"Evidence Gap" in Heart-Failure Indications for Aldosterone Inhibitors: Does it Matter?

May 23, 2008

May 23, 2008 (Buenos Aires, Argentina) - There is a guidelines "evidence gap" regarding use of aldosterone antagonists in patients with heart failure, in that the only two relevant major randomized trials to explore the issue, ultimately supporting their post-MI use and in NYHA class 3-4 disease, respectively, essentially excluded patients in NYHA class 2. That much was agreed by Dr Willem J Remme (Sticares Cardiovascular Research Foundation, Rhoon, the Netherlands) and Dr José Luis López-Sendón (Hospital Universitario La Paz, Madrid, Spain) at a debate held during the World Congress of Cardiology 2008 scientific meeting. Their point of contention: does it matter?

With López-Sendón advocating steadfast adherence to evidence-based medicine and therefore not to use the drugs in NYHA class 2, Remme produced a mountain of non–clinical-trial evidence to support the contrary view.

The two trials, both placebo-controlled, were the Randomized Aldactone Evaluation Study (RALES) [1], which tested spironolactone on top of standard medical therapy in patients with chronic NYHA 3-4 heart failure and an LVEF <35%, and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [2], which explored the use of eplerenone in post-MI patients with an LVEF <40--some of whom were in NYHA class 2 at study entry. Aldosterone blockade was life-prolonging and reduced morbidity in both trials, López-Sendón and Remme both noted.

"Impressionistic Medicine"

López-Sendón's first line of reasoning included a classic observation about many heart-failure drug trials. "If you're a gambler and you want to win, you should bet that a drug tested in [heart-failure] clinical trials will be a loser," he said, displaying a long list of drugs just like that, including xamoterol, enoximone, milrinone, flosequinan, vesnarinone, epoprostenol, sotalol, and others. Not that all those agents are worthless, he said, simply that in heart failure, the right target population for them or perhaps the right dosing has not been identified.

"So we are in great need of the evidence. But what sort of evidence do we need?" Not anecdotal clinical experience ("worthless"), surrogate end points ("terrible"), or observational registries or case-control studies ("of poor value"), he said. Meta-analyses or a large clinical trial ("getting better")? The evidence should be sound, consistent with an evidence level of A in the guidelines--that is, it should come from at least two appropriate clinical trials. "The rest is so-called impressionistic medicine, where one has the impression that a particular drug will of benefit to the patient."

Acknowledging that there are, in fact, two trials supporting aldosterone antagonism in heart failure, he pointed out that NYHA class was not among the entry criteria of EPHESUS. Furthermore, many heart-failure patients seen in clinical practice have ejection fractions higher than the trial's 40% cutoff point. "So we don't know the effects of blocking the aldosterone system in patients with [higher] ejection fractions," López-Sendón said.

"Sorry, Guys . . . "

In return, Remme acknowledged that "the guidelines people" would contend that there are inadequate data supporting the drugs in class 2. But he also noted that heart failure in patients with post-MI systolic dysfunction will ultimately reach NYHA class 3 if nothing major is done. "I'd say, sorry guys, but am I really going to stop treating my EPHESUS-type patients [with aldosterone blockers], when I've already started doing it, or should I wait until my patient in class 2, who is definitely not very happy, gets really sick in class 3? Why shouldn't I treat all my class 2 patents?"

Remme presented a long list of aldosterone's deleterious physiologic effects and then proceeded to cite evidence that blocking the hormone would improve nearly all of them. Aldosterone promotes myocardial fibrosis, increased ACE and catecholamine production, hemodynamic deterioration, and rises in oxygen free radicals and therefore vascular inflammation and injury--all of which are major contributors to cardiovascular disease.

Myocardial collagen deposition occurs early in the development of cardiomyopathy and heart failure and is common among patients in NYHA class 2 patients, he observed. Preclinical studies support and clinical studies show that treatment with spironolactone is associated with significant reductions in myocardial collagen in patients with "very mild heart failure, indicating that already at this state, spironolactone does reduce myocardial fibrosis."

In a study from Japan, four months of spironolactone therapy led to significant reductions in collagen formation, diastolic and systolic volumes, and ventricular mass. "So the effect on fibrosis in these patients has already translated into a very significant improvement in remodeling," he said.

"But wait! There's more. Aldosterone antagonists are actually also a very good ACE inhibitor, and you wouldn't, I think, want to wait with an ACE inhibitor in class 2 heart failure, would you?" Administration of either spironolactone or eplerenone can very nearly completely suppress the production of angiotensin 2 from angiotensin 1, while eplerenone has been shown to attenuate the rise in ACE after an MI.

With all these important effects of aldosterone antagonists, all present in mild heart failure, are you going to deny all those goodies to your patients because they are not yet NYHA class 3?

Remme went on to show further evidence that aldosterone inhibition reduces levels of oxygen free radicals, restores diminished endothelial nitric-oxide synthase production in heart failure, thereby improving endothelial function, and stems atherogenesis in various animal models. The antifibrosis effects are probably related to reductions in ventricular arrhythmias and reduced risk of sudden cardiac death in patients already on standard optimal medical therapy, which was demonstrated in EPHESUS. Other evidence suggests that spironolactone improves heart-rate variability and QT dispersion.

"Now, with all these important effects of aldosterone antagonists, all present in mild heart failure, are you going to deny all those goodies to your patients because they are not yet NYHA class 3? Or worse, would you stop treatment sometime after infarction?" Some clinicians do stop aldosterone blockade before the patient reaches class 2, he said, which is "the wrong interpretation of EPHESUS."

Trials of NYHA-2 on the Horizon

But using such drugs just because they are available, without support from clinical trials, can be dangerous, López-Sendón countered. "After the publication of RALES, with its superb benefit of spironolactone in severe heart failure, there was an epidemic of hyperkalemia in some patient registries," he said, referring to a 2004 observation of steep increases in spironolactone prescription rates at the same time that hyperkalemia-related hospitalizations and related in-hospital deaths were rising sharply in Ontario [3].

The evidence base is going to grow soon, he noted. A trial launched in 2006, called EMPHASIS-HF, will enroll about 2500 patients with NYHA class-2 chronic heart failure, randomizing them to eplerenone or placebo, according to López-Sendón. Scheduled for completion in 2011, "this study will answer the question of whether or not we should treat patients in NYHA class 2." Another trial in the works, which will enroll a similar population, called AREA-IN-CHF, he said, is looking at the effects of aldosterone antagonism on remodeling end points.

For his final remarks, López-Sendón momentarily stepped outside his debate persona as defender of the evidence-based approach and offered a kind of conflict-of-interest disclosure. "I am not participating in those aldosterone-blocker trials, and that is because I use aldosterone blockers in all class 2 patients. But I am afraid that is impressionistic medicine, and you have to be very careful with that."

Guidelines or no guidelines, you're a doctor, use your common sense!

Patients in class 2 have the same disease as those in class 3, so why wouldn't aldosterone antagonists work in both groups? Remme asked rhetorically. "Guidelines or no guidelines, you're a doctor, use your common sense! If you do that, you are not alone." He pulled a finding from the Study on Heart Failure Awareness and Perception in Europe (SHAPE) that demonstrates the point: 70% of surveyed European cardiologists reported they do not primarily use the guidelines to manage their patients with heart failure; rather, they tend to follow "expert opinion," review articles, or other information sources.

Then Remme gave his own twist on the position he had been assigned to defend. "Guidelines aside, Dr López-Sendón argued that we need data from a large, randomized, controlled trial for these patients, and I agree. The proof is always in the pudding, and the pudding is the EMPHASIS-HF study." Elaborating on the trial's design and progress, he said the patients will be followed for the primary end point of cardiovascular mortality or heart-failure hospitalization, as well as some secondary clinical end points.

"Although I think you should give this medication to all class 2 heart failure patients, I am willing to wait for the results. After all, I am the chairman of the events committee of EMPHASIS-HF and committed to proof. Therefore, I think it will not be long before we know the definitive answer," Remme said, smiling, "which of course will be positive."

  1. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 34110:709-717. Abstract

  2. Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med. 2003; 348:1309-1321. Abstract

  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

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