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Chronic HF and the effect of aldosterone antagonists
Aldosterone remains an important target for the management of HF.
ACE inhibitors (or angiotensin receptor blockers) and beta-blockers are the foundation of pharmacologic treatment for HF, but these agents only partially and transiently suppress aldosterone production. Given the effect of aldosterone on HF progression, it remains an important target for HF management.
Spironolactone (Aldactone, Pfizer) and eplerenone (Inspra, Pfizer) are the two available aldosterone blockers (or mineralocorticoid receptor antagonists) available for use in the United States. Unlike spironolactone, eplerenone is a selective mineralocorticoid receptor antagonist (MRA) with lower affinity for the androgen and progesterone receptors. Spironolactone is hepatically metabolized via non-CYP450 mechanisms to active metabolites, whereas eplerenone undergoes extensive metabolism through the CYP3A4 enzymes to inactive metabolites.
Clinical trials
Jingyang Fan
In RALES, 1,663 patients with severe systolic HF were randomly assigned to spironolactone 25 mg or placebo. Spironolactone was associated with a 30% risk reduction for all-cause mortality, 31% risk reduction for CV mortality and 30% risk reduction for cardiac-related hospitalizations. However, only about 10% of RALES patients were treated with a beta-blocker and mean ACE inhibitor doses were lower than target, thereby potentially heightening the benefits of spironolactone. Gynecomastia and breast pain were reported in 10% of men receiving spironolactone and, overall, more patients in the spironolactone group (8%) discontinued therapy vs. the placebo group (5%). Serious hyperkalemia (potassium >6 mmol/L), however, did not differ significantly, although the rate may have been higher had ACE inhibitor doses been optimized.
EPHESUS evaluated eplerenone 25 mg to 50 mg in 6,642 patients with left ventricular dysfunction and HF after an acute MI. Eplerenone, when added to optimal therapy 3 to 14 days post-MI, significantly decreased all-cause mortality by 15% and CV deaths or CV hospitalization by 13%. Unlike in RALES, 75% of EPHESUS patients were treated with a beta-blocker. Eplerenone was associated with a higher rate of serious hyperkalemia compared with placebo. However, no differences were observed in gynecomastia or impotence in men and breast pain in women between the eplerenone and placebo groups.
EMPHASIS-HF enrolled more than 2,700 patients with mild systolic HF who were recently hospitalized for CV reasons or had elevated brain natriuretic peptide (BNP) or pro-BNP. Eplerenone 25 mg to 50 mg was associated with a significant 37% decrease in CV death or HF hospitalization, as compared with placebo. Eplerenone also decreased all-cause mortality and all-cause hospitalization. Although more patients in the eplerenone group developed potassium >5.5 mmol/L, rates of serious hyperkalemia (potassium >6 mmol/L) did not differ between the two groups. Similar to the EPHESUS study, there was no difference in gynecomastia and other breast disorders between eplerenone and placebo. The EMPHASIS-HF trial expanded the role of eplerenone in HF management beyond post-MI and also provided compelling evidence to initiate an MRA in high-risk patients with mild systolic HF.
Unfortunately, the data on MRAs in HF patients with preserved ejection fraction are less robust. The RAAM-PEF trial evaluated the effect of eplerenone on functional outcomes in 44 patients with mild to moderate HF and LV ejection fraction =50%. After 24 weeks of treatment, eplerenone did not improve exercise capacity, quality of life or NYHA functional class, compared with placebo. However, researchers observed significant improvement in diastolic function. The RAAM-PEF trial was too small and too short to draw any conclusions from regarding benefits of MRAs in HF patients with preserved ejection fraction. Results from two ongoing trials — Aldo-DHF and TOPCAT — will hopefully fill this knowledge gap.
Translation of evidence to practice
Current guidelines from the American College of Cardiology, American Heart Association and Heart Failure Society of America include recommendations for use of MRAs; however, the guidelines were all published before availability of the EMPHASIS-HF results.
Although the beneficial effects of MRAs are impressive, extreme caution should be taken to select appropriate patients. Data published since RALES suggest the rate of hospitalization for hyperkalemia increased more than fourfold and associated mortality increased by more than sixfold in HF patients treated with MRAs. Additionally, 25% to 31% of all spironolactone prescriptions were filled by HF patients whose characteristics did not match those in RALES. Furthermore, although patients with serum creatinine >2.5 mg/dL were excluded from clinical trials of MRAs, the average serum creatinine was 1.1 mg/dL in both EPHESUS and EMPHASIS-HF, while the mean glomerular filtration rate (GFR) in the EMPHASIS-HF study was 70 mL/min. All of these findings highlighted the differences between the study populations and “real world” patients, as well as the importance of carefully selecting appropriate patients for MRA treatment to minimize potentially severe adverse effects.
Therefore, MRAs should be initiated at lower doses when GFR is <60 mL/min and avoided when GFR is <30 mL/min. Potassium should be monitored frequently and all potassium supplements should be discontinued unless there is profound hypokalemia. Triple therapy with an ACE inhibitor, angiotensin receptor blocker and MRA is strongly discouraged due to the increased risk for hyperkalemia.
It is also important to keep in mind that ACE inhibitors and beta-blockers were background therapies in the aforementioned studies. Therefore, an MRA should be considered only after ACE inhibitors and beta-blockers have been optimized. However, the order by which the next agent should be added has not been studied. Given the lack of mortality benefit seen in studies that evaluated ACE inhibitor plus angiotensin receptor blocker combinations, it is reasonable to suggest that an MRA rather than an angiotensin receptor blocker be the next add-on therapy. Although the combination of hydralazine and nitrate is another option, the evidence to support its use as an add-on therapy came from the A-HeFT study, which enrolled black patients with advanced HF. Therefore, it may be appropriate to add an MRA in high-risk patients with mild HF after ACE inhibitors and beta-blockers, followed by hydralazine and nitrate if patients remain symptomatic. However, the decision for the first-line add-on therapy should be individualized based on patient characteristics.
Lastly, to date, no study has compared spironolactone and eplerenone directly. Since the two agents were studied in different HF populations it is unknown whether they are interchangeable. There is also a substantial cost difference between the two drugs — approximately $100 to $150 per month for eplerenone vs. $4 to $14 per month for spironolactone. Therefore, drug selection should be based on evidence, adverse effects, drug interactions and cost.
The role of MRAs
MRAs provide clinical benefit in patients with systolic HF. Recent data expand the role of MRAs to a broader range of patients, providing compelling reasons to start MRAs early during disease progression. However, appropriate patient selection, dosing, and monitoring are essential to the success of this add-on therapy.
For more information:
- Butler J. J Cardiac Fail. 2012;18:265-281.
- Pitt B. N Engl J Med. 1999;341:709-717.
- Pitt B. N Engl J Med. 2003;348:1309-1321.
- Zannad F. N Engl J Med. 2011;364:11-21.