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Eur J Heart Fail. 2015 Dec;17(12):1252-61. doi: 10.1002/ejhf.401. Epub 2015 Sep 30.

Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials.

Author information

Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, NL-6202AZ, Maastricht, the Netherlands.
Department of Medicine, University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.
National University Heart Centre Singapore, Singapore.
Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
Department of Cardiology, University Hospital Basel, Basel, Switzerland.
Department of Cardiology and Department of Medical and Health Sciences, Linkoping University, Department of Cardiology, Linkoping, Sweden.
Academic Medical Centre, Amsterdam, the Netherlands.
Division of Cardiology, Department of Medicine, County Hospital Ryhov, Jonkoping, Sweden.
Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
Department of Cardiology, Medical University of Vienna, Vienna, Austria.
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Department of Cardiology, LKH, St Poelten, Austria.



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.


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).


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.


Biomarkers; Co-morbidity; Heart failure; Heart failure with preserved ejection fraction; Treatment response

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