Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin: An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.

BACKGROUND

Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP).

OBJECTIVES

The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin.

METHODS

Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP.

RESULTS

Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months.

CONCLUSIONS

In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).