Mihai Gheorghiade1, Stephen J Greene2, Javed Butler3, Gerasimos Filippatos4, Carolyn S P Lam5, Aldo P Maggioni6, Piotr Ponikowski7, Sanjiv J Shah8, Scott D Solomon9, Elisabeth Kraigher-Krainer10, Eliana T Samano11, Katharina Müller12, Lothar Roessig12, Burkert Pieske13. 1. Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 2. Division of Cardiology, Duke University Medical Center, Durham, North Carolina. 3. Division of Cardiology, Stony Brook University, Stony Brook, New York. 4. Heart Failure Unit, Department of Cardiology, Athens University Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 5. Department of Cardiology, National Heart Centre Singapore and Duke, National University of Singapore, Singapore. 6. Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy. 7. Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland. 8. Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 9. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 10. Department of Internal Medicine and Cardiology, Charité University Medicine Berlin-Campus Virchow Klinikum, Berlin, Germany. 11. Bayer, São Paulo, Brazil. 12. Bayer Pharma, Wuppertal, Germany. 13. Department of Internal Medicine and Cardiology, Charité University Medicine Berlin-Campus Virchow Klinikum, Berlin, Germany13Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany.
Abstract
IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS:Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. RESULTS: Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. CONCLUSIONS AND RELEVANCE: Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01951625.
RCT Entities:
IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. RESULTS: Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. CONCLUSIONS AND RELEVANCE: Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01951625.
Authors: Sanjiv J Shah; Dalane W Kitzman; Barry A Borlaug; Loek van Heerebeek; Michael R Zile; David A Kass; Walter J Paulus Journal: Circulation Date: 2016-07-05 Impact factor: 29.690
Authors: Sven Persoon; Michael Paulus; Stephan Hirt; Carsten Jungbauer; Alexander Dietl; Andreas Luchner; Christof Schmid; Lars S Maier; Christoph Birner Journal: Heart Vessels Date: 2018-03-15 Impact factor: 2.037
Authors: Stephen J Greene; Robert J Mentz; Mona Fiuzat; Javed Butler; Scott D Solomon; Andrew P Ambrosy; Cyrus Mehta; John R Teerlink; Faiez Zannad; Christopher M O'Connor Journal: Circulation Date: 2018-09-04 Impact factor: 29.690