,” said Dr. Gheorghiade. “The population is living longer with heart failure, but living longer equals congestion."

The trend towards a mortality benefit in these at-risk patients is an important avenue for further research, according to the authors. A larger, long-term Phase III study of tolvaptan called EVEREST is already underway to determine whether the drug reduces the rates of death among heart failure patients.

The DCRI coordinated ACTIV in CHF and provided clinical event adjudication. Dr. O’Connor was the principal investigator at DCRI and Dr. Gheorghiade was the overall trial leader. The DCRI’s Wendy Gattis, PharmD, served as the project leader for ACTIV in CHF.