PARADIGM-HF: Sacubitril/valsartan may reduce incidence of severe hyperkalemia in certain patients with HFrEF

NEW ORLEANS — Researchers found that among patients with HF with reduced ejection fraction from the PARADIGM-HF study treated with mineralocorticoid receptor antagonists, severe hyperkalemia was more likely in those assigned enalapril vs. those assigned sacubitril/valsartan.

Guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for select patients with symptomatic HF and reduced ejection fraction (HFrEF) to reduce rates of morbidity and mortality. The use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system, however, has been linked to increased risk for hyperkalemia.

“I think that the implication is that if we are going to use multiple agents, we want to do it as safely as possible,” Scott D. Solomon, MD, told Cardiology Today. “I believe that PARADIGM data show that as the US guidelines have described, if a patient can tolerate being on an ACE inhibitor or [angiotensin receptor blocker], then those with Class II or III [HFrEF] ought to be switched from an ACE inhibitor or an [angiotensin receptor blocker] to sacubitril/valsartan because there is a really substantial morbidity and mortality benefit.”

Solomon and colleagues set out to determine whether hyperkalemia risk due to MRA use for HFrEF can be reduced by sacubitril/valsartan (Entresto, Novartis) compared with enalapril. Solomon presented the findings, which were simultaneously published in JAMA Cardiology, at the American Heart Association Scientific Sessions.

Patients with chronic HF, New York Heart Association class II to IV symptoms and left ventricular EF of ≤ 40%, were randomized to treatment of 10 mg enalapril twice daily or 97 mg or 103 mg sacubitril/valsartan twice daily in addition to guideline-directed therapy.

Although it was encouraged, the use of MRAs was left to the discretion of investigators.

At every study visit, researchers measured serum potassium levels.

Patients taking an MRA at baseline were commonly younger, had lower EF, had lower systolic BP and had more advanced symptoms of HF when compared to those who were not taking MRA at baseline.

Rates of any hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in those assigned enalapril vs. those assigned sacubitril/valsartan (3.1 per 100 patient-years vs 2.2 per 100 patient-years; HR = 1.37; 95% CI, 1.06-1.76).

An analysis of patients who had newly started taking MRAs during the study showed that severe hyperkalemia was more common in those randomly assigned to enalapril vs. those assigned to sacubitril/valsartan (3.3 per 100 patient-years vs. 2.3 per 100 patient-years; HR 1.43; 95% CI, 1.13-1.81).

In a related editorial, Justin A. Ezekowitz, MBBCh, MSc, wrote that the answer to the question of whether a patient should be switched from enalapril to sacubitril/valsartan so he or she can start taking an MRA “should be driven by many factors, including the efficacy of the overall trial and the regional guidelines that integrate this information into clinically appropriate recommendations.”

The AHA/American College of Cardiology guidelines are silent on this matter, but the European Society of Cardiology guidelines recommend “initiating MRA treatment before switching a patient to sacubitril/valsartan,” he wrote. – by Dave Quaile and Erik Swain

Reference:

Solomon, SD. Abstract M4189. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Desai AS, et al. JAMA Cardiol. 2016;doi:10.1001/jamacardio.2016.4733.

Ezekowitz, JA. JAMA Cardiol. 2016; 10.1001/jamacardio.2016.4731.

Disclosure: PARADIGM-HF was funded by Novartis. Solomon reports receiving research support from and consulting for Novartis. Ezekowitz reports receiving grants or honoraria from Amgen, Bayer, Merck, Novartis, Servier and Trevena, and being a co-owner of the copyright for the Med-HF application.