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PRIORITY PRESS - 83rd Scientific Sessions of the American Heart Association

Chicago, Illinois / November 13-17, 2010

Two large heart failure (HF) studies included in late-breaker sessions at the AHA are expected to alter current clinical practice.

In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure), the aldosterone antagonist eplerenone demonstrated large reductions in the composite primary end point of death from cardiovascular (CV) causes or hospitalization for HF when administered to patients with New York Heart Association (NYHA) functional class II disease. In ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial), the recombinant B-type natriuretic peptide (BNP) nesiritide had no significant effect on events, including the prespecified end point of dyspnea.

Anticipated Results from EMPHASIS-HF

The EMPHASIS-HF trial was stopped prematurely by the Data and Safety Monitoring Committee due to the magnitude of benefit in the active treatment arm. This “is certainly going to change the guidelines for mild HF,” stated principal investigator Dr. Faiez Zannad, Director, Clinical Investigation Centre, Centre Hospitalier Universitaire (CHU), Nancy, France, characterizing the consistency of benefit across end points as “impressive.”

In EMPHASIS-HF, 2737 patients in 29 countries were randomized to eplerenone 25 mg uptitrated to 50 mg or placebo and administered on top of other standard therapies. While eligibility was limited to patients with NYHA class II HF, several eligibility criteria were designed to enrich the risk for events in order to better evaluate the effect of the active therapy. Specifically, patients were required to have a left ventricular ejection fraction (LVEF) <30% or between 30% and 35% if they had a QRS interval >130 msec. Patients were also required to have been hospitalized for HF within 6 months of entering the study or to have an elevated BNP plasma level of =250 pg/mL (or pro-BNP =500 pg/mL in men and =750 pg/mL in women). Major exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 mL/1.73 m² or a serum potassium level >50 mmol/L.

Eplerenone produced a 37% reduction (HR 0.63; 95% CI, 0.54-0.74; P<0.001) in the composite primary end point of CV death or hospitalization for HF relative to placebo after a median follow-up of only 21 months (Table 1). At 3 years of follow-up, the curves were still separating. In addition, there was a 24% relative reduction (HR 0.76; 95% CI, 0.62-0.83; P<0.001) in all-cause mortality. The death from CV causes was also reduced by 24% (P=0.01) and there was a 39% (P<0.001) reduction in hospitalizations for HF, a 28% reduction (P<0.001) in hospitalization for CV causes and a 22% reduction (P<0.001) in hospitalization for any cause. A 23% reduction (P=0.12) in sudden cardiac death did not reach statistical significance, but like almost all of the measured outcomes, trended in the right direction.

Table 1.

The consistency of the results was reinforced by the subgroup analyses. Of the more than 20 subgroups evaluated—including those defined by age, gender, region of treatment, baseline blood pressure, baseline heart rate, eGFR, LVEF, history of comorbidities such as diabetes or atrial fibrillation, and presence or absence of co-therapies, such as beta blockers or ACE inhibitors—no stratification identified an absence of benefit. In this trial, almost 95% of patients were taking an ACE inhibitor or an angiotensin receptor blocker, >85% were taking a beta blocker and nearly 85% were on a diuretic and an antithrombotic drug. More than 60% were on a lipid-lowering agent.

The benefits were achieved with few adverse events. As expected, the rates of hyperkalemia were significantly greater on eplerenone than on placebo (8% vs. 3.7%; P<0.001), but the differences in the rates of discontinuation for this adverse event were not (1.1% vs. 0.9%; P=0.57). The rate of renal failure was lower on eplerenone than on placebo but not statistically different (1.9% vs. 2.3%; P=0.51). Gynecomastia, an adverse event that can lead to discontinuation of spironolactone, a non-specific aldosterone antagonist, was reported in 0.7% of those taking eplerenone and 1% of those taking placebo (P=0.54). Overall, this safety profile, in the context of efficacy, suggests eplerenone could be part of routine HF management.

“The effect on death from CV causes or hospitalization for HF translates into an impressively low number needed to treat of 19 patients. The number needed to treat to prevent one death is 51 patients, positioning this therapy in the front rank of therapeutic choices,” observed Dr. Paul Armstrong, Professor of Medicine, University of Alberta, Edmonton, in an editorial that accompanied the electronic publication of EMPHASIS-HF results on November 14 in the New England Journal of Medicine. Referring to aldosterone antagonists in general, not just eplerenone, Dr. Armstrong commented, “It is now time to overcome undertreatment by ensuring that this form of therapy is incorporated into all HF regimens.”

Aldosterone Antagonists in HF Trials

EMPHASIS-HF has closed the gap regarding the use of aldosterone antagonists across the spectrum of HF, according to Dr. Armstrong and other experts. Previously, RALES (Randomized Aldosterone Evaluation Study) associated spironolactone with a large mortality benefit in late-stage HF (Pitts et al. N Engl J Med 1999;341:709-17). EPHESUS (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) associated eplerenone with a large mortality benefit in patients after an acute myocardial infarction (MI) with LV dysfunction (Pitt et al. N Engl J Med 2003;348:1309-21). The EMPHASIS-HF trial completes this spectrum, confirming that aldosterone antagonists are effective in all forms of HF.

The ASCEND-HF study, in contrast, was a disappointment relative to promising studies previously conducted with nesiritide. In this study, 7141 patients in 30 countries with acute, severe HF were randomized to receive continuous intravenous (i.v.) nesiritide or placebo on top of standard therapy. Although previous studies had demonstrated that it can relieve dyspnea if given within 3 hours of worsening HF, the hypothesis of this study was that this therapy could prevent disease progression, providing persistent protection from dyspnea and reducing the risk of events over a 30-day period.

Neither outcome was achieved. Although more patients on nesiritide had improved breathing function compared to placebo over the first 24 hours of treatment, there was no difference in dyspnea as the symptom was prespecified. The difference in rates of significant improvement in dyspnea at 6 hours was only modestly better on active treatment than on placebo (15% vs. 13.4%). At 30 days, the rates of death from any cause or hospital readmission for HF were slightly lower on nesiritide relative to placebo but not significantly different (9.4% vs. 10.1%). These results challenge the current practice of offering this agent in advanced HF.

“I think the main message is that we need to carry out adequately powered studies to really understand the balance of safety and effectiveness of any therapy in CV disease,” remarked Dr. Adrian F. Hernandez, Associate Professor of Medicine, Duke University School of Medicine, Durham, North Carolina. Dr. Hernandez, who presented the results of ASCEND-HF, emphasized that nesiritide is safe in HF “but there is no mandate to use it because of its modest effects.”

Summary

Large multinational trials presented as late-breakers at the AHA scientific sessions are expected to alter clinical practice in the care of HF. The EMPHASIS-HF trial demonstrated that the aldosterone antagonist eplerenone can save lives when administered to patients with mild HF; ASCEND-HF trial indicated that nesiritide has no impact on outcome and only provides modest protection against symptomatic dyspnea in advanced HF. Each trial provides guidance for redefining evidence-based standards of care.