Blood pressure, safety and clinical efficacy of vericiguat in chronic heart failure with reduced ejection fraction: Insights from the VICTOR trial.

BackgroundAlthough safety and tolerability of vericiguat were established in the VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial in patients with heart failure with reduced ejection fraction, some subgroups may be more susceptible to symptomatic hypotension, such as older patients, those with lower baseline systolic blood pressure (SBP), or those concurrently taking angiotensin receptor neprilysin inhibitors. We described the SBP trajectories over time and compared the occurrence of symptomatic hypotension or syncope by treatment arm in potentially vulnerable subgroups in VICTORIA. We also evaluated the relation between the efficacy of vericiguat and baseline SBP.Methods and ResultsAmong patients receiving at least 1 dose of the study drug (n=5034), potentially vulnerable subgroups were those >75 years old (n=1395), those with baseline SBP 100–110 mm Hg (n=1344), and those taking angiotensin receptor neprilysin inhibitors (n=730). SBP trajectory was plotted as mean change from baseline over time. The treatment effect on time to symptomatic hypotension or syncope was evaluated overall and by subgroup, and the primary efficacy composite outcome (heart failure hospitalization or cardiovascular death) across baseline SBP was examined using Cox proportional hazards models. SBP trajectories showed a small initial decline in SBP with vericiguat in those >75 years old (versus younger patients), as well as those receiving angiotensin receptor neprilysin inhibitors (versus none), with SBP returning to baseline thereafter. Patients with SBP <110 mm Hg at baseline showed a trend to increasing SBP over time, which was similar in both treatment arms. Safety event rates were generally low and similar between treatment arms within each subgroup. In Cox proportional hazards analysis, there were similar numbers of safety events with vericiguat versus placebo (adjusted hazard ratio [HR], 1.18; 95% CI, 0.99–1.39; P=0.059).No difference existed between treatment arms in landmark analysis beginning after the titration phase (ie, post 4 weeks) (adjusted HR, 1.14; 95% CI, 0.93–1.38; P=0.20). The benefit of vericiguat compared with placebo on the primary composite efficacy outcome was similar across the spectrum of baseline SBP (P for interaction=0.32).ConclusionsThese data demonstrate the safety of vericiguat in a broad population of patients with worsening heart failure with reduced ejection fraction, even among those predisposed to hypotension. Vericiguat’s efficacy persisted regardless of baseline SBP.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.

Guideline-Directed Medical Management of Heart Failure with Reduced Ejection Fraction: Improved Outcomes With Quadruple Therapy

IntroductionGuideline-directed medical therapy (GDMT) has unequivocal mortality benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, real world studies show that their uptake is often limited due...

The current review aimed to study the effectiveness and safety of angiotensin receptor-neprilysin inhibitor (ARNI) combined with sodium-glucose cotransporter-2 (SGLT2) inhibitors versus ARNI or SGLT2 inhibitors monotherapy in patients with heart failure with reduced ejection fraction (HFrEF). Studies containing patients with HFrEF who used ARNI combined with SGLT2 inhibitors versus ARNI or SGLT2 inhibitors alone were retrieved from the Medline, Embase, and Cochrane Library databases. From the selected studies, the pooled risk ratios with 95% confidence intervals of dichotomous outcomes were assessed by a random or fixed effects model in our meta-analysis. Compared with ARNI monotherapy, the reduction in ARNI combined with SGLT2 inhibitors in a composite of the first hospitalization for heart failure or cardiovascular death was 32%, hospitalization for heart failure was 35% and cardiovascular death was 35%; also all-cause death was 30%, worsening renal function was 35%, respectively, for patients with HFrEF. In addition, compared with SGLT2 inhibitors monotherapy, the reduction in ARNI combined with SGLT2 inhibitors in cardiovascular death was 36% and all-cause death was 28%, respectively, for patients with HFrEF. Although the estimated treatment effect is a 55% increase in volume depletion, overall, ARNI combined with SGLT2 inhibitors might be effective and safe for patients with HFrEF, and volume depletion should be given more attention.

Background: Angiotensin receptor-neprilysin inhibitor (ARNI) improves heart failure outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Similarly, sodium-glucose cotransporter 2 (SGLT2) inhibitors have also shown significant beneficial effects in this patient population. It is unclear if adding SGLT2 inhibitors to patients already using ARNI-containing regimen will have additional benefits in improving heart failure outcomes in patients with HFrEF. Methods: PubMed and MEDLINE search was performed using the search words – ARNI, SGLT2 inhibitor, and heart failure. Among the studies identified, we looked for randomized controlled, prospective, and retrospective studies on HFrEF that included patient groups using ARNI with SGLT2 inhibitors and ARNI without SGLT2 inhibitors and had heart failure outcomes. We identified three studies and performed a meta-analysis. Results: A total of 671 patients in the treatment group and 808 patients in the placebo group are included in our meta-analysis. The heart failure outcome analyzed is the composite of hospitalization for heart failure and cardiovascular death. Among the patients using ARNI without SGLT2 inhibitors, the outcome occurred in a total of 215 out of 808 patients (26.61%). In comparison, it occurred in 114 out of 671 patients (16.99%) among those who are on both ARNI and SGLT2 inhibitors. This study shows that there is a significant improvement in this heart failure outcome in patients with HFrEF taking an SGLT2 inhibitor and ARNI-containing regimen compared to those taking ARNI without an SGLT2 inhibitor with a relative risk (RR) of 0.67 and 95% confidence interval (CI) of 0.55 to 0.83 (p=0.0001). Conclusion: Though ARNI and SGLT2 inhibitors individually are known to improve heart failure outcomes, adding an SGLT2 inhibitor to ARNI significantly improves the heart failure outcome of the composite of hospitalization for heart failure and cardiovascular death in patients with HFrEF.

How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction?: A Redefinition of Evidence-Based Medicine.

AimsNo studies have comprehensively compared the efficacy of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, renin–angiotensin system (RAS) inhibitors, and angiotensin receptor neprilysin (ARN) inhibitors based on different type of heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The aim of this network meta‐analysis was to evaluate the relative efficacy of SGLT2 inhibitor (SGLT2i), RAS inhibitor (RASi) and ARN inhibitor (ARNI) in different types of heart failure.MethodsA systemic literature search was performed from inception to 19 November 2022 for randomized control trials assessing the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) of these drugs in HF. A network meta‐analysis was performed. Risk ratio (RR) with 95% confidence intervals (CI) were synthesized.ResultsSeventeen studies were selected with a total of 61 489 patients. In patients with HFrEF, ARNI led to a reduced risk of a composite outcome of CV death or HHF when compared with placebo (RR = 0.83, 95% CI 0.77–0.89). Similar trends were observed when focusing on the outcome of CV death or HHF alone. In patients with HFpEF, SGLT2i showed the beneficial effects on the CV death or HHF events when compared with placebo and RASi (RR = 0.82, 95% CI 0.74–0.92; RR = 1.16, 95% CI 1.02–1.31). For CV death, all these three drugs could not show beneficial effects in HFpEF. For the incidence of HHF in HFpEF, both SGLT2i and ARNI demonstrated the beneficial effects but SGLT2i was superior to ARNI. There were no differences in the events of discontinuation under these drugs when compared with placebo or each other in either HFrEF or HFpEF patients. SGLT2i showed the least renal injury among these interventions in HFrEF and there were no differences in the incidence of renal injury of these interventions in HFpEF.ConclusionsAmong these drugs, ARNI showed the greatest ability to lower the incidence of CV death or HHF and SGLT2i exerted the least renal injury in patients with HFrEF. In patients with HFpEF, SGLT2i was associated with a reduction in the risk of CV death or HHF. There were no differences in the incidence of renal injury of these interventions in HFpEF. The intolerance of these drugs were comparable in both HFrEF and HFpEF.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis

Combined ARNI and SGLT2i impacts on peak tricuspid regurgitant velocity and echocardiographic probability of pulmonary hypertension

Background:Angiotensin receptor neprilysin inhibitors (ARNI), sodium-glucose cotransporter 2 inhibitors (SGLT2i), soluble guanylate cyclase stimulators (sGCs), and the traditional golden triangle standard-of-care (SOC) are effective drugs for heart failure. We aimed to assess the efficacy of 4 interventions in these patients.Methods:PubMed, The Cochrane Library, Embase, and Web of Science databases were electronically searched to collect randomized controlled trials of 3 novel drugs in the treatment of heart failure from inception to September 1st, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk bias of included studies. Stata 16.0 software was used for network meta-analysis.Results:A total of 17 randomized controlled trial involving 38,088 patients were included. The results of network meta-analysis: in terms of heart failure rehospitalization rate, 3 novel drugs lower than SOC [ARNI (OR = 0.77, 95% CI: 0.71–0.83), SGLT2i (OR = 0.70, 95% CI: 0.63–0.77), sGCs (OR = 0.88, 95% CI: 0.78–0.99)], and SGLT2i was also lower than sGCs (OR = 0.79, 95% CI: 0.68–0.93). In terms of all-cause mortality, ARNI was lower than SOC (OR = 0.81, 95% CI: 0.66–0.99). In terms of cardiovascular mortality, ARNI and SGLT2i was lower than SOC (ARNI [OR = 0.80, 95% CI: 0.70–0.92], SGLT2i [OR = 0.87, 95% CI: 0.76–0.99]). In terms of rates of cardiovascular death or heart failure rehospitalization, 3 novel drugs lower than SOC (ARNI [OR = 0.76, 95% CI: 0.71–0.82], SGLT2i [OR = 0.76, 95% CI: 0.70–0.82], sGCs [OR = 0.87, 95% CI: 0.78–0.97]). In terms of Kansas city cardiomyopathy questionnaire score, ARNI and SGLT2i was superior to SOC (ARNI [MD = 1.43, 95% CI: 0.43–2.42], SGLT2i [MD = 1.88, 95% CI: 1.12–2.65]). In terms of N-terminal pro-B-type natriuretic peptide outcome indexes, SGLT2i was superior to SOC (MD = −134.63, 95% CI: −237.70 to −31.56). The results of Surface under the cumulative ranking sequencing: in terms of heart failure rehospitalization rate and rates of cardiovascular death or heart failure rehospitalization, the ranking was SGLT2i>ARNI>sGCs>SOC. in terms of all-cause mortality and cardiovascular mortality, the ranking was ARN>SGLT2i>sGCs>SOC. in terms of Kansas city cardiomyopathy questionnaire score and N-terminal pro-B-type natriuretic peptide outcome indexes, the ranking was SGLT2i>ARN>SOC.Conclusions:The available evidence suggests that all 3 novel heart failure drugs can improve the prognosis of heart failure. ARNI may be the most effective in reducing mortality, SGLT2i may be the most effective in improving quality of life, while sGCs may be inferior to ARNI and SGLT2i.

Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

AimsThis study aimed to determine the effects of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) in heart failure with reduced ejection fraction (HFrEF), compare the effect of SGLT2i with angiotensin receptor neprilysin inhibitor (ARNI), and find whether combination of SGLT2i and ARNI is better than monotherapy.Methods and resultsEmbase, Medline, and Cochrane Central Registry of Controlled Trials were searched for randomized controlled trials evaluating SGLT2i or ARNI in HFrEF. And a total of six trials were included. SGLT2i was found to significantly reduce the risk of cardiovascular death or hospitalization for heart failure by 27% [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67–0.80], hospitalization for heart failure by 31% (HR 0.69, 95% CI 0.62–0.77), cardiovascular death by 16% (HR 0.84, 95% CI 0.74–0.95), and all‐cause death by 16% (HR 0.84, 95% CI 0.75–0.94) in HFrEF only with a statistically higher risk of genital infection (risk ratio (RR) 2.78, 95% CI 1.46–5.29). The reduction in cardiovascular death or hospitalization for heart failure was of similar magnitude in patients with or without diabetes mellitus (HR 0.71, 95% CI 0.64–0.80 vs. HR 0.75, 95% CI 0.65–0.87) using SGLT2i. Indirect treatment comparison showed that SGLT2i and ARNI had similar effects on primary outcome (HR 0.93, 95% CI 0.82–1.06). And combination of SGLT2i and ARNI achieved a better prognosis performance (HR 0.68, 95% CI 0.53–0.89) compared with ARNI monotherapy.ConclusionsSGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect.

Combining sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors in heart failure patients with reduced ejection fraction and diabetes mellitus: A multi-institutional study

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.