title: Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study.
abstract: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. Perspective The ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF.
authors.affiliation: Centre of Cardiovascular Research & Education in Therapeutics, Department of Epidemiology & Preventive Medicine, Monash University/Alfred Hospital, Melbourne VIC 3004, Australia. henry.krum@med.monash.edu.au
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Barry
authors.initials: B
authors.lastname: Massie
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dickstein
authors.forename: Lars
authors.initials: L
authors.lastname: Kober
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Ashkay
authors.initials: A
authors.lastname: Desai
authors.forename: Claudio
authors.initials: C
authors.lastname: Gimpelewicz
authors.forename: Albert
authors.initials: A
authors.lastname: Kandra
authors.forename: Bernard
authors.initials: B
authors.lastname: Reimund
authors.forename: Henning
authors.initials: H
authors.lastname: Rattunde
authors.forename: Juergen
authors.initials: J
authors.lastname: Armbrecht
mesh_terms: D000577:Amides / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use; D005650:Fumarates / Q000627:therapeutic use*; D054143:Heart Failure, Systolic / Q000188:drug therapy*; D006801:Humans; D020097:Natriuretic Peptide, Brain / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D012083:Renin / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012107:Research Design; D013318:Stroke Volume; D016277:Ventricular Function, Left; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004656:Enalapril; D005650:Fumarates; D020097:Natriuretic Peptide, Brain; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren