In another study by the same group, patients with advanced heart failure who had antibodies that fostered reduced calcium movement and depressed myocyte contractility responded to removal of these antibodies through immunoabsorption with a significant increase in ejection fraction; patients without these antibodies didn't respond.
Statins
Statins are known to have anti-inflammatory effects. In a study involving 1,186 heart transplant recipients at 12 centers participating in the Heart Transplant Lipid Registry, those on statin therapy had 4% mortality and a 2.4% fatal rejection rate, compared with 13.7% and 7.2%, respectively, in patients not on a statin (Am. J. Cardiol. 2005;95:367–72).
Celacade Immune Modulation Therapy
Dr. Torre-Amione was the principal investigator in a favorable phase II clinical trial of a novel proprietary technology to deliver controlled oxidative stress to a small sample of a patient's blood, which is then returned to the patient via intramuscular injection. The oxidative stress results in cell apoptosis, which in turn induces a favorable immune response marked by reduced inflammatory cytokines and increased production of the anti-inflammatory cytokines interleukin-10 and transforming growth factor-β.
In the double-blind, randomized, 6-month trial involving 75 patients with advanced heart failure, there was one death among patients on monthly Celacade therapy, compared with seven in the placebo therapy group. The Celacade group also had significantly fewer hospitalizations.
On the basis of these results, which Dr. Torre-Amione termed “highly provocative,” the pivotal ACCLAIM study is under way. ACCLAIM (Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation) is a phase III, 2,000-patient randomized trial headed by James Young, M.D., chairman of the division of medicine at the Cleveland Clinic.
The study sponsor, Vasogen, is also developing Celacade as a therapy for peripheral artery disease. Dr. Torre-Amione is a consultant to the company.
If cumbersome extracorporeal therapies such as immunoabsorption and plasmapheresis prove to have sustained benefit, they may find a role analogous to the role now played by short-term hospitalization for medication adjustment in patients with acute decompensated heart failure.
Vasopressin Antagonists
Turning to the vasopressin antagonists, Mihai Gheorghiade, M.D., said these agents address two major underserved aspects of heart failure: congestion and hyponatremia. Worsening congestive symptoms are the main reasons for hospital admission in heart failure patients. Yet current therapy targeting congestion is limited to diuretics, which have well-known adverse effects and limited efficacy. Moreover, roughly 25% of patients hospitalized for heart failure have mild hyponatremia, a strong predictor of poor short-term prognosis.
Three investigational vasopressin antagonists are being developed for patients with both heart failure and hyponatremia. Dr. Gheorghiade is most familiar with tolvaptan, the Otsuka Pharmaceutical Co. drug for which he has conducted clinical trials. Tolvaptan produces a rapid and sustained reduction in body weight due to diuresis without disrupting electrolytes in heart failure patients. This effect is accompanied by normalization of serum sodium within 24 hours in hyponatremic patients, but no significant increase in serum sodium is seen in patients with a normal baseline sodium value. These favorable outcomes are achieved without changes in blood pressure, heart rate, serum potassium, or blood urea nitrogen, unlike with loop diuretics, said Dr. Gheorghiade, professor of cardiology at Northwestern University, Chicago.
The relatively small trials completed to date have shown a trend toward reduced mortality in tolvaptan-treated heart failure patients with hyponatremia, increased BUN levels, or signs of congestion. This suggested benefit is now being definitively evaluated in more than 1,800 patients hospitalized for heart failure in the phase III Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). The primary end point is 60-day mortality.
“The vasopressin antagonists are going to be an extremely powerful tool, I think, for this population of sick patients with hyponatremia,” commented session cochair Michael B. Fowler, M.D., professor of medicine and director of the cardiomyopathy center at Stanford (Calif.) University.
Adrian Iaina, M.D., noted that the prevalence of anemia in patients with heart failure is 40%–50%. Anemia is a powerful risk factor for mortality in heart failure. In 54 published studies, for each 1-g reduction in hemoglobin the risk of mortality increased almost 16%.
Both controlled and uncontrolled small studies indicate that correction of heart failure anemia with weekly subcutaneous erythropoietin and monthly intravenous iron improves cardiac and renal function and exercise capacity and reduces shortness of breath and fatigue, with a resultant marked decrease in the number of hospitalizations. Definitive large randomized trials are ongoing, said Dr. Iaina, head of nephrology at Tel Aviv Sourasky Medical Center.