By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: In a secondary analysis of the PARADIGM-HF trial, the risk of severe hyperkalemia in heart failure patients taking a mineralocorticoid receptor antagonist was lower among patients treated with sacubitril/valsartan compared to those receiving enalapril.

SOURCE: Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with minteralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: A secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2016. [Epub ahead of print].

Current guidelines recommend mineralocorticoid receptor antagonists (MRAs) for patients with symptomatic heart failure with reduced ejection fraction (HFrEF). MRAs are associated with hyperkalemia, and the risk increases when administered with angiotensin-converting enzyme (ACE) inhibitors. Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that is approved as an alternative to ACE inhibitors for HFrEF. Whether the risk of MRA-associated hyperkalemia is lower in patients receiving sacubitril/valsartan than ACE inhibitors is unknown.

To evaluate differences in risk of hyperkalemia, Desai et al analyzed data from PARADIGM-HF, which randomized 8,399 patients suffering from chronic HFrEF to sacubritil/valsartan vs. enalapril. The trial ended early due to a marked reduction in the composite outcome of cardiovascular death or hospitalization for heart failure in the sacubitril/valsartan arm. Use of MRAs was encouraged, though left to investigators’ discretion. For this secondary analysis, the authors compared the rates of hyperkalemia (defined as any serum potassium > 5.5 mEq/L) and severe hyperkalemia (> 6.0 mEq/L) in patients receiving MRAs.

Among 4,671 taking an MRA at baseline, the overall rate of hyperkalemia was similar between patients treated with sacubitril/valsartan and enalapril. However, the rate of severe hyperkalemia was significantly higher in the enalapril group (3.1 vs. 2.2 per 100 patient-years; hazard ratio [HR], 1.37; P = 0.02), and the difference persisted after adjusting for baseline differences between the two treatment groups. Similarly, when including all patients who started MRAs during the study period, those receiving enalapril demonstrated significantly higher rates of hyperkalemia (HR, 1.43; P = 0.003).

Changes in serum creatinine were similar between the two groups, and changes in potassium levels did not correlate with serum creatinine over time. Patients who did not receive an MRA during the study period demonstrated lower rates of hyperkalemia, and among these patients there were no significant differences in hyperkalemia or severe hyperkalemia between those randomized to enalapril vs. sacubitril/valsartan. The authors concluded that among HFrEF patients treated with an MRA, severe hyperkalemia is more common during treatment with enalapril than with sacubitril/valsartan, suggesting neprilysin inhibition may attenuate the risk of MRA-associated hyperkalemia.


In large, randomized trials, both spironolactone and eplerenone have been shown to improve outcomes in HFrEF. Despite the overwhelming evidence and strong recommendations from practice guidelines, studies show that many eligible HFrEF patients are not treated with MRAs. This often is due to concern regarding hyperkalemia, especially in patients already treated with ACE inhibitors. This secondary analysis provides strong evidence that switching from an ACE inhibitor to sacubitril/valsartan reduces this risk of severe hyperkalemia by approximately one-third and hopefully will encourage clinicians to prescribe MRAs more frequently.

Among patients not receiving MRAs, there was little difference in the risk of hyperkalemia between those randomized to enalapril vs. sacubitril/valsartan. The authors suggested that by increasing levels of circulating natriuretic peptides, neprilysin inhibition specifically attenuates the risk of hyperkalemia when combining MRAs with other inhibitors of the renin-angiotensin-aldosterone system (RAAS). Given the importance of both MRAs and RAAS inhibition in the treatment of HFrEF, this is a clinically relevant advantage for sacubitril/valsartan.

This was a secondary analysis, with important limitations. Patients were not randomized according to MRA use, and there may have been residual differences between MRA-treated patients randomized to enalapril vs. sacubitril/valsartan. PARADIGM-HF included a run-in period during which patients who did not tolerate either sacubitril/valsartan or enalapril were excluded. Therefore, the true rate of hyperkalemia may have been underestimated in both groups.

Is the lower risk of hyperkalemia enough to warrant switching all HFrEF patients from ACE inhibitors to sacubitril/valsartan? Taken in the context of the overall markedly positive results of PARADIGM-HF, this substudy adds further weight to the argument for switching most patients with symptomatic HFrEF despite ACE inhibitors to sacubitril/valsartan. At the very least, patients who are not receiving MRAs due to perceived concern regarding the risk of hyperkalemia should be considered candidates for switching.

Another relevant question is whether to initiate an MRA before or after switching from an ACE inhibitor to sacubitril/valsartan. Current American guidelines do not specifically address this issue. However, European guidelines recommend initiating an MRA before switching. The results of this substudy suggest clinicians switch patients to sacubitril/valsartan before adding an MRA to minimize the risk of hyperkalemia. Regardless of the exact strategy used, the importance of monitoring serum potassium and creatinine after any initiation or dose adjustment cannot be overstated. With close monitoring, clinicians should now feel even more empowered to reach target doses for all major therapeutic classes for HFrEF.