IMPRESSIVE RESULTS WITH EPLERENONE FOR MILD HEART FAILURE

November 14, 2010 (Chicago, Illinois) — The aldosterone antagonist eplerenone (Inspra, Pfizer) produced large reductions in both the risk of death and the risk of hospitalization compared with placebo in patients with systolic heart failure and mild symptoms in the EMPHASIS-HF trial [1].

The results showed a 37% reduction in the primary end point of the composite of death from cardiovascular causes or hospitalization for heart failure, a 24% reduction in cardiovascular death, and a 42% reduction in hospitalization for heart failure. The study was published early online today in the New England Journal of Medicine to coincide with a press conference here at the American Heart Association (AHA) 2010 Scientific Sessions; full results were also presented later today during the first late-breaking clinical-trial session of the meeting later in the day.

Huge Expansion of Eligible Patients

Aldosterone blockade--with either spironolactone or the newer more selective eplerenone--has already shown benefits in class 3-4 heart failure and in post-MI patients with heart failure. The current results now extend the benefit to patients with mild heart failure, a much broader population.

Presenting the EMPHASIS-HF results, Dr Faiez Zannad (INSERM, Nancy University, France) said: "We believe that the robustness of these findings, in conjunction with the consistent finding from RALES in severe heart failure and EPHESUS in post-MI patients with LV dysfunction, provides compelling evidence for a change in clinical practice. I would say that all patients with systolic dysfunction are now eligible for an aldosterone antagonist, except for those with contraindications." The contraindications are patients with renal dysfunction and others likely to develop hyperkalemia.

Co–principal investigator of the EMPHASIS-HF study, Dr Bertram Pitt (University of Michigan School of Medicine, Ann Arbor), commented to heartwire : "We were overwhelmed by the results. We expected them to be good, but we were surprised by how good they were, especially as eplerenone was given on top of really good contemporary therapy."

Discussant More Cautious
The main issue that will limit use of eplerenone or spironolactone is the increased risk of hyperkalemia, which can be fatal, and this was highlighted by the designated discussant of the study, Dr Lynne Warner Stevenson (Brigham and Women's Hospital, Boston, MA). She stated: "Before we recommend expanding the population to receive aldosterone antagonists, we need to learn how to use them without causing life-threatening hyperkalemia. This may be particularly true for patients with reduced renal function, diabetes, and advanced age. The risk/benefit ratio should be specifically assessed for patients who do not require loop diuretic therapy, in whom the risk for heart-failure events may be particularly low but the risk for hyperkalemia may be higher."
But Pitt countered that the hyperkalemia issue should not prevent these drugs from being prescribed. "I would say aldosterone antagonists should now be recommended for all patients with mild heart failure unless they have severe renal dysfunction or a potassium level over 5. But it is essential to monitor the potassium. If you are not willing to do that, then you shouldn’t prescribe this drug. However, while it is right to be concerned about the hyperkalemia, the tremendous benefits on outcomes completely justify the extra work required to use these drugs."

Speaking at an AHA press conference on the study, Dr Mariel Jessup (University of Pennsylvania School of Medicine, Philadelphia) said: "We have very good data now that aldosterone antagonists work for patients with heart failure and are saving lives, but we need to better understand the hyperkalemia and how exactly these drugs are working. This is an exciting day indeed, as we have a large new patient population for this drug, but we still have a lot of work ahead of us."

"Added Real Value"

In an accompanying editorial [2], Dr Paul Armstrong (University of Alberta, Edmonton) says: "The EMPHASIS-HF investigators have added real value to the management of heart failure. . . . It is now time to overcome undertreatment by ensuring that this form of therapy is incorporated into all heart-failure regimens."
He adds that the effect of death from cardiovascular causes or hospitalization for heart failure translates into an impressively low number needed to treat to prevent one event: just 19 patients. And the number needed to treat to prevent one death is 51, which he says positions this therapy "in the front rank of therapeutic choices."

The trial involved 2737 patients with NYHA class 2 heart failure and an ejection fraction of no more than 35%. They were randomized to eplerenone (up to 50 mg daily) or placebo in addition to recommended therapy. After a median follow-up of 21 months, the trial was stopped early because of a significant benefit in the eplerenone group.Death from any cause and hospitalization for any cause were also significantly reduced.

Beware of Hyperkalemia

The main side effect was hyperkalemia, with potassium levels exceeding 5.5 mmol/L occurring in 11.8% of eplerenone patients vs 7.2% of those in the placebo group (p<0.001). The authors note that the increase in hyperkalemia with eplerenone was expected, but it underscores the need to measure serum potassium levels serially and to adjust the dose of eplerenone accordingly. In contrast, the incidence of hypokalemia was significantly reduced in the eplerenone group, which the authors point out is also important, as a potassium level below 4 mmol/L can increase the risk of death.

The issue of how much the risk of hyperkalemia would limit the use of eplerenone was a major talking point at the press conference. This side effect of aldosterone antagonists was highlighted in a New England Journal of Medicine paper by Juurlink et al in 2004 that showed that after the publication of the RALES trial with spironolactone, prescription of aldosterone antagonists increased significantly, but so too did deaths from hyperkalemia [3].
But Zannad stressed that if the potassium levels are monitored closely and the drugs are not given to patients at risk of hyperkalemia, they are safe. "The hyperkalemia is predictable, preventable, and manageable, with lowering the dose or discontinuing therapy. In the Juurlink paper, the vast majority of patients with hyperkalemia were treated outside the label, and many had risk factors for hyperkalemia," he noted.

Commenting on the issue for heartwire , Dr Clyde Yancy (Baylor College of medicine, Houston, TX), who was not involved in the study, said: "I am enthusiastic about expansion of the population for these drugs to include patients with mild heart failure, but my enthusiasm is tempered by the hyperkalemia issue."

He commented: "There is an ever-present risk of hyperkalemia, and doctors need to be continuously vigilant in this regard. These drugs should not be used in patients with established kidney disease or those prone to developing hyperkalemia."

Yancy noted that raising potassium levels slightly can be beneficial as it reduces irregular heart rhythms, but care must be taken not to exceed levels of 5.5 mmol/L, when the incidence of fatal heart rhythms increases. He added: "The hyperkalemia issue is bound to prevent blanket use of these agents. Doctors don't like risks with drugs. The more provisos there are, the less the uptake will be. And in this case there are good reasons to be careful. But the benefit of these drugs is considerable, and they should be used a lot more than they are at present."

Jessup took a similar line: "This is definitely going to lower the threshold to add an aldosterone antagonist, but I wouldn't advise use in all patients with systolic dysfunction. I would perhaps still start patients on an ACE/[angiotensin-receptor blocker] ARB and a beta blocker at first presentation of heart failure, and perhaps a diuretic, then add in an aldosterone antagonist a little later on. But hyperkalemia is a still a very real concern. You can't just put a patient on this drug and say see you in two months. It requires close monitoring that will increase the workload for both doctor and patient, and that will stop many people using it, but I would still say it is worth the effort."

Jessup drew a comparison with warfarin. "Like warfarin, aldosterone antagonists have great potential to lower events, but they have to be monitored carefully to be able to use them safely."

Pitt said for patients with normal renal function, without any other signs of hyperkalemia, he would recommend that potassium levels be measured in the first 24 hours, then again after a month, and then checked around twice a year. "This is not too much different from what we already do for ACE inhibitors/ARBs. But if the patient has any degree of renal dysfunction, potassium levels need much closer monitoring, at least every three months," he added.

Pitt said he would extrapolate the EMPHASIS results to the mildest patients with systolic dysfunction. "While this trial did not include the mildest patients--those who have never been hospitalized and have low [brain-natriuretic-peptide] BNP levels--I personally would still want to take eplerenone if I were one of these patients."

Use in more severe patients should also now increase

Yancy explained that concerns about hyperkalemia are probably the reason why aldosterone antagonists are not being used as much as they should be in the severe heart-failure population. "I hope this study will be the trigger for patients to start using aldosterone antagonists more frequently. These data are persuasive; they will be given strong consideration when we rewrite the heart-failure guidelines. But before we start advocating mass use in the milder population, we need to increase the take-up of aldosterone antagonists in more severe heart-failure patients. Although we already have impressive results in this group, still two-thirds of patients eligible are not getting these drugs. I am hoping that this very significant study should raise the confidence of doctors to use these drugs more."

Class Effect

All the experts agreed that the effect seen with eplerenone in EMPHASIS-HF was probably a class effect of aldosterone antagonists and should also be seen with spironolactone. Zannad commented: "The results are very consistent with those of the RALES trial with spironolactone in more severe disease. I would say use eplerenone if you can afford it; if not, then better to take spironolactone than nothing."

Yancy agreed with this stance. "My assessment of what has been seen so far is that this is a class effect. Yes, you can probably use spironolactone instead and save some money, but spironolactone does have the drawback of producing gynecomastia in men and loss of libido in women in about 10% of patients. Eplerenone does not do this." He said the two drugs were similar in their risks of hyperkalemia.

Pitt pointed out that as eplerenone is available generically now in the US, the cost implications are not that great. "While it is still more expensive than spironolactone, it is not that expensive anymore." Eplerenone is, however, still under patent in Europe and Canada.

How Does EMPHASIS Fit in With RAFT?

Discussing how the EMPHASIS results would fit in with the other new study in mild heart-failure patients, RAFT, also presented today and showing a benefit of using CRT devices, Pitt said: "While devices also seem to add benefit in some mild patients, it would be interesting to know how much benefit the devices would add if everyone were on an aldosterone antagonist. I would much rather be on another drug first than having a device fitted. I think it is important to optimize medical therapy, which now includes aldosterone antagonists, before considering a device."

Patients Were at Higher Risk Than Thought?

In his editorial, Armstrong suggests that the 37% reduction in the composite end point in EMPHASIS-HF seems "surprisingly large for a trial of mildly symptomatic patients," but then he points out that on further investigation of baseline characteristics, the population involved in the study was actually quite high risk. He notes that half had previously been hospitalized for heart failure and had a history of MI and that hypertension, atrial fibrillation, and diabetes were also common. He adds that the mean ejection fraction of 26% (which is almost identical to the more severely symptomatic patients in the RALES trial) is "a cogent reminder of the discordance between functional class and left ventricular function."

He also points out that another feature signaling high risk is that one-quarter of the patients in EMPHASIS-HF had left bundle branch block and the overall mean QRS duration was 122 ms. And although use of ACE inhibitors and beta blockers were common, the infrequent use of defibrillators or CRT "raises the question as to whether eplerenone would have fared as impressively had a larger proportion of the population received implantable electrical devices, in alignment with current guidelines." He says: "This points to the need for further investigation, given that even the trial participants receiving active therapy had a one-year mortality rate of approximately 5%."

Worth the Extra Cost?

Armstrong questions whether eplerenone is worth the extra cost over spironolactone. Noting that spironolactone is available for "pennies a day," he says that a reasonable tactic might be to assume that the current findings also apply to the cheaper drug and to reserve eplerenone for those few patients in whom the side effects of spironolactone are disabling.

Noting that aldosterone antagonists are also being tested in diastolic dysfunction and in acute MI and a preventive approach in patients at high cardiovascular risk may also be on the horizon, Armstrong concludes: "Of the quartet of therapies that have served us well over the past half century, aldosterone antagonism seems most likely to be the last man standing."
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References

1. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. New Eng J Med 2010; DOI:10.1056/NEJMoa1009492. Available at: http://www.nejm.org.
2. Armstrong P W. Aldosterone antagonists--Last man standing? New Eng J Med 2010; DOI:10.1056/NEJMe1012547. Available at: http://www.nejm.org.
3. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351:543-551. Abstract