Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2023 Apr 1;8(4):366-375.
doi: 10.1001/jamacardio.2023.0065.

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

Mark Ledwidge  1   2 , Jonathan D Dodd  2   3 , Fiona Ryan  1 , Claire Sweeney  1 , Katherine McDonald  1 , Rebecca Fox  1 , Elizabeth Shorten  1 , Shuaiwei Zhou  1 , Chris Watson  1   2   4 , Joseph Gallagher  2 , Niall McVeigh  2   3 , David J Murphy  2   3 , Kenneth McDonald  1   2
Affiliations
Randomized Controlled Trial

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

Mark Ledwidge et al. JAMA Cardiol. .

Abstract

Importance: Pre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management.

Objective: To investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF.

Design, setting, and participants: The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/m2, and preserved ejection fraction greater than 50% were included.

Interventions: Patients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily.

Main outcomes and measures: Maximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events.

Results: Among the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, -6.3 to 7.7; P < .001) despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group (-4.2 mm Hg; 95% CI, -7.2 to -1.21 and -17.7%; 95% CI, -36.9 to 7.4, respectively; P < .001) than the valsartan group (-1.2 mm Hg; 95% CI, -4.1 to 1.7 and 9.4%; 95% CI, -15.6 to 4.9, respectively; P < .001). Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan (adjusted hazard ratio, 0.38; 95% CI, 0.17 to 0.89; adjusted P = .04).

Conclusions and relevance: In this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF.

Trial registration: ClinicalTrials.gov Identifier: NCT04687111.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ledwidge reports board membership and shares in Solvotrin Therapeutics; is a named inventor on several patents relating to anti-inflammatory effects of isosorbide prodrugs and novel formulations of iron; is currently in receipt of grant funding from Novartis, Abbott Diagnostics, and the European Commission Framework Programme 7; and has received grants from Genuity Science, Abbott, and the Health Research Board of the Irish Government outside the submitted work. Dr Dodd reported serving as associate editor for Radiology and an editorial board member of Radiology Cardiothoracic Imaging; has received grants from St Vincent’s Hospital Group Foundation and the European Commission Framework Programme 7 outside the submitted work; and has received royalties as a coauthor in the Stat-Dx book series Diagnostic Imaging: Cardiovascular and as a coauthor in the textbook CT and MRI in Cardiology, Elsevier. Dr Ryan reported serving on the Health Research Board of the Government of Ireland and has received grants from the European Commission Framework Programme 7, the Heartbeat Trust, and Novartis during the conduct of the study. Dr Gallagher received payment for lectures from Merck, Servier Laboratories, Pfizer, and Grunenthal and travel expenses to meetings from Merck. Dr Gallagher reported personal fees from Novartis and Boehringer Ingelheim outside the submitted work. Dr Kenneth McDonald reported grants from the Health Research Board of the Government of Ireland, the European Commission Framework Programme 7, and Novartis during the conduct of the study; honoraria from Pfizer, Alere, A. Menarini, Novartis, Servier, Abbott, AstraZeneca, Boehringer Ingelheim, and Vifor outside the submitted work; and is a named inventor on several patents relating to biomarkers of cardiovascular disease. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
AHA/ACC indicates American Heart Association/American College of Cardiology; BNP, B-type natriuretic peptide; e′, mitral annular early diastolic velocity; E/e′, the ratio between early mitral inflow velocity and e′; eGFR, estimated glomerular filtration rate; LAVI, left atrial volume index; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging; STOP-HF, St Vincent’s Screening to Prevent Heart Failure.
Figure 2.
Figure 2.. Change in Maximal Left Atrial Volume Index (LAVI) and Left Ventricular End Diastolic Volume Index (LVEDVI)
Cardiac magnetic resonance imaging–estimated change in maximal LAVI was greater in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, −6.3 to 7.7) (P < .001). Similarly, sacubitril/valsartan treatment showed greater increase in LVEDVI (7.1 mL/m2; 95% CI, −1.7 to 15.9) vs the valsartan group (1.4 mL/m2; 95% CI, −7.2 to 10.0) (P = .02). P value indicates between-group comparison of change values over time, adjusted for age, sex, hypertension, diabetes, obesity, vascular disease, and baseline measures of the outcome measure. Bars indicate means.
Figure 3.
Figure 3.. Time to Cardiovascular Death and First Major Adverse Cardiovascular Event (MACE)
Sacubitril/valsartan vs valsartan was associated with an unadjusted hazard ratio (HR) for cardiovascular death and major adverse cardiovascular events of 0.35 (95% CI, 0.17 to 0.74; P = .006). Error bars indicate 95% CIs.
See this image and copyright information in PMC

References

    1. Heidenreich PA, Bozkurt B, Aguilar D, et al. . 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063 - DOI - PubMed
    1. Ledwidge M, Gallagher J, Conlon C, et al. . Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA. 2013;310(1):66-74. doi:10.1001/jama.2013.7588 - DOI - PubMed
    1. Beckett NS, Peters R, Fletcher AE, et al. ; HYVET study group . Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898. doi:10.1056/NEJMoa0801369 - DOI - PubMed
    1. Wright JT Jr, Williamson JD, Whelton PK, et al. ; SPRINT research group . A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939 - DOI - PMC - PubMed
    1. Scirica BM, Morrow DA, Cannon CP, et al. ; PROVE IT-TIMI 22 investigators . Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2006;47(11):2326-2331. doi:10.1016/j.jacc.2006.03.034 - DOI - PubMed

Publication types

Associated data