Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial

Abstract

Importance: The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.

Objective: To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial.

Design, setting, and participants: Analysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.

Intervention: Vericiguat titrated to 10 mg daily vs placebo.

Main outcomes and measures: The primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH.

Results: Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.

Conclusions and relevance: Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.

Trial registration: ClinicalTrials.gov Identifier: NCT02861534.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lam reported personal fees from Merck Steering Committee of VICTORIA and Bayer Steering Committee of VICTORIA during the conduct of the study; grants from National Medical Research Council of Singapore Supported by a Clinician Scientist Award, Boston Scientific Investigator-sponsored research program (Asian Sudden Cardiac Death in Heart Failure Registry), Medical Advisory Board, Bayer investigator-led research (Asian Sudden Cardiac Death in Heart Failure Registry), Roche Diagnostic, grants from Medtronics, Vifor Pharma, AstraZeneca; and personal fees from Novartis, Amgen, Merck, Janssen Research and Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia Advisory board, Cytokinetics, WebMD, Radcliffe Group Ltd, and Corpus utside the submitted work; in addition, Dr Lam had a patent for PCT/SG2016/050217 and for 16/216,929 pending and is and cofounder and nonexecutive director of Us2.ai. Dr Giczewska reported other support from Merck during the conduct of the study. Dr Sliwa-Hahnle reported grants from Merck during the conduct of the study. Dr Edelmann reported personal fees from Bayer, Merck, Novartis, Vifor, Pharmacosmos, Berlin Chemie, AstraZeneca, Boehringer Ingelheim, and Servier and grants from Thermo Fischer and Servier during the conduct of the study; personal fees from Bayer, Merck, Novartis, Vifor, Pharmacosmos, Berlin Chemie, AstraZeneca, Boehringer Ingelheim, Servier, and Thermo Fischer outside the submitted work; and grants from Servier outside the submitted work. Dr Bocchi reported personal fees from Bayer/Merck during the conduct of the study; personal fees from Servier, AstraZeneca, Novartis, Jansen, and Boehringer Ingelheim; and grants from Baldacci outside the submitted work. Dr Ezekowitz reported personal fees from Bayer and Merck during the conduct of the study and from Amgen, AstraZeneca, Boeringher-Ingelheim, Servier, and Novartis outside the submitted work. Dr Hernandez reported grants from Merck and Bayer during the conduct of the study; personal fees from AstraZeneca, Amgen, Bayer, Cytokinetics, Myokardia, Novartis, and Relypsa; and grants from Verily outside the submitted work. Dr O'Connor reported serving as a consultant for Bayer, Bristol Myers Squibb Foundation, Dey, and LP Merck. Dr Roessig reported working as a full-time employee for Bayer AG during the conduct of the study and outside the submitted work. Dr Patel reported working as full-time employee at the Merck Research Laboratories. Dr Pieske reported personal fees from Merck, Bayer, Novartis, BMS, Servier, and AstraZeneca during the conduct of the study. Dr Anstrom reported grants from Merck during the conduct of the study. Dr Armstrong reported grants and personal fees from Merck and Bayer during the conduct of the study; grants from Sanofi-Aventis, Boehringer Ingelheim, and CSL Limited; and personal fees from AstraZeneca and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Graphs by Index Event Subgroup Showing Time to First Primary Composite End Point by Treatment Arm

Black lines represent patients randomized within 3 months of HF hospitalization, orange lines those randomized within 3 to 6 months of HF hospitalization, and blue lines those randomized with 3 months of intravenous (IV) diuretic use for heart failure. Reported hazard ratios are populated from unadjusted models. HRH indicates heart failure hospitalization.

Figure 2.. Risk of the Primary Composite End Point, and Treatment Effect of Vericiguat Compared With Placebo, Analyzed by Finer Cuts of Time From Index Heart Failure (HF) Event (A) as Well as Using Time From Index Hospitalization as a Continuous Variable (B)

A, Incidence rates (and their 95% confidence intervals) of the primary composite end point are shown according to finer cuts of time from index event. Data on days to index event were missing in 16 patients. B, The treatment effect of vericiguat (hazard ratio [HR] with 95% confidence interval) is shown as a function of time as a continuous variable from index event to randomization among hospitalized patients. Data are presented for 4219 patients randomized within 200 days.