Eplerenone Gains in Mild HF Cut Across High-Risk Subgroups

August 29, 2011

August 29, 2011 (Paris, France) — Even patients with such high-risk features as diabetes or renal compromise showed highly significant drops in CV mortality or heart-failure hospitalizations from treatment with eplerenone (Inspra, Pfizer) in EMPHASIS-HF, suggested a prespecified analysis presented here today at the European Society of Cardiology (ESC) 2011 Congress.

Dr Bertram Pitt

That primary end point in the trial, which had randomized patients with NYHA class 2 systolic heart failure to receive the aldosterone blocker or placebo on top of standard heart-failure meds, fell sharply in the high-risk subgroups to about the same degree, with only mild effects on serum potassium levels, as what was observed in the overall trial.

"So, overwhelmingly the data are positive," co–principal investigator Dr Bertram Pitt (University of Michigan School of Medicine, Ann Arbor), who presented the new insights, told heartwire .

"The diabetics, those with renal disease, the elderly, and the low ejection fraction and low blood-pressure [subgroups] all showed the same efficacy, more or less, and the same safety. We saw an excess of hyperkalemia [potassium >5.5 mmol/L] . . . and less hypokalemia, but there was less serious hyperkalemia [potassium >6.0 mmol/L], no significant excess of hospitalization for hyperkalemia or renal disease, and not a single patient that we know about died due to hyperkalemia on eplerenone. So to us, the data are pretty straightforward and pretty compelling for the use of eplerenone in patients with NYHA class 2 heart failure."

As previously reported by heartwire when the trial's primary results [1] were presented at the American Heart Association 2010 Scientific Sessions, EMPHASIS-HF randomized 2737 patients with mild heart failure and an LVEF <30% (30% to 35% was allowed if QRS >130 ms) to receive eplerenone or placebo on top of standard therapy. The trial was stopped early on emergence of a significant eplerenone benefit.

By then, after a mean follow-up of 21 months, eplerenone recipients had shown a 37% reduction in the primary end point (p<0.001), 24% reduction in cardiovascular death (p=0.01), and a 42% reduction in hospitalization for heart failure (p<0.001) compared with the placebo group.

Other new findings from the trial presented at the ESC sessions, Pits said, come from a subcohort follow-up extended by up to seven more months with preserved double-blinding (total mean follow-up, 25 months). The primary end point reduction was steadfast, at about 34% (p<0.0001).

For patients with mild heart failure, hospitalization really matters--really matters for survival, for the progression of the disease, and for quality of life.

Pitt explained that the trial's primary end point accounted only for first heart-failure hospitalizations, but in the extended analysis, "there's a striking reduction over time for repeated hospitalizations that has cost implications as well as long-term quality-of-life implications."

Obviously, mortality is important; "however, for patients with mild heart failure, hospitalization really matters--really matters for survival, for the progression of the disease, and for quality of life," observed Dr Piotr Ponikowski (Medical University, Clinical Military Hospital, Wroclaw, Poland) as the discussant following Pitt's formal presentation.

"EMPHASIS-HF provides the final piece of evidence that mineralocorticoid-receptor antagonists can be and should be considered across the whole spectrum of heart failure, starting from post-MI LV dysfunction [EPHESUS], via mild to moderate heart failure [EMPHASIS-HF], and ending in those with severe heart failure [RALES]."

Yet the drug class is grossly underused in both Europe and the US, Ponikowski said, reaching only 40% to 50% and 32% of eligible patients, respectively, according to data from several years ago. Significant predictors of no treatment with aldosterone blockers despite eligibility, he said, include older age, lower systolic blood pressure, lack of an implantable defibrillator, a history of renal insufficiency, and diabetes.

The new EMPHASIS-HF insights presented by Pitt directly address such shortfalls in aldosterone-blocker use, he said, and show that their benefits seen in trials to date are "real, consistent, and clinically meaningful."

Rate of Primary End Point (HR, 95% CI Eplerenone Vs Placebo) for All Subjects and by High-Risk Subgroup in EMPHASIS-HF, Prespecified Analysis

Population Eplerenone Placebo HR (95% CI) p
All subjects 18.3 25.9 0.63 (0.54–0.74) <0.0001
Age >75 y 23.6 32.7 0.66 (0.49–0.88 0.004
Diabetes 21.6 35.2 0.54 (0.42–0.70) <0.0001
eGFR <60 mL/min/1.73 m2 24.4 34.5 0.62 (0.49–0.79) 0.0001
LVEF <30% 19.3 27.3 0.65 (0.53–0.78) <0.0001
Systolic BP <123 mm Hg (trial median) 20.6 29.4 0.63 (0.51–0.79) <0.0001

eGFR=estimated glomerular filtration rate

LVEF=left ventricular ejection fraction

"Paradoxically," according to Pitt, "heart-failure patients with renal disease are among the highest risk, so physicians are overly cautious [with them], and they get the worst treatment--you have people at very high risk [being undertreated]." But it's in those patients, he said, that physicians should be more aggressive.

"I understand no one wants to cause difficulty or harm. But here, we've done it without causing harm. Obviously you have to follow the [trial's] inclusion and exclusion criteria. You can't give it to people with high potassium--over 5.0 mmol/L. You've got to monitor serum potassium. If you're not willing to do that, you shouldn't go there. But if you're willing to do it, you get a lot of benefit."

Pitt says he expects the US and European guidelines to soon be updated to include a recommendation for aldosterone blockade, generically, in mild heart failure and in these high-risk groups in particular. "After this, we think they should say specify that you should use eplerenone, at least in the diabetic subset, because there's good data now that spironolactone in diabetes makes endothelial function worse--it raises hemoglobin A1c, raises cortisol, and reduces adiponectin--whereas eplerenone does not."

EMPHASIS-HF was funded by Pfizer. The primary EMPHASIS-HF report [1] states that Pitt disclosed "receiving fees for serving on the board of Novartis; consulting fees from Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, BG Medicine, Nile Therapeutics, Merck, Forest Laboratories, and Novartis; grant support from Forest Laboratories and Novartis; and stock options from Relypsa, BG Medicine, Nile Therapeutics, and Aurasenc; his institution receives grant support from Forest Laboratories on his behalf, and he and his institution receive grant support from Bayer." Ponikowski disclosed consulting for or receiving honoraria for speaking from Vifor Pharma, Amgen, Servier, Sanofi-Aventis, Corthera, Novartis, Johnson & Johnson, Bayer, Pfizer, Merck-Serono, Merck, and Respicardia.