Vericiguat Achieves High Target-Dose Rates in Indian Worsening Heart Failure Study

Indian patients with worsening heart failure and reduced ejection fraction who received the oral drug vericiguat alongside their existing heart failure medications showed high rates of reaching and maintaining the drug’s target dose over 48 weeks, according to results from the VERINA study published in Cardiology and Therapy. The phase IV, prospective, multicenter, open-label, single-arm trial enrolled adults with chronic heart failure with reduced ejection fraction who had experienced a worsening heart failure event, defined as hospitalization for heart failure or use of intravenous diuretics without hospitalization. Of 231 patients screened across 13 Indian centres, 205 received at least one dose of vericiguat and formed the safety analysis set, while 203 patients with at least one post-baseline assessment constituted the full analysis set.

The primary endpoint was the composite of cardiovascular death or first hospitalization for heart failure, adjudicated by an independent Clinical Events Committee. During approximately 48 weeks of follow-up, 19 of 203 participants (9.4%) experienced the primary composite endpoint, corresponding to an annualized absolute risk of 11.2% (95% confidence interval 6.7–17.4%) and a week-48 Kaplan–Meier estimate of 10.1% (95% CI 5.8–14.4%). Of these 19 first events, 17 were hospitalizations for heart failure (8.4%) and two were cardiovascular deaths (1.0%, annualized absolute risk 1.1%). When all committee-adjudicated cardiovascular deaths were counted regardless of any preceding hospitalization, cardiovascular death occurred in six participants (3.0%), with a week-48 Kaplan–Meier estimate of 3.3% (95% CI 0.7–5.9%).

Secondary endpoint analyses at week 48 yielded Kaplan–Meier estimates of 9.1% (95% CI 5.0–13.3%) for first hospitalization for heart failure, 11.5% (95% CI 7.0–16.1%) for all-cause death or first hospitalization for heart failure, and 5.9% (95% CI 2.5–9.3%) for all-cause death. The corresponding annualized absolute risks were 10.0% (95% CI 5.8–16.0%), 12.9% (95% CI 8.1–19.6%) and 6.2% (95% CI 3.1–11.1%), respectively. Because VERINA was a single-arm study without a control group, these figures describe observed event rates during vericiguat treatment rather than demonstrating a treatment effect relative to an alternative therapy.

Dose titration outcomes were a central focus of the trial. Vericiguat was initiated at 2.5 mg once daily and uptitrated approximately every two weeks to 5 mg and then to the target dose of 10 mg once daily, as tolerated, with adjustments guided by systolic blood pressure and overall clinical tolerability. Among the 203 participants in the full analysis set, 186 (91.6%) attained the 10 mg target dose, and 141 (69.5%) completed target titration by week 4 and maintained that dose for at least 80% of the intervention period. Only ten participants (4.9%) reached a maximum dose of 5 mg and seven (3.4%) remained at 2.5 mg. Mean exposure durations were 16.5 days at 2.5 mg, 21.7 days at 5 mg and 280.5 days at 10 mg.

Treatment persistence was similarly high. The average and median durations of vericiguat treatment were 42.8 weeks (standard deviation 13.6) and 48.0 weeks, respectively. Nearly half of the participants (47.3%) received the drug for more than 48 weeks, and 39.0% received it for more than 32 but less than 48 weeks. Overall, 169 patients (82.4%) completed treatment, while 36 (17.6%) discontinued prematurely, most commonly because of patient decision (5.9%) or death (4.9%). Compliance was measurable in 202 of the 205 participants, with a mean compliance rate of 94.9%; 15 participants (7.3%) had compliance rates below 80%.

The cohort was relatively young but high risk. Mean age was 58.0 years, with 34.1% aged 65 or older; 73.7% were men and 54 (26.3%) were women. Severe systolic dysfunction, defined as a left ventricular ejection fraction below 30%, was present in 48.8% of patients, and most were in New York Heart Association classes II or III. The most prevalent comorbidities were coronary artery disease (63.9%), diabetes mellitus (45.9%) and hypertension (42.4%). Reduced renal function, with an estimated glomerular filtration rate below 60 mL/min/1.73 m², affected 42.0% of participants, and median N-terminal pro-B-type natriuretic peptide was 1262 pg/mL. Background foundational medical therapy was extensive, including beta-blockers (84.9%), mineralocorticoid receptor antagonists (80.5%), sodium–glucose cotransporter-2 inhibitors (75.6%) and angiotensin receptor–neprilysin inhibitors (52.7%). During treatment, 96.6%, 74.1% and 37.1% of patients received dual, triple and quadruple heart failure therapy pillars, respectively.

Subgroup analyses identified higher event rates among older patients and those with more advanced symptoms. In patients younger than 65 versus those aged 65 or older, the annualized absolute risk for the primary composite endpoint rose from 8.6% to 16.5%, and the week-48 Kaplan–Meier estimate rose from 7.8% to 14.9%. Among patients with New York Heart Association class II symptoms versus class III/IV, annualized risk increased from 6.2% to 26.7% and the Kaplan–Meier estimate from 5.9% to 22.0%. Renal function also tracked with risk: week-48 primary composite event estimates increased from 6.4% in patients with an estimated glomerular filtration rate above 60 mL/min/1.73 m² to 15.4% and 20.0% in those with values above 30 to 60 and at or below 30 mL/min/1.73 m², respectively. Based on index event, the week-48 estimate was 16.5% (95% CI 8.3–24.7%) among patients hospitalized for heart failure within three months before enrolment (13 of 83 patients), 4.3% (95% CI 0.0–12.7%) among those hospitalized three to six months before enrolment (1 of 24), and 6.1% (95% CI 0.9–11.3%) among patients with an earlier hospitalization history (5 of 96).

Safety findings were generally favourable. In the safety analysis set of 205 participants, treatment-emergent adverse events occurred in 53.7% of patients, of which 9.3% were severe, 3.4% were considered study drug-related, 2.0% led to discontinuation and 10.7% were serious. The most frequent treatment-emergent adverse event categories, each affecting more than 10% of participants, were gastrointestinal events (13.7%), general or administration-site disorders (11.7%), cardiac disorders (10.7%) and infections or infestations (10.2%). Other events occurring in at least 3% of participants included pyrexia (4.4%), cough (4.4%), anaemia (3.4%) and type 2 diabetes mellitus (3.4%). Haemodynamic events were infrequent: symptomatic hypotension was reported in 2.9% of participants, orthostatic hypotension in 1.0% and dizziness in 1.5%, and no cases of syncope were observed. Dose reductions occurred in 6.0% of participants, and permanent discontinuation due to adverse events occurred in 1.5%.

Eleven deaths occurred in total, ten as treatment-emergent adverse events and one as a non-treatment-emergent event. In the safety analysis set, eight deaths were classified as cardiovascular, including deaths not adjudicated by the Clinical Events Committee; one was non-cardiovascular and two were undetermined, which differs from the six committee-adjudicated cardiovascular deaths reported as an effectiveness endpoint. None of the fatal adverse events were considered related to the study intervention. A sensitivity analysis that classified undetermined deaths as cardiovascular deaths did not alter the interpretation of the effectiveness results. Only minor mean shifts in vital signs were observed from baseline to end of treatment, and electrocardiogram assessments revealed two clinically significant abnormalities with no new safety concerns.

The authors note important design limitations. VERINA was mandated by the Indian regulator, the Central Drugs Standard Control Organization, as a single-arm, open-label study, so it included no control group and describes outcomes observed during vericiguat treatment rather than comparative efficacy. Selection and survivor bias, physician-directed concomitant treatment and residual confounding remain possible, limited follow-up after treatment discontinuation introduces potential informative censoring, and the low number of events limits precision. Unlike the pivotal VICTORIA trial, VERINA did not require a natriuretic-peptide threshold and set no maximum interval between the qualifying worsening event and enrolment; 29.8% of participants had their most recent heart failure hospitalization more than 12 months before enrolment. Compared with the VICTORIA vericiguat arm, where 35.5% of patients experienced the primary composite endpoint over a median follow-up of 10.8 months, the observed 9.4% event proportion in VERINA reflects a younger cohort with higher background use of angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter-2 inhibitors, and the study was not designed to compare the two trials directly. Within those constraints, the investigators conclude that vericiguat can be implemented within established foundational therapy in Indian routine practice, with high target-dose attainment and no new safety signals over 48 weeks.

Subject of Research: Vericiguat treatment outcomes in Indian patients with worsening heart failure and reduced ejection fraction

Article Title: VERINA: A Phase IV Prospective Multicenter Study of Vericiguat in Indian Patients with Worsening Heart Failure and Reduced Ejection Fraction

Article References: Seth, S., Abhyankar, A., Abdullakutty, J., Banerjee, S., Sharma, K., Vijan, V., Bhalani, N. C., Chopra, V. K., Aggarwal, R. K., Oomman, A., Bansal, S., Jain, R. K., Kahale, P., Sodhi, P., Gupta, D., & Gawde, A. (2026). VERINA: A Phase IV Prospective Multicenter Study of Vericiguat in Indian Patients with Worsening Heart Failure and Reduced Ejection Fraction. Cardiology and Therapy. https://doi.org/10.1007/s40119-026-00482-4

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00482-4

Keywords: vericiguat, heart failure, reduced ejection fraction, VERINA study, phase IV trial, India, cardiovascular death, hospitalization, soluble guanylate cyclase stimulator, drug safety, dose titration, HFrEF