Comparing LCZ696 With Enalapril According to Baseline Risk

Study Questions:

Does response to LZ696 vary by heart failure (HF) risk?


To evaluate the spectrum of risk in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, and the effect of LCZ696 across the risk spectrum, the MAGICC (Meta-Analysis Global Group in Chronic Heart Failure) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk scores were used to categorize patients. The primary outcome was the composite of cardiovascular death or HF hospitalization. Rates of the primary outcome, its composites, and all-cause death were analyzed. The effect of LCZ696 and enalapril were analyzed for each outcome.


Data were available for 8,375 patients. The median MAGICC score was 20 (interquartile range, 16-24). An increase of 1 point was associated with a 6% (95% confidence interval [CI], 5%-7%) increased risk in the primary composite endpoint (p < 0.001) and 7% (95% CI, 6%-8%) increase in cardiovascular death (p < 0.001). The effect of LCZ696 when compared to enalapril was consistent across the range of the risk scores. The absolute treatment effect of LCZ696 was greater in patients with higher risk scores. Thus, treating 100 patients with a risk score of 26-40 points for 2 years with LCZ696 (compared to enalapril) would lead to six fewer patients experiencing an event compared to two in the group with 4-15 points. There was no interaction between risk score and treatment effect. Results with the EMPHASIS-HF score were similar. The number needed to treat (NNT) in the high risk category over 2 years to avoid one primary outcome is 15 and to avoid one death is 16. In the lowest risk category, the NNT for the primary outcome is 33 and NNT is 63 to avoid one death.


Although most patients in the PARADIGM-HF study had mild symptoms, when categorized by risk, many were at high risk of adverse outcomes and had a large benefit from LCZ696 compared to enalapril.


Symptoms and functional limitations do not correlate well with risk of adverse events in HF patients, and patients with mild symptoms may remain at high risk for events. LCZ696 when compared to enalapril is beneficial across a spectrum of risk. Additional studies are required to more consistently determine risk in HF patients and impact of therapy.

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