Comparing Analytical Methods for Composite End Points in Clinical Trials: Insights from the Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction Trial.

BACKGROUND: In VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), participants with heart failure (HF) and reduced ejection fraction, vericiguat decreased the primary composite outcome (time to first HF hospitalization [HFH] or cardiovascular death [CVD]) (897 events) compared with placebo (972 events) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82-0.98; P = .02). In this prespecified secondary analysis, we applied the weighted composite end point (WCE) and the win ratio (WR) methods to provide complementary assessments of treatment effect. METHODS AND RESULTS: The WCE method estimated the mean HFH-adjusted survival based on prespecified weights from a Delphi panel of the VICTORIA executive committee and national leaders: mild (weight per event, 0.39), moderate (0.5), or severe (0.67) HFH, and CVD (1.0). The unmatched WR was estimated for the descending hierarchy of CVD, then recurrent HFH. The WCE used all 3412 primary clinical events: 875 severe HFH (vericiguat, 416/ placebo, 459), 1614 moderate HFH (767/847), 68 mild HFH (38/30), and 855 CVD (414/441). Improved HFH-adjusted survival occurred with vericiguat (mean 78.2% vs 75.6%, difference 2.4%, 95% CI, 1.7%-3.2%, P < .0001). Based on a comparison of 6,375,624 pairs, the WR of 1.13 (95% CI 1.03-1.24, P = .01) also indicated improved clinical outcomes with vericiguat. CONCLUSIONS: The results of the WCE and WR methods were consistent with the primary analysis of the time to first HFH or CVD. Although both WCE and WR assessed recurrent events, the WCE allowed inclusion of all recurrent events, insights on the severity of HFH events, and an absolute measure of the participant-treatment experience. This approach complements conventional assessment, better informing consumers of new therapeutics and future trial designs.

Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

Vericiguat in heart failure with reduced ejection fraction: hope or solid reality?

In recent years, thanks to the advent of new classes of drugs (ARNI and SGLT2-i), the prognosis of patients suffering from heart failure with reduced ejection fraction (HFrEF) has gradually improved. Nonetheless, there is a residual risk that is not targeted by these therapies. Currently, it is recognized that vericiguat, an oral stimulator of soluble guanylate cyclase (sGC), can restore the NO-sGC-cGMP pathway, through stimulation and activation of sGC, aiming to increase cGMP levels with a reduction in heart failure-related oxidative stress and endothelial dysfunction. Even though the Victoria trial demonstrated that HFrEF patients in treatment with vericiguat showed a 10% reduction in the composite of cardiovascular mortality and rehospitalization for heart failure, statistically significantly reducing heart failure hospitalization, the international guidelines limit its use as a second-line drug for patients with worsening symptomatology despite optimized medical therapy. Furthermore, vericiguat has proved to be a valid therapeutic ally especially in those patients with comorbidities such that they cannot receive the classic four-pillar therapy of HF (in particular renal failure). In this review, the authors report on randomized clinical trials, substudies, and meta-analysis about vericiguat in HFrEF, emphasizing the strengths that would suggest the possible role of vericiguat as the fifth pillar of the HFrEF treatment, acknowledging that there are still gaps in the evidence that need to be clarified.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

PURPOSE: Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. METHODS: This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. RESULTS: Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. CONCLUSION: In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Add-on multidrug treatment based on quadruple therapy successfully treated worsening heart failure caused by anthracycline-induced cardiomyopathy in a survivor of cancer as a young adult: a case report.

BACKGROUND: The overall mortality and morbidity benefit in patients with heart failure with a reduced ejection fraction is greatest with a treatment combination of sacubitril/valsartan, beta-blockers, mineralocorticoid-receptor antagonists, and sodium-glucose transporter-2 inhibitors, termed the "fantastic four" or "quadruple therapy." The addition of vericiguat (an oral soluble guanylate cyclase stimulator) is believed to aid in managing worsening heart failure after quadruple therapy. Among childhood and young adult cancer survivors, cardiovascular complications that develop more than 10 years after anthracycline-based chemotherapy have a poor prognosis. Therefore, this study reports the efficacy of multidrug regimen based on quadruple therapy for worsening heart failure in cancer survivors with anthracycline-induced cardiomyopathy. CASE PRESENTATION: A survivor of cancer as a young adult who received high-dose anthracycline chemotherapy presented with acute decompensated heart failure 20 years post-chemotherapy and worsening heart failure 1.5 years after discharge. The patient showed signs of improvement after a step-wise introduction of carvedilol, empagliflozin, sacubitril/valsartan, ivabradine, and spironolactone for worsening heart failure. Vericiguat was accelerated owing to the risk of more severe cardiovascular events associated with ongoing aortic stenosis and the poor prognosis of anthracycline-induced cardiomyopathy. Heart failure symptoms continued to improve, with significant cardiac reverse remodeling, and the patient successfully underwent aortic valve replacement for severe aortic stenosis. CONCLUSIONS: Our case highlighted that multidrug treatment with add-on vericiguat and ivabradine based on quadruple therapy can potentially treat worsening heart failure in young adult cancer survivors with severe anthracycline-induced cardiomyopathy.

Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

Cost-utility analysis of add-on vericiguat for the treatment of chronic heart failure with reduced ejection fraction in China.

OBJECTIVE: This study aimed to evaluate the cost-utility of the addition of vericiguat for treating chronic heart failure (CHF) in China from the healthcare payer's perspective. METHODS: A Markov model was built to estimate the cost and utility of treating CHF using vericiguat plus standard treatment (vericiguat group) vs. standard treatment alone (standard treatment group). The clinical parameters (mortality of cardiovascular and hospitalization rate of HF) were calculated according to the VICTORIA clinical trial. The HF cost and utility data were obtained from the literature published in China. One-way sensitivity analysis and probability sensitivity analysis were performed. RESULTS: According to the 13-year model, vericiguat was more expensive (155599.07 CNY vs. 259396.83 CNY) and more effective (4.41 QALYs vs. 4.54 QALYs). The incremental cost-utility ratio (ICUR) was 802389.27 CNY per QALY. One-way sensitivity analysis revealed that cardiovascular mortality in the two groups was the parameter that had the greatest impact on the results. The GDP per capita in 2022 in China was 85,700 CNY. The probability sensitivity analysis (PSA) showed that the probability of vericiguat being cost-effective was only 41.7% at the willingness-to-pay (WTP) threshold of 3 times GDP per capita (257,100 CNY). CONCLUSIONS: In China, the treatment of CHF with vericiguat is not cost-effective. The drug price could decrease to 145.8 CNY, which could be considered cost-effective.

Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights.

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome.

The Role of Vericiguat in Early Phases of Anterior Myocardial Infarction: A Potential Game-Changer?

Anterior myocardial infarction is a critical condition with significant implications for cardiac function and patient prognosis. Despite advancements in reperfusion therapies, optimizing recovery during the early phases of myocardial infarction remains challenging. Anterior myocardial infarction can lead to substantial long-term effects on a patient's health due to extensive damage to the heart muscle, particularly the left ventricle, impacting both quality of life and overall prognosis. Vericiguat, a soluble guanylate cyclase stimulator, has shown promise in heart failure, but its role in early anterior myocardial infarction has not yet been fully explored. By enhancing soluble guanylate cyclase activity, vericiguat may increase cyclic guanosine monophosphate production, leading to vasodilation, inhibition of platelet aggregation, and potential cardioprotective effects. Currently, treatment options for anterior myocardial infarction primarily focus on reperfusion strategies and managing complications. However, there is a critical need for adjunctive therapies that specifically target the pathophysiological changes occurring in the early phases of myocardial infarction. Vericiguat's mechanism of action offers a novel approach to improving vascular function and myocardial health, potentially contributing to innovative treatment strategies that could transform the care and prognosis of patients with anterior myocardial infarction.

Practical Patient Care Considerations With Use of Vericiguat After Worsening Heart Failure Events.

Vericiguat is a soluble guanylate cyclase stimulator approved by multiple global regulatory bodies and recommended in recently updated clinical practice guidelines to reduce morbidity and mortality in patients with worsening chronic heart failure (HF) with reduced ejection fraction (HFrEF). Despite the growing armaments of evidence-based medical therapy for HFrEF that have demonstrated clinical outcome benefits, there is a need to address residual risk following worsening HF events. When considering therapies aimed to mitigate postevent cardiovascular risk, potential barriers preventing the prescription of vericiguat in eligible patients may include providers' lack of familiarity with it, clinical inertia, limited knowledge about monitoring response to therapy, and concerns about potential adverse effects as well as integration of its routine use during an era of in-person and telehealth hybrid ambulatory care. This review provides an overview of vericiguat therapy and proposes an evidence-based and practical guidance strategy toward implementing its use in various clinical settings. This review additionally summarizes patient counseling points for its initiation and maintenance.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy.

BACKGROUND: Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. METHODS AND RESULTS: High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14-1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. CONCLUSIONS: hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Chronic heart failure: the role of di vericiguat.

The introduction of multiple new pharmacological agents over the past three decades in the field of heart failure with reduced ejection fraction (HFrEF) has led to reduced rates of mortality and hospitalizations, and consequently, the prevalence of HFrEF has increased, and up to 10% of patients progress to more advanced stages, characterized by high rates of mortality and hospitalizations and poor quality of life. Vericiguat, a novel oral soluble guanylate cyclase stimulator, has proved effective in patients with HFrEF who had recently been hospitalized or had received intravenous diuretic therapy. In these patients, vericiguat reduced the primary outcome of death from cardiovascular causes or first hospitalization for heart failure in comparison with placebo. By reducing hospital admissions in a population at a very high risk of re-hospitalization, vericiguat might have a positive impact on healthcare costs for the management of HFrEF.

ANMCO position paper on vericiguat use in heart failure: from evidence to place in therapy.

In the growing therapeutic armamentarium for heart failure (HF) management, vericiguat represents an innovative therapeutic option. The biological target of this drug is different from that of other drugs for HF. Indeed, vericiguat does not inhibit neuro-hormonal systems overactivated in HF or sodium-glucose co-transporter 2 but stimulates the biological pathway of nitric oxide and cyclic guanosine monophosphate, which is impaired in patients with HF. Vericiguat has recently been approved by international and national regulatory authorities for the treatment of patients with HF and reduced ejection fraction who are symptomatic despite optimal medical therapy and have worsening HF. This ANMCO position paper summarises key aspects of vericiguat mechanism of action and provides a review of available clinical evidence. Furthermore, this document reports use indications based on international guideline recommendations and local regulatory authority approval at the time of writing.

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure.

PURPOSE OF REVIEW: This review sought to summarize the current emerging soluble guanylate cyclase activators and stimulators in patients with heart failure, both heart failure with reduced and preserved ejection fraction, to provide a reference for soluble guanylate cyclase activators and stimulators discovery. RECENT FINDINGS: Heart failure is a common disease with considerable morbidity, hospitalization, and mortality Soluble guanylate cyclase is a key enzyme in the nitric oxide signaling pathway and has attracted rapidly growing interest as a therapeutic target in heart failure. Currently, several soluble guanylate cyclase agonists are in clinical development. Cinaciguat and praliciguat have shown no clear clinical benefit in patients with heart failure in clinical trials. Riociguat increased the 6-min walk distance, cardiac index, and stroke volume index as well as decreased N-terminal pro-B-type natriuretic peptide. Although these populations cover nearly every range of ejection fractions, these were not clinical trials directly in patients with heart failure but were designed in patients with pulmonary hypertension. Vericiguat is recommended in the latest American guideline for patients with heart failure with reduced ejection fraction; however, it gets mixed results in patients with heart failure with preserved ejection fraction. To date, only vericiguat reduces the composite of death from cardiovascular causes or first hospitalization for heart failure in patients with heart failure with reduced ejection fraction and riociguat might improve clinical symptoms and quality of life in patients with heart failure, both heart failure with reduced and preserved ejection fraction. We need more exploration about soluble guanylate cyclase activators and stimulators in patients with heart failure.

A Systematic Review of the Effect of Vericiguat on Patients with Heart Failure.

Despite recent advances in heart failure (HF) therapy, the risk of cardiovascular (CV) mortality, morbidity, and HF hospitalization (HFH) are major challenges in HF treatment. We aimed to review the potential of vericiguat as a treatment option for HF. A systematic literature review was performed using the PubMed database and ClinicalTrials.gov. Four randomized controlled trials were identified, which study the safety and efficacy of vericiguat in HF patients. Vericiguat activates soluble guanylate cyclase (sGC) by binding to the beta-subunit, bypassing the requirement for NO-induced activation. The nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway plays an essential role in cardiovascular (CV) regulation and the protection of healthy cardiac function but is impaired in HF. Vericiguat reduced the risk of CV death and HFH in HF patients with reduced ejection fraction (HFrEF) but showed no therapeutic effect on HF with preserved ejection fraction (HFpEF). The trials demonstrated a favorable safety profile with most common adverse events such as hypotension, syncope, and anemia. Therefore, vericiguat is recommended for patients with HFrEF and a minimum systolic blood pressure of 100 mmHg. Treatment with vericiguat is considered when the individual patient experiences decompensation despite being on guideline-recommended medication, e.g., angiotensin-converting inhibitor/AT1 receptor antagonist, beta-adrenoceptor antagonist, spironolactone, and sodium-glucose transporter 2 inhibitors. Furthermore, larger studies are required to investigate any potential effect of vericiguat in HFpEF patients. Despite the limitations, vericiguat can be recommended for patients with HFrEF, where standard-of-care is insufficient, and the disease worsens.

Soluble Guanylyl Cyclase Activators-Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA).

BACKGROUND: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. METHODS: Anemia was defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization Anemia). Adverse events reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization) and the time-updated hemoglobin relationship to outcomes. RESULTS: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo (P<0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, adverse event anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (versus placebo) on the primary outcome. In addition, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (versus placebo) on the primary outcome. CONCLUSIONS: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534.

Epidemiology of Worsening Heart Failure in a Population-based Cohort from Alberta, Canada: Evaluating Eligibility for Treatment With Vericiguat.

BACKGROUND: Patients with heart failure (HF) and a reduced ejection fraction (HFrEF) who experience worsening HF (WHF) events are at increased risk of adverse outcomes and experience significant morbidity and mortality. We herein describe the epidemiology of these patients and identify those potentially eligible for vericiguat therapy in this population-based study. METHODS AND RESULTS: This retrospective cohort study included hospitalized or emergency department patients with a primary diagnosis of HF and a left ventricular ejection fraction (LVEF) of less than 45% diagnosed between April 1, 2009, and March 31, 2019 in Alberta, Canada, with follow-up to March 31, 2020. Inclusion criteria from the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection (VICTORIA) trial were applied to explore eligibility for vericiguat. Among 25,629 patients with HF and LVEF data, 9948 (38.8%) had HFrEF, of which 5259 (52.8%) experienced WHF at some point during a median 5.8 years of follow-up, and 38.3% of those met the vericiguat trial eligibility criteria. Compared with patients with HFrEF without WHF, those with WHF were older, with more comorbidities, worse renal function, and similar LVEF status, but greater use of HF medications at baseline. At the time of WHF, 27% of those with HFrEF and WHF were on triple therapy, 50.6% were on dual therapy, and 15.4% were on monotherapy. All-cause mortality and the composite outcome of all-cause mortality or cardiovascular hospitalization at 1-year of follow-up were higher in the HFrEF with WHF cohort compared with HFrEF without WHF (adjusted hazard ratios of 1.92 and 1.51, respectively, both P < .0001). CONCLUSIONS: Approximately one-half of patients with HFrEF experienced WHF over the long-term follow-up. Most were not on triple therapy, highlighting the underuse of the existing standard-of-care treatments and opportunities for application of newer therapies; more than one-third of patients with HFrEF may be eligible for vericiguat. LAY SUMMARY: Among patients with heart failure (HF), those who experience worsening HF (WHF) are at increased risk of adverse outcomes. A few new therapies, including vericiguat, have emerged recently for patients with HF and reduced ejection fraction. However, the epidemiology, treatment patterns, and outcomes of patients with WHF in large representative populations is unclear. In the current study, approximately one-half of the patients with HF and reduced ejection fraction experienced WHF and 38.3% were potentially eligible for vericiguat therapy. The guideline-recommended therapies were under-utilized among patients with WHF, which highlights the need for initiatives to address this care gap.

The place of vericiguat in the landscape of treatment for heart failure with reduced ejection fraction.

The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.

Where are we in 2021 with heart failure with reduced ejection fraction?-current outlook and expectations from new promising clinical trials.

Guideline-directed optimal medical therapy is a well-established therapy in treating patients with heart failure with reduced ejection fraction (HFrEF). Despite clear recommendations, the prognosis in this group of patients is still poor with high mortality. After publishing results of the PARADIGM-HF trial (Prospective Comparison of ARNI-Angiotensin Receptor/Neprilysin Inhibitors-with ACEI-Angiotensin-Converting Enzyme Inhibitor-to Determine Impact on Global Mortality and Morbidity in Heart Failure) clinical investigators accelerated their research. Recently, many new trials have been designed to evaluate the efficacy and safety of promising management, taking into account heterogeneity of population with chronic HFrEF. Determining target doses still poses the biggest problem in standard pharmacotherapy. Implementation of new substances for the HFrEF therapy makes it possible to formulate simple rules of treatment-in most cases, administering a dose of drug in one tablet provides a faster therapeutic effect. The aim of this article is to summarize current knowledge on recently announced findings on novel molecules and to propose a new revolutionary and individualised approach to treatment of HFrEF patients.