Muthiah Vaduganathan1, Baljash Cheema2, Erin Cleveland2, Kamya Sankar2, Haris Subacius2, Gregg C Fonarow3, Scott D Solomon1, Eldrin F Lewis1, Stephen J Greene4, Aldo P Maggioni5, Michael Böhm6, Faiez Zannad7, Javed Butler8, Mihai Gheorghiade9. 1. Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA. 2. Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. 3. Ahmanson-UCLA Cardiomyopathy Center, University of California Los Angeles, Los Angeles, CA, USA. 4. Division of Cardiology, Duke University Medical Center, Durham, NC, USA. 5. ANMCO Research Center, Florence, Italy. 6. Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany. 7. INSERM, CHRU Nancy, Université de Lorraine, Centre d'Investigation Clinique CIC1433, Nancy, France. 8. Stony Brook University, Stony Brook, NY, USA. 9. Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Abstract
AIMS: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren. METHODS AND RESULTS: This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13). CONCLUSIONS:Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.
RCT Entities:
AIMS: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren. METHODS AND RESULTS: This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13). CONCLUSIONS: Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.
Authors: Jonathan G Amatruda; Rebecca Scherzer; Veena S Rao; Juan B Ivey-Miranda; Michael G Shlipak; Michelle M Estrella; Jeffrey M Testani Journal: Kidney Med Date: 2022-04-08
Authors: Meaghan Lunney; Marinella Ruospo; Patrizia Natale; Robert R Quinn; Paul E Ronksley; Ioannis Konstantinidis; Suetonia C Palmer; Marcello Tonelli; Giovanni Fm Strippoli; Pietro Ravani Journal: Cochrane Database Syst Rev Date: 2020-02-27
Authors: Masatake Kobayashi; Susan Stienen; Jozine M Ter Maaten; Kenneth Dickstein; Nilesh J Samani; Chim C Lang; Leong L Ng; Stefan D Anker; Macro Metra; Gregoire Preud'homme; Kevin Duarte; Zohra Lamiral; Nicolas Girerd; Patrick Rossignol; Dirk J van Veldhuisen; Adriaan A Voors; Faiez Zannad; João Pedro Ferreira Journal: ESC Heart Fail Date: 2020-03-13