Vericiguat and Exercise Hemodynamics in Patients With HFrEF (EVERHETT-HF)

The Effect of Vericiguat on Exercise Hemodynamics and Exercise Tolerance in Patients With Heart Failure and Reduced Ejection Fraction: The EVERHETT-HF Prospective Observational Cohort Study

Heart failure with reduced ejection fraction (HFrEF) is associated with impaired exercise capacity and abnormal exercise hemodynamics despite contemporary guideline-directed medical therapy (GDMT). Vericiguat, a soluble guanylate cyclase stimulator, has demonstrated clinical benefits in selected patients with HFrEF, but its effects on exercise physiology remain incompletely understood.

The EVERHETT-HF study is a prospective observational cohort study designed to evaluate the effects of treatment with vericiguat on exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF receiving maximally tolerated guideline-directed medical therapy (GDMT). Participants undergo comprehensive cardiopulmonary exercise testing (CPET) and exercise right heart catheterization (ERHC) to assess functional and hemodynamic responses during exercise.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure; Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Vericiguat; Other: Guideline-directed medical therapy (GDMT) for heart failure

Detailed Description

Patients with chronic heart failure with reduced ejection fraction (HFrEF) frequently demonstrate persistent impairment in exercise tolerance and abnormal exercise hemodynamics despite contemporary guideline-directed medical therapy (GDMT). Although vericiguat has demonstrated clinical benefits in selected HFrEF populations, the physiological effects of soluble guanylate cyclase stimulation on exercise performance and invasive exercise hemodynamics remain incompletely characterized.

The EVERHETT-HF study is a prospective observational cohort study designed to evaluate the association of vericiguat therapy with changes in exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF receiving maximally tolerated GDMT. Treatment decisions, including the initiation and dose titration of vericiguat, are made according to routine clinical practice and the judgment of the treating physician, independent of the study protocol.

Consecutive eligible adult patients with chronic HFrEF are prospectively enrolled and categorized into two cohorts according to the treatment prescribed by their treating physician: patients receiving guideline-directed medical therapy (GDMT) alone and patients receiving GDMT plus vericiguat. Clinical management is not influenced by study participation.

All participants undergo comprehensive baseline evaluation, including clinical assessment, laboratory testing, cardiopulmonary exercise testing (CPET), and exercise right heart catheterization (ERHC). Follow-up assessments are performed after approximately 12 months using the same standardized evaluation protocol.

Cardiopulmonary exercise testing is performed on a cycle ergometer using a symptom-limited incremental exercise protocol. Functional parameters include peak oxygen uptake (peak VO₂), percentage of predicted peak VO₂, ventilatory efficiency (VE/VCO₂ slope), oxygen uptake efficiency slope (OUES), peak oxygen pulse, anaerobic threshold, respiratory exchange ratio (RER), and exercise duration.

Exercise right heart catheterization is performed using a Swan-Ganz catheter with serial invasive hemodynamic measurements obtained at rest and during standardized supine bicycle exercise. Hemodynamic variables include right atrial pressure (RAP), pulmonary artery systolic, diastolic and mean pressures (sPAP, dPAP, and mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), cardiac index (CI), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), cardiac power output (CPO), cardiac power index (CPI), transpulmonary gradient (TPG), diastolic pressure gradient (DPG), pulmonary artery pulsatility index (PAPi), and other derived exercise hemodynamic indices.

The primary objective of the study is to evaluate the association of vericiguat therapy with longitudinal changes in exercise capacity and invasive exercise hemodynamics in patients with stable HFrEF. Secondary objectives include the assessment of additional cardiopulmonary exercise variables, invasive hemodynamic parameters, laboratory biomarkers, echocardiographic measurements, and overall functional status during follow-up.

This investigator-initiated study aims to provide detailed mechanistic insights into the relationship between vericiguat therapy and exercise physiology in patients with stable HFrEF under routine clinical practice through the combined use of cardiopulmonary exercise testing and invasive exercise hemodynamic assessment.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Greece
  • Attica
    • Athens, Attica, Greece, 11528
      • Alexandra General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population consisted of consecutive adult patients (≥18 years) with stable chronic heart failure with reduced ejection fraction (LVEF ≤40%) receiving maximally tolerated guideline-directed medical therapy (GDMT). Patients were clinically stable and underwent standardized cardiopulmonary exercise testing (CPET) and exercise right heart catheterization (ERHC) as part of their clinical evaluation at Alexandra General Hospital. Participants were prospectively enrolled and classified according to routine clinical treatment with GDMT alone or GDMT plus vericiguat.

Description

Inclusion Criteria:

Adults aged ≥18 years. Chronic heart failure with reduced ejection fraction (LVEF ≤40%). Stable chronic heart failure receiving maximally tolerated guideline-directed medical therapy (GDMT).

Clinically stable for at least 6 months prior to enrollment without hospitalization for worsening heart failure or major modification of heart failure therapy.

Able to perform symptom-limited cardiopulmonary exercise testing (CPET). Eligible to undergo exercise right heart catheterization (ERHC). Able to provide written informed consent.

Exclusion Criteria:

Acute decompensated heart failure. Recent hospitalization for worsening heart failure (<6 months). Systolic blood pressure <110 mmHg. Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m². Severe hepatic dysfunction. Severe anemia (hemoglobin <9 g/dL). Contraindication to right heart catheterization. Inability to perform CPET. Pregnancy or breastfeeding. Any condition judged by the treating physician to preclude safe participation.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Vericiguat + GDMT; Participants receiving oral vericiguat in addition to maximally tolerated guideline-directed medical therapy (GDMT) as part of routine clinical care. Treatment decisions were made by the treating physician independently of the study protocol.	Drug: Vericiguat; Oral vericiguat prescribed as part of routine clinical care in addition to maximally tolerated guideline-directed medical therapy (GDMT). Dose titration up to 10 mg once daily was performed according to the treating physician's clinical judgment and routine clinical practice.; Other: Guideline-directed medical therapy (GDMT) for heart failure; Participants received maximally tolerated guideline-directed medical therapy (GDMT) according to contemporary heart failure management guidelines and routine clinical practice throughout the study period.
GDMT Alone; Participants receiving maximally tolerated guideline-directed medical therapy (GDMT) without vericiguat as part of routine clinical care. Treatment decisions were made by the treating physician independently of the study protocol.	Other: Guideline-directed medical therapy (GDMT) for heart failure; Participants received maximally tolerated guideline-directed medical therapy (GDMT) according to contemporary heart failure management guidelines and routine clinical practice throughout the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in peak oxygen consumption (peak VO2) assessed by cardiopulmonary exercise testing	Assessment of the change in peak oxygen consumption (peak VO₂) measured by cardiopulmonary exercise testing (CPET) between baseline and the 12-month follow-up.	Baseline to 12 months
Change in pulmonary capillary wedge pressure (PCWP)	Assessment of the change in pulmonary capillary wedge pressure measured during exercise right heart catheterization between baseline and the 12-month follow-up.	Baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in VE/VCO2 slope	Assessment of the change in VE/VCO₂ slope measured by cardiopulmonary exercise testing (CPET) between baseline and the 12-month follow-up.	Baseline to 12 months
Change in mean pulmonary artery pressure (mPAP)	Assessment of the change in mean pulmonary artery pressure measured during exercise right heart catheterization between baseline and the 12-month follow-up.	Baseline to 12 months
Change in cardiac output	Assessment of the change in cardiac output measured during exercise right heart catheterization between baseline and the 12-month follow-up.	Baseline to 12 months
Change in cardiac index	Assessment of the change in cardiac index measured during exercise right heart catheterization between baseline and the 12-month follow-up.	Baseline to 12 months
Change in pulmonary vascular resistance (PVR)	Assessment of the change in pulmonary vascular resistance measured during exercise right heart catheterization between baseline and the 12-month follow-up.	Baseline to 12 months
Change in oxygen uptake efficiency slope (OUES)	Assessment of the change in oxygen uptake efficienc y slope measured during cardiopulmonary exercise testing between baseline and the 12-month follow-up.	Baseline to 12 months
Change in oxygen pulse	Assessment of the change in oxygen pulse measured during cardiopulmonary exercise testing between baseline and the 12-month follow-up.	Baseline to 12 months
Change in anaerobic threshold	Assessment of the change in anaerobic threshold measured during cardiopulmonary exercise testing between baseline and the 12-month follow-up.	Baseline to 12 months

Collaborators and Investigators

• Sponsor: Argyrios Ntalianis
• Investigators: Principal Investigator: Argyrios Ntalianis, MD, PhD, Alexandra General Hospital, Athens, Greece

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: July 5, 2026
• First Submitted That Met QC Criteria: July 5, 2026
• First Posted (Actual): July 13, 2026

Study Record Updates

• Last Update Posted (Actual): July 13, 2026
• Last Update Submitted That Met QC Criteria: July 5, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Heart Failure; HFrEF; Vericiguat; Cardiopulmonary Exercise Testing; Exercise Right Heart Catheterization; Exercise Hemodynamics
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; vericiguat
• Other Study ID Numbers: EVERHETT-HF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared because this is a single-center, investigator-initiated study with a small sample size, and no data-sharing plan has been established.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No