Hernandez AF, Mi X, Hammill BG, et al.
JAMA. 2012;308:2097-107. doi: 10.1001/jama.2012.14795.

Background

Many therapies have been evaluated for reducing mortality among patients with heart failure and reduced ejection fraction [1]. The aldosterone antagonists spironolactone and eplerenone are very efficacious. Although their efficacy has been proven [2,3], the use of aldosterone antagonists is still lower than expected [1,4,5], maybe due to uncertainty about the effectivity/safety in clinical practice. The Comparative Effectiveness of Therapies for Heart Failure (COMPARE- HF) program used a national clinical registry linked to Medicare claims data to examine the clinical effectiveness of therapies such as aldosterone antagonists and associations with long-term outcomes of older patients discharged from a hospitalization for heart failure [6].

Main results

• Rates of all-cause mortality (49.9% vs 51.2%; P=.62) and cardiovascular readmission (63.8% vs 63.9%; P=.65) were similar between the treatment groups at 3 years.
• The cumulative incidence of the first heart failure readmission was significantly lower in the treated group (38.7% vs 44.9%; P<.001).
• The hyperkalemia readmission rates at 30 days (2.9% vs 1.2%; P<.001) and 1 year (8.9% vs 6.3%; P=.002) were higher in the treated group; however, hyperkalemia was seldom the primary diagnosis for these readmissions, and the absolute increase in hyperkalemia as a primary diagnosis was small.
• After inverse weighting for the probability of treatment, there were no significant differences in the hazards of all-cause mortality or cardiovascular readmission. The hazard of heart failure readmission was however significantly lower in the treated group.
• Readmission associated with hyperkalemia was higher with aldosterone antagonist therapy within 30 days after discharge (2.54; 95% CI, 1.51-4.29; P<.001) and within 1 year after discharge (1.50; 95% CI, 1.23- 1.84; P<.001).

Conclusion

Initiation of aldosterone antagonist therapy at hospital discharge was not independently associated
with improved mortality or cardiovascular readmission, but was associated with a modest reduction in the risk of hospitalization for heart failure. There was a significant increase in readmission risk with hyperkalemia as with any diagnosis early after hospital discharge. The clinical effectiveness of aldosterone antagonists in the broad population of patients with heart failure should be further investigated; strategies to overcome disparities between findings of clinical efficacy and clinical effectiveness must be found.

Editorial comment [7]

“The authors appropriately acknowledge the limitations of a nonrandomized cohort and note that their study population was older and sicker than cohorts studied in randomized trials involving patients with heart failure with reduced ejection fraction. However, as in all observational studies, not all potentially confounding variables could be accounted for and important differences between treatment groups persisted. Aldosterone antagonists are effective drugs in heart failure with reduced ejection fraction but should be used carefully and selectively.”

References

1. Jessup M, Abraham WT, Casey DE, et al. ACCF/ AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):1977-2016.
2. Zannad F, McMurray JJ, Krum H, et al; EMPHASISHF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.
3. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-717.
4. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA. 2009;302(15):1658-1665.
5. Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J. 2011;161(6):1024-1030.e3.
6. Curtis LH, Mi X, Qualls LG, et al. Design and rationale of a retrospective clinical effectiveness study of aldosterone antagonist therapy in patients with heart failure. Am Heart J. 2012;163(6):946-953.e1.
7. Fang JC. Heart failure therapy: what should clinicians believe? JAMA. 2012;308:2144-6.

Abstract

Context:
Aldosterone antagonist therapy for heart failure and reduced ejection fraction has been highly efficacious in randomized trials. However, questions remain regarding the effectiveness and safety of the therapy in clinical practice.

Objective:
To examine the clinical effectiveness of newly initiated aldosterone antagonist therapy among older patients hospitalized with heart failure and reduced ejection fraction.

Design, setting, and participants:
Using clinical registry data linked to Medicare claims from 2005 through 2010, we examined outcomes of eligible patients hospitalized with heart failure and reduced ejection fraction. We used Cox proportional hazards models and inverse-weighted estimates of the probability of treatment to adjust for treatment selection bias.
Main outcome measures: All-cause mortality, cardiovascular readmission, and heart failure readmission at 3 years, and hyperkalemia readmission at 30 days and 1 year.

Results:
Among 5887 patients who met the inclusion criteria, the mean age was 77.6 years; of those 1070 (18.2%) started aldosterone antagonist therapy at discharge. Cumulative incidence rates among treated and untreated patients were 49.9% vs 51.2% (P = .62) for mortality; 63.8% vs 63.9% (P = .65) for cardiovascular readmission; and 38.7% vs 44.9% (P < .001) for heart failure readmission at 3 years; and 2.9% vs 1.2% (P < .001) for hyperkalemia readmission within 30 days and 8.9% vs 6.3% (P = .002) within 1 year. After inverse weighting for the probability of treatment, there were no significant differences in mortality (hazard ratio [HR], 1.04; 95% CI, 0.96-1.14; P = .32) and cardiovascular readmission (HR, 1.00; 95% CI, 0.91-1.09; P = .94). Heart failure readmission was lower among treated patients at 3 years (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Readmission associated with hyperkalemia was higher with aldosterone antagonist therapy at 30 days (HR, 2.54; 95% CI, 1.51-4.29; P < .001) and 1 year (HR, 1.50; 95% CI, 1.23-1.84; P < .001).

Conclusions:
Initiation of aldosterone antagonist therapy at hospital discharge was not independently associated with improved mortality or cardiovascular readmission but was associated with improved heart failure readmission among eligible older patients with heart failure and reduced ejection fraction. There was a significant increase in the risk of readmission with hyperkalemia, predominantly within 30 days after discharge.