BACKGROUND: Despite sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor/neprilysin inhibitors (ARNi) being cost-effective evidenced-based therapies for the management of Heart Failure with Reduced Ejection Fraction (HFrEF), research shows that less than 30% of patients with HFrEF are prescribed these agents.
OBJECTIVE: This study aimed to understand clinician-perceived barriers and facilitators to prescribing ARNi and SGLT2i in patients with HFrEF.
METHODS: We conducted virtual and in-person semi-structured interviews in a large integrated healthcare delivery system in the United States. Twenty cardiology clinicians managing patients with HFrEF were recruited using purposeful sampling to target providers across professions and practice sites. The interview guide was developed based on a literature review and insights from a practicing cardiologist. It inquired about perceived prescribing behaviors, focusing on factors affecting the use of ARNi and SGLT2i. We identified key themes using rapid qualitative analysis.
RESULTS: Twenty clinicians were interviewed: 13 physicians, five advanced practitioners, and two clinic-based pharmacists. Eighteen interviews were analyzed; we excluded two as the clinicians interviewed did not meet the inclusion criteria. Three major themes were identified: 1) clinician-reported prescribing patterns don\'t always align with the American College of Cardiology/American Heart Association guidelines for the use of SGLT2i and ARNi due to clinical inertia, lack of familiarity, knowledge, and comfort with use, and concerns over polypharmacy or adverse events, 2) clinician-perceived and actual out-of-pocket cost reduced prescribing of ARNi or SGLT2i to patients, exacerbated by a lack of visibility into patients\' prescription coverage, denials of coverage by insurance, and navigating prior authorization related workflows, and 3) incorporation of a clinic-based pharmacist increased the prescribing of these medications.
CONCLUSIONS: Increasing cost transparency, implementing interventions to overcome clinical inertia and cost hurdles, and increasing clinic-based pharmacist support may improve evidenced-based prescribing in patients with HFrEF, especially for comparatively novel classes such as ARNi and SGLT2i.

Background: Heart failure (HF) is a highly prevalent syndrome in elderly subjects. Currently, multiple drugs have shown clinical benefits in patients with HF and reduced ejection fraction (HFrEF). However, evidence is scarce in elderly patients (beyond 75 years old), even more so for the latest drugs, such as angiotensin receptor-neprilysin inhibitors (ARNIs). This study aims to evaluate the use and benefits of ARNIs in elderly patients with HFrEF. Methods: A prospective observational cohort study was designed. Patients with left ventricular systolic dysfunction (defined by left ventricular ejection fraction [LVEF] < 40%) and age ≥ 75 years from January 2016 to December 2020 were prospectively included. Patients with an indication for ARNIs at inclusion or throughout follow-up were selected. Clinical, electrocardiographic and echocardiographic variables were collected. Results: A total of 616 patients were included, 34.4% of them female, with a mean age of 83.3 years, mean LVEF of 28.5% and ischemic etiology in 53.9% of patients. Only 14.3% of patients were taking ARNIs. After a mean follow-up of 34 months, 50.2% of patients died, and 62.2% had a cardiac event (total mortality or hospital admission due to HF). Multivariate Cox regression analysis showed that the use of ARNIs was independently and significantly associated with lower rates of mortality [HR 0.36 (95% CI 0.21-0.61)], with similar results in relation to all-cause mortality in a propensity-score-matched analysis [HR 0.33 (95% CI 0.19-0.57)]. Conclusions: We observed an important underuse of ARNIs in a cohort of elderly HFrEF patients, in which treatment with ARNIs was associated with a significant reduction in mortality. Greater implementation of clinical practice guidelines in this group of patients could improve their prognosis.

Angiotensin receptor-neprilysin inhibitors (ARNI) are effective against heart failure (HF) with reduced ejection fraction, but hypotension is a significant complication. Predictors of ARNI-associated hypotension remain unclear. This study aimed to determine predictors of hypotension after administering an ARNI to patients with HF accompanied by ARNI.This retrospective multicenter observational study analyzed data from 138 consecutive patients with HF treated with an ARNI between August 2020 and July 2021. Hypotension attributed to an ARNI after treatment was defined as (A) systolic blood pressure (SBP) below the 1st quartile ≤ 25 mmHg, and as (B) absolute SBP ≤ 103 mmHg. SBP was measured at baseline, after ARNI treatment, at first follow-up as outpatients and on day 7 for inpatients. Presence of atrial fibrillation, and greater BUN/Cr ratio, and SBP at baseline were significant independent predictors for hypotension after ARNI administration on multivariate analyses. Among 43 patients with AF, fine f-waves on electrocardiograms were significantly more prevalent in the hypotensive group.A robust reduction in blood pressure after ARNI administration is associated with AF and elevated BUN/Cr. This highlights the need for caution when administering ARNI to patients with HF.

BACKGROUND: Heart failure with reduced ejection fraction is associated with potentially deleterious imbalance of the cardiac autonomic nervous system. Sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNI]) reduces cardiovascular mortality and hospitalization for heart failure with reduced ejection fraction. Whether ARNI affects the cardiac autonomic nervous system has not been studied.
RESULTS: This investigator-initiated, prospective, single-center cohort study compared heart rate (HR) variability, HR, deceleration capacity, and periodic repolarization dynamics as noninvasive measures of the cardiac autonomic nervous system before and after initiation of ARNI therapy. Patients underwent standardized 12-lead Holter-ECG, echocardiography and laboratory testing before and 3 months after start of therapy. End points were changes in HR variability (SD of normal-to-normal intervals, mean square of differences between consecutive R-R intervals), HR, deceleration capacity, and periodic repolarization dynamics as well as ventricular function and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Of 63 patients with heart failure with reduced ejection fraction enrolled, 48 (76.2%) patients were still on ARNI at follow-up. SD of normal-to-normal intervals increased from 25 to 36 milliseconds (P<0.001), mean square of differences between consecutive R-R intervals increased from 12 to 19 milliseconds (P<0.001), HR decreased from 73±9 bpm to 67±4 bpm, (P<0.001), and deceleration capacity increased from 2.1 to 4.4 milliseconds (P<0.001). A trend for periodic repolarization dynamics reduction was observed (5.6 deg2 versus 4.7 deg2, P=0.09). Autonomic changes were accompanied by increased left ventricular ejection fraction (29±6% versus 40±8%, P<0.001) and reduced NT-proBNP (3548 versus 685 ng/L, P<0.001). Correlation analysis showed a significant relationship between volume-unloading (as evidenced by NT-proBNP reduction) and autonomic improvement.
CONCLUSIONS: Three months of ARNI therapy resulted in a significant increase in cardiac parasympathetic tone. The improvement in autonomic properties may be mediated by \"volume unloading\" and likely contributes to the beneficial effects of ARNI in heart failure with reduced ejection fraction.
BACKGROUND: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04587947.

This review article examines the mechanism of action of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) and Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2is) in managing chronic right ventricular (RV) dysfunction. Despite advancements in heart failure (HF) treatment, RV dysfunction remains a significant contributor to morbidity and mortality. This article explores the The article explores the impact of ARNIs and SGLT2is on RV function based on clinical and preclinical evidence, and the potential benefits of combined therapy. It highlights the need for further research to optimize patient outcomes and suggests that RV function should be considered in future clinical trials as part of risk stratification for HF therapies. This review underscores the importance of the early initiation of ARNIs and SGLT2is as per guideline-directed medical therapy for eligible HFrEF and HFpEF patients to improve co-existing RV dysfunction.

Novel therapies for heart failure with reduced ejection fraction (HFrEF) are angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose co-transporter 2 inhibitor (SGLT2i), etc. The purpose of this review is to determine the effects of ARNI and SGLT2i in heart failure (HF), compare the impact of SGLT2i with ARNI, and finally evaluate the current data regarding the combination of these two drugs in HF. Various trials on the respective medications have shown some significant reduction in all-cause mortality and cardiovascular (CV) death. The combination of these drugs has shown more CV benefits than monotherapy. There is emerging data about these two drugs in patients with heart failure with preserved ejection fraction (HFpEF). At present, there are less head-to-head comparison trials of these two drugs. This review provides insights on the current evidence, comparative efficacy, and combination therapy of ARNI and SGLT2i in managing HF, focussing on HFrEF and HFpEF.

Background: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI.

OBJECTIVE: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown.
RESULTS: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients\' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001).
CONCLUSIONS: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

Background: Sacubitril/valsartan improves heart failure (HF) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, randomized controlled trials (RCTs) in patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) have shown inconsistent results. We conducted this meta-analysis to comprehensively evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan within this specific patient population. Methods: We searched the MEDLINE database and ClinicalTrials.gov and identified four RCTs that could be included in our analysis, with 3375 patients in the sacubitril/valsartan group and 3362 in the valsartan group. Results: Our study shows that, in patients with HFmrEF and HFpEF, sacubitril/valsartan was superior to valsartan in some of the key HF outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), with a small but significant mean difference of 1.13 (95% confidence interval or CI of 0.15 to 2.11, p-value 0.024), an improvement in the New York Heart Association (NYHA) class (odds ratio or OR of 1.32, 95% CI 1.11 to 1.58, p-value 0.002), and the composite outcome of hospitalizations for HF and cardiovascular death, with a relative risk (RR) of 0.86 (95% CI 0.75 to 0.99, p-value 0.04). However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality. In terms of side effects, sacubitril/valsartan was associated with a higher risk of hypotension when compared to valsartan (OR 1.67, 95% CI 1.27 to 2.19, p-value < 0.0001), but did not show an increased risk of hyperkalemia or worsening renal function. Conclusions: In individuals with HFmrEF or HFpEF, sacubitril/valsartan can result in improvements in the HF outcomes of the KCCQ CSS, the NYHA class, and the composite outcome of hospitalization for HF and cardiovascular death when compared to valsartan. While there was a higher risk of hypotension with sacubitril/valsartan compared to valsartan, there was no corresponding increase in the risk of hyperkalemia or worsening renal function.

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