Effect of Vericiguat on cardiAc Remodeling in Patients With Heart faiLure and Reduced Ejection fractioN (HFrEF): A Prospective sTudy usIng NOvel Echocardiographic Imaging Techniques (VALENTINO)

Inclusion criteria

• Age ≥ 18y
• Chronic HF; New York Heart Association (NYHA) class II-III, LVEF ≤40% (recent 12 months), and on guideline-directed heart failure therapy
• Recent (6 months) heart failure hospitalization or intravenous diuretic use (without hospitalization) within 3 months
• Elevated NT-proBNP 1000-6000 pg/ml (1600-6000 pg/ml if atrial fibrillation) within 30 days
• Clinically stable (systolic blood pressure ≥100 mm Hg and no intravenous diuretics for 48 hours)
• Meet one of the following criteria:
• a. Male
• b. Female who is not of reproductive potential, defined as a female who either: (1) postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR (3) has a congenital or acquired condition that prevents childbearing
• c. Female who is of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: (1) practice abstinence from heterosexual activity, OR (2) use (or have her partner use) acceptable contraception during heterosexual activity. Acceptable methods of contraception are:
• i. Single method (one of the following is acceptable):
• • Intrauterine device, vasectomy of a female subject's male partner, or contraceptive rod implanted into the skin
• ii. Combination method (use of two of the following)
• • Diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male condom or female condom, or hormonal contraceptive

Exclusion criteria

• Prior or screening echocardiographic images of suboptimal image quality
• Any addition, discontinuation, or dose modification of heart failure medications (i.e. ARB, ACEi, SGLT2i, ARNI, beta-blocker, MRA) within 4 weeks before vericiguat treatment initiation
• Use of long-acting nitrates, phosphodiesterase type 5 inhibitor, riociguat
• Awaiting heart transplantation, continuous intravenous diuretics, or current/anticipated ventricular assist device
• Chronic kidney disease (estimated glomerular filtration rate <15 ml/min/1.73 m2) or dialysis
• Severe pulmonary disease requiring continuous oxygen
• Severe hepatic insufficiency
• Has primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention
• Has hypertrophic obstructive cardiomyopathy
• Has acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy
• Has post-heart transplant cardiomyopathy
• Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia
• Has acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) or coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) within 6 months, or indication for coronary revascularization at the time of screening
• Has symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days
• Has complex congenital heart disease
• Has active endocarditis or constrictive pericarditis
• Breastfeeding or plans to breastfeed during the course of the trial