Rx CARE

HEART SUCCESS

Angiotensin inhibitor and new vasodilator promising for heart failure patients

Approximately five million Americans suffer from congestive heart failure, a potentially life-threatening disorder that can require urgent treatment—and pharmaceutical companies are continuing their search for newer and better drugs for this condition.

Clinical trial results of three drugs were among the highlights of this year's annual meeting of the American Heart Association, held recently in New Orleans.

One trial showed that adding the angiotensin II receptor blocker valsartan (Diovan, Novartis) to standard treatment with beta-blockers, ACE inhibitors, diuretics, and digoxin significantly reduced both morbidity and mortality. The 5,000-patient multinational trial involved a diverse population group.

Jay Cohn, M.D., professor of medicine, cardiovascular division, at the University of Minnesota, said that patients in the trial were randomized to 40 mg b.i.d. of valsartan initially, which was titrated to 160 mg b.i.d., or to placebo. Patients in both arms of the study continued on their usual standard therapy, which included ACE inhibitors, diuretics, digoxin, and beta-blockers. Valsartan, he said, reduced all-cause mortality and morbidity by 13.3%, reduced hospitalizations for heart failure by 27.5%, and improved significantly the New York Heart Association functional class, the ejection fraction, the patients' signs and symptoms, and their quality of life.

Cohn said in an interview that "the data from Val-HeFT [Valsartan Heart Failure Trial] would suggest that valsartan is a useful drug to add to existing therapy," particularly either an ACE inhibitor or a beta-blocker. He added also that he would not hesitate to use valsartan as monotherapy. "I think valsartan is an ideal drug to begin a patient on." Acute exacerbation of heart failure, or acute decompensated heart failure, is another big problem in such patients for which better therapy has been sought.

In another multi-institutional trial, involving 498 patients, the dyspnea and unfavorable hemodynamic measures associated with acute decompensated heart failure were significantly reduced with the use of a recombinant B-natrurietic peptide nesiritide (Natrecor, Scios Inc.). Results from a phase III trial compared this new drug with the standard nitroglycerin treatment, or placebo, reported James Young, M.D. He is head of the section of heart failure and transplant medicine at the Cleveland Clinic Foundation and director of the Kaufman Center for Heart Failure there.

Young, who also chaired the steering committee of the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, told Drug Topics that the cost of this new treatment would probably lie somewhere "between that of nitroglycerin, made by several companies, and that of milrinone (Primacor Injection, Sanofi)." He added that nesiritide should be especially useful in the emergency room, where it would provide rapid relief of symptoms and rapid control of pulmonary wedge pressure by inducing rapid vasodilation or relaxation of blood vessels. Although it was never formally approved for this purpose, he said, IV nitroglycerin has been the usual parenteral agent used for this acute condition.

In the VMAC study, nesiritide reduced pulmonary wedge pressure in as little as 15 minutes, and its effectiveness continued for 48 hours. At three hours, response was better with the new drug than with either nitroglycerin or placebo. Young said that the most common adverse event with nesiritide was headache, which occurred in 8% of patients on this new drug, compared with a 20% occurrence in patients randomized to the standard nitroglycerin treatment.

In another trial, one involving patients with congestive heart failure who suffer chronic angina, the first of a new class of compounds called partial fatty acid oxidation (pFOX) inhibitors, ranolazine (CV Therapeutics), showed promise in increasing the exercise time possible before the onset of pain in patients ranging in age from 21 to 65.

Vincent DeQuattro, M.D., professor of medicine at the University of Southern California, reported that in a crossover phase III trial in 191 patients not receiving any other anti-angina drugs, ranolazine was given as monotherapy and compared with placebo. Three doses (500 mg, 1,000 mg, and 1,500 mg) were studied. Ranolazine significantly increased exercise duration at trough plasma concentrations, which occur about 12 hours after the previous dose, compared with placebo.

Another study showed that in a trial of 525 patients with acute angina or non-Q-wave myocardial infarction who were also taking aspirin, the combination of the low molecular weight heparin enoxaparin sodium (Lovenox Injection, Aventis) and tirofiban (Aggrastat Injection, Merck) was well tolerated. There were rates of major and minor bleeding similar to that of another study arm in which tirofiban was given with unfractionated heparin.

New treatments for angina

Each year about 1.5 million people are hospitalized for heart attacks or worsening chest pain (unstable angina). There are now some trial results showing how these patients might be better treated medically, although many will, of course, require other procedures, such as angioplasty and surgery, as well. One such medical study indicated that aggressive lowering of blood lipids immediately after a heart attack is beneficial. This statin study also showed that such a drug not only benefits patients at risk of heart attacks but also can help patients if it is given immediately after the patients develop either unstable angina or a non-Q-wave myocardial infarction.

A trial in 3,000 patients showed that early intensive lipid-lowering with atorvastatin (Lipitor, Pfizer) resulted in a cumulative incidence reduction to 14.8% from 17.4% in the primary trial end points of death, cardiac arrest with resuscitation, or recurrent chest pain requiring rehospitalization, compared with those who did not get such treatment. Atorvastatin also reduced the risk of stroke over the next four months after the lipid-lowering treatment from about 1.5% to 0.5%, Gregory Schwartz, M.D., Ph.D., reported. He is chief of cardiology at the Denver Veterans Affairs Medical Center and principal investigator of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial. The need for rehospitalization as a result of worsening angina was also reduced to 6.2% from 8.4% for the placebo group at four months.

Another study in more than 300 patients coming to the hospital with heart attacks (confirmed by electrocardiogram) showed that an antiplatelet agent combined with a reduced dose of a clot buster may be better than a higher dose of the thrombolytic alone.

One study showed that the antiplatelet agent Integrilin Injection (eptifibatide, Cor Therapeutics, Schering Plough) was more effective when combined with half-dose alteplase (Activase IV, Genentech)—compared with using a full dose of alteplase. The study showed that the combo therapy was effective in terms of restoring flow through clogged coronary vessels, according to Eric Topol, M.D., chief of cardiology at the Cleveland Clinic Foundation. He reported that Integrilin was dosed as a 180-mcg/kg bolus, followed by a 90-mcg/kg bolus and a 2.0-mcg/kg/min infusion for up to 48 hours, and administered with alteplase dosed as a 15-mg bolus and 35-mg infusion for 60 minutes. He said that Integrilin restored normal blood flow at 60 minutes in 56% of patients compared with 40% of patients given the full standard dose of alteplase alone.

Topol also reported results of another trial showing that abciximab (ReoPro, Lilly) resulted in fewer deaths at 30 days, compared with tirofiban. This study involved patients who had stents placed in their coronary arteries to keep them open after angioplasty. ReoPro, a monoclonal antibody, was found to be more expensive.

As good as device

A multicenter randomized trial comparing amiodarone with implantable cardiac defibrillators (the AMIOVIRT trial) came out in favor of the drug for patients having so-called nonischemic dilated cardiomyopathy, a weakening of the heart muscle that can cause fainting or sudden death. Adam Strickberger, M.D., associate professor of internal medicine at the University of Michigan, said this was the first time that implantable defibrillators had been compared with the use of amiodarone in preventing sudden death. In this trial of 178 patients (102 of whom were randomized and the rest were in the registry), the mortality was the same, according to Strickberger, indicating that surgery can be avoided in such patients.

Jean McCann

Based in Ohio, the author has extensive experience covering national and international medical and pharmaceutical meetings.

Jean Mccann. Angiotensin inhibitor and new vasodilator promising for heart failure patients.

Drug Topics

2001;1:16.