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Reverse Cardiac Remodeling May Underlie Benefit of Sacubitril/Valsartan in HFrEF

Key findings

  • PROVE-HF, a phase 4 trial of sacubitril/valsartan in patients with heart failure with reduced ejection fraction, showed that reductions in NT-proBNP (N-terminal pro-B–type natriuretic peptide) correlated with improvements in cardiac remodeling
  • This prespecified exploratory analysis of PROVE-HF evaluated associations between cardiac remodeling and changes in NT-proBNP and other biomarkers over the 12-month study period
  • Initiation of sacubitril/valsartan was associated with significant reductions in circulating NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT) and soluble suppressor of tumorigenicity 2 (sST2)
  • Greater reductions in NT-proBNP and hs-cTnT, but not sST2, were associated with greater simultaneous improvements in measures of cardiac remodeling (left ventricular ejection fraction and particularly left atrial volume index)
  • Lack of reduction in NT-proBNP and hs-cTnT in patients taking sacubitril/valsartan may indicate the need for more intense guideline-directed therapies or closer follow-up

In 2015, the FDA approved sacubitril/valsartan (S/V) for the reduction of hospitalization and death related to heart failure with reduced ejection fraction (HFrEF). Subsequently, investigators at Massachusetts General Hospital participated in the PROVE-HF trial sponsored by the drug's manufacturer. As reported in JAMA, it showed that S/V treatment in patients with HFrEF was associated with a reduction in NT-proBNP (N-terminal pro-B–type natriuretic peptide), and that reduction correlated with improvement in cardiac remodeling.

In a prespecified exploratory analysis of PROVE-HF, Sean Murphy, MB, BCh, BAO, internal medicine resident at Massachusetts General Hospital, James L. Januzzi, Jr, MD, director of the Dennis and Marilyn Barry Fellowship in Cardiology Research at the Corrigan Minehan Heart Center, and colleagues characterized associations between NT-proBNP and other biomarkers and evaluated how longitudinal change in each biomarker influenced reverse cardiac remodeling. Their findings appear in Circulation: Heart Failure.

Study Methods

PROVE-HF was a 52-week, multicenter, open-label, single-arm, phase 4 study in which 794 patients with chronic HFrEF received S/V. At multiple time points, the investigators took blood samples for measurement of circulating concentrations of NT-proBNP and two other biomarkers that reflect ventricular wall stress and myocardial injury.

Transthoracic echocardiography was performed at baseline, six months and 12 months, and interpretation included assessment of reverse cardiac remodeling as defined by left ventricular ejection fraction (LVEF) and left atrial volume index (LAVi).

715 patients had valid biomarker and echocardiographic measurements at baseline and were included in the current analysis.

Changes in Biomarkers

From baseline to month 12, there were significant reductions in biomarker concentrations (P<0.001 for all), even after adjustment for covariates:

  • −27.9% for NT-proBNP
  • −6.7% for high-sensitivity cardiac troponin T (hs-cTnT)
  • −1.6% for soluble suppressor of tumorigenicity 2 (sST2)

Changes in LVEF and LAVi

In a multivariate model that adjusted for all biomarkers and clinical variables, relative changes in measures of reverse cardiac modeling averaged:

  • +27% for LVEF (P<0.01)
  • −22% for LAVi (P<0.001)

Correlations Between Biomarker Trajectories

  • Changes in NT-proBNP and hs-cTnT concentrations were associated across all time points
  • Earlier changes in NT-proBNP (at months 3 and 6) more strongly predicted later changes in hs-cTnT (at months 6 and 9, P<0.001 for both) than simultaneous hs-cTnT reductions
  • Changes in sST2 were only weakly correlated with either NT-proBNP or hs-cTnT at any time point

Correlations of Biomarker Trajectories with LVEF and LAVi

  • The largest reductions in both NT-proBNP and hs-cTnT were associated with greater simultaneous improvements in LVEF, and particularly, LAVi
  • There was no obvious association between changes in sST2 and measures of reverse cardiac remodeling

Implications for the Clinic

Reductions in NT-proBNP and hs-cTnT after initiation of S/V therapy may indicate reverse cardiac remodeling, removing the need for intensive imaging. Conversely, a lack of reduction in these biomarkers may signal patients who need more intense guideline-directed therapies or closer follow-up.

Importantly, after month 6, changes in all three biomarkers slowed significantly in this study, and some participants showed slight increases in biomarker concentrations. The implications are unclear and emphasize the need for additional research into the role of biomarkers in long-term follow-up.

reduction in N-terminal pro-B–type natriuretic peptide over the year after initiation of sacubitril/valsartan

reduction in high-sensitivity cardiac troponin T over the year after initiation of sacubitril/valsartan

increase in left ventricular ejection fraction over the year after initiation of sacubitril/valsartan

reduction of left atrial volume index over the year after initiation of sacubitril/valsartan

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