sacubitril and Hypotension

Data on the effects of sacubitril/valsartan compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) on health-related quality of life (HRQoL) are limited.. To evaluate the comparative effects between sacubitril/valsartan and ACEI/ARB on HRQoL, a systematic review and meta-analysis were performed.. PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched from inception to March 2, 2022 for randomized controlled trials that compared the HRQoL scores, including Kansas City Cardiomyopathy Questionnaire (KCCQ), Minnesota Living with Heart Failure Questionnaire (MLHFQ), or Medical Outcomes Study Short-Form Health Survey 12 or 36 (SF-12/36), between sacubitril/valsartan and ACEI/ARB. After screening, studies that met the inclusion criteria were eventually included and analyzed.. A total of 8 studies with 17 390 patients (8693 patients used sacubitril/valsartan, and 8697 patients used ACEI/ARB) were included in this study. Five of these studies used KCCQ, 1 used SF-12/36, 1 used MLHFQ, and 1 used both KCCQ and SF-12/36. The KCCQ overall summary score and its subscales were significantly higher in sacubitril/valsartan compared with ACEI/ARB in heart failure patients with reduced ejection fraction, but were similar in heart failure patients with preserved ejection fraction. Sacubitril/valsartan conferred similar HRQoL scores in MLHFQ and SF-12/36 to ACEI/ARB. The most frequently reported adverse event for sacubitril/valsartan is hypotension and the risk is higher than for ACEI/ARB.. Sacubitril/valsartan may have the potential to improve HRQoL in heart failure patients with reduced ejection fraction compared with ACEI/ARB. Hypotension is the most common adverse event with sacubitril/valsartan compared with ACEI/ARB. The results of this study may contribute to the rational use of sacubitril/valsartan.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Combinations; Heart Failure; Humans; Hypotension; Quality of Life; Stroke Volume; Tetrazoles; Valsartan

In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use.. We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0.. Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice.. With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

Topics: Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Hyperkalemia; Hypotension; Kidney Diseases; Pharmacovigilance; Randomized Controlled Trials as Topic; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

Angiotensin receptor blocker and a neprilysin inhibitor (ARNI) has emerged as an innovative therapy for patients of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to assess the safety and tolerability of Sacubitril/Valsartan in patient with HFrEF in Pakistani population.. This proof-of-concept, open label non-randomized clinical trial was conducted at a tertiary care cardiac center of Karachi, Pakistan. Patients with HFrEF were prescribed with Sacubitril/Valsartan and followed for 12 weeks for the assessment of safety and tolerability. Safety measures included incidence of hypotension, renal dysfunction, hyperkalemia, and angioedema.. Among the 120 HFrEF patients, majority were male (79.2%) with means age of 52.73 ± 12.23 years. At the end of 12 weeks, four (3.3%) patients died and eight (6.7%) dropped out of the study. In the remaining 108 patients, 80.6% (87) of the patients were tolerant to the prescribed dose. Functional class improved gradually with 75.0% (81) in class I and 24.1% (26) in class II, and only one (0.9%) patient in class III at the end of 12 weeks. Hyperkalemia remains the main safety concern with incidence rate of 21.3% (23) followed by hypotension in 19.4% (21), and renal dysfunction in 3.7% (4) of the patients.. Sacubitril/Valsartan therapy in HFrEF patients is safe and moderately tolerated among the Pakistani population. It can be used as first line of treatment for these patients.. NCT05387967. Registered 24 May 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967.

Topics: Adult; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Female; Heart Failure; Humans; Hyperkalemia; Hypotension; Kidney Diseases; Male; Middle Aged; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left

U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown.. PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event.. PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP.. In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95).. Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Hypotension; Neprilysin; Stroke Volume; Tetrazoles; Valsartan

We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.. The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.. Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.. ClinicalTrials.gov NCT02861534.

Topics: Aminobutyrates; Biphenyl Compounds; Drug Combinations; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Hyperkalemia; Hypotension; Pyrimidines; Stroke Volume; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left

Sacubitril/valsartan is a commonly used medicine for treating heart failure (HF) patients, but the treatment effects significantly vary. Neprilysin (NEP) and carboxylesterase 1 (CES1) play an important role in the efficacy of sacubitril/valsartan. The purpose of this study was to explore the relationship between NEP and CES1 gene polymorphisms and the efficacy and safety of sacubitril/valsartan treatment in HF patients.. Genotyping of 10 single nucleotide polymorphisms (SNPs) of the NEP and CES1 genes in 116 HF patients was performed by the Sequenom MassARRAY method, and logistic regression and haplotype analysis were used to evaluate the associations between SNPs and the clinical efficacy and safety of sacubitril/valsartan in HF patients.. A total of 116 Chinese patients with HF completed the whole trial, and T variations in rs701109 in NEP gene were an independent risk factor (P = 0.013, OR = 3.292, 95% CI:1.287-8.422) for the clinical efficacy of sacubitril/valsartan. Furthermore, haplotype analysis of 6 NEP SNPs (including rs701109) was performed and showed that the CGTACC and TGTACC haplotypes were significantly associated with clinical efficacy (OR = 0.095, 95%CI: 0.012-0.723, P = 0.003; OR = 5.586, 95% CI: 1.621-19.248, P = 0.005). Moreover, no association was found between SNPs of other selected genes in terms of efficacy in HF patients, and no association was observed between SNPs and symptomatic hypotension.. Our results suggest an association between rs701109 and sacubitril/valsartan response in HF patients. Symptomatic hypotension is not associated with the presence of NEP polymorphisms.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; East Asian People; Heart Failure; Humans; Hypotension; Neprilysin; Polymorphism, Genetic; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

Despite previous studies showing that patients with low systolic blood pressure (sBP) in heart failure with reduced ejection fraction (HFrEF) has a poor prognosis, it has few treatment options. This study aimed to investigate the efficacy and safety of sacubitril/valsartan (S/V) in HFrEF patients with hypotension. We included 43 consecutive HFrEF patients with sBP < 100 mmHg despite guideline-directed medical therapy for at least 3 months and who received S/V between September 2020 and July 2021. Patients admitted for acute heart failure were excluded and 29 patients were evaluated for safety endpoints. Furthermore, patients who performed non-pharmacological therapy or died within 1 month were excluded, finally, 25 patients were evaluated for efficacy endpoints. The mean initial S/V dose was 53.0 ± 20.5 mg/day and the mean dosage was increased to 84.0 ± 34.5 mg/day in 1 month. Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values significantly decreased from 2200 [interquartile range (IQR): 1462-3666] pg/ml to 1409 (IQR: 964-2451) pg/ml. (p < 0.0001). No significant change in sBP occurred (pre-sBP: 93.2 ± 4.9 mmHg, post-sBP: 93.4 ± 9.6 mmHg, p = 0.91), and no patients discontinued the S/V due to symptomatic hypotension in 1 month after S/V initiation. S/V can be safely introduced in HFrEF patients with hypotension to reduce serum NT-proBNP values. Thus, S/V may be useful for the treatment of HFrEF patients with hypotension.

Topics: Drug Combinations; Heart Failure; Humans; Hypotension; Stroke Volume; Tetrazoles; Valsartan

沙库巴曲缬沙坦作为一种新型的血管紧张素受体脑啡肽酶抑制剂，已经成为射血分数降低的心力衰竭（HFrEF）患者的一线用药，同时，沙库巴曲缬沙坦也具有降压作用，所以，目前对于合并低血压的HFrEF（HFrEF-LSBP）患者能否从沙库巴曲缬沙坦中获益存在争议。该文对低血压对沙库巴曲缬沙坦滴定的影响进行综述，并提出了HFrEF-LSBP患者中滴定沙库巴曲缬沙坦的策略，为该类患者的治疗提供参考。.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Drug Combinations; Heart Failure; Humans; Hypotension; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Function, Left

Severe heart failure in chronic hemodialysis (HD) patients is a great treatment challenge. Here we reported a chronic HD patient with the lowest ejection fraction reported so far and hypotension who well tolerated and benefited from angiotensin-receptor neprilysin inhibitor (ARNI) treatment.. This case was a 67 year old lady with decompensated heart failure and hypotension who was on regular HD. Intensified hemofiltration failed to improve her heart failure symptoms and was also retarded by hypotension.. Chronic HD with decompensated heart failure.. In addition to regular HD, low does sacubitril/valsartan was initiated and titrated from 12/13 mg to 24/26 mg twice daily.. Sacubitril/valsartan treatment was well tolerated and did not affect ultrafiltration during HD treatment. Transthoracic echocardiology at 3 months after initiation of ARNI treatment indicated significant improvement of both systolic and diastolic cardiac function. The patient has improved from New York Heart Association class 4 to class 2.. Low does ARNI treatment could effectively improve cardiac function in HD patients with heart failure and hypotension. It was also safe and well tolerated.

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Female; Heart Failure; Humans; Hypotension; Neprilysin; Renal Dialysis; Tetrazoles; Valsartan

Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide).. Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides.. We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects.. These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

Topics: Aminobutyrates; Atrial Natriuretic Factor; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Hypotension; MicroRNAs; Neprilysin; Stroke Volume; Valsartan

The effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines.. The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (p. The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Hypotension; Male; Mineralocorticoid Receptor Antagonists; Stroke Volume; Tetrazoles; Valsartan