Hypochloremia and clinical outcomes in patients treated with sacubitril/valsartan: insights from the REVIEW-HF registry

Backgrounds

Hypochloremia, which activates the renin-angiotensin-aldosterone system (RAAS) through tubuloglomerular feedback, is known to be associated with worse prognosis in patients with heart failure (HF). However, whether this relationship persists under treatment with strong RAAS inhibition—sacubitril/valsartan—is still unknown.

Methods

We analyzed data from a nationwide, multicenter (17 hospitals), Japanese registry investigating patients initiated sacubitril/valsartan (REVIEW-HF). Patients were divided into three groups according to baseline chloride levels: hypochloremia (≤98 mEq/L), normal-chloremia (99–103 mEq/L), and hyperchloremia (≥104 mEq/L). The primary outcome was a composite of cardiovascular death or HF hospitalization.

Results

Baseline chloride levels were available in 982 patients (101 with hypokalemia, 358 with normal-chloremia, and 523 with hyperchloremia). Compared to those with higher chloride levels (i.e., normal-chloremia and hyperchloremia), patients with hypochloremia (≤98 mEq/L) had a higher risk of the primary outcome, even after initiation of sacubitril/valsartan (P<0.001) (Figure). This association was consistent across all other outcomes examined (Figure). Hypochloremia remained independently associated with worse outcomes, even after adjustment for key prognostic variables (e.g., adjusted hazard ratio for the primary outcome: 1.72 [95% confidence interval: 1.09-2.71], P=0.02, compared to normal-chloremia).

Conclusions

Hypochloremia was associated with worse HF outcomes, even under RAAS inhibition with sacubitril/valsartan.

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