Effects of LCZ696 on Clinical Outcomes in Heart Failure
Effects of LCZ696 on Clinical Outcomes in Heart Failure
Table 1 provides a summary of patient characteristics and baseline treatment in SOLVD-T, CHARM-Alternative, and PARADIGM-HF.
The subjects enrolled in PARADIGM-HF were similar to those enrolled in SOLVD-T in terms of the age, sex, NYHA functional class distribution, LVEF, and eGFR. Hypertension was more common in PARADIGM-HF and prior myocardial infarction was more common in SOLVD-T. Beta-blocker use was much more common, and digoxin use less common, in PARADIGM-HF, compared with SOLVD-T. Mineralocorticoid use was not reported in SOLVD-T.
The patients enrolled in PARADIGM-HF (and SOLVD-T) were younger and less often female compared with those in CHARM-Alternative. The NYHA class distribution was different with more patients in NYHA class II in PARADIGM-HF (and SOLVD-T) and fewer in NYHA class III and IV, than in CHARM-Alternative. Systolic blood pressure was lower in PARADIGM-HF (and SOLVD-T) than in CHARM-Alternative. Beta-blocker and MRA use was more common in PARADIGM-HF than in CHARM-Alternative.
Table 2 shows the number of events and event rates in the three trials for the clinical outcomes of interest. Table 3 summarizes the treatment effects for these outcomes of interest in the three trials. In SOLVD-T and CHARM-Alternative, active therapy was superior to placebo, leading to statistically significant risk-reductions in the composite of cardiovascular death or heart failure hospitalization (and heart failure hospitalization alone) with both treatments tested. However, while the reductions in cardiovascular and all-cause mortality with enalapril were statistically significant in SOLVD-T, they were not in CHARM-Alternative, although they were qualitatively and quantitatively similar to SOLVD-T. In PARADIGM-HF, all outcomes were reduced significantly by LCZ696 compared with enalapril.
Figure 2A– D shows the putative placebo analyses for LCZ696. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 16–39%; P < 0.0001). Qualitatively and quantitatively, very similar effects were seen when LCZ696 was compared with a putative placebo from CHARM-Alternative (Figure 2).
(Enlarge Image)
Figure 2.
Putative placebo analysis based upon the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an angiotensin converting enzyme inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alt.) as the reference trial for comparison of an angiotensin receptor blocker to placebo. (A) Composite of death from cardiovascular causes or heart failure hospitalization, (B) cardiovascular death, (C) heart failure hospitalization, and (D) all-cause mortality.
Using the analysis based on CHARM-Alternative, compared with a putative placebo, LCZ696 would have avoided or postponed 71 composite cardiovascular death or heart failure hospitalization events, 31 cardiovascular deaths, 59 first heart failure hospitalizations, and 18 deaths from any cause per 1000 patient-years of treatment.
Results
Table 1 provides a summary of patient characteristics and baseline treatment in SOLVD-T, CHARM-Alternative, and PARADIGM-HF.
The subjects enrolled in PARADIGM-HF were similar to those enrolled in SOLVD-T in terms of the age, sex, NYHA functional class distribution, LVEF, and eGFR. Hypertension was more common in PARADIGM-HF and prior myocardial infarction was more common in SOLVD-T. Beta-blocker use was much more common, and digoxin use less common, in PARADIGM-HF, compared with SOLVD-T. Mineralocorticoid use was not reported in SOLVD-T.
The patients enrolled in PARADIGM-HF (and SOLVD-T) were younger and less often female compared with those in CHARM-Alternative. The NYHA class distribution was different with more patients in NYHA class II in PARADIGM-HF (and SOLVD-T) and fewer in NYHA class III and IV, than in CHARM-Alternative. Systolic blood pressure was lower in PARADIGM-HF (and SOLVD-T) than in CHARM-Alternative. Beta-blocker and MRA use was more common in PARADIGM-HF than in CHARM-Alternative.
Table 2 shows the number of events and event rates in the three trials for the clinical outcomes of interest. Table 3 summarizes the treatment effects for these outcomes of interest in the three trials. In SOLVD-T and CHARM-Alternative, active therapy was superior to placebo, leading to statistically significant risk-reductions in the composite of cardiovascular death or heart failure hospitalization (and heart failure hospitalization alone) with both treatments tested. However, while the reductions in cardiovascular and all-cause mortality with enalapril were statistically significant in SOLVD-T, they were not in CHARM-Alternative, although they were qualitatively and quantitatively similar to SOLVD-T. In PARADIGM-HF, all outcomes were reduced significantly by LCZ696 compared with enalapril.
Figure 2A– D shows the putative placebo analyses for LCZ696. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 16–39%; P < 0.0001). Qualitatively and quantitatively, very similar effects were seen when LCZ696 was compared with a putative placebo from CHARM-Alternative (Figure 2).
(Enlarge Image)
Figure 2.
Putative placebo analysis based upon the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an angiotensin converting enzyme inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alt.) as the reference trial for comparison of an angiotensin receptor blocker to placebo. (A) Composite of death from cardiovascular causes or heart failure hospitalization, (B) cardiovascular death, (C) heart failure hospitalization, and (D) all-cause mortality.
Using the analysis based on CHARM-Alternative, compared with a putative placebo, LCZ696 would have avoided or postponed 71 composite cardiovascular death or heart failure hospitalization events, 31 cardiovascular deaths, 59 first heart failure hospitalizations, and 18 deaths from any cause per 1000 patient-years of treatment.
