Abstract
Aims In 2021, vericiguat was approved by the US Food and Drug Administration (FDA) and the European Commission (EC) for reducing cardiovascular mortality and heart failure (HF) hospitalizations in patients with HF with reduced ejection fraction (HFrEF) based on the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial. However, there has been no report for characterizing the generalizability of vericiguat to real‐world clinical practice.
Methods and results The Korean Acute Heart Failure (KorAHF) registry is a multicentre prospective cohort study. A total of 5625 patients who were admitted for HF decompensation were consecutively enrolled. We excluded the patients without left ventricular ejection fraction (LVEF) quantification, patients with LVEF > 45%, patients with in‐hospital death or urgent heart transplantation, and patients without natriuretic peptide measurement. Among a total of 3014 enrolled patients, there were 21.9% patients with lower systolic blood pressure (SBP) (<100 mmHg) and 20.1% patients without elevated natriuretic peptide. Regarding chronic kidney disease (CKD) status, 5.1% patients had CKD Stage V [estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2] and 11.8% patients had CKD Stage IV (15 ≤ eGFR < 30 mL/min/1.73 m2). When we analysed these criteria sequentially, 21.9% were excluded from lower SBP, 15.9% were excluded from elevated natriuretic peptide, and 4.2% were excluded from advanced CKD Stage V (9.6% for CKD Stages IV and V). Among the KorAHF registry patients, we found two main reasons for not meeting the inclusion criteria of the VICTORIA trial such as low SBP and non‐elevated natriuretic peptide.
Conclusions Among the Korean hospitalized HFrEF patients, 94.9% met the FDA/EC label criteria, while 58% met the inclusion criteria of the VICTORIA trial. Our findings suggest the need for better strategies to integrate up‐to‐date HF treatment in a real‐world HF population, especially decompensated HF patients with low SBP and non‐elevated natriuretic peptide.
Keywords: Vericiguat, Heart failure, Eligibility, Clinical pharmacology, Registries
Introduction
In January 2021, vericiguat was approved by the US Food and Drug Administration (FDA) for reducing cardiovascular mortality and heart failure (HF) hospitalizations in HF patients with left ventricular ejection fraction (LVEF) <45%, requiring outpatient intravenous diuretic therapy or hospitalization, based on the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial. 1 In July 2021, the European Commission (EC) also approved vericiguat for the treatment of symptomatic chronic HF in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event requiring intravenous therapy. Vericiguat can stimulate soluble guanylate cyclase to produce cyclic guanosine monophosphate and restore nitric oxide sensitivity. It is another first‐in‐class drug in HF with reduced ejection fraction (HFrEF). 2
Methods
The Korean Acute Heart Failure (KorAHF) registry is a multicentre prospective cohort study from March 2011 to February 2014. 5 , 6 A total of 5625 patients who were admitted for HF decompensation were consecutively enrolled in 10 tertiary university hospitals in Korea. After excluding 522 patients without LVEF quantification, 1648 patients with LVEF > 45%, 154 patients with in‐hospital death or urgent heart transplantation, and 287 patients without natriuretic peptide measurement, 3014 patients were finally analysed. Continuous data were presented as mean ± standard deviation or median [inter‐quartile range], as appropriate. Categorical data were presented as proportions.
Results
In the VICTORIA trial, 22.4% Asians were enrolled (100% Asians in our registry). To compare the baseline characteristics between two studies, we collected the clinical and laboratory parameters from discharge after hospitalization or the first outpatient visit in KorAHF registry (Table 1 ). The patients in Korean registry were similar with those in the VICTORIA trial regarding age, LVEF, and serum sodium and potassium level. However, the patients enrolled in the VICTORIA trial were more male and had higher prevalence for ischaemic origin HF, diabetes, hypertension, chronic obstructive pulmonary disease, and atrial fibrillation, higher body mass index, systolic blood pressure (SBP), and haemoglobin level, and lower estimated glomerular filtration rate (eGFR) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with those in our registry. Regarding HF treatments, the patients from the VICTORIA were more likely to use medical treatments such beta‐blockers and mineralocorticoid receptor antagonists compared with those from our registry.
Table 1.
Baseline characteristics in KorAHF registry and VICTORIA patients
| Characteristics | KorAHF | VICTORIA |
|---|---|---|
| (N = 3014) | (N = 5050) | |
| Male (%) | 58.4% | 76.4% |
| Age (years) | 67 ± 15 | 67 ± 12 |
| BMI (kg/m2) | 23.2 ± 3.8 | 27.8 ± 5.9 |
| Ischaemic origin (%) | 41.8% | 58.3% |
| Diabetes (%) | 36.2% | 46.9% |
| Hypertension (%) | 56.2% | 79.1% |
| COPD (%) | 10.4% | 17.2% |
| Atrial fibrillation (%) | 29.8% | 44.9% |
| Systolic blood pressure (mmHg) | 114 ± 19 | 121 ± 16 |
| Diastolic blood pressure (mmHg) | 67 ± 13 | 73 ± 11 |
| Heart rate (b.p.m.) | 81 ± 17 | 73 ± 13 |
| LVEF (%) | 28.7 ± 8.7 | 28.9 ± 8.3 |
| eGFR (mL/min/1.73 m2) | 68.2 ± 34.0 | 61.5 ± 27.2 |
| >60 (%) | 58.7% | 47.1% |
| >30 to ≤60 (%) | 29.5% | 42.7% |
| ≤30 (%) | 11.8% | 10.2% |
| Haemoglobin (g/dL) | 12.7 ± 2.2 | 13.4 ± 1.9 |
| Sodium (mmol/L) | 138.4 ± 3.8 | 139.9 ± 3.4 |
| Potassium (mmol/L) | 4.5 ± 0.6 | 4.5 ± 0.5 |
| BNP (pg/mL) | 1040 [544–1730] | |
| NT‐proBNP (pg/mL) | 3544 [1875–8052] | 2816 [1556–5314] |
| Heart failure treatments | ||
| ACEi/ARB/ARNI (%) | 77.2% | 87.9% |
| BB (%) | 58.3% | 93.1% |
| MRA (%) | 51.2% | 70.3% |
ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta‐blocker; BMI, body mass index; BNP, B‐type natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; KorAHF, Korean Acute Heart Failure registry; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; VICTORIA, Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction.
Table 2 showed the eligibility for the inclusion criteria of the VICTORIA trial in KorAHF registry. Among a total of 3014 patients, there were 21.9% patients with lower SBP (<100 mmHg) and 20.1% patients without elevated natriuretic peptide [brain natriuretic peptide (BNP) ≥300 pg/mL or NT‐proBNP ≥ 1000 pg/mL for sinus rhythm and BNP ≥ 500 pg/mL or NT‐proBNP ≥ 1600 pg/mL for atrial fibrillation]. Regarding chronic kidney disease (CKD) status, 5.1% patients had CKD Stage V (eGFR < 15 mL/min/1.73 m2) and 11.8% patients had CKD Stage IV (15 ≤ eGFR < 30 mL/min/1.73 m2). When we analysed these criteria sequentially, 21.9% were excluded from lower SBP, 15.9% were excluded from elevated natriuretic peptide, and 4.2% were excluded from advanced CKD Stage V (9.6% for CKD Stages IV and V). Among the KorAHF registry patients, we found two main reasons for not meeting the inclusion criteria of the VICTORIA trial such as low SBP and non‐elevated natriuretic peptide. However, these two factors were not mentioned in the FDA/EC approval label. When we compared clinical characteristic between patients who meet the FDA/EC label and inclusion criteria of the VICTORIA trial (Table 3 ), the prevalence of ischaemic origin HF, hypertension, and diabetes history was higher and eGFR level was lower in the patients who can meet the inclusion criteria.
Table 2.
The individual and sequential impact of each eligibility criterion according to VICTORIA in KorAHF registry population with complete information for eligibility assessment
| VICTORIA criteria | Prevalence | |
|---|---|---|
| Individually (%) | Sequentially (%) | |
| 1. Age ≥18 years | 100% | |
| 2. LVEF ≤ 45% | 100% | |
| 3. Prior HF hospitalization within 6 months | 100% | |
| 4. SBP ≥ 100 mmHg | 78.1% | 78.1% |
| 5. Elevated natriuretic peptide a | 79.9% | 62.2% |
| 6. eGFR ≥ 15 mL/min/1.73 m2 | 94.9% | 58.0% |
| 7. eGFR ≥ 30 mL/min/1.73 m2 | 88.2% | 52.5% |
BNP, B‐type natriuretic peptide; eGFR, estimated glomerular filtration rate; HF, heart failure; KorAHF, Korean Acute Heart Failure registry; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; SBP, systolic blood pressure; VICTORIA, Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction.
BNP ≥ 300 pg/mL or NT‐proBNP ≥ 1000 pg/mL for sinus rhythm and BNP ≥ 500 pg/mL or NT‐proBNP ≥ 1600 pg/mL for atrial fibrillation.
Table 3.
Baseline characteristics according to the FDA/EC label and VICTORIA inclusion criteria
| Characteristics | FDA/EC label | VICTORIA inclusion criteria |
|---|---|---|
| (N = 2861) | (N = 1748) | |
| Male (%) | 58.4% | 56.2% |
| Age (years) | 67 ± 15 | 69 ± 14 |
| BMI (kg/m2) | 23.2 ± 3.8 | 23.1 ± 3.8 |
| Ischaemic origin (%) | 40.9% | 46.2% |
| Diabetes (%) | 35.0% | 39.1% |
| Hypertension (%) | 54.9% | 61.8% |
| COPD (%) | 10.5% | 10.7% |
| Atrial fibrillation (%) | 30.4% | 27.8% |
| Systolic blood pressure (mmHg) | 113 ± 19 | 120 ± 16 |
| Diastolic blood pressure (mmHg) | 67 ± 13 | 70 ± 11 |
| Heart rate (b.p.m.) | 81 ± 17 | 81 ± 17 |
| LVEF (%) | 28.6 ± 8.7 | 28.9 ± 8.7 |
| eGFR (mL/min/1.73 m2) | 71.4 ± 32.0 | 67.4 ± 32.0 |
| >60 (%) | 61.8% | 55.8% |
| >30 to ≤60 (%) | 31.1% | 34.7% |
| ≤30 (%) | 7.1% | 9.6% |
| Haemoglobin (g/dL) | 12.9 ± 2.2 | 12.6 ± 2.2 |
| Sodium (mmol/L) | 138.4 ± 3.8 | 138.7 ± 3.7 |
| Potassium (mmol/L) | 4.5 ± 0.5 | 4.6 ± 0.6 |
| BNP (pg/mL) | 1020 [523–1670] | 1010 [553–1615] |
| NT‐proBNP (pg/mL) | 3476 [1848–7883] | 3334 [1862–7584] |
| Heart failure treatments | ||
| ACEi/ARB/ARNI (%) | 77.8% | 76.0% |
| BB (%) | 58.3% | 57.5% |
| MRA (%) | 53.3% | 49.9% |
EC, European Commission; FDA, Food and Drug Administration. Other abbreviations in Table 1 .
Aims
Considering the difference in clinical characteristics of HF patients from between randomized clinical trial and registry or real world, 3 , 4 the study for evaluating candidacy for vericiguat should be warranted for encouraging administration rate of evidence‐based HF medical treatment. However, there has been no report for characterizing the generalizability of vericiguat to real‐world clinical practice. Therefore, we aimed to assess the real‐world eligibility for vericiguat based on the inclusion criteria of the VICTORIA trial for the first time in decompensated HF patients.
Conclusions
The clinical evidence for HF guideline‐directed medical therapy (GDMT) in CKD population was limited especially in patients with advanced CKD (Stages IV and V, eGFR < 30 mL/min/1.73 m2). The recent pivotal clinical trials such as the PARADIGM‐HF and DAPA‐HF also excluded these advanced CKD patients. However, many CKD patients have administered GDMT like as non‐CKD HF patients in real world. In our study, only 5.1% patients were ineligible for the VICTORIA inclusion criteria based on advanced CKD (eGFR < 15 mL/min/1.73 m2). Our data from a large, contemporary HF patients suggest that almost 90% patients with hospitalized HF (LVEF < 45%) would be candidates for initiation of vericiguat, supporting its broad generalizability to real‐world clinical practice, especially in advanced CKD patients with HF decompensation. However, other potential confounding factors such as ethnical difference between the VICTORIA trial (22.4% Asians) and the KorAHF registry (100% Asians), lower HF GDMT prescription rates, and other components in the exclusion criteria of the VICTORIA trial should be considered.
This is the first study to assess the eligibility for vericiguat according to the inclusion criteria of the VICTORIA trial in a large, real‐world decompensated HF population. Among the Korean hospitalized HFrEF patients, 94.9% met the FDA label criteria, while 58% met the inclusion criteria of the VICTORIA trial. Therefore, our findings highlight the need for better strategies to integrate up‐to‐date GDMT in a real‐world HF population, especially decompensated HF patients with low SBP and non‐elevated natriuretic peptide. Another ongoing vericiguat study, the VICTOR (NCT05093933) trial which has a plan to enroll the outpatient HFrEF patients with lower NT‐proBNP level than the VICTORIA trial, will answer this question.
Conflict of interest
None declared.
Funding
None.
Oh, J. , Lee, C. J. , Park, J. J. , Lee, S. E. , Kim, M.‐S. , Cho, H.‐J. , Choi, J.‐O. , Lee, H.‐Y. , Hwang, K.‐K. , Kim, K. H. , Yoo, B.‐S. , Choi, D.‐J. , Baek, S. H. , Jeon, E.‐S. , Kim, J.‐J. , Cho, M.‐C. , Chae, S. C. , Oh, B.‐H. , and Kang, S.‐M. (2022) Real‐world eligibility for vericiguat in decompensated heart failure with reduced ejection fraction. ESC Heart Failure, 9: 1492–1495. 10.1002/ehf2.13837.
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