title: Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials.
abstract: OBJECTIVE
  Previous analyses suggest that heart failure (HF) therapy guided by (N-terminal pro-)brain natriuretic peptide (NT-proBNP) might be dependent on left ventricular ejection fraction, age and co-morbidities, but the reasons remain unclear.
  
  
  RESULTS
  To determine interactions between (NT-pro)BNP-guided therapy and HF with reduced [ejection fraction (EF) ≤45%; HF with reduced EF (HFrEF), n = 1731] vs. preserved EF [EF > 45%; HF with preserved EF (HFpEF), n = 301] and co-morbidities (hypertension, renal failure, chronic obstructive pulmonary disease, diabetes, cerebrovascular insult, peripheral vascular disease) on outcome, individual patient data (n = 2137) from eight NT-proBNP guidance trials were analysed using Cox-regression with multiplicative interaction terms. Endpoints were mortality and admission because of HF. Whereas in HFrEF patients (NT-pro)BNP-guided compared with symptom-guided therapy resulted in lower mortality [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.62-0.97, P = 0.03] and fewer HF admissions (HR = 0.80, 95% CI 0.67-0.97, P = 0.02), no such effect was seen in HFpEF (mortality: HR = 1.22, 95% CI 0.76-1.96, P = 0.41; HF admissions HR = 1.01, 95% CI 0.67-1.53, P = 0.97; interactions P < 0.02). Age (74 ± 11 years) interacted with treatment strategy allocation independently of EF regarding mortality (P = 0.02), but not HF admission (P = 0.54). The interaction of age and mortality was explained by the interaction of treatment strategy allocation with co-morbidities. In HFpEF, renal failure provided strongest interaction (P < 0.01; increased risk of (NT-pro)BNP-guided therapy if renal failure present), whereas in HFrEF patients, the presence of at least two of the following co-morbidities provided strongest interaction (P < 0.01; (NT-pro)BNP-guided therapy beneficial only if none or one of chronic obstructive pulmonary disease, diabetes, cardiovascular insult, or peripheral vascular disease present). (NT-pro)BNP-guided therapy was harmful in HFpEF patients without hypertension (P = 0.02).
  
  
  CONCLUSIONS
  The benefits of therapy guided by (NT-pro)BNP were present in HFrEF only. Co-morbidities seem to influence the response to (NT-pro)BNP-guided therapy and may explain the lower efficacy of this approach in elderly patients.
authors.affiliation: Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, NL-6202AZ, Maastricht, the Netherlands.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Brunner-La Rocca
authors.affiliation: Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, NL-6202AZ, Maastricht, the Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Eurlings
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.|National University Heart Centre Singapore, Singapore.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Pfisterer
authors.affiliation: Department of Cardiology and Department of Medical and Health Sciences, Linkoping University, Department of Cardiology, Linkoping, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dahlström
authors.affiliation: Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Division of Cardiology, Department of Medicine, County Hospital Ryhov, Jonkoping, Sweden.
authors.forename: Patric
authors.initials: P
authors.lastname: Karlström
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Erntell
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Berger
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Persson
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.affiliation: Department of Cardiology, LKH, St Poelten, Austria.
authors.forename: Deddo
authors.initials: D
authors.lastname: Moertl
authors.affiliation: Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Hanna K
authors.initials: HK
authors.lastname: Gaggin
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Frampton
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: M Gary
authors.initials: MG
authors.lastname: Nicholls
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
mesh_terms: D000367:Age Factors; D000368:Aged; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000032:analysis*; D010446:Peptide Fragments / Q000032:analysis*; D016032:Randomized Controlled Trials as Topic; D013318:Stroke Volume
chemical_list: D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
keywords: Biomarkers; Co-morbidity; Heart failure; Heart failure with preserved ejection fraction; Treatment response