Clinical trials of aldosterone antagonists (AAs) have established substantial reductions in mortality when added to background therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) ((1),2). Although use of AAs has increased over time, it remains less than expected, on the basis of the results of clinical trials and clinical practice guideline recommendations (3). Chronic kidney disease (CKD) is common among patients with HF and is independently associated with increased morbidity and mortality (4). Several studies demonstrate that, despite the higher risk in this population, history of CKD is associated with underuse of evidence-based therapies ((3),5). The paradoxical decline in the use of effective therapies among these higher-risk patients might be partially explained by: 1) the exclusion of patients with significant CKD from many clinical trials; and 2) the increased risk of adverse events among patients with CKD (3). The increased morbidity of CKD in patients with HF is therefore likely to be multi-factorial, with contributions from associated comorbidities, increased fluid retention, and underuse of effective treatments (5).

Vardeny et al. (6) present data from RALES (Randomized Aldactone Evaluation Study) in this issue of the Journal with regard to the use of AAs in patients with HF and CKD. Although they confirm prior observations that baseline CKD is associated with higher mortality, the primary finding is that spironolactone retains its therapeutic efficacy among patients with moderate CKD. Although baseline CKD is associated with increased risk of adverse events, this risk did not negate the overall net clinical benefit. These data provide reassurance with regard to the relative safety and net benefit of AAs among patients with HF, reduced LVEF, and moderate CKD. Although the authors conclude that the absolute benefit of spironolactone is greatest among patients with reduced glomerular filtration rate (GFR), this statement must be qualified, because patients with more severe CKD (serum creatinine >2.5 mg/dl) were excluded from the trial.

The authors hypothesize that the greater benefit of spironolactone seen in patients with CKD might be related to the ability of AAs to reduce renal injury; however, a beneficial effect of AAs on GFR in patients with CKD has not been demonstrated (7). A major health risk for patients with CKD is an increased risk of death from cardiovascular causes. Elevated levels of aldosterone are seen in CKD and might impair ventricular and vascular function via pro-inflammatory and pro-fibrotic pathways (8). Although data with regard to the ability of AAs to improve myocardial remodeling are mixed, these agents have shown favorable effects on interstitial collagen turnover and cardiac fibrosis ((9),10). Among patients with CKD, AAs have also been demonstrated to improve arterial stiffness, vascular tone, and function, independent of their effect on blood pressure ((11),12). It seems that the benefit of AA among patients with co-existing CKD and HF is more likely related to their beneficial effect on the heart and vasculature.

Vardeny et al. (6) confirm reports that worsening renal function (WRF) in patients with HF is a marker of poor long-term outcomes. However, similar to findings with enalapril within SOLVD (Studies of Left Ventricular Dysfunction) (13), there was a significant interaction between the treatment group and WRF with respect to outcome. WRF was associated with increased mortality only among patients randomized to placebo, whereas patients taking spironolactone derived benefit, independent of WRF. An explanation for this finding is that WRF in patients with HF signals a heterogeneous set of physiologic effects, with distinct mechanisms and prognostic implications (13). The anticipated decrease in filtration fraction after angiotensin converting enzyme inhibitor initiation represents a marker of therapeutic efficacy and does not carry an adverse prognosis (13). The mechanism by which AAs lead to WRF is unknown. The authors hypothesize the reduction in GFR might be the result of reduction in blood pressure affecting renal blood flow. However, differences in blood pressure between groups at the end of titration did not exist, and patients taking spironolactone had higher rates of WRF.

In contrast to the present report, WRF after eplerenone initiation in patients with HF and/or reduced LVEF after myocardial infarction is associated with worse outcomes (14), and the prognostic implication of WRF short-term after AA initiation remains uncertain. A total of 117 early deaths account for 17% of all deaths in the RALES analysis, and patients who died early were not included in the landmark analysis (6). WRF occurred in 17% of patients taking spironolactone, compared with 7% of patients taking placebo (p < 0.001); the greatest risk of hyperkalemia occurred in patients with WRF taking spironolactone: 32.4% versus 6.8% for patients with stable renal function randomized to placebo. Therefore it is not possible to dismiss a significant early risk of death associated with WRF among patients taking spironolactone. Although an association between hyperkalemia and risk of death is not presented, an analysis from the HEAAL (Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan) study demonstrated that, for patients receiving angiotensin receptor blockers, rates of hyperkalemia increase among patients also receiving AAs, and these events are associated with an increased risk of dying (15).

In conclusion, baseline renal function does not attenuate the 30% relative risk reduction of mortality seen with AAs in patients with HF and reduced LVEF. Although risks of AAs, including that of hyperkalemia in patients with CKD, must continue to be considered, the present analysis should serve to promote use of AAs, under careful monitoring, among patients with mild to moderate CKD and should lead to increased use of this life-prolonging therapy. Although abnormal and worsening kidney function are associated with worse prognosis in patients with HF, the mechanistic inter-relationships among clinical HF, kidney function, and morbid events are complex. Improved understanding of these interactions will increase our ability to apply available HF treatments toward achieving improving clinical outcomes.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.