• Joanne Simpson, Pardeep S Jhund, Jose Silva Cardoso, Felipe Martinez, Arend Mosterd, Felix Ramires, Adel R Rizkala, Michele Senni, Iain Squire, Jianjian Gong, Martin P Lefkowitz, Victor C Shi, Akshay S Desai, Jean L Rouleau, Karl Swedberg, Michael R Zile, John J V McMurray, Milton Packer, Scott D Solomon, and PARADIGM-HF Investigators and Committees.
• BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
• J. Am. Coll. Cardiol. 2015 Nov 10; 66 (19): 2059-71.

BackgroundAlthough most patients in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial had mild symptoms, there is a poor correlation between reported functional limitation and prognosis in heart failure.ObjectivesThe aim of this study was to examine the spectrum of risk in PARADIGM-HF and the effect of LCZ696 across that spectrum.MethodsThis study analyzed rates of the primary composite outcome of cardiovascular death or heart failure hospitalization, its components, and all-cause mortality using the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk scores to categorize patients. The authors determined whether risk, on the basis of these scores, modified the treatment effect of LCZ696.ResultsThe complete MAGGIC risk score was available for 8,375 of the 8,399 patients in PARADIGM-HF. The median MAGGIC score was 20 (IQR: 16 to 24). An increase of 1 point was associated with a 6% increased risk for the primary endpoint (p < 0.001) and a 7% increased risk for cardiovascular death (p < 0.001). The benefit of LCZ696 over enalapril for the primary endpoint was similar across the spectrum of risk (p = 0.159). Treating 100 patients for 2 years with LCZ696 instead of enalapril led to 7 fewer patients in the highest quintile of risk experiencing primary outcomes, compared with 3 in the lowest quintile. Analyses using the EMPHASIS-HF risk score gave similar findings.ConclusionsAlthough most PARADIGM-HF patients had mild symptoms, many were at high risk for adverse outcomes and obtained a large absolute benefit from LCZ696, compared with enalapril, over a relatively short treatment period. LCZ696's benefit was consistent across the spectrum of risk. (PARADIGM-HF trial [Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure]; NCT01035255).Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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