Early Initiation of Sacubitril/Valsartan in Patients With Acute Heart Failure and Renal Dysfunction: An Analysis of the TRANSITION Study.

BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.

Safety and tolerability of Sacubitril/Valsartan in heart failure patient with reduced ejection fraction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: NCT05387967. Registered 24 May 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967.

Newer Drugs to Reduce High Blood Pressure and Mitigate Hypertensive Target Organ Damage.

PURPOSE OF REVIEW: This review aims to investigate the blood pressure (BP)-lowering effects of emerging drugs developed to treat diabetic kidney disease and heart failure (HF). We summarize the potential pathophysiological mechanisms responsible for mitigating hypertensive target organ damage and evaluating the available clinical data on these newer drugs. RECENT FINDINGS: Nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists (MRAs), dual angiotensin II receptor-neprilysin inhibitors (valsartan with sacubitril), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and soluble guanylate cyclase stimulators are new classes of chemical agents that have distinct mechanisms of action and have been shown to be effective for the treatment of cardiovascular (CV) disease (CVD), HF, and type 2 diabetes mellitus (T2D). These drugs can be used either alone or in combination with other antihypertensive and CV drugs. Among these, SGLT2i and valsartan with sacubitril offer new avenues to reduce CVD mortality. SGLT2i have a mild-to-moderate effect on BP lowering with a favorable effect on CV and renal hemodynamics and have been shown to produce a significant reduction in the incidence of major adverse CVD events (as monotherapy or add-on therapy) compared with controls (placebo or non-SGLT2i treatment). Most of the participants in these studies had hypertension (HTN) at baseline and were receiving antihypertensive therapy, including renin-angiotensin system blockers. The combination of valsartan with sacubitril also lowers BP in the short term and has demonstrated a striking reduction in CVD mortality and morbidity in HF patients with a reduced left ventricular ejection fraction. If widely adopted, these novel therapeutic agents hold significant promise for reducing the public health burden posed by HTN and CVD. Based on the results of several clinical trials and considering the high prevalence of HTN and T2D, these new classes of agents have emerged as powerful therapeutic tools in managing and lowering the BP of patients with diabetic kidney disease and HF.

Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.

Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.

Sacubitril/valsartan improves the prognosis of acute myocardial infarction: a meta-analysis.

OBJECTIVE: To systematically evaluate the effect of sacubitril/valsartan (SV) on the prognosis of patients with acute myocardial infarction (AMI), and to provide evidence for expanding the clinical application of SV. METHODS: PubMed, EMbase, Web of Science, and Cochrane Library were searched from inception to October 2023 for randomized controlled trials (RCTs) of SV in patients with AMI. The article was screened and evaluated by the Cochrane 5.1.0 bias risk assessment tool. RevMan5.3 was used for meta-analysis of the outcome indicators. RESULTS: Ten RCTs involving 7230 patients were included. The results showed that SV increased left ventricular eject fraction ( MD  = 2.86, 95% CI [1.81-3.90], P  < 0.00001) and reduced readmission rate ( RR  = 0.46, 95% CI [0.32-0.68], P  < 0.0001), decreased N-terminal pro-brain natriuretic peptide ( MD = -477.46, 95% CI [-914.96 to -39.96], P  = 0.03), and reduced major adverse cardiovascular and cerebrovascular event (MACCE) ( RR  = 0.48, 95% CI [0.27-0.85], P  = 0.01). There was no significant difference in the rate of adverse reaction (AR) between the trial group and the control group ( RR  = 0.88, 95% CI [0.60-1.30], P  = 0.52). CONCLUSION: SV can effectively improve the prognosis of AMI, prevent complications, and there is no significant difference in safety compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Sacubitril/valsartan-induced liver injury: A case report and literature review.

RATIONALE: Sacubitril/valsartan (Entresto) is the first drug approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction in adult patients. There have been no reports of hepatotoxicity secondary to sacubitril/valsartan administration. Here, we report the first case of severe liver injury caused by sacubitril/valsartan. PATIENT CONCERNS: A 90-year-old female patient taking sacubitril/valsartan was admitted due to chronic heart failure. Subsequently, the patient developed serious liver injury with increased hepatic transaminases. DIAGNOSIS: Drug-induced liver injury, sacubitril/valsartan-related. No liver injury caused by other reasons was observed after thorough examination. After the withdrawal of sacubitril/valsartan, the liver function of the patient gradually returned to normal. INTERVENTIONS: We chose general liver protection methods to improve her hepatic function, including magnesium isoglycyrrhizinate at 100 mg daily and polyene phosphatidylcholine capsules at 456 mg 3 times daily. We consulted with a hepatologist to discuss the best plan for her treatment. The last, we stopped sacubitril/valsartan. OUTCOMES: After the withdrawal of sacubitril/valsartan, the liver function of the patient gradually returned to normal. LESSONS: Sacubitril/valsartan-induced liver injury is very rare. Clinicians should pay particular attention to the possibility of hepatotoxicity during sacubitril/valsartan treatment.

Urinary cGMP (Cyclic Guanosine Monophosphate)/BNP (B-Type Natriuretic Peptide) Ratio, Sacubitril/Valsartan, and Outcomes in Heart Failure With Reduced Ejection Fraction: An Analysis of the PARADIGM-HF Trial.

BACKGROUND: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides. METHODS: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death. RESULTS: Compared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01035255.

Sacubitril/valsartan, sodium-glucose cotransporter 2 inhibitors and vericiguat for congestive heart failure therapy.

Heart failure is associated with notable morbidity and mortality, and therefore, novel therapies are needed. This minireview focused on the effects and mechanisms of action of sacubitril/valsartan, sodium-glucose cotransporter 2 inhibitors and vericiguat in heart failure patients. A systematic review of the current literature was conducted. Seventeen randomised clinical trials regarding the effects of these drug classes were included. The mechanism of action of each treatment could improve pathophysiological imbalances present in heart failure. All three drug classes revealed a reduction in hospitalisations for heart failure or death from cardiovascular causes in patients with reduced ejection fraction. Sacubitril/valsartan also reduced hospitalisations and death from cardiovascular causes in patients with mid-range ejection fraction, but not in patients with preserved ejection fraction. The sodium-glucose cotransporter 2 inhibitors, sotagliflozin and empagliflozin, reduced hospitalisations and death from cardiovascular causes in heart failure patients with preserved ejection fraction. None of the three drug classes was associated with a higher prevalence of treatment discontinuation due to increases in adverse effects in large-scale randomised clinical trials compared with placebo. Further studies are required to clarify the extent of effects of these medications in different subpopulations-especially in patients with mid-range and preserved ejection fraction.

Use of Angiotensin Receptor Neprilysin Inhibitor in Patients on Maintenance Hemodialysis with Reduced Cardiac Ejection Fraction, Real-World Experience From a Single Center.

INTRODUCTION: Angiotensin receptor neprilysin inhibitor (ARNI) has been recommended by major guidelines as the leading therapy for heart failure with reduced ejection fraction (HFrEF). But little is known about its safety and effectiveness among maintenance hemodialysis patients with HFrEF in real-word practice. METHODS: An observational study was conducted among maintenance hemodialysis patients who received ARNI at our dialysis center. Enrollment commenced on June 1, 2018; and follow-up was completed on May 31, 2019. RESULTS: A total of 110 patients included in the study (age: 54.2 ± 14.8 y, 59% males). After 12 months of treatment, the average ARNI daily dose increased from 135 mg to 308 mg. The mean NT-pro- BNP concentration at baseline was 14455 pg/mL and 6435 pg/ mL after 12 months of treatment (P < .001). The left ventricular ejection fraction improved (35.1 vs. 49.8%, P < .001) over the 12 months, while left ventricular end-diastolic diameter, left ventricular mass index, left ventricular end-systolic diameter, and left atrial diameter also changed significantly (167.8 vs. 154.9 g/m, P < .001; 52.2 vs. 51.5 mm, P < .05; 35.9 vs. 36.9 mm, P < .001; 42.2 vs. 40.3 mm, P < .001). Furthermore, we found the quality of life and the NYHA symptom severity class improved significantly (P < .001). Kaplan-Meier analysis indicated that higher dose of ARNI and less vintage of HD were associated with best survival. CONCLUSION: In our study, ARNI appeared to be safe, relieved heart failure symptoms, and improved the scores of KCCQ physical and social activities in hemodialysis patients in real-world practice.

The potential role of valsartan + AHU377 ( LCZ696 ) in the treatment of heart failure.

INTRODUCTION: Heart failure remains a syndrome with a very high mortality rate and a poor quality of life. For patients with heart failure and a preserved ejection fraction (HFpEF), no drugs have shown to improve mortality and morbidity, and therefore novel drugs are highly needed. LCZ696 , a first in class angiotensin receptor neprilysin inhibitor (ARNi), might be an interesting novel drug for the treatment of heart failure. AREAS COVERED: Previous studies have shown promising effects of a combination drug with a neutral endopeptidase and an angiotensin-converting enzyme inhibitor (omapatrilat) for the treatment of patients with heart failure. However, the occurrence of angioedema prevented the drug from further development. The majority of this paper will discuss the metabolism, pharmacokinetics, pharmacodynamics, clinical effects, and safety of LCZ696, with a particular focus on heart failure. EXPERT OPINION: LCZ696 is superior to valsartan alone in reducing blood pressure. Preliminary results from a Phase II trial showed that LCZ696 reduced NT-proBNP to a greater extent than valsartan alone, and in addition LCZ696 had beneficial effects on symptoms. With these promising first results, the results of ongoing further studies in heart failure are eagerly awaited.