EPHESUS: Eplerenone reduces mortality, morbidity in post-MI LV dysfunction, heart failure

Susan Jeffrey

March 31, 2003

Chicago, IL - Treatment with eplerenone (Inspra®, Pharmacia) in addition to optimal medical therapy early after MI in patients with LV dysfunction and heart failure reduced overall mortality in this population by 15%, a new study shows. Rates of death from cardiovascular causes and the combination of death from cardiovascular causes and hospitalization for cardiovascular events were also significantly reduced with eplerenone compared with placebo.

The findings, from the Eplerenone Post-AMI Heart Failure Efficacy and Survival Trial (EPHESUS), were presented here at the American College of Cardiology 2003 Scientific Sessions, coinciding with the results being posted to the New England Journal of Medicine's website. The paper and an accompanying editorial will appear in the April 3, 2003 issue of the Journal.,

Dr Bertram Pitt

"With an estimated number needed to treat of 50 to save one life in one year and an estimated number needed to treat of 33 to prevent one death from cardiovascular causes or one hospitalization for a cardiovascular event in one year, the addition of eplerenone to optimal medical therapy contributes to the continued improvement in survival and hospitalization rates among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure," the researchers, led by Dr Bertram Pitt (University of Michigan, Ann Arbor), conclude in their report.

"These results confirm the effectiveness of aldosterone blockade in patients with systolic LV dysfunction and have important implications not only for patients with acute myocardial infarction and heart failure but for a variety of cardiovascular diseases currently treated with an ACE inhibitor and a beta blocker," Pitt told doctors here.

Eplerenone is already approved by the FDA for treatment of hypertension, and Pharmacia indicated in December 2002 that on the strength of the EPHESUS trial meeting both primary end points, it intended to submit the drug for approval in this new indication early this year.

The importance of aldosterone blockade

ACE inhibition and beta blockers are the therapy of choice in patients with systolic LV dysfunction postinfarction and heart failure, but the morbidity and mortality in these patients remains relatively high, Pitt told doctors here. Recent work with alternative strategies such as TNF antibodies, endothelin antagonists, and angiotensin receptor blockers on top of ACE inhibitors and beta blockers has not been effective.

In 1999, results of the Randomized Aldactone Evaluation Study (RALES)of which Pitt was also principal investigatorshowed that aldosterone blockade with spironolactone, in addition to optimal treatment including an ACE inhibitor, could reduce mortality in patients with severe heart failure. Aldosterone blockade has also been shown to prevent ventricular remodeling and collagen formation in patients with LV dysfunction after an MI, and it affects several pathological mechanisms thought to be important after MI, the researchers write.

However, Pitt noted, "in our prior trial, only 10% to 11% of patients were on a beta blocker."

Eplerenone, a selective aldosterone blocker that has been called a "cleaner, safer" version of spironolactone, blocks the mineralocorticoid receptor, but not the glucocorticoid, progesterone, or androgen receptors. In EPHESUS, Pitt et al tested the hypothesis that eplerenone might reduce mortality, both overall mortality and that related to cardiovascular causes, as well as hospitalization for cardiovascular events compared with placebo, when given in addition to contemporary standard therapy in patients with acute MI complicated by LV dysfunction and heart failure.

A total of 6632 patients with an ejection fraction <40% and rales were randomized to receive eplerenone in a starting dose of 25 mg, titrated to a maximum of 50 mg per day, or to placebo. Patients with diabetes required only an EF of <40%. Randomization took place an average of seven days after the MI (range 3 to14 days), and patients were followed until 1012 deaths had occurred. The mean dose of eplerenone reached was 43 mg/day.

Over 16 months of follow-up, there were significantly fewer deaths and cardiovascular deaths in treated patients as well as a significant reduction in the end point of death from cardiovascular causes or hospitalization for cardiovascular events.

EPHESUS: Primary and secondary end points

End point

Eplerenone, n (%)

Placebo, n (%)

Relative risk (95% CI)

p

  478 (14.4) 554 (16.7) 0.85
(0.75-0.96)
0.008
  407 (12.3) 483 (14.6) 0.83
(0.72-0.94)
0.005
  885 (26.7) 993 (30.0) 0.87
(0.79-0.95)
0.002

*Primary end points

Additional secondary end points were also reduced by eplerenone treatment, including death from any cause or any hospitalization (relative risk [RR] 0.92, 95% CI 0.86-0.98, p=0.02), and sudden death from cardiac causes (RR 0.79, 95% CI 0.64-0.97, p=0.03). They retrospectively examined the data, dichotomizing it using the MADIT II criteria of EF greater than or less than 30%, he said, and saw a significant 33% reduction in sudden cardiac death with treatment in those with an EF of less than 30%, patients who would now qualify for ICD therapy. "The implication of this to me is that defibrillators will likely be effective in these patients, but the cost-effectiveness given these numbersthe sudden death rate at one year is 6%I just can't believe they're going to be cost-effective," Pitt said.

Subgroup analysis showed a relatively uniform effect of treatment, but Pitt pointed out that patients who were on recommended therapy with an ACE or ARB and a beta blocker had a 27% reduction in all-cause mortality. Further, those who were on what he called "optimal" therapy, with an ACE/ARB, a beta blocker, aspirin, statin, and reperfusion therapy, had a 26% reduction in all-cause mortality.

Monitoring serum potassium

There was an increased incidence of hyperkalemia among patients treated with eplerenone, and the risk became statistically significant among patients with decreased creatinine clearance (<50 ml per minute) at baseline, the researchers point out. "Although there were no deaths attributed to hyperkalemia, this finding emphasizes the need to monitor serum potassium and adjust the dose of eplerenone accordingly," they write.

They attempted to minimize the risk of hyperkalemia by excluding patients with a baseline serum potassium concentration of more than 5.0 mmol/L, a baseline serum creatinine concentration of more than 2.5 mg/dL, or both, but they emphasize that for patients with a low body mass index or diabetes, serum creatinine concentration may not accurately reflect renal function.

They suggest that determination of creatinine clearance using the Cockcroft-Gault formula, exclusion of patients with moderate to severe renal insufficiency, and adherence to the range of doses used in this study, 25 mg/day to 50 mg/day, should minimize the risk of hyperkalemia and "further improve the risk/benefit ratio of this drug."

Finally, Pitt et al point out that the risk of hypokalemia was more than twice as high as the risk for serious hyperkalemia and was actually reduced by eplerenone treatment.

The increase in hyperkalemia was "more than offset" by the decrease in hypokalemia, he said. "As you recall from the SHEP trial, those patients who developed hypokalemia lost all of their benefit of blood-pressure reduction, so I think this data has important implications."

EPHESUS: Serious hyperkalemia and hypokalemia by treatment group

End point

Eplerenone (%)

Placebo (%)

p

  5.5 3.9 0.002
  8.4 13.1 <0.001

Otherwise, rates of side effects with treatment were low. In particular, menstrual disorders, gynecomastia, and impotence, seen with spironolactone in the RALES trial, were no more common with treatment than with placebo, he said, "attesting to the selectiveness of eplerenone for the aldosterone sector." There was a small but significant increase in minor GI disorders, he said, and a small but significant decrease in respiratory disorders with eplerenone.

"Very few people are choosing to use spironolactone in hypertension because of the known side-effect profile, so I think this new drug really has the potential to extend the benefits that we're showing with aldosterone blockade to a much larger group of patients and will hopefully have a great impact," Pitt said.

Real-world practice requires evidence-based medicine

In an editorial that will accompanying the article, Dr Mariell Jessup (University of Pennsylvania, Philadelphia) points out that ACC/AHA guidelines for heart failure recommend low-dose spironolactone be considered in patients with recent or current symptoms of heart failure despite best medical therapy. The guidelines add that its use in mild to moderate heart failure has not been tested and urge caution in prescribing spironolactone for patients with elevated potassium or creatinine.

"Despite these recommendations, published data and many anecdotes suggest that spironolactone has been widely used in patients with heart failure without consideration of their functional class or ejection fraction and without optimization of background treatment," Jessup writes.

The introduction of eplerenone, reportedly with fewer side effects than spironolactone, "could theoretically increase the inappropriate use of this drug," she writes, and will "undoubtedly" be more costly than the older generic drug.

"Physicians are understandably eager to apply this lifesaving therapy in their own patients but should acknowledge that real-world practice has to begin with evidence-based medicine," she writes. "The use of aldosterone antagonists may be well worth the expense or extra effort required to monitor the potential adverse effects, but patients who are treated with them should be screenedand their cases managedas carefully as those in the published studies."

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