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 TrialLiterature - 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 . 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 . 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.
Effects on cardiac structure
- The adjusted change in maximal LAVI as measured by cardiac MRI was greater in patients treated with sacubitril/valsartan (6.9 mL/m²; 95%CI: 0.0 to 13.7) compared to valsartan (0.7 mL/m²; 95%CI: −6.3 to 7.7; P<0.001). Of note, there were differences in mean maximal LAVI at baseline (47.5 in the sacubitril/valsartan group vs 52.4 in the valsartan group; P=0.01).
- The increase in LV end-diastolic volume index was greater in patients treated with sacubitril/valsartan (7.1 mL/m²; 95%CI: -1.7 to 15.9) compared to valsartan (1.4 mL/m²; 95%CI: −7.2 to 10.0; P=0.02).
- Sacubitril/valsartan, but not valsartan, was associated with a reduction in LA diastolic stiffness index (-0.06 mm Hg/mL/m² (95%CI: -0.12 to 0.03) vs 0.0 mm Hg/mL/m² (95%CI: -0.04 to 0.06); P<0.001), LV diastolic stiffness index (-0.04 mm Hg/mL/m² (95%CI: -0.06 to 0.00) vs 0.00 mm Hg/mL/m² (95%CI: -0.03 to 0.02); P<0.001), arterial elastance (-0.2 mm Hg/mL/m² (95%CI: -0.5 to 0.1) vs 0.0 mm Hg/mL/m² (95%CI: -0.3 to 0.3); p<0.001), and systemic vascular resistance (-102 mm Hg/mL/min (95%CI: -335 to 113) vs -10 mm Hg/mL/min (95%CI: -211 to 249); P<0.001).
- Sacubitril/valsartan was associated with an increase in arterial compliance compared to valsartan (0.1 mL/mm Hg (95%CI: -0.1 to 0.5) vs 0.0 mL/mm Hg (95%CI: -0.4 to 0.2); P<0.001).
Effects on cardiac function
- Changes in LA stroke volume index and LV stroke volume index were greater in the sacubitril/valsartan group compared to the valsartan group (3.6 mL/m² (95%CI: -1.0 to 7.6) and 3.1 mL/m² (95%CI: -0.87 to 9.5), respectively in the sacubitril/valsartan group and -0.7 mL/m² (95%CI: -4.0 to 2.9; P<0.001) and -0.6 mL/m², respectively (95%CI: -5.8 to 5.1; P<0.001) in the valsartan group).
- There was no difference in change in LVEF, LAEF and doppler echocardiography-measured E/e’ between treatment groups.
Effects on blood pressure, pulse pressure, eGFR and natriuretic peptide
- Sacubitril/valsartan significantly reduced 24-h SBP (-5.0 mm Hg (95%CI: -12.5 to 1.0) and 24-h pulse pressure (-3.0 mm Hg (95%CI: -7.0 to 0.5) compared to valsartan (-2.0 mm Hg (95%CI: -9.3 to 7.0; P=0.03) and -1.0 mm Hg (95%CI: -6.0 to 4.0; P=0.01), respectively).
- The adjusted change in pulse pressure over the total study period was greater in patients treated with sacubitril/valsartan (-4.2 mm Hg; 95%CI: -7.2 to -1.21) compared to valsartan (-1.2 mm Hg; 95%CI: -4.1 to 1.7; P<0.001).
- The reduction in eGFR was smaller in patients treated with sacubitril/valsartan (-0.9 mL/min/1.72m²) compared to valsartan (-4.9 mL/min/1.72m²; P=0.005).
- NT-proBNP levels were reduced in the sacubitril/valsartan group (-17.7%; 95%CI: -36.9 to 7.4), whereas NT-proBNP levels were elevated in the valsartan group (9.4%; 95%CI: -15.6 to 4.9; P<0.001).
Adverse CV events
- There were 55 serious adverse events reported in the sacubitril/valsartan group, whereas 69 serious adverse events were reported in the valsartan group. The most common category of serious adverse events was atrial fibrillation or flutter.
- MACE (including CV mortality) occurred in 6 patients (4.9%) in the sacubitril/valsartan group and in 17 patients (13.3%) in the valsartan group.
- The risk for first MACE was lower in the sacubitril/valsartan group compared to the valsartan group (adjusted HR: 0.38; 95%CI: 0.17 to 0.89; adjusted P=0.04).
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.