Sunday, November 14, 2010

The Aldosterone Antagonist Eplerenone in Populations with Heart Failure: Another Task for Disease Management Programs

After the Disease Management Care Blog read this New England Journal of Medicine report back in 1999, it began to prescribe the aldosterone antagonist "spironolactone" for its patients with low ejection fraction chronic heart failure. Aldosterone is one of many normal human hormones that increase in response to a struggling heart. High levels of aldosterone contribute to a downward spiral of additional heart damage and impaired blood flow.

Unhappily, some of the DMCB patients developed dangerously high blood potassium levels. At the same time, reports of that side effect began to appear, for example here and also discussed here. Convinced that this was another example of the gulf between notions of academic efficacy and real world clinic effectiveness, the DMCB decided to return to the basic principle of "first, do no harm." It dropped spironolactone from its heart failure tool box.

With time, however, other reports like this began to appear, suggesting that if physicians were careful, spironolactone was still a good option. What's more, recommendations in favor of spironolactone appeared in the American Heart Association guidelines for the treatment of heart failure:

Recommendations Concerning Aldosterone Antagonists. The addition of low-dose aldosterone antagonists is recommended in carefully selected patients...based on the strong data demonstrating reduced death and rehospitalization in 2 clinical trial populations... For both of these major trials, patients were excluded for a serum creatinine level in excess of 2.5 mg per dL, but few patients were actually enrolled with serum creatinine levels over 1.5 mg per dL.... The average serum creatinine of enrolled patients was 1.1 mg per dL, above which there was no demonstrable benefit for survival. To minimize the risk of life-threatening hyperkalemia... patients should have initial serum creatinine less than 2.0 to 2.5 mg per dL without recent worsening and serum potassium less than 5.0 (page 1987).

And now the results from this huge international multi-site study have just been released. Over 2700 patients with heart failure who were already on aggressive state-of-the-art treatment for their heart failure were randomly assigned to another aldosterone antagonist called "eplerenone" or placebo. After 21 months, there was an absolute 7 % risk reduction for the combined end points along with statistically significant drops in deaths and hospitalizations. According to the accompanying editorial, the number-needed-to-treat (NNT) is an impressive 19. As expected, there were an increased number of patients who developed potentially dangerous increases in potassium levels in the treatment (11.8%) group vs. the placebo group 7.2%), but compared to the survival benefit, it seemed worth it.

This is noteworthy publication for the science of population health/disease management community. This report gives reason to advocate for the use of "aldosterone antagonists" in populations defined by the presence of dilated cardiomyopathy/low ejection fraction heart failure. Patients should be alerted about this treatment option, helped to understand it's risks, benefits and alternatives and coached to ask their docs about this. Since changes in kidney function can lead to high potassium levels, physicians in the real world may be understandably reluctant to start this therapy. Disease management can help by providing an important extra margin of safety by helping to make sure that patients have as well as keep any and all scheduled laboratory testing appointments. If the disease management program can get the lab test results, it can work with the physician to contact the patient to stop the medicine if there are any problems.


Phil 314 said...

Two comments:
1)It will be interesting to see how docs implement this given their fear of hyperkalemia. It will be similar to the glucophage and renal insuff issue in Type 2 diabetics. We're reluctant to use it when the Creatinine rises even though the studies suggest

Damn the torpedoes; full sspeed ahead

2) Was it a set dose of epleronone? spironolactone is supposed to be a set dose but it seemed so hard for docs not to want to treat it as a titratable intervention

Jaan Sidorov said...

Yes, the dose was adjusted. The dose was started at 25 mg qd, unless the estimated GFR was less than 50 (but greater than 30), in which case it was 25 qod. If the K remained less than 5 over the next month, the dose was then doubled (50 or 25 qd) which the K was watched at least every 4 months. If it was high, the drug was stopped, the K monitored and when it dropped, restarted at a lower dose. Sounds like a need for what nurses call "standing orders."

Dr. Brindis said...

The results of the EMPHASIS-HF trial caused quite the discussion at AHA. Numerous doctors at the meeting recognized a wider use of spironolactone as a less costly alternative to eplerenone -- the generic spironolactone costs less than 20 cents a day compared to $133 a month for eplerenone. Given the results, past president of the American College of Cardiology, Dr. Alfred Bove, was led to say, “It’s hard to tell now which patients should get the pricey medicine.” Given all the emphasis on controlling costs in health care and appreciating that previous studies demonstrated a similar benefit with the generic spironolactone I agree with Dr Bove's assessment as to not knowing clinically when eplerenone would be preferred over spironolactone particularly appreciating the marked cost differences between the two medications.