The Combination of Valsartan and Sacubitril in the Treatment of Hypertension and Heart Failure – an Update

Nielsen, Peter Munch; Grimm, Daniela; Wehland, Markus; Simonsen, Ulf; Krüger, Marcus

doi:10.1111/bcpt.12912

Cited by 21 publications

(16 citation statements)

References 52 publications

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“…Our data indicate that co-administration of bosentan with LCZ 696 in MCT-injected rats is more efficient on TPVR, pulmonary vascular remodeling and cardiac fibrosis than bosentan or LCZ 696 used alone. As frequently observed in several patients treated with LCZ 696 25 , the highest dose of LCZ 696 tested in our MCT-injected rats was associated with a significant reduction in mBP. We found that LCZ 696 at a dose of 30mg/kg/day in association with bosentan (100mg/kg/day) did not impact the mBP neither in MCT-injected rats nor in SuHx rats, and thus represents the best efficacy-safety profile.…”

Section: Discussionsupporting

confidence: 86%

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension

Chaumais

Djessas

Thuillet

et al. 2020

Cardiovascular Research

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Aims Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We therefore evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH). Methods and Results Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodeling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68mg/kg/day for 2 weeks, per os) and bosentan (100mg/kg/day for 2 weeks, per os) started 7-day after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodeling and right ventricular hypertrophy and fibrosis in rats. Consistent with these observations, cotreatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30mg/kg/day for 3 weeks, per os) and bosentan (100mg/kg/day for 3 weeks, per os) started 5 weeks after sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells (PA-SMCs) derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of ANP and cGMP are higher in rats co-treated with LCZ 696 (30mg/kg/day) and bosentan (100mg/kg/day) than in MCT and SuHx rats treated with vehicle. Conclusion Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodeling and severity of experimental PH. Translational Perspective Herein, we obtained several in vivo and in vitro evidence supporting that LCZ 696 could be used as an add-on therapy to bosentan to potentially prevent or even limit the remodeling of pulmonary blood vessels and to enhance cardiac function in patients with severe PH.

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Section: Discussionsupporting

confidence: 86%

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension

Chaumais

Djessas

Thuillet

et al. 2020

Cardiovascular Research

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“…Sacubitril/valsartan is superior to RAAS inhibition alone in patients with heart failure and preclinical heart failure animal models 15 – 19 , in which the superiority of sacubitril/valsartan in reducing systemic blood pressure (and thereby unloading of LV) is one of the reasons for the favorable outcomes 38 . In order to study the direct effects of sacubitril/valsartan on the pressure overloaded hearts independent of changes in afterload, we selected AAC surgery to induce LV pressure overload in rats, which is a well-characterized, fixed LV afterload model and has been widely used in studies including testing efficacy of novel therapeutic strategies 22 – 24 .…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of early intervention with sacubitril/valsartan on pressure overloaded rat hearts

Braza

Mende

et al. 2021

Sci Rep

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Left ventricular remodeling due to pressure overload is associated with poor prognosis. Sacubitril/valsartan is the first-in-class Angiotensin Receptor Neprilysin Inhibitor and has been demonstrated to have superior beneficial effects in the settings of heart failure. The aim of this study was to determine whether sacubitril/valsartan has cardioprotective effect in the early intervention of pressure overloaded hearts and whether it is superior to valsartan alone. We induced persistent left ventricular pressure overload in rats by ascending aortic constriction surgery and orally administrated sacubitril/valsartan, valsartan, or vehicle one week post operation for 10 weeks. We also determined the effects of sacubitril/valsartan over valsartan on adult ventricular myocytes and fibroblasts that were isolated from healthy rats and treated in culture. We found that early intervention with sacubitril/valsartan is superior to valsartan in reducing pressure overload-induced ventricular fibrosis and in reducing angiotensin II-induced adult ventricular fibroblast activation. While neither sacubitril/valsartan nor valsartan changes cardiac hypertrophy development, early intervention with sacubitril/valsartan protects ventricular myocytes from mitochondrial dysfunction and is superior to valsartan in reducing mitochondrial oxidative stress in response to persistent left ventricular pressure overload. In conclusion, our findings demonstrate that sacubitril/valsartan has a superior cardioprotective effect over valsartan in the early intervention of pressure overloaded hearts, which is independent of the reduction of left ventricular afterload. Our study provides evidence in support of potential benefits of the use of sacubitril/valsartan in patients with resistant hypertension or in patients with severe aortic stenosis.

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“…However, symptomatic hypotension was not found in this study. The NPs, RAAS, sympathetic nervous system, endothelial function and immune system are all involved in the regulation of blood pressure [35][36][37]. Sacubitril/valsartan is a dual-acting ARNI in a single molecule, angiotensin-receptor blockade via its valsartan molecular moiety, and neprilysin inhibition via its sacubitril molecular moiety [34] This suggests that enhancement of NPs through neprilysin inhibition is an effective approach to improve the BP-lowering effect associated with RAS inhibition in patients with a low-or less-responsive RAS (e.g., salt-sensitive patients with hypertension or elderly patients with hypertension) [38] The NPs have been used as a new target against hypertension, participating in multiple aspects of cardiovascular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Benefits of sacubitril/valsartan use in patients with chronic heart failure after cardiac valve surgery: a single-center retrospective study

Zheng

et al. 2022

Preprint

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Objective: To evaluate the efficacy of sacubitril/valsartan for the treatment of patients with chronic heart failure (CHF) after cardiac valve surgery (CVS).Methods: Data of 259 patients who underwent CVS due to organic heart disease, and who were admitted to the hospital with CHF from January 2018 to December 2020, were collected. The patients were divided into Group A (treatment with sacubitril/valsartan) and Group B (treatment without sacubitril/valsartan). The duration of treatment and follow-up was 6 months. Prior-treatment clinical characteristics, post-treatment data, mortality, and follow-up data of the two groups were analyzed.Results: The total effective rate of Group A was higher than that of Group B (82.56% versus 65.52%, P < 0.05). The left ventricular ejection fraction (LVEF) was improved in both groups (11.14 ± 10.16 versus 7.15 ± 11.18, P = 0.004). The left ventricular end-diastolic/-systolic diameter (LVEDD/LVESD) in Group A decreased more than that in Group B (3.58 ± 9.21 versus 0.27 ± 14.44, P=0.026; 4.21 ± 8.15 versus 1.14 ± 12.12, P=0.016, respectively). The N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in both groups decreased (1305.65 ± 2000.85 versus 675.91 ± 1649.84, P=0.012). The systolic and diastolic blood pressure (SBP/DBP) in Group A decreased more than that in Group B (13.13 ± 23.98 versus 1.81 ± 10.89, P < 0.001; 8.28 ± 17.79 versus 2.37 ± 11.41, P = 0.005, respectively). Liver and renal insufficiency, hyperkalemia, symptomatic hypotension, Angioedema or acute heart failure have no statistical differences between the two groups.Conclusion: Sacubitril/valsartan can effectively improve the cardiac function of CHF patients after CVS by increasing LVEF, reducing LVEDD, LVESD, NT-proBNP and BP, with good safety.

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The Combination of Valsartan and Sacubitril in the Treatment of Hypertension and Heart Failure – an Update

Cited by 21 publications

References 52 publications

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension

Cardioprotective effects of early intervention with sacubitril/valsartan on pressure overloaded rat hearts

Benefits of sacubitril/valsartan use in patients with chronic heart failure after cardiac valve surgery: a single-center retrospective study

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