Physicians' Academy for Cardiovascular Education

Effects of ARNI in patients with pre-HFpEF

Effect of Sacubitril/Valsartan vs Valsartan on Left Atrial Volume in Patients With Pre-Heart Failure With Preserved Ejection Fraction: The PARABLE Randomized Clinical Trial

Literature - Ledwidge L, Dodd JD, Ryan F, et al. - JAMA Cardiol. 2023 Mar 8;e230065. doi: 10.1001/jamacardio.2023.0065.

Introduction and methods


Pre-HFpEF, which is common in patients with hypertension or diabetes [1-3], is characterized by structural cardiac abnormalities, preserved LVEF and elevated biomarkers of cardiac dysfunction, without symptoms of HF [4]. There are currently no specific treatment options for patients with pre-HFpEF, besides CV risk factor management. The STOP-HF (St Vincent’s Screening to Prevent Heart Failure) trial previously demonstrated that natriuretic peptide-based screening in patients with pre-HF reduced CV events and progression of pre-HF, mostly pre-HFpEF [5]. However, the STOP-HF trial lacked a pharmacological intervention. The effects of Sacubitril/valsartan have been investigated in patients with symptomatic HFpEF, but data is lacking in a prespecified cohort with patients with pre-HFpEF.

Aim of the study

The authors compared the effects of sacubitril/valsartan treatment with valsartan treatment on markers of cardiovascular structure and function in patients with pre-HFpEF after a 18 month study period.


The PARABLE (The Personalized Prospective Comparison of ARNI with ARB in Patients With Natriuretic Peptide Elevation) trial was a randomized, double-blind, double-dummy, active comparator trial, conducted at a single outpatient cardiology center in Dublin, Ireland. Patients aged 40 years or older with systematic hypertension and/or T2DM were included. A total of 250 patients with elevated BNP (20 to 280 pg/mL) or NT-proBNP (100 to 1000 pg/mL); and enlarged transthoracic left atrial volume index (LAVI; >28 mL/m² obtained using echocardiography) were included. Exclusion criteria were features of symptomatic HF, left ventricular systolic dysfunction (EF <50%) or serious valvular disease or kidney dysfunction. Patients were randomized to sacubitril/valsartan 48 mg/51 mg twice daily, titrated to 97 mg/103 mg twice daily after two weeks (122 patients) or valsartan 80 mg twice daily, titrated to 160 mg twice daily after two weeks (128 patients).


The primary outcome was the adjusted change in maximal LAVI measured by volumetric cardiac MRI. Secondary outcomes were changes related to markers of cardiovascular structure and function, and adverse CV events.

Main results

Effects on cardiac structure

Effects on cardiac function

Effects on blood pressure, pulse pressure, eGFR and natriuretic peptide

Adverse CV events


The PARABLE trial demonstrated that treatment with sacubitril/valsartan is associated with a greater increase in maximal LAVI despite reduced markers of filling pressure in patients with pre-HFpEF and with hypertension and/or T2DM compared to valsartan. Sacubitril/valsartan was associated with a reduction in blood pressure, pulse pressure, and NT-proBNP, less decline in kidney function and reduced risk for serious CV events compared to valsartan. More research is needed to better understand the long-term effects of sacubitril/valsartan in patients with pre-HFpEF.


Show references

Find this article online at JAMA Cardiol.

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