Efficacy and Safety of Vericiguat in a Real-life Population with Heart Failure after 1 Year of Treatment: The VERITA Study

Heart failure (HF) is associated with a high risk of mortality and morbidity, particularly HF-related hospitalisations.¹ Management of patients with HF with reduced ejection fraction (HFrEF) has changed in recent years. Compared with the traditional approach of renin–angiotensin system inhibitors plus β-blockers, current guideline-directed medical HF therapies – angiotensin receptor–neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) – are associated with substantial reductions in the risk of cardiovascular death or admission with HF.² Consequently, quadruple therapy is currently considered the optimal treatment for HFrEF.³

However, despite these therapies, mortality rates remain high, with no clear decrease in the past decade.⁴ Moreover, (re-)hospitalisations for HF have increased, particularly when a recent HF episode worsens, mainly because of low use of recommended HF therapies, but also because of the need for comprehensive management that targets all the neurohormonal systems involved in the pathogenesis of HFrEF, including the guanylate cyclase system.^5–9 In this context, the VICTORIA trial, which analysed patients with symptomatic HFrEF and a recent worsening HF episode, showed that vericiguat combined with standard therapy was associated with a significant reduction in the risk of the primary composite outcome of cardiovascular death or first hospitalisation for HF, mainly because of a substantial reduction in the risk of hospitalisations for HF.¹⁰

Importantly, since clinical trials have strict inclusion and exclusion criteria, and patients tend to be selected, real-world data are essential to ascertain whether the information provided by randomised clinical trials can be extended to all patients with HFrEF.¹¹

The aim of the VERITA study was to determine the clinical profile, associated events and safety of vericiguat in a real-world cohort of patients with HFrEF. We previously published the preliminary data of a prospective study of 103 patients with HFrEF taking vericiguat, half of whom were followed for at least 6 months.¹² In this article, we update information on patients taking vericiguat after a 1-year follow-up.

Methods

The study design has been addressed elsewhere.¹² Briefly, VERITA was a non-interventional and prospective cohort study that enrolled patients with HFrEF and worsening of a recent HF episode requiring IV therapy. Patients had started or were already taking vericiguat, together with standard guideline-directed medical HF therapies, between December 2022 and February 2024. Patients were recruited from the advanced HF unit of a tertiary institution in Spain. Since this was a non-interventional study, the follow-up visits coincided with routine visits, and no specific diagnostic or therapeutic procedures were performed. The vericiguat titration dose was made according to routine clinical practice and the physicians’ judgement. The investigation conforms with the principles outlined in the Declaration of Helsinki. The study was approved by the Research Ethics Committee of Hospital Universitario de Gran Canaria Dr Negrín (Code 2022-592-1). Before being enrolled, all patients provided their written informed consent.

At baseline, the information recorded from the patient’s clinical history included biodemographic data, clinical conditions, the aetiology of HF, the criteria for initiating vericiguat in the VICTORIA trial, addition of levosimendan infusion, New York Heart Association (NYHA) functional class, echocardiographic parameters, biochemical parameters and HF treatments. In addition, baseline clinical characteristics were compared according to age (<75 versus ≥75 years) and renal function (estimated glomerular filtration rate; eGFR <45 ml/min versus ≥45 ml/min/1.73m²).

All patients were followed up for 1 year. During this period, changes in HF treatments, including the dosage of ARNI, MRA and loop diuretics, together with changes in NYHA functional class, were analysed, as were adverse effects, discontinuation rates and titration of vericiguat during the follow-up period. Other events evaluated during the study period included HF-related hospitalisation/emergency department (ED) visit and death (HF, cardiovascular, non-cardiovascular). Events were analysed in the overall study population, and according to age and renal function. Patients’ clinical profiles were analysed according to the development of decompensated HF during follow-up.

The 6-minute walking test was performed at baseline and at study end. Additionally, patients completed three questionnaires at baseline, and at 6 and 12 months of follow-up: the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D and a visual analogue scale (VAS). The KCCQ is a 23-item, self-administered, disease-specific instrument that quantifies symptoms, physical function, quality of life and social function within the previous 2 weeks, with a score that ranges from 0 to 100, where greater scores indicate better health status.¹³ The EQ-5D is a standardised, generic questionnaire that evaluates health status in five dimensions (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression), ranging from 0 (worst health status) to 1 (best health status).¹⁴ Finally, the VAS uses a 100 mm horizontal line with descriptors at each end to document disease-related symptom severity.¹⁵

Statistical Analysis

Quantitative data are presented using the mean and standard deviation or median and interquartile range (IQR), as appropriate. Qualitative data are presented as frequencies and percentages (n and %). The t-test and the Mann–Whitney U-test were used to compare two means, as indicated, and the c² test was used to compare categorical variables. Kaplan–Meier survival curves were plotted to evaluate HF-related hospitalisation/ED visit according to the criteria met for initiating vericiguat in the VICTORIA trial, age and renal function. A subanalysis was performed to determine the profile of patients who presented decompensation during follow-up. For this purpose, we performed a univariate analysis according to readmissions, followed by a multivariate linear regression model, including variables with p<0.10 in the univariate model. All statistical tests were based on a two-tailed alpha of 0.05. All statistical procedures were performed using jamovi version 2.3.21.0 (the jamovi project).

Results

A total of 103 patients with 1 year of follow-up were included in the study. At baseline, the mean age was 71.3 ± 9.4 years, and 27.2% of patients were women. The most common comorbidities were hypertension (86.4%), AF (66%), chronic kidney disease (61.2%) and diabetes (56.3%). Patients were NYHA functional class II (36.9%) or III (63.1%). According to the criteria for initiating vericiguat in the VICTORIA trial, 35.9% had been hospitalised for HF during the previous 3 months, 28.2% had been hospitalised for HF during the previous 3–6 months and 28.2% had received an IV diuretic for HF (without hospitalisation) during the previous 3 months. Additionally, 7.8% required infusion of levosimendan. The baseline median systolic blood pressure was 117 mmHg (IQR 103–128 mmHg). The left end-diastolic ventricular diameter was 62 mm (IQR 55–67 mm) and the left ventricular ejection fraction was 34% (IQR 28–39%). According to biochemical parameters, the median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2034 pg/ml (IQR 910–3,372 pg/ml), cancer antigen 125 18 U/ml (IQR 12–29 U/ml), eGFR 51 ml/min/1.73m² (IQR 36–65 ml/min/1.73m²) and haemoglobin 13.8 ± 1.7 (Table 1 and Supplementary Table 1).

At baseline, patients more frequently received HF drugs, with 99% of patients taking β-blockers, 97.1% SGLT2i, 96.1% ARNI (22.3% at a dose of 97/103 mg), 91.2% MRA (50.0% at a dose of 25 mg), and 93.2% loop diuretics (Table 2). The results for the baseline 6-minute walking test and the baseline questionnaires KCCQ, EQ5D and VAS were 360 m (IQR 300–422 m), 60.6 (IQR 45.5–76.8), 0.84 (IQR 0.77–0.92) and 60 (IQR 50–75), respectively (Supplementary Table 2).

Baseline clinical characteristics were compared according to age (<75 versus ≥75 years) and renal function (<45 versus ≥45 ml/min). Older people (38.8% of the study population) more frequently had chronic kidney disease (77.5 versus 50.8%; p=0.007) and less frequently received MRA (77.5 versus 98.4%; p<0.001), with no other significant differences in the clinical profile. People with worse renal function (<45 ml/min/1.73m²) were older (75.5 ± 8.4 years versus 68.4 ± 9.1 years; p<0.001), and more frequently had hypertension (95.2% versus 80.3%; p=0.03), dyslipidaemia (92.9% versus 77%; p=0.034), moderate-to-severe mitral regurgitation (52.4 versus 31.1%; p=0.031), lower levels of haemoglobin (13.2 ± 1.8 versus 14.3 ± 1.5 g/dl; p=0.002) and higher NT-proBNP levels (2,955 versus 1,553 pg/ml; p<0.001). In addition, they less frequently received MRA (81 versus 96.7%; p=0.008) than patients with eGFR ≥45 ml/min/1.73m² (Supplementary Table 3).

The NYHA functional class was assessed at baseline and during follow-up. After 1 year of treatment with vericiguat, we observed an improvement in classes II and III, from 36.9 and 63.1 to 72.1 and 16.3%, respectively (p<0.001). In addition, 11.6% of patients achieved NYHA class I (Figure 1). During this period, there was a significant decrease in NT-proBNP levels, from 2,034 pg/ml (IQR 910–3,372 pg/ml) to 1,282 pg/ml (IQR 562–3,303 pg/ml; p=0.034; Figure 2 and Supplementary Table 1). This trend was observed independently of age or renal function (Supplementary Table 4). The dosage of ARNI increased significantly (p<0.001), and the dose of furosemide decreased significantly (p=0.032) after the introduction of vericiguat. Additionally, there was a trend towards higher titration of MRA (p=0.146; Table 2, Supplementary Figures 1 and 2). No improvement was observed in the 6-minute walking test after 1 year of treatment with vericiguat. Regarding the questionnaires, only a significant increase was observed in the VAS (from 60 [IQR 50–75] to 70 [IQR 50– 85]; p<0.001), with a trend towards non-significant improvements in the EQ-5D and KCCQ scores (Supplementary Table 2).

Our study showed vericiguat to be safe. During the first month of treatment, systolic blood pressure decreased by 5 mmHg, although this decrease was less marked during the rest of the follow-up (Figure 2). Asymptomatic and symptomatic hypotension were observed in 14.6 and 11.7% of patients, respectively, although only 11.7% discontinued treatment because of adverse effects (6.8% due to hypotension). Most patients (77.7%) achieved the target dose of 10 mg of vericiguat (Table 3 and Supplementary Figure 3). The incidence of adverse effects was independent of age and renal function (Supplementary Table 5).

During the study period, 32.0% of patients were hospitalised or visited the ED for decompensated HF. Before starting vericiguat, the mean number of admissions for HF or ED visits during the previous 12 months was 1.9 ± 1.3; after treatment with vericiguat, this decreased to 0.55 ± 0.98 (p<0.001; Figure 2). Higher BMI, number of prior HF hospitalisations/ED visits, and use of levosimendan and thiazides at baseline were independently associated with readmission with HF/ED visits during the follow-up (Tables 4 and 5). Survival curves for HF hospitalisations/ED visits were plotted according to the criteria for initiating vericiguat in the VICTORIA trial (p=0.020), age (p=0.829) and renal function (p=0.027). Patients taking levosimendan and those with worse renal function (eGFR <45 ml/min/1.73m²) showed more HF events during follow-up (Supplementary Figures 4–6). At study end, eight patients had died, two of HF (Table 3).

Discussion

Our study of a large sample of patients with HFrEF showed that the addition of vericiguat to standard guideline-directed medical HF therapy markedly reduced the number of worsening HF episodes (HF-related hospitalisations/ED visits) and the level of natriuretic peptides. It also improved NYHA functional class and quality of life, and enabled titration of HF therapies, with a low risk of adverse effects.

Studies performed in recent years have analysed the use of vericiguat in clinical practice. However, many of these studies had a limited number of patients or follow-up, provided only the baseline clinical profile of patients, or focused on a specific point (e.g. functional class, hospitalisations).^16–29 For example, in Spain, the VERISEC registry was a multicentre cross-sectional study that provided the baseline clinical profile of 776 patients taking vericiguat in clinical practice.¹⁶ VERICIDuAT was a single-centre retrospective study of 123 patients (98 completed the study, with a median follow-up of 162 days) that provided information about the impact of vericiguat on biochemical parameters, functional class and events.¹⁷ Escobar et al. retrospectively analysed 14 patients with HFrEF and an ICD who started treatment with vericiguat and focused on the effects of vericiguat on ventricular arrhythmias.¹⁸

Therefore, our data are relevant, since we performed a prospective cohort study in which we provide complete information about the use of vericiguat in clinical practice in Spain, focusing not only on the clinical profile of patients and safety of vericiguat, but also on the impact of vericiguat on functional class, quality of life, biochemical parameters, drugs that improve the prognosis of HF and clinical events after 1 year of treatment.

In our study, the mean age was 71 years, approximately three-quarters of patients were men, and comorbidities were common, particularly hypertension (86%), chronic kidney disease (61%) and diabetes (56%). Moreover, almost two-thirds of patients were in NYHA functional class III, the median left ventricular ejection fraction was 34% and NT-proBNP was 2,034 pg/ml.

Compared with the baseline clinical characteristics of the VICTORIA trial, patients in the VERITA study were older (71 versus 67.5 years) and more often in NYHA class III (63 versus 40%), although they had lower NT-proBNP levels (2,034 versus 2,803 pg/ml; p<0.001), likely owing to more frequent use of guideline-directed medical HF therapies in the VERITA study.¹⁰

In the VERISEC study, the mean age was 72 years, 80% were men, three-quarters had hypertension, 53% had diabetes, 58% were in NYHA functional class II, the mean left ventricular ejection fraction was 30% and the median NT-proBNP was 3,551 pg/ml.¹⁶ In VERICIDuAT, the mean age was 78 years, 62% were men, three-quarters had hypertension, 49% had diabetes, 53% were in NYHA functional class II, the mean left ventricular ejection fraction was 35% and the median NT-proBNP was 7,055 pg/ml.¹⁷ In both studies, most patients were taking guideline-directed medical therapy, albeit to a lesser extent than in our study.^16,17 As a result, there are relevant differences between patients taking vericiguat in clinical practice and those included in the VICTORIA trial. Therefore, real-world data should be considered to provide a more comprehensive view of the role of vericiguat in the management of patients with HFrEF.

After 1 year of follow-up, the NYHA functional class had markedly improved, especially in class III, where it fell from two-thirds to only 16%. Of note, the improvement in functional class was early and persisted over time, suggesting that it was not produced by a stricter follow-up during the titration phase (placebo effect), but rather by a direct effect of vericiguat. Additionally, we observed a significant improvement in the VAS score. In contrast to the VICTORIA trial, in which no significant differences were observed in the KCCQ, studies performed in real-life populations observed an improvement in both NYHA functional class and quality of life.^{17,25,30–32} The disparities found between these studies could be related to different baseline functional health status, the type of questionnaires used and the background HF therapy.

We also observed a marked decrease in natriuretic peptide levels within the 1 year of treatment with vericiguat. Various studies have analysed the effects of vericiguat on natriuretic peptides, showing a decrease in most cases, probably because of differences in the baseline levels of natriuretic peptides, follow-up periods, HF background therapy and activation of the guanylate cyclase pathway.^{17,18,23–25,33} Of note, the benefits of vericiguat observed in the VICTORIA trial were obtained in patients with NT-proBNP levels <8,000 pg/ml.^34,35 However, the fact is that in real-world studies, baseline NT-proBNP levels are within the range of natriuretic peptides shown to be significantly beneficial in the VICTORIA trial.

Although > 90% of patients were taking guideline-directed medical HF therapies, only 22% were taking the maximum doses of ARNI, and many patients required loop diuretics to maintain euvolemic status at baseline. However, treatment with vericiguat enabled the dose of ARNI to be titrated, together with a decrease in the dose of loop diuretics, suggesting a facilitating effect of vericiguat. In the VICTORIA trial, the benefits of vericiguat were independent of the use of sacubitril–valsartan, with no significant increase in the risk of symptomatic hypotension, renal dysfunction or hyperkalaemia.³⁶ The use of drugs with complementary mechanisms of action, such as ARNI and vericiguat, translates not only into greater efficacy, but also into a lower risk of adverse effects.³⁷

Patients with HFrEF and a recent worsening HF episode have a high risk of adverse events.⁹ After 1 year of follow-up, almost one-third of patients in our study were hospitalised or visited the ED for decompensated HF, and eight patients died (two of HF). However, the addition of vericiguat translated into a substantial reduction in the number of HF-related hospitalisations/ED visits (from 1.9 to 0.55). In the vericiguat arm of the VICTORIA trial, the rate of HF-related hospitalisation was 25.9 events/100 patient-years (versus 29.6 events/100 patient-years in the placebo group).¹⁰ Real-world studies have shown rates of HF hospitalisation or death lower than those reported in the VICTORIA trial, and the comparative studies revealed a reduction in the risk of events with vericiguat.^{10,12,17,18,22,31,32,38}

Finally, in our study, patients with more previous HF-related hospitalisations, higher BMI and more frequent use of levosimendan or thiazides were more likely to be readmitted for HF during follow-up. These results are in line with those of the VICTORIA trial, in which patients with higher NT-proBNP levels benefited less from vericiguat, suggesting that vericiguat should be started as soon as possible and that prescription should not be delayed until advanced stages of HF.^6,9,34,35

Our findings showed that in clinical practice, vericiguat was safe within the first year of treatment. Thus, only 11.7% of patients discontinued treatment with vericiguat (6.8% due to hypotension), and nearly 80% achieved the 10 mg dose. Importantly, this study was observational in nature. Conse­quently, adjustments to the vericiguat dose were made based on routine clinical practice and the physicians’ judgement. As such, no specific uptitration regimen was implemented. Despite that, most patients achieved the target dose of vericiguat. In the VICTORIA trial, nearly 90% of patients were treated with vericiguat 10 mg, and <2% experienced serious adverse events.¹⁰ In contrast, while the VICTORIA trial reported a notable increase in the incidence of anaemia with vericiguat compared with placebo (7.6 versus 5.7%), our study did not observe a significant change in haemoglobin levels over the course of the investigation. This favourable safety profile has been confirmed in real-world studies.^{12,17,18,22,23,28,31,32}

Our study is subject to limitations. It was a prospective cohort study, without a control group. Therefore, we could not directly compare the effects of vericiguat in clinical practice with other therapeutic approaches and were only able to compare with the previous period. Since this was a single-centre study with patients treated in an HF unit, the findings may not be extended to other populations with HFrEF. In any case, our results were consistent with those of the VICTORIA trial and other real-life studies, thus, strengthening the validity of our data.

Conclusion

Our data suggest that the addition of vericiguat to guideline-directed medical HF therapies among patients with HFrEF in clinical practice may be associated with substantial improvements in functional class and quality of life, as well as with reductions in the levels of natriuretic peptides and adverse events, with a good safety profile. Although more studies are needed, our results emphasise the need for early use of vericiguat as add-on therapy in patients with HFrEF and a previous worsening episode of HF.

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