Early initiation of a soluble guanylate cyclase stimulator in an elderly patient with refractory HFrEF
23 Apr 2025
byDr. Cyril Ko, Specialist in Cardiology, Private practice, Hong Kong
Presentation, medical history and initial treatment
The patient was an 80-year-old male with multiple comorbidities, including diabetes mellitus controlled with a sodium-glucose cotransporter-2 inhibitor (SGLT2i), hypertension and coronary artery disease, for which he underwent stenting in October 2023. He also had a pacemaker implanted for heart block. His left ventricular ejection fraction (LVEF) ranged between 40–50 percent. For several years, he had been managed as an outpatient for mild heart failure (HF) symptoms and maintained independence in activities of daily living (ADL).
On 17 April 2024, the patient’s condition deteriorated, necessitating his first hospitalization for decompensated HF (HHF). At admission, he exhibited symptoms of pulmonary oedema and congestion, including leg and abdominal swelling, and increased body weight (BW; from estimated 60+ kg to 74 kg), and was determined to be New York Heart Association (NYHA) functional class IV. Echocardiography revealed a significantly reduced LVEF, which dropped to 17 percent, with severe mitral and tricuspid regurgitation. His renal function was compromised, with baseline creatinine level of 150 μmol/L elevated to 200 μmol/L during HHF. Systolic blood pressure (SBP) readings were approximately 90–100 mm Hg. (Table)
During HHF, the patient was treated with diuretics, including furosemide and metolazone, but his symptoms remained refractory. Consequently, he required multiple dopamine infusions, which resulted in a temporary improvement in renal function, with creatinine level decreasing to 110–120 μmol/L. However, upon withdrawal of dopamine, creatinine levels rebounded to 170 μmol/L. (Table) The patient was put on ivabradine 5 mg BID and optimally tolerated guideline-directed medical therapy (GDMT), including spironolactone 12.5 mg QD, sacubitril/valsartan 25 mg QD, and carvedilol 3.125 mg QD. Despite a partial response to this regimen, further uptitration was hindered by hypotension and impaired renal function. Throughout hospitalization, despite repeated attempts at mobilization, the patient remained almost entirely bedbound due to congestion symptoms, and his appetite was very poor due to gastrointestinal swelling.
Vericiguat treatment and response
After some fluctuation, the patient’s condition stabilized, with some improvements noted, including BW reduction to 59 kg. He was discharged on 21 May 2024 after 34 days of hospitalization and required assistance from a caregiver. Upon follow-up on 31 May 2024, he presented with worsening renal function (creatinine, 140 μmol/L), shortness of breath (SOB) just after a few minutes of walking (NYHA class III), and oedema, with BW increasing to 64 kg, and required a daily intake of metolazone. Subsequently, he began treatment with vericiguat 2.5 mg daily, despite an SBP of around 90–95 mm Hg.
Following 2 weeks of vericiguat therapy, the patient’s SBP improved to >100 mm Hg. His general condition improved significantly (he was able to walk to the clinic without SOB), along with an increase in appetite. Creatinine level decreased to 126 μmol/L, indicating improved renal function, although some oedema persisted. (Table) The vericiguat dose was subsequently increased to 5 mg.
By late June 2024, the patient’s general condition further improved. His BP increased to >120/60 mm Hg, appetite was robust, and his weight increased, not due to oedema, but likely due to muscle gain. Oedema nearly resolved, with no notable facial puffiness, which indicated that he was becoming euvolaemic. His creatinine level further dropped to 98 μmol/L. (Table) On 10 July 2024, the vericiguat dose was further increased to the target dose of 10 mg daily, and the dose of sacubitril/valsartan was increased from 25 mg QD to BID.
Throughout treatment, the patient tolerated vericiguat well, with no notable side effects, while his renal function remained stable. Echocardiography on 14 August 2024 showed an improvement in LVEF to 40–45 percent with satisfactory right ventricular function. Creatinine rose to 136 μmol/L due to excess diuresis; therefore, furosemide was reduced from 40 mg BID to QD. During a follow-up visit in October 2024, the patient’s SBP remained stable at around 130 mm Hg. His exercise tolerance significantly improved (NYHA class I), allowing him to walk as briskly as pre-HHF, and oedema resolved completely. His creatinine level increased slightly, which may be attributed to increased diuresis following cardiac function improvement.
At the last follow-up on 14 January 2025, the patient’s creatinine level decreased to 115 μmol/L, BP rose to 130/69 mm Hg, and pulse rate was 60 beats per minute. He was well enough to travel overseas during holidays. The treatment plan is to continue vericiguat 10 mg QD along with GDMT, with regular monitoring every 3 months.
Discussion
Worsening HF (WHF) events are associated with an increased risk of HHF and worse prognosis. Data from the National Cardiovascular Data Registry PINNACLE revealed that approximately 1 in 6 patients with HF with reduced EF (HFrEF) develop WHF within 18 months of HF diagnosis, with 56 percent of these patients rehospitalized within 30 days of the WHF event.1
To reduce the risk of HHF and cardiovascular (CV) mortality in patients with HFrEF, the European Society of Cardiology (ESC) recommends GDMT comprising four foundational pillars: an angiotensin-converting enzyme inhibitor or angiotensin receptor–neprilysin inhibitor (ARNi), a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2i – all at the maximally tolerated dose unless contraindicated. The ESC guidelines also recommend initiating vericiguat, which targets the distinct nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway, in addition to quadruple GDMT for patients with worsening HF to further improve outcomes.2 However, implementation of GDMT in clinical practice is often challenging due to tolerability issues.3,4
In the phase III randomized VICTORIA study (n=5,050), vericiguat significantly reduced the risk of CV death or HHF by 10 percent vs placebo in HFrEF patients with recent WHF (hazard ratio, 0.90; 95 percent confidence interval, 0.83–0.98; p=0.02). The occurrence of adverse events was similar between the vericiguat and placebo groups, with no statistically significant difference in rates of symptomatic hypotension (9.1 vs 7.9 percent; p=0.12), consistent with our patient’s good tolerance of vericiguat.5
The real-world VERITA study (n=103) demonstrated vericiguat’s efficacy in reducing WHF episodes and improving functional status in patients with HFrEF. A subanalysis of 52 patients followed for ≥6 months showed significant improvements in NYHA functional class, with a reduction in the proportion of patients in class III, from 67.3 percent at vericiguat initiation to 22.4 percent at study end, while the proportion of patients in class II increased from 32.7 to 75.5 percent (p<0.001).6 (Figure) These findings are consistent with our patient’s experience, as his NYHA classification substantially improved from class III to class I, and he regained his prehospitalization appetite and ability to move unaided following vericiguat initiation.
Our patient’s HF symptoms remained refractory despite optimized GDMT during HHF. Due to his advanced age, low BP and impaired renal function, there was no other choice besides vericiguat to prevent rehospitalization and enable further uptitration of GDMT. The addition of vericiguat to GDMT shortly after discharge effectively alleviated his symptoms within 4 weeks of treatment, resulting in marked improvements in exercise tolerance and enabling him to regain independence in ADL.
Our patient’s continuous improvements in BP and renal function following vericiguat initiation enabled uptitration of ARNi. Multiple real-world studies showed that receiving vericiguat correlated with GDMT intensification. A nationwide longitudinal cohort study in Germany (n=2,916) demonstrated that vericiguat initiation was followed by a higher proportion of patients uptitrating or initiating components of GDMT. The proportion of patients receiving HF-specific medications increased across all four pillars of GDMT, with the most notable increase in uptake observed for SGLT2i, from 51 to 73 percent. The overall proportion of patients receiving all four pillars of GDMT increased from 29 to 44 percent following vericiguat initiation.7 The VERITA study also showed a similar finding – the dosage of sacubitril/valsartan increased significantly after introduction of vericiguat in HFrEF patients.6
Despite rapid symptom resolution at the 5 mg QD dose, vericiguat was further uptitrated to the target dose of 10 mg QD once our patient’s BP stabilized. Our patient’s condition continued to improve with increasing dose, in-line with SOCRATES-REDUCED dose-finding study (n=456) results, which suggested a higher dose of vericiguat correlated with greater benefits, even if initial improvements are observed with lower doses. Among patients with WHF on vericiguat 2.5 mg, 5 mg or 10 mg QD, the higher-dose groups demonstrated lower rates of the composite outcome of CV death or HHF vs placebo (20, 12 and 11 percent vs 20 percent).8
Final thoughts
Our previously energetic and independent elderly patient spent 34 days predominantly bed-bound during his first HHF, and required assistance from a caregiver following discharge. Attempts to uptitrate his GDMT regimen were hindered by hypotension and impaired renal function, with his condition remaining unsatisfactory. However, following vericiguat initiation, it began to improve rapidly, and the patient eventually regained his prehospitalization exercise tolerance, appetite and, importantly, independence. Improvements in BP and renal function attained once vericiguat’s target dose of 10 mg QD was reached allowed optimization of other GDMT components.
Based on this experience and existing clinical evidence, use of vericiguat can be considered earlier in the course of HF management, before the maximization of GDMT.
