Reduced risk of hyperkalemia with sacubitril/valsartan compared to enalapril in presence of mineralocorticoid receptor antagonist: The PARADIGM-HF trial

1. In this secondary analysis of the PARADIGM-HF trial, amongst patients receiving mineralocorticoid receptor antagonists, rates of severe hyperkalemia (>6.0 mEq/L) were reduced in the group randomized to sacubitril/valsartan as compared to the group receiving enalapril.

2. Overall rates of any hyperkalemia (>5.5 mEq/L or >6.0 mEq/L) were not significantly different between the two groups.

Evidence Rating Level: 2 (Good)

Study Rundown: The use of mineralocorticoid receptor antagonists (MRAs), like spironolactone, have been proven to have mortality benefit in specific subset of patients with heart failure with reduced ejection fraction (HFrEF). However, there may be an increased risk of hyperkalemia if MRAs are also used with other renin-angiotensin-aldosterone system (RAAS) inhibitors, like angiotensin converting enzyme (ACE) inhibitors. This secondary analysis of the PARADIGM-HF trial aimed to determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF was reduced by sacubitril/valsartan (study drug) compared to enalapril.

Amongst patients taking MRAs in the PARADIGM-HF trial, either chronically or at the onset of the trial, the risk of severe hyperkalemia (defined as level >6.0 mEq/L) was higher amongst those randomized to enalapril compared with those receiving sacubitril/valsartan. However, overall rates of hyperkalemia (both moderate and severe) were not significantly increased across groups. Strengths of this study included the high quality randomization design and the multi-center involvement. Limitations of this study included the fact that this was a secondary analysis of pre-existing data, which may bias the results.

Click to read the study, published today in JAMA Cardiology

Relevant Reading: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure (PARADIGM-HF)

In-Depth [secondary analysis]: This analysis used data from the PARADIGM-HF trial, which randomized patients with HFrEF and symptoms in the range of NYHA class II to IV to enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg (study drug) twice daily. Patients were also placed on MRAs at the discretion of the study investigators according to clinical indications. Serial potassium levels were measured during all trial follow-up. This analysis examined the risk of hyperkalemia (potassium >5.5 mEq/L) or severe hyperkalemia (potassium >6.0 mEq/L) in patients on MRAs at baseline and those who were put on an MRA during the study, across the two drug groups. Cox proportional hazard models were used to determine risk of hyperkalemia.

At baseline, 4671 patients were taking an MRA. In this group, the overall rates of both moderate and severe hyperkalemia were similar, however severe hyperkalemia was more common in patients in the enalapril group as compared to sacubitril/valsartan group (HR 1.37; 95%CI 1.06-1.76; p = 0.02). In patients who ended up on an MRA during the trial, the results were similar: no significant difference in overall rates of hyperkalemia but increased rates of severe hyperkalemia in the enalapril group as compared to sacubitril/valsartan (HR 1.43; 95%CI 1.13-1.81; p = 0.003).

Image: PD

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