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Less MRA-Related Hyperkalemia With Sacubitril/Valsartan Combo in Heart Failure

November 17, 2016

By Will Boggs MD

NEW YORK (Reuters Health) - The risk of mineralocorticoid receptor antagonist (MRA)-related hyperkalemia in patients with heart failure may be lower with sacubitril/valsartan than with enalapril, according to results from the PARADIGM-HF trial.

"The risk of serious hyperkalemia during use of an MRA in heart failure with reduced ejection fraction (HFrEF) is lower with use of sacubitril/valsartan than enalapril," said Dr. Akshay S. Desai from Brigham and Women's Hospital in Boston.

"Accordingly, tolerability of MRAs may be increased with use of an angiotensin-receptor/neprilysin inhibitor (ARNI) in preference to an ACE-inhibitor," he told Reuters Health by email.

Current guidelines recommend the addition of an MRA for most heart failure patients who remain symptomatic on beta-blockers and renin-angiotensin-aldosterone system inhibitors, but concern for the heightened risk of hyperkalemia with MRAs limits their use.

For the study, online November 14 in JAMA Cardiology, Dr. Desai and colleagues did a secondary analysis of data from PARADIGM-HF. Although 83.4% of participants in the trial were eligible for MRA treatment, only 56.5% were taking an MRA at baseline. A similar percentage of participants not meeting guideline-recommended criteria for MRA (51.4%) were nevertheless using one.

As expected, the incidences of hyperkalemia and severe hyperkalemia were significantly higher among MRA-treated patients than untreated patients during study follow-up.

Hyperkalemia and severe hyperkalemia rates among patients not taking an MRA at baseline were similar for those assigned to sacubitril/valsartan and those assigned to enalapril.

In contrast, severe hyperkalemia (potassium >5 mEq/L) among patients taking an MRA at baseline was significantly more common among patients assigned to enalapril than among those assigned to sacubitril/valsartan (3.1 vs. 2.2 cases per 100 patient-years, p=0.02).

Hyperkalemia rates, however, did not differ significantly between the groups.

Results were similar when patients who started taking MRAs during the trial were included in the analysis.

The reduction in the rates of death and hospitalization for heart failure in the sacubitril/valsartan arm of the trial was consistent among MRA-treated patients and untreated patients.

"The ACC/AHA guidelines now recommend that in patients with chronic, symptomatic HF and reduced EF (NYHA II or III) who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality," Dr. Desai said.

"There is limited evidence for use of ARNIs in HF patients who were ineligible for participation in PARADIGM-HF, such as those with borderline blood pressure (systolic BP < 100 mm Hg on 10 mg enalapril or the equivalent), those with acute decompensated heart failure, and those with advanced heart failure (NYHA Class IV)," he said. "For these groups, clinicians may wish to continue to use the established agents until additional data supporting a role for sacubitril/valsartan is available."

"These data supporting lower risk of hyperkalemia with MRAs during use of sacubitril/valsartan (compared with enalapril) may facilitate broader application of guideline-directed medical therapy," Dr. Desai concluded. "However, the obligation to monitor potassium and creatinine in patients who are prescribed MRAs persists."

Dr. Justin A. Ezekowitz from the University of Alberta in Edmonton, Canada, who wrote an invited commentary on the report, told Reuters Health by email, "The lower overall risk of hyperkalemia on sacubitril/valsartan compared with enalapril provides a unique opportunity to start MRAs where we might not have been able to before."

"Triple therapy (ACE-ARB-ARNI, beta-blocker, MRA) is critical, so consider all options to optimize life-saving therapy," he said.

Dr. Ezekowitz added, "Physicians and/or other clinicians need to be more comfortable managing patients with potassium elevation in the 5.0-5.5 mEq/L range. This is important for long-term care of HF."

The PARADIGM-HF trial was funded by Novartis Pharmaceuticals. Dr. Desai has been a consultant for the company.


JAMA Cardiol 2016.

(c) Copyright Thomson Reuters 2016. Click For Restrictions -

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