Justin A Ezekowitz1, Christopher M O'Connor2, Richard W Troughton3, Wendimagegn G Alemayehu1, Cynthia M Westerhout1, Adriaan A Voors4, Javed Butler5, Carolyn S P Lam6, Piotr Ponikowski7, Michele Emdin8, Mahesh J Patel9, Burkert Pieske10, Lothar Roessig11, Adrian F Hernandez12, Paul W Armstrong13. 1. Division of Cardiology, Department of Medicine, Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada. 2. Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, North Carolina; Inova Heart and Vascular Institute, Falls Church, Virginia. 3. Department of Medicine, University of Otago, Christchurch, New Zealand. 4. Department of Cardiology and Thorax Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 5. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi. 6. Department of Cardiology and Thorax Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Cardiology, National Heart Centre Singapore and Duke-National University of Singapore. 7. Wroclaw Medical University, Department of Heart Disease, Wroclaw, Poland. 8. Cardiothoracic Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; and Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy. 9. Merck & Co. Inc., Kenilworth, New Jersey. 10. Department of Internal Medicine-Cardiology, Charité University Medicine, German Heart Center, Berlin, Germany. 11. Bayer AG, Wuppertal, Germany. 12. Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, North Carolina. 13. Division of Cardiology, Department of Medicine, Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada. Electronic address: parmstro@ualberta.ca.
Abstract
OBJECTIVES: The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization. BACKGROUND: Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further. METHODS: This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome. CONCLUSIONS: A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).
RCT Entities:
OBJECTIVES: The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization. BACKGROUND:Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further. METHODS: This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome. CONCLUSIONS: A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).
Authors: Daniela Tomasoni; Julie K K Vishram-Nielsen; Matteo Pagnesi; Marianna Adamo; Carlo Mario Lombardi; Finn Gustafsson; Marco Metra Journal: ESC Heart Fail Date: 2022-03-30
Authors: Mona Fiuzat; Carine E Hamo; Javed Butler; William T Abraham; Ersilia M DeFilippis; Gregg C Fonarow; Joann Lindenfeld; Robert J Mentz; Mitchell A Psotka; Scott D Solomon; John R Teerlink; Muthiah Vaduganathan; Orly Vardeny; John J V McMurray; Christopher M O'Connor Journal: J Am Coll Cardiol Date: 2022-02-08 Impact factor: 27.203
Authors: Carolyn S P Lam; Hillary Mulder; Yuri Lopatin; Jose B Vazquez-Tanus; David Siu; Justin Ezekowitz; Burkert Pieske; Christopher M O'Connor; Lothar Roessig; Mahesh J Patel; Kevin J Anstrom; Adrian F Hernandez; Paul W Armstrong Journal: J Am Heart Assoc Date: 2021-11-06 Impact factor: 5.501