Key result
LCZ696 consistently beats enalapril across baseline risk, preventing up to ~7 primary events per 100.
Why the study?
Most patients in the PARADIGM-HF trial had mild symptoms, yet reported functional limitation correlates poorly with prognosis in heart failure, prompting this evaluation of the baseline risk spectrum and the effect of LCZ696 across that spectrum.
Does baseline risk assessed by the MAGGIC and EMPHASIS-HF risk scores modify the treatment effect of LCZ696 compared with enalapril on cardiovascular death or heart failure hospitalization in patients with heart failure?
RCT (n=8,375)
Does baseline risk assessed by the MAGGIC and EMPHASIS-HF risk scores modify the treatment effect of LCZ696 compared with enalapril on cardiovascular death or heart failure hospitalization in patients with heart failure?
The relative benefit of LCZ696 over enalapril in reducing cardiovascular death or heart failure hospitalization is consistent across the baseline risk spectrum in PARADIGM-HF, yielding a greater absolute risk reduction in high-risk patients despite predominantly mild symptoms.
Answers are grounded in this paper and cite their sources.
Supports prioritizing LCZ696 in high-risk HF for larger absolute gains; extends PARADIGM-HF by quantifying risk-stratified absolute benefits.
Background Although 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. Objectives The aim of this study was to examine the spectrum of risk in PARADIGM-HF and the effect of LCZ696 across that spectrum. Methods This 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. Results The 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. Conclusions Although 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).
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Simpson et al. (2015) conducted an RCT in Heart Failure (n=8,375). LCZ696 vs. Enalapril was evaluated on Composite of cardiovascular death or heart failure hospitalization (p=0.159). LCZ696 showed consistent benefit over enalapril across baseline risk, preventing 7 primary outcomes per 100 patients treated for 2 years in the highest risk quintile vs 3 in the lowest.
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