Highlights
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This study investigated the associations between patient characteristics, hypotension, and outcomes after initiating vericiguat in patients with heart failure and reduced ejection fraction (HFrEF).
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Although symptomatic or asymptomatic hypotension was relatively common within 90 days of starting vericiguat (25.3%), drug discontinuation due to hypotension was infrequent (only 4.4%), suggesting that these complications might not be mainly attributable to vericiguat.
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Patients experiencing hypotension had a greater subsequent risk of HF outcomes, but this association likely reflect their baseline vulnerability.
ABSTRACT
Background
Real-world characteristics and outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF) treated with vericiguat remain unclear. We investigated patient characteristics, hypotension—the most relevant clinical event—, and outcomes after initiating vericiguat in patients with HFrEF.
Methods
In this nationwide, multicentre retrospective study involving 22 hospitals in Japan, we examined symptomatic or asymptomatic hypotension and drug discontinuation within 90 days after initiation of vericiguat in patients with left ventricular ejection fraction <45%. The association between hypotension and HF outcomes was also examined.
Results
Among the 799 patients with HFrEF, the mean age was 69.6 years, and 218 (27.3%) were female. Of them, 316 (39.5%) had New York Heart Association classification III or IV, and 329 (41.8%) had systolic blood pressure (sBP) <100 mm Hg. Hypotension was observed in 25.3% of patients within 90 days, with asymptomatic hypotension being the most common (17.9%). By contrast, drug discontinuation related to hypotension was less frequent (4.4%). After adjustment, sBP <100 mm Hg, low body mass index, and in-hospital vericiguat initiation were associated with the incidence of hypotension within 90 days. Patients who experienced hypotension had a greater risk of cardiovascular death or HF hospitalization than those who did not ( P =.01).
Conclusions
Although hypotension was relatively common soon after starting vericiguat, they were not often associated with drug discontinuation. Patients experiencing hypotension had a greater risk of HF outcomes, but this would be primarily associated with their vulnerability, given the infrequent discontinuation.
Graphical abstract
Background
The VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial showed that vericiguat, compared to placebo, reduced the risk of the primary outcome—the composite of cardiovascular death or heart failure (HF) hospitalization—in patients with “ worsening ” HF and reduced ejection fraction (HFrEF). However, the relative risk reduction (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.82-0.98, P =.02) was modest compared to other guideline directed medical therapies, such as sacubitril/valsartan or sodium-glucose co-transporter 2 (SGLT2) inhibitors. ,, Therefore, so far, vericiguat has not been at the top of the list of HF treatments in current international guidelines. ,,, By contrast, an analysis from VICTORIA suggested that the benefits of vericiguat may be greater in less sick patients, leading to a hypothesis that this drug could provide a greater risk reduction in more compensated patients with HF compared to the population examined in VICTORIA. , This hypothesis was tested in the recently published VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial, which did not achieve statistical significance for the primary outcome. In addition to these potential—but somewhat uncertain—benefits, VICTORIA also demonstrated an interesting safety profile for vericiguat: a relatively lower risk of hypotension compared to other HF therapies (e.g., sacubitril/valsartan , ) and an increased risk of anemia compared to placebo . Given this complex benefit/risk balance, a better understanding of real-world characteristics, tolerability, and outcomes of patients treated with vericiguat could clarify its role in HF management.
Therefore, we aimed to investigate the associations between patient characteristics, clinically relevant HF complications, especially hypotension, and outcomes after initiating vericiguat in patients with HFrEF.
Methods
Study design and population
The VERIFY-HF (Verifying Characteristics and Outcomes in Heart Failure Patients Treated With Vericiguat) registry is a nationwide, multicenter retrospective study conducted at 22 hospitals in Japan, designed to evaluate the characteristics and outcomes of patients with HF who were newly prescribed vericiguat in either inpatient or outpatient settings between June 2021 and September 2023. All adult patients (≥20 years) who initiated vericiguat for the management of HF during this period were retrospectively enrolled from the participating institutions, regardless of left ventricular ejection fraction (LVEF), including HF with mildly reduced and preserved ejection fraction. In this primary analysis, we evaluated characteristics and outcomes of patients with LVEF <45% to compare our findings with the results of VICTORIA.
The study protocol was approved by the ethics committee of Toho University Omori Medical Center (no. A23090) and the local ethics committees of all participating institutions, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Furthermore, this study was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN-ID: UMIN000054318) before data collection, in accordance with the International Committee of Medical Journal Editors. In accordance with the Japanese “Ethical Guidelines for Medical and Health Research Involving Human Subjects” and the “Act on the Protection of Personal Information,” informed consent was obtained from all participants prior to study enrolment, with a waiver of consent applied in cases where an opt-out approach was employed.
Data collection
In VERIFY-HF, data at baseline and during follow-up and outcomes were retrospectively collected by study investigators and/or clinical research coordinators using an electronic data capture system. All data collected were thoroughly reviewed and validated through data queries managed by a central data laboratory (National Cerebral and Cardiovascular Center).
Baseline characteristics and prespecified longitudinal data, including laboratory findings (at 2 weeks, 1 month, 3 months, 6 months, and 1 year), and clinical outcomes were collected.
Hypotension and clinically relevant HF complications
In this study, we examined patient characteristics and outcomes according to hypotension, with or without symptoms, observed within 90 days. In addition, clinically relevant HF complications, including events not likely attributable to vericiguat, were evaluated. Each event was defined as follows, referring to previous HF studies ,,,,, : (1) hypotension: asymptomatic hypotension (systolic blood pressure [sBP] reduction to <90 mm Hg if the baseline sBP ≥100 mm Hg or sBP reduction >10% if the baseline sBP <100 mm Hg) or symptomatic hypotension (sBP reduction with symptoms); (2) syncope: temporary loss of consciousness related to sBP reduction; (3) anemia: hemoglobin decline ≥20%; (4) hyperkalemia: a potassium level of ≥5.6 mmol/L; and (5) worsening renal function: a reduction in estimated glomerular filtration rate (eGFR) ≥50% from baseline, an absolute reduction in eGFR >30 mL/min/1.73 m 2 from baseline, or the initiation of dialysis.
Clinical outcomes examined
We assessed the time to the first occurrence of the composite of cardiovascular death or HF hospitalization, each component of the composite outcome, and all-cause mortality. The predefined definition of cardiovascular death and HF hospitalization is summarized in Supplementary Table I. In addition, discontinuation of vericiguat (excluding discontinuation due to death) was examined.
Statistical analysis
Patient characteristics according to symptomatic or asymptomatic hypotension were described using numbers/percentages (%) for categorical variables, and the mean value (±standard deviation) or median value with interquartile range (quartiles 1–3) for continuous variables. Differences between the two groups (no hypotension and hypotension) were assessed using the Student’s t-test or Mann-Whitney test for continuous variables, and the chi-square test for categorical variables. Change in sBP over time according to hypotension within 90 days was analyzed using a linear mixed model for repeated measurements, adjusted for baseline sBP levels, and the interaction between hypotension and visit, with a random intercept and slope per patient.
To estimate predictors of hypotension, discontinuation of vericiguat, and up-titration to the target dose (10 mg/d), the following key prognostic variables were used in multivariable analysis models: age ≥75 years (vs <75 years), sex, NYHA class III or IV (vs NYHA class I or II), body mass index (BMI) <25 kg/m 2 (vs ≥25 kg/m 2), sBP <100 mm Hg (vs ≥100 mm Hg), eGFR <30 mL/min/1.73m 2 (vs ≥30 mL/min/1.73 m 2), atrial fibrillation, diabetes mellitus, prior hospitalization for HF, and vericiguat initiation during HF hospitalization. In addition, a multivariable analysis model including NT-proBNP was constructed as a sensitivity analysis, in which all continuous variables were treated as continuous. A multivariable model excluding patients with incomplete follow-up—defined as those without survival information at 90 days and without any hypotension during that period—was also evaluated as a sensitivity analysis. Furthermore, a model including vericiguat up-titration to 10 mg/d within 90 days was analyzed. As another sensitivity analysis, hospital was also included in the adjustment.
Clinical outcomes according to hypotension within 90 days were reported as the number of events and rates per 100 person-years. Time-to-first event data were evaluated with time-updated Cox proportional hazards models to calculate HRs with 95% CIs, with hypotension as a time-updated binary variable, to assess the association between hypotension and subsequent outcomes. In these analyses, day 0 in the time to first event analysis was the date of the event in patients who experienced hypotension, to address potential immortal time bias. Additionally, HRs were adjusted for age, sex, body mass index, estimated glomerular filtration rate, New York Heart Association functional classification, heart rate, systolic blood pressure, type 2 diabetes mellitus, prior hospitalization for HF, myocardial infarction, and atrial fibrillation.
All analyses were performed using STATA version 18.0 (StataCorp), and a 2-sided p -value <.05 was considered statistically significant.
Results
A total of 983 patients with HF who initiated vericiguat were enrolled in the VERIFY-HF registry. Among 975 patients with available baseline LVEF, 799/975 (81.9%) patients with LVEF <45% were included in the current analysis. The median follow-up in this study population was 16.8 (IQR: 10.8-21.9) months.
Baseline characteristics according to hypotension within 90 days
Baseline characteristics of patients who did and did not experience symptomatic or asymptomatic hypotension within 90 days are shown in Table 1 . Overall, 581 (72.7%) were male, and the mean age was 69.6 years, with 57.1% of participants aged >70 years and 22.5% aged >80 years. Vericiguat was most commonly initiated at a daily dose of 2.5 mg/d (97.0%).
Table 1
Baseline characteristics according to hypotension within 90 days.
| Overall | No hypotension within 90 days | Hypotension within 90 days | P value | |
|---|---|---|---|---|
| N = 799 | N = 597 | N = 202 | ||
| Age (years) | 69.6±13.9 | 69.5±13.9 | 69.7±14.0 | .87 |
| Age>70 y | 456 (57.1) | 339 (56.8) | 117 (57.9) | .78 |
| Age>80 y | 180 (22.5) | 140 (23.5) | 40 (19.8) | .28 |
| Male | 581 (72.7) | 439 (73.5) | 142 (70.3) | .37 |
| BMI (kg/m 2) | 22.7±4.5 | 23.0±4.5 | 21.8±4.5 | <.01 |
| BMI category | <.01 | |||
| <18.5 | 137 (17.2) | 92 (15.5) | 45 (22.3) | |
| 18.5-24.9 | 458 (57.5) | 335 (56.4) | 123 (60.9) | |
| 25-29.9 | 144 (18.1) | 123 (20.7) | 21 (10.4) | |
| ≥30 | 57 (7.2) | 44 (7.4) | 13 (6.4) | |
| Initial dose of vericiguat | .11 | |||
| ≤1.25 mg/d | 8 (1.0) | 8 (1.3) | 0 | |
| 2.5 mg/d | 775 (97.0) | 574 (96.1) | 201 (99.5) | |
| 5 mg/d | 15 (1.9) | 14 (2.3) | 1 (0.5) | |
| 7.5 mg/d | 1 (0.1) | 1 (0.2) | 0 | |
| 10 mg/d | 0 | 0 | 0 | |
| NYHA | .001 | |||
| I | 112 (14.4) | 94 (16.2) | 18 (9.1) | |
| II | 351 (45.1) | 268 (46.1) | 83 (41.9) | |
| III | 192 (24.6) | 142 (24.4) | 50 (25.3) | |
| IV | 124 (15.9) | 77 (13.3) | 47 (23.7) | |
| Initiation of vericiguat during admission | 357 (44.7) | 227 (38.0) | 130 (64.4) | <.001 |
| Ischemic etiology | 346 (43.3) | 258 (43.2) | 88 (43.6) | .93 |
| Heart rate (bpm) | 74.3±14.1 | 74.0±13.9 | 75.2±14.7 | .29 |
| Systolic blood pressure (mm Hg) | 105.2±19.1 | 107.2±19.9 | 99.5±15.2 | <.001 |
| Systolic blood pressure <100 mm Hg | 329 (41.8) | 223 (38.0) | 106 (53.0) | <.001 |
| Diastolic blood pressure (mm Hg) | 63.3±12.4 | 64.2±12.6 | 60.8±11.6 | <.001 |
| Pressure pulse (mm Hg) | 41.8±14.9 | 42.9±15.6 | 38.7±11.8 | <.001 |
| LVEF (%) | 29.8±8.1 | 30.6±7.7 | 27.4±8.6 | <.001 |
| LVEF <30% | 366 (45.8) | 248 (41.5) | 118 (58.4) | <.001 |
| Hemoglobin (g/dL) | 12.9±2.2 | 13.1±2.2 | 12.3±2.1 | <.001 |
| Potassium (mEq/L) | 4.3±0.5 | 4.3±0.5 | 4.3±0.5 | .45 |
| eGFR (mL/min/1.73m 2) | 59.6±28.2 | 60.6±29.1 | 56.7±25.3 | .08 |
| eGFR <60 mL/min/1.73m 2 | 439 (54.9) | 318 (53.3) | 121 (59.9) | .10 |
| eGFR <30 mL/min/1.73m 2 | 130 (16.3) | 98 (16.4) | 32 (15.8) | .85 |
| NT-proBNP (pg/mL) | 3408 (1581-7001) | 3161 (1456-6604) | 4007 (1996-8897) | .02 |
| Medical history | ||||
| Prior hospitalization for HF | 562 (70.3) | 418 (70.0) | 144 (71.3) | .73 |
| Diabetes mellitus | 383 (47.9) | 283 (47.4) | 100 (49.5) | .61 |
| Hypertension | 445 (55.7) | 339 (56.8) | 106 (52.5) | .29 |
| Myocardial infarction | 229 (28.7) | 170 (28.5) | 59 (29.2) | .84 |
| CABG | 100 (12.5) | 77 (12.9) | 23 (11.4) | .57 |
| PCI | 291 (36.4) | 213 (35.7) | 78 (38.6) | .45 |
| Type of atrial fibrillation | .76 | |||
| No AF | 460 (57.6) | 346 (58.0) | 114 (56.4) | |
| Paroxysmal AF | 164 (20.5) | 124 (20.8) | 40 (19.8) | |
| Persistent/permanent AF | 175 (21.9) | 127 (21.3) | 48 (23.8) | |
| COPD | 36 (4.5) | 22 (3.7) | 14 (6.9) | .06 |
| Stroke | 72 (9.0) | 49 (8.2) | 23 (11.4) | .17 |
| Treatment | ||||
| SGLT2-i | 564 (70.6) | 433 (72.5) | 131 (64.9) | .04 |
| ACE-I | 156 (19.5) | 103 (17.3) | 53 (26.2) | <.01 |
| ARB | 84 (10.5) | 61 (10.2) | 23 (11.4) | .64 |
| ARNI | 413 (51.7) | 329 (55.1) | 84 (41.6) | <.001 |
| ACE-I/ARB/ARNI | 652 (81.6) | 492 (82.4) | 160 (79.2) | .31 |
| Beta-blocker | 710 (88.9) | 532 (89.1) | 178 (88.1) | .70 |
| MRA | 626 (78.3) | 462 (77.4) | 164 (81.2) | .26 |
| Any diuretics | 615 (77.0) | 444 (74.4) | 171 (84.7) | <.01 |
| Loop diuretics | 577 (72.2) | 423 (70.9) | 154 (76.2) | .14 |
| Digoxin | 40 (5.0) | 28 (4.7) | 12 (5.9) | .48 |
| Pimobendane | 169 (21.2) | 122 (20.4) | 47 (23.3) | .39 |
| Pacemaker | 54 (6.8) | 33 (5.5) | 21 (10.4) | .02 |
| CRT-P/CRT-D | 139 (17.4) | 97 (16.2) | 42 (20.8) | .14 |
| ICD | 83 (10.4) | 59 (9.9) | 24 (11.9) | .42 |
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