Soluble Guanylate Cyclase Stimulator Research Articles

Favorable osteogenic activity of vericiguat doped in β-tricalcium phosphate: In vitro and in vivo studies.

Recently, more and more studies have shown that guanylate cyclase, an enzyme that synthesizes cyclic guanosine monophosphate (cGMP), plays an important role in bone metabolism. Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization. Recent studies have shown beneficial effects of VIT in animal models of osteoporosis, but very little is currently known about the effects of VIT on bone defects in the osteoporotic states. Therefore, in this study, β-tricalcium phosphate (β-TCP) was used as a carrier to explore the effect of local VIT administration on the repair of femoral metaphyseal bone defects in ovariectomized (OVX) rats. When MC3T3-E1 was cultured in the presence of H2H2, VIT, similar to Melatonin (MT), therapy could increase the matrix mineralization and ALP, SOD2, SIRT1, and OPG expression, reduce ROS and Mito SOX production, RANKL expression, Promote the recovery of mitochondrial membrane potential. In the OVX rat model, VIT increases the osteogenic effect of β-TCP and better results were obtained at a dose of 5mg. Local use of VIT can inhibit increased OC, BMP2 and RUNX2 expressions in bone tissue, while decreased SOST and TRAP expressions by RT-PCR and immunohistochemistry. Thereby, VIT stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis.

Cardiovascular Effects of Stimulators of Soluble Guanylate Cyclase Administration: A Meta-analysis of Randomized Controlled Trials.

Heart failure (HF) is one of the main causes of cardiovascular mortality in the western world. Despite great advances in treatment, recurrence and mortality rates remain high. Soluble guanylate cyclase is an enzyme which, by producing cGMP, is responsible for the effects of vasodilation, reduction of cardiac pre- and after-load and, therefore, the improvement of myocardial performance. Thus, a new therapeutic strategy is represented by the stimulators of soluble guanylate cyclase (sGCs). The aim of this meta-analysis was to analyze the effects deriving from the administration of sGCs, in subjects affected by HF. A systematic literature search of Medline, SCOPUS, and Google Scholar was conducted up to December 2022 to identify RCTs assessing the cardiovascular effects, as NT-pro-BNP values and ejection fraction (EF), and all-cause mortality, of the sGCs. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. The results obtained documented a statistically significant improvement in NT-proBNP values (SMD: - 0.258; 95% CI: - 0.398, - 0.118; p < 0.001) and EF (WMD: 0.948; 95% CI: 0.485, 1.411; p < 0.001) in subjects treated with sGCs; however, no significant change was found in the all-cause mortality rate (RR 0.96; 95% CI 0.868 to 1.072; I2, p = 0). The sGCs represent a valid therapeutic option in subjects suffering from HF, leading to an improvement in cardiac performance.

Management of Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction.

To review the current evidence and modalities for treating pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF). In recent years, several therapies have been developed that improve morbidity in HFpEF, though these studies have not specifically studied patients with PF-HFpEF. Multiple trials of therapies specifically targeting the pulmonary vasculature such as phosphodiesterase (PDE) inhibitors, prostacyclin analogs, endothelin receptor antagonists (ERA), and soluble guanylate cyclase stimulators have also been conducted. However, these therapies demonstrated lack of consistency in improving hemodynamics or functional outcomes in PH-HFpEF. There is limited evidence to support the use of pulmonary vasculature-targeting therapies in PH-HFpEF. The mainstay of therapy remains the treatment of the underlying HFpEF condition. There is emerging evidence that newer HF therapies such as sodium-glucose transporter 2 inhibitors and angiotensin-receptor-neprilysin inhibitors are associated with improved hemodynamics and quality of life of patients with PH-HFpEF. There is also a growing realization that more robust phenotyping PH and right ventricular (RV) function may hold promise for therapeutic strategies for patients with PH-HFpEF.

Pharmacological Stimulation of Soluble Guanylate Cyclase Counteracts the Profibrotic Activation of Human Conjunctival Fibroblasts.

Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor β (TGFβ)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFβ1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFβ1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFβ1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFβ1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1β and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.

Resistant Hypertension: Disease Burden and Emerging Treatment Options.

To define resistant hypertension (RHT), review its pathophysiology and disease burden, identify barriers to effective hypertension management, and to highlight emerging treatment options. RHT is defined as uncontrolled blood pressure (BP) ≥ 130/80mm Hg despite concurrent prescription of ≥ 3 or ≥ 4 antihypertensive drugs in different classes or controlled BP despite prescription of  ≥ to 4 drugs, at maximally tolerated doses, including a diuretic. BP is regulated by a complex interplay between the renin-angiotensin-aldosterone system, the sympathetic nervous system, the endothelin system, natriuretic peptides, the arterial vasculature, and the immune system; disruption of any of these can increase BP. RHT is disproportionately manifest in African Americans, older patients, and those with diabetes and/or chronic kidney disease (CKD). Amongst drug-treated hypertensives, only one-quarter have been treated intensively enough (prescribed > 2 drugs) to be considered for this diagnosis. New treatment strategies aimed at novel therapeutic targets include inhibition of sodium-glucose cotransporter 2, aminopeptidase A, aldosterone synthesis, phosphodiesterase 5, xanthine oxidase, and dopamine beta-hydroxylase, as well as soluble guanylate cyclase stimulation, nonsteroidal mineralocorticoid receptor antagonism, and dual endothelin receptor antagonism. The burden of RHT remains high. Better use of currently approved therapies and integrating emerging therapies are welcome additions to the therapeutic armamentarium for addressing needs in high-risk aTRH patients.

Soluble guanylate cyclase stimulators and activators: new horizons in the treatment of priapism associated with sickle cell disease.

Priapism, defined as a prolonged and often painful penile erection occurring without sexual stimulation or desire, is a common complication in sickle cell disease (SCD), affecting up to 48% of male patients. This condition presents significant clinical challenges and can lead to erectile dysfunction if not properly managed. Current pharmacological treatments for SCD-related priapism are primarily reactive rather than preventative, highlighting a gap in effective medical intervention strategies. A critical factor in developing priapism is the reduced basal bioavailability of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in erectile tissues. New prevention strategies should ideally target the underlying pathophysiology of the disease. Compounds that stimulate and activate soluble guanylate cyclase (sGC) emerge as potential therapeutic candidates since these compounds have the property of inducing cGMP production by sGC. This review explores the potential of sGC stimulators and activators in treating priapism associated with SCD. We discuss the advantages of these agents in the face of the challenging pathophysiology of SCD. Additionally, the review underscores the impact of intravascular hemolysis and oxidative stress on priapism pathophysiology in SCD, areas in which sGC stimulators and activators may also have beneficial therapeutic effects.

New possibilities in pharmacotherapy for the heart failure with reduced ejection fraction treatment in patients with recent deterioration

Heart failure with reduced ejection fraction (HFrEF) is a public health issue, because some patients, despite using standard treatment, still develop worsening heart failure. The risk of adverse outcomes is especially high in patients who require readmission or emergency care on an outpatient basis. They need a new type of treatment. Vericiguat is the first oral soluble guanylate cyclase stimulator approved for the treatment of adults with symptomatic HFrEF. This article summarizes the main results of the use of this drug. The effectiveness and tolerability of vericiguat, the dependence of its action on the initial state of patients (the presence of coronary heart disease, atrial fibrillation, renal failure, the level of N-terminal pro b-type natriuretic peptide (NT-proBNP) and the duration of the period after hospitalization) are considered. It is reported that the use of the drug reduces the risk of hospitalization for worsening HF and death from cardiovascular diseases in all patients with HFrEF, regardless of the considered baseline parameters, but does not significantly affect the patients’ quality of life of. These results may be useful in determining the place of vericiguat in the management of a growing population of patients with chronic HFrEF who have experienced recent deterioration despite receiving standard therapy.

Soluble guanylate cyclase stimulators for heart failure: a network meta-analysis and subgroup analyses of reduced and preserved ejection fraction

BackgroundSoluble guanylate cyclase (sGC) stimulators have been investigated for heart failure (HF) in several randomized controlled trials (RCTs). However, its place in the management guidelines of either HFrEF or HfpEF is still inconclusive.MethodsWe conducted a network meta-analysis synthesizing RCTs investigating sGC for HF management, which were retrieved by systematically searching five databases until January 24th, 2023. Dichotomous outcomes were pooled using risk ratio (RR) along with confidence interval (CI).ResultsEight RCTs with a total of 7307 patients were included. Vericiguat 10 mg significantly reduced the composite cardiovascular (CVS) mortality and HF hospitalization in HF (RR: 0.88, 95% CI [0.79; 0.98]) and in HFrEF (RR: 0.87, 95% CI [0.78; 0.97]); however, it was not effective in HFpEF (RR: 0.69, 95% CI [0.15; 3.05]). Also, vericiguat 10 mg showed no difference compared to placebo regarding the incidence of all-cause mortality (RR: 0.96, 95% CI [0.84; 1.10]), any adverse events (AEs) (RR: 0.94, 95% CI [0.83; 1.07]), any serious AEs (RR: 0.91, 95% CI [0.81; 1.01]), and any AEs leading to drug discontinuation (RR: 1.14, 95% CI [0.92; 1.40]).ConclusionVericiguat 10 mg was effective in reducing the composite CVS mortality and HF hospitalization, with an acceptable safety profile. This was only observed in HFrEF patients, but not in HFpEF patients. However, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered, warranting further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale trials.

Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions.

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced NO-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased ROS levels that inactive NO, and testosterone deficiency that leads to eNOS downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. Significant strides have been made in understanding the pathophysiology of SCD-associated priapism. Significance Statement This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.

The role of soluble guanylate cyclase stimulator riociguat in preventing the development of reperfusion lung injury after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

Aim. To evaluate the effect of prior administration of the soluble guanylate cyclase stimulator riociguat on the incidence and severity of reperfusion lung injury after balloon pulmonary angioplasty (BPA) in patients with inoperable form of chronic thromboembolic pulmonary hypertension (CTEPH).Materials and methods. 70 patients with inoperable CTEPH were included in the study. Patients were divided into 2 groups: Group 1 (n=41) – patients who had received PAH-specific therapy with riociguat at the time of BPA, Group 2 (n=29) – patients who underwent BPA without prior administration of riociguat. In the postoperative period all the patients underwent noninvasive artificial ventilation in continuous positive airway pressure mode in order to prevent the development of reperfusion damage of lungs.Results. Patients of group 1 received treatment with riocigiat for 6 months. At the time of BPA patients of both groups were matched for hemodynamic characteristics. In group 1, reperfusion edema above grade 1 occurred in 17.1% of patients, in group 2 – in 20.7% of patients, p=0.702. In group 1, manifestations of grade 3 reperfusion edema were found in 9.8% patients vs. 6.9% patients in group 2, (p=0.638). None of the patients in both groups had grade 4 or 5 reperfusion edema. Values of the index predicting the probability of reperfusion injury (PEPSI) were not significantly different in the group of patients who were pretreated with riociguat and in the group of patients who did not get PAH-specific therapy (p=0,588).Conclusion. There was no reliable evidence that administration of riociguat in recommended doses at least 6 months before BPA results in additional reduction in the incidence and severity of reperfusion pulmonary edema in patients with inoperable CTEPH.

Role of vericiguat in management of patients with heart failure with reduced ejection fraction after worsening episode.

Worsening heart failure (HF) is a vulnerable period in which the patient has a markedly high risk of death or HF hospitalization (up to 10% and 30%, respectively, within the first weeks after episode). The prognosis of HF patients can be improved through a comprehensive approach that considers the different neurohormonal systems, with the early introduction and optimization of the quadruple therapy with sacubitril-valsartan, beta-blockers, mineralocorticoid receptor antagonists, and inhibitors. Despite that, there is a residual risk that is not targeted with these therapies. Currently, it is recognized that the cyclic guanosine monophosphate deficiency has a negative direct impact on the pathogenesis of HF, and vericiguat, an oral stimulator of soluble guanylate cyclase, can restore this pathway. The effect of vericiguat has been explored in the VICTORIA study, the largest chronic HF clinical trial that has mainly focused on patients with recent worsening HF, evidencing a significant 10% risk reduction of the primary composite endpoint of cardiovascular death or HF hospitalization (number needed to treat 24), after adding vericiguat to standard therapy. This benefit was independent of background HF therapy. Therefore, optimization of treatment should be performed as earlier as possible, particularly within vulnerable periods, considering also the use of vericiguat.

Cytoglobin regulates NO-dependent cilia motility and organ laterality during development

Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer’s vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase–soluble guanylate cyclase–cyclic GMP that is necessary for normal cilia motility and left-right patterning.

The Evolving Role of Vericiguat in Patients With Chronic Heart Failure.

Heart failure (HF) is a chronic and progressive clinical disorder characterized by an inability to pump sufficient blood to meet metabolic demands. It poses a substantial global healthcare burden, leading to high morbidity, mortality, and economic impact. Current treatments for HF include lifestyle modifications, guideline-directed medical therapies (GDMT), and device interventions, but the need for novel therapeutic approaches remains significant. The introduction of vericiguat, a soluble guanylate cyclase stimulator, has shown promise in improving outcomes for heart failure patients. Vericiguat addresses the underlying pathophysiological mechanisms of heart failure by augmenting the cyclic guanosine monophosphate (cGMP) pathway, leading to enhanced cardiac contractility and vasodilation. Clinical trials evaluating the efficacy and safety of vericiguat, such as the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, have demonstrated promising results. It has been shown that vericiguat, when added to standard therapy, reduces the risk of HF hospitalization and cardiovascular death in patients with symptomatic chronic HF with reduced ejection fraction (HFrEF). The addition of vericiguat to the current armamentarium of HF treatments provides clinicians with a novel therapeutic option to further optimize patient outcomes. Its potential benefits extend beyond symptom management, aiming to reduce hospitalizations and mortality rates associated with HF. As with any new treatment, the appropriate patient selection, monitoring, and management of potential adverse effects are essential. Further research is warranted to determine the long-term benefits, optimal dosing strategies, and potential combination therapies involving vericiguat. Its ability to target the cGMP pathway provides a unique mechanism of action, offering potential benefits in improving clinical outcomes for HF patients. Continued investigation and clinical experience will further elucidate the role of vericiguat in the management of HF and its overall impact on reducing the healthcare burden associated with this debilitating condition.

SOLUBLE GUANYLATE CYCLASE STIMULATORS IN HEART FAILURE WITH PRESERVED EJECTION FRACTION: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Aims: We conducted a systemic review and meta-analysis to evaluate the therapeutic efficacy and safety of soluble guanylate cyclase (sGC) stimulators in patients with heart failure with preserved ejection fraction (HFpEF). Methods : We systematically searched PubMed, Embase, and Cochrane Library databases for original randomized controlled trials comparing sGC stimulators with placebo in HFpEF patients. A random-effects model was applied to evaluate the mortality, quality of life, and drug-related adverse events. This meta-analysis is registered in PROSPERO under the number CRD42023457382. Results : We included five studies involving 1,600 HFpEF patients. Comprehensively, the combined risk ratio (RR) for mortality was not significant (RR [95% CI] = 1.44 [0.71 to 2.91], P = 0.31). Furthermore, there were no statistically significant differences in the Kansas City Cardiomyopathy Questionnaire results, including the clinical summary score (weighted mean difference [WMD] [95% CI] =0.32 [-7.38 to 8.02], P = 0.94) and the overall summary score (WMD [95% CI] = -0.87 [-8.87 to 7.14], P = 0.83). Similarly, there was no significant improvement in the 6-minute walk distance (WMD [95% CI] = -6.22 [-18.56 to 6.12], P = 0.32). In addition, drug-related adverse events were more common in patients treated with sGC stimulators (RR [95% CI] = 1.63 [1.25-2.14], P < 0.05). Conclusion : Oral sGC stimulators do not significantly improve mortality outcomes, functional capacity, and quality of life in HFpEF patients but are associated with increased drug-related adverse events. Therefore, we should consider using sGC stimulators in HFpEF patients carefully.

Candidacy and predicted efficacy of vericiguat in contemporary heart failure outpatient clinics

Abstract Background Vericiguat is a novel drug class (soluble guanylate cyclase stimulator) approved for the treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) patients who are stable after recent decompensation. Its safety and efficacy in high-risk HFrEF patients (ejection fraction &amp;lt;45%) with recent hospitalisation was demonstrated in the VICTORIA trial, along with advantages: lesser impact on blood pressure, sustained efficacy up to eGFR 15 mL/min/1.73m2. Subgroup analyses have shown variability in heart failure hospitalisation (HFH) and cardiovascular death (CVD) reduction according to NT-proBNP levels. While real-world candidacy for Vericiguat have been described in hospitalised patients, data on Vericiguat eligibility within contemporary heart failure outpatient (HF OPD) clinics is limited. Purpose We describe the proportion of HFrEF patients reviewed in HF OPD clinics eligible for vericiguat (according to the VICTORIA trial criteria) and likely to benefit from therapy based on NT-proBNP levels. Methods A retrospective review was performed on HFrEF patients reviewed in HF OPD services in 2022. Hospital records were assessed to identify community managed HFrEF patients experiencing HFH in 2022 and the VICTORIA trial's selection criteria was applied to determine Vericiguat eligibility. Predicted efficacy (reduction in HFH and/or CVD) in Vericiguat eligible patients was based on NT-proBNP level cut-off: &amp;gt;8000 ng/L: no benefit; ≤8000 ng/L: net benefit; ≤5314 ng/L: strong benefit. Stable NT-proBNP value was taken as the peak value within 30 days of discharge of the HFH event. Results 333 HFrEF patients were reviewed in HF OPD services in 2022. 94 (28.2%) patients experienced HFH in 2022, of which 33 (9.9%) occurred after guideline directed medical therapy (GDMT) was optimized in HF OPD review. Pharmacotherapy patterns of patients with HFH were identified at HF OPD review: 24 (33.8%) quadruple GDMT, 18 (25.4%) triple GDMT, 21 (40.8%) dual or single GDMT. 71 (21.3%) patients with HFH met the VICTORIA trial criteria and were eligible for Vericiguat. When subdivided according to NT-proBNP level cut-off, the following predicted efficacy were identified: 52 (15.6%) net benefit, 42 (12.6%) strong benefit, and 19 (5.7%) no benefit. Conclusions In HF OPD services, 28.2% of HFrEF patients may experience HFH within 1 year with 9.9% occurring despite GDMT optimization. 40.8% of community managed HFrEF patients were still only on dual or single GDMT. The proportion of community managed HFrEF patients eligible for Vericiguat is 21.3%. Based on NT-proBNP levels, the proportion likely to experience net and strong beneficial effects from Vericiguat were 15.6% and 12.6% respectively. Considering Vericiguat has advantages over the traditional barriers (hypotension, renal function) of conventional HFrEF pharmacotherapy agents, our findings provide insight into the potential real-world use of Vericiguat within contemporary HF OPD clinics.Figure 1Table 1

SGLT2 inhibitors and vericiguat in real-world patients admitted for worsening heart failure

Abstract Introduction Worsening heart failure (WHF) is an emerging concept that is defined by escalating signs and symptoms of heart failure (HF) in patients with chronic heart failure (CHF) despite stable therapy. After a WHF event, there is a vulnerable period in which the risk of hospitalization and mortality is high. Sodium-glucose-co-transporter inhibitors (SGLT2i) and vericiguat, a soluble guanylate cyclase stimulator (sGCs), have been investigated in patients with WHF bother during hospitalization (EMPULSE) and right after the discharge (VICTORIA and SOLOIST-WHF) in the management of this condition with positive results. Aims This study aims to investigate the eligibility of VICTORIA, SOLOIST-WHF and EMPULSE in real-world population of patients admitted for worsening heart failure (WHF) and to analyze the differences between these groups of patients. Material and methods In this retrospective cohort study, 275 patients admitted for worsening heart failure in our cardiology department between 2017 and 2022 were enrolled. The percentages of eligible patients according to VICTORIA, SOLOIST-WHF and EMPULSE inclusion and exclusion criteria were analyzed, then the differences between the characteristics of our population and trials population were evaluated. Results 83 patients (30,2%) were eligible according to VICTORIA trial criteria, 35 patients (12,7%) according to SOLOIST-WHF and 186 patients (67,6%) according to EMPULSE. Limiting factors were ejection fraction (EF) &amp;gt; 45% in VICTORIA, the presence of diabetes in SOLOIST-WHF and the cut-off levels of NT-proBNP and BNP. Our patients were older (mean 78 years and median 80 years) than trials populations (67 years; 69 years; 71 years). EF was higher (mean 38% and median 35%) than VICTORIA (29%) and than EMPULSE (31%), but similar compared to SOLOIST-WHF (35%). Estimated glomerular filtration rate (eGFR) was lower compared to VICTORIA (56,0 ml/min vs 61,5 ml/min) whereas higher compared to EMPULSE and SOLOIST (54,0 ml/min vs 49,2 ml/min vs 50,0 ml/min). Diabetes was less common in our population (32,7% vs 47,1% vs 100% vs 46,8%); on the other hand, there were higher levels of NT-proBNP (median 5080 pg/ml) in our population compared to trials (3377 pg/ml; 1816,8 pg/ml; 3299 pg/ml). Conclusion SGLT2i and vericiguat are important drugs in the management of WHF. At the moment, vericiguat can be used only in patients with EF &amp;lt; 45% and this is the most limiting factor, whereas SGLT2i can be used regardless of EF. These data show that their applicability is high in patients with WHF and that the characteristics of trials populations reflect a real-world population. More data are needed about the use of vericiguat and SGLT2i, mostly in the first days of hospitalization. Recommendations for how to manage patients with WHF must be defined, national and international registries of HF hospitalizations may resolve this issue.Eligibility of vericiguat and SGLT2iComparison of baseline characteristics

Soluble guanylate cyclase in heart failure: A network meta-analysis and subgroup analyses of reduced and preserved ejection fraction

Abstract Background Heart failure (HF), either with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), is a significant healthcare burden, with about one million hospitalizations annually in the United States alone. Soluble guanylate cyclase (sGC) stimulators have been investigated for HF treatment in several randomized controlled trials (RCTs). However, its place in the management guidelines of either HFrEF or HfpEF is still inconclusive. Purpose We aim to evaluate the efficacy and safety of sGC in HF and determine the most effective agent and dosage for the management of either HFrEF or HFpEF. Methods We conducted a systematic review and network meta-analysis synthesizing RCTs investigating sGC, including vericiguat, riociguat, and praliciguat for HF management, which were retrieved by systematically searching five databases until January 24th, 2023. Dichotomous outcomes were pooled using risk ratio (RR) along with confidence interval (CI). Frequentist random-effects network meta-analysis was conducted via R software using meta and netmeta packages. Results Eight RCTs with a total of 7307 patients were included in our analysis. Four RCTs investigated vericiguat, three investigated riociguat, and another investigated praliciguat. Five RCTs investigated HFpEF patients, and three investigated HFrEF patients. Vericiguat 10 mg significantly reduced the incidence of composite cardiovascular (CVS) mortality and HF hospitalization in HF (RR: 0.88, 95% CI [0.79; 0.98], P = 0.02) and in HFrEF (RR: 0.87, 95% CI [0.78; 0.97], P = 0.02); however, it was not effective in HFpEF (RR: 0.69, 95% CI [0.15; 3.05], P = 0.62). Also, vericiguat 10 mg showed no difference compared to placebo regarding the incidence of all-cause mortality (RR: 0.96, 95% CI [0.84; 1.10], P = 0.57), any adverse events (AEs) (RR: 0.94, 95% CI [0.83; 1.07], P = 0.34), any serious AEs (RR: 0.91, 95% CI [0.81; 1.01], P = 0.08), and any AEs leading to drug discontinuation (RR: 1.14, 95% CI [0.92; 1.40], P = 0.23). However, all other comparisons of vericiguat, riociguat, and praliciguat showed no difference compared to placebo regarding the composite CVS mortality and HF hospitalization, with a similar safety profile. Conclusion Only vericiguat 10 mg was effective in reducing the incidence of the composite CVS mortality and HF hospitalization in patients with HFrEF, with an acceptable safety profile. However, this observation is mainly weighted by the VICTORIA trial, constituting 69.2% of our analyzed sample size, which investigated vericiguat 10 mg in patients with HFrEF. Therefore, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered. This warrants further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale adequately designed trials.Figure 1Figure 2

Abstract 12557: Vericiguat Use in a Real-World HFrEF Patient Population: Two Years Post-Launch

Background: Worsening heart failure events (WHFE) affect up to one-third of patients with HFrEF. Vericiguat, the first agent indicated specifically for a WHF population, is a novel soluble guanylate cyclase (sGC) stimulator approved in 2021 to reduce the risk of cardiovascular death and HF hospitalization. Objective: To describe baseline characteristics, comorbidities, and comedication among patients on vericiguat therapy during the first two years after FDA approval. Methods: We identified adults in the TriNetX Open Claims Database who filled a prescription for vericiguat between 1 Jan 2021 and 24 April 2023. Summary statistics were computed describing patient and treatment patterns including those of other guideline-directed medical therapy (GDMT), stratified by record of achieving 10mg target dose. Categorical variables compared across groups using Pearson Chi-Square tests and continuous variables were compared across groups using non-parametric Kruskal-Wallis tests. Results: Among 5527 patients treated with vericiguat, mean age was 68 years, most were men (67%), and insured by Medicare (47%). Just over one third had a record of achieving the 10mg target dose before data cutoff. Other common GDMT used included beta-blockers (71%), ARNi (47%), MRA (38%) and SGLT2i (39%). Although comorbidities were similar between groups, use of these GDMT classes was statistically significantly higher among patients with a record of achieving target dose of vericiguat (P &lt; 0.05). Similar trends were observed among use of GDMT combinations based on record of achieving target dose (P &lt;0.002). Conclusions: Patients with a record of achieving vericiguat target dose were significantly more likely to be on other recommended GDMT and on GDMT combinations despite a similar comorbidity burden. Additional analyses are needed to better understand factors associated with patients reaching classes and target doses of GDMT, including vericiguat.

An Investigation of Pharmacokinetic Interaction of Vericiguat with Apigenin based on a Newly Developed Ultra-performance Liquid Chromatography-tandem Mass Spectrometry Assay.

Vericiguat, as a new stimulator of soluble guanylate cyclase (sGC), was recently approved as a first-in-class treatment for reducing risks in patients with ejection fraction less than 45 percent and heart failure (HF) in the USA. The main aim of the present experiment was to establish an acceptable, sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentration levels of vericiguat in rats, and to further evaluate the effect of apigenin on the metabolism of vericiguat in vivo. In sample processes, acetonitrile was finally chosen for quickly precipitating protein. The levels of vericiguat in plasma were analyzed by a Xevo TQ-S triple quadrupole tandem mass spectrometry (Milford, MA, USA) in a positive ion mode. The scope of the calibration standard for vericiguat ranged from 0.5 to 1000 ng/mL, where a great linearity was acceptable. The lower limit of quantification (also called LLOQ) of vericiguat presented the sensitivity of this assay was evaluated as low as 0.5 ng/mL. Additionally, selectivity, accuracy and precision, extraction recovery, matrix effect, and stability were all verified. Subsequently, this approach also supported to assess the plasmatic concentrations of vericiguat from an interaction survey on herb-- drug, in which oral administration of apigenin (20 mg/kg) obviously increased the plasmatic levels of vericiguat and altered the pharmacokinetics of vericiguat in rats. These results would help us to further understand the pharmacokinetic properties of vericiguat when co-administration with apigenin, and to avoid unexpected clinical risks in the future.

Determination of vericiguat in rat plasma by UPLC-MS/MS and its application to drug interaction

Vericiguat (VER) is a novel soluble guanylate cyclase stimulator treating symptomatic chronic heart failure (HF), and it is a substrate of both transporters P-glycoprotein and breast cancer resistance protein (BCRP). Astragaloside IV (ASIV) is the main active ingredient in Radix Astragali (Huangqi), a traditional Chinese medicine widely used for HF treatment in China. ASIV's effect on the protein expression of P-glycoprotein and BCRP has been observed, its impact on VER metabolism remain uncertain. In the present study, male Sprague-Dawley rats were administered with 20 mg/kg ASIV and 1 mg/kg VER to study their pharmacokinetics. Blood samples were subject to liquid-liquid extraction, and riociguat was employed as the internal standard (IS). The analytical method involved a C18 column (XSelect® HSS T3 column, 2.1 × 100 mm, 2.5 μm) with a mobile phase of 0.1% formic acid and acetonitrile for gradient elution. The flow rate of the mobile phase was set at 0.2 mL/min, and 5 µL of the sample was used for analysis. The positive ion multi-response monitoring mode was utilized with a transition of m/z 427.4→109.1 for VER and m/z 423.3→109.1 for the IS. The method exhibited good linearity within the concentration range of 0.1 to 300 ng/mL (r = 0.9987), and all the validation processes were conducted in accordance with the requirements of biological analysis. The pharmacokinetic results revealed that ASIV did not significantly alter the main parameters of VER, except for Cmax, which decreased by 33.2% (P < 0.05). Overall, our study successfully established a selective, sensitive and repeatable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis for detecting VER in rat plasma.