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CLINICAL RESEARCH: HEART FAILURE

Plasma Concentration of Amino-Terminal Pro-Brain Natriuretic Peptide in Chronic Heart Failure: Prediction of Cardiovascular Events and Interaction With the Effects of Rosuvastatin

A Report From CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure)

John G.F. Cleland, MD^_*,_*, John J.V. McMurray, MD, John Kjekshus, MD, PhD, Jan H. Cornel, MD, Peter Dunselman, MD, PhD^||, Cândida Fonseca, MD^¶, Åke Hjalmarson, MD, PhD^#, Jerzy Korewicki, MD, PhD^_**, Magnus Lindberg, MSc, Naresh Ranjith, MD, Dirk J. van Veldhuisen, MD, PhD, Finn Waagstein, MD, PhD^||||, Hans Wedel, PhD^¶¶, John Wikstrand, MD, PhD^## on behalf of the CORONA Study Group

^_* Department of Cardiology, University of Hull, Kingston-upon-Hull, United Kingdom
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
Rikshospitalet, Oslo, Norway
Medisch Centrum Alkmaar, Alkmaar, the Netherlands
^|| Amphia Ziekenhuis, Breda, the Netherlands
^¶ Hospital de S. Francisco Xavier, Lisbon, Portugal
^# Institute of Heart and Lung Diseases, Göteborg, Sweden
^_** Institute of Cardiology, Warsaw, Poland
Biostatistics Department, AstraZeneca, Mölndal, Sweden
Nelson R. Mandela School of Medicine, Durban, South Africa
University Medical Center Groningen, Groningen, the Netherlands
^|||| University of Göteborg, Göteborg, Sweden
^¶¶ Nordic School of Public Health, Göteborg, Sweden
^## Wallenberg Laboratory for Cardiovascular Research, Göteborg, Sweden

Manuscript received February 19, 2009; revised manuscript received June 15, 2009, accepted June 29, 2009.

^_* Reprint requests and correspondence: Prof. John G. F. Cleland, Department of Cardiology, Hull York Medical School at the University of Hull, Medical Research Building, Gate 2, Castle Hill Hospital, Kingston-upon-Hull, East Yorkshire HU16 5JQ, United Kingdom (Email: j.g.cleland{at}hull.ac.uk).

Objectives: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective.

Background: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile.

Methods: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke.

Results: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin.

Conclusions: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.

Key Words: amino-terminal pro-brain natriuretic peptide • heart failure • mortality • randomized controlled trial • rosuvastatin

Abbreviations and Acronyms   HR = hazard ratio   LVEF = left ventricular ejection fraction   MI = myocardial infarction   NT-proBNP = amino-terminal pro-brain natriuretic peptide

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