title: Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges.
abstract: Thrombotic events (coronary thrombosis, venous thromboembolism, intraventricular thrombosis, intracranial and systemic thromboembolism) occur frequently in patients with heart failure. These events may be precipitated by several mechanisms including hypercoagulability through enhancement of procoagulant reactions, impairment of the protein C pathway, protease activated receptor (PAR) activation, adenosine-mediated thrombosis, or neurohormonal activation; stasis secondary to low cardiac output; and endothelial dysfunction from neurohormonal activation or systemic inflammation. Pathophysiologic evidence and analyses of retrospective data support the hypothesis that antithrombotic agents may improve outcomes in patients with heart failure. Warfarin has not been shown to reduce clinical events in patients with heart failure, although several of the completed randomized trials were underpowered, and the most recent was not placebo-controlled. Many unanswered questions remain that justify continued research in this area. This paper examines the conceptual framework, opportunities, and challenges of clinical investigative approaches with the newer anti-thrombotic agents in patients with heart failure. Critical questions are raised with regard to clinical trial designs that warrant consideration as the field progresses.
authors.affiliation: INSERM, Centre d'Investigation Clinique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Université de Lorraine, Nancy, France. f.zannad@chu-nancy.fr
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.forename: Wendy Gattis
authors.initials: WG
authors.lastname: Stough
authors.forename: Véronique
authors.initials: V
authors.lastname: Regnault
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Efthymios
authors.initials: E
authors.lastname: Deliargyris
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.forename: Stefan
authors.initials: S
authors.lastname: Agewall
authors.forename: Scott D
authors.initials: SD
authors.lastname: Berkowitz
authors.forename: Paul
authors.initials: P
authors.lastname: Burton
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo
authors.forename: Sidney
authors.initials: S
authors.lastname: Goldstein
authors.forename: Freek W A
authors.initials: FW
authors.lastname: Verheugt
authors.forename: Joerg
authors.initials: J
authors.lastname: Koglin
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D003328:Coronary Thrombosis / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy; D006333:Heart Failure / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D018377:Neurotransmitter Agents / Q000097:blood; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy
chemical_list: D018377:Neurotransmitter Agents
keywords: Clinical trial; Heart failure; Research design; Thrombosis