Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach

Abstract

Objectives: The purpose of this study was to quantitatively assess the relationship between therapy-induced changes in left ventricular (LV) remodeling and longer-term outcomes in patients with left ventricular dysfunction (LVD).

Background: Whether therapy-induced changes in left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) are predictors of mortality in patients with LVD is not established.

Methods: Searches for randomized controlled trials (RCTs) were conducted to identify drug or device therapies for which an effect on mortality in patients with LVD was studied in at least 1 RCT of > or = 500 patients (mortality trials). Then, all RCTs involving those therapies were identified in patients with LVD that described changes in LVEF and/or volumes over time (remodeling trials). We examined whether the magnitude of remodeling effects is associated with the odds ratios for death across all therapies or associated with whether the odds ratio for mortality was favorable, neutral, or adverse (i.e., statistically significantly decreased, nonsignificant, or statistically significantly increased odds for mortality, respectively).

Results: Included were 30 mortality trials of 25 drug/device therapies (n = 69,766 patients; median follow-up 17 months) and 88 remodeling trials of the same therapies (n = 19,921 patients; median follow-up 6 months). The odds ratio for death in the mortality trials was correlated with drug/device effects on LVEF (r = -0.51, p < 0.001), EDV (r = 0.44, p = 0.002), and ESV (r = 0.48, p = 0.002). In (ordinal) logistic regressions, the odds for neutral or favorable effects in the mortality RCTs increased with mean increases in LVEF and with mean decreases in EDV and ESV in the remodeling trials.

Conclusions: In patients with LVD, short-term trial-level therapeutic effects of a drug or device on LV remodeling are associated with longer-term trial-level effects on mortality.

Figure 1

Figure 1A. Search Pathway for Identification of Mortality Trials. RCT = Randomized Controlled Trial Figure 1B. Search Pathway for Identification of Remodeling Trials. *86 trials evaluated 89 drug-placebo comparisons (83 parallel arm trials; 3 trials evaluated two drugs versus placebo). RCT = Randomized Controlled Trial

Figure 1

Figure 1A. Search Pathway for Identification of Mortality Trials. RCT = Randomized Controlled Trial Figure 1B. Search Pathway for Identification of Remodeling Trials. *86 trials evaluated 89 drug-placebo comparisons (83 parallel arm trials; 3 trials evaluated two drugs versus placebo). RCT = Randomized Controlled Trial

Figure 2

Figure 2A. Quantitative Relationship Between Drug/Device Effects on Ejection Fraction and Mortality. Each data point represents a placebo-corrected change in EF from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Interventions were classified as favorable if the upper limit of the 95% confidence interval of the odds ratio for death from the mortality trials was less than 1, neutral if the confidence interval crossed 1 and adverse if the lower limit of the confidence interval was greater than 1. Remodeling data derived from analysis of 85 RCTs of 25 interventions, including 14,668 total patients. RCT = Randomized Controlled Trial; EF = Ejection Fraction Figure 2B. Predicted Probability of a Categorical Mortality Outcome Based on Drug/Device Effect on Ejection Fraction. The solid lines represent the likelihood of a categorical mortality outcome based on an intervention’s trial-level effect on ejection fraction compared with placebo. The dashed lines signify the corresponding 95% confidence interval. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. EF = Ejection Fraction

Figure 2

Figure 2A. Quantitative Relationship Between Drug/Device Effects on Ejection Fraction and Mortality. Each data point represents a placebo-corrected change in EF from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Interventions were classified as favorable if the upper limit of the 95% confidence interval of the odds ratio for death from the mortality trials was less than 1, neutral if the confidence interval crossed 1 and adverse if the lower limit of the confidence interval was greater than 1. Remodeling data derived from analysis of 85 RCTs of 25 interventions, including 14,668 total patients. RCT = Randomized Controlled Trial; EF = Ejection Fraction Figure 2B. Predicted Probability of a Categorical Mortality Outcome Based on Drug/Device Effect on Ejection Fraction. The solid lines represent the likelihood of a categorical mortality outcome based on an intervention’s trial-level effect on ejection fraction compared with placebo. The dashed lines signify the corresponding 95% confidence interval. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. EF = Ejection Fraction

Figure 3

Figure 3A. Quantitative Relationship Between Drug/Device Effects on End-Diastolic Volume and Mortality. Each data point represents a placebo-corrected change in EDV from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. Remodeling data derived from analysis of 50 RCTs of 19 interventions, including 8,499 total patients. RCT = Randomized Controlled Trial; EDV = End-Diastolic Volume Figure 3B. Predicted Probability of a Categorical Mortality Outcome Based on Drug/Device Effect on End-Diastolic Volume. The solid lines represent the likelihood of a categorical mortality outcome based on an intervention’s trial-level effect on end-diastolic volume compared with placebo. The dashed lines signify the corresponding 95% confidence interval. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. EDV = End-Diastolic Volume

Figure 3

Figure 3A. Quantitative Relationship Between Drug/Device Effects on End-Diastolic Volume and Mortality. Each data point represents a placebo-corrected change in EDV from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. Remodeling data derived from analysis of 50 RCTs of 19 interventions, including 8,499 total patients. RCT = Randomized Controlled Trial; EDV = End-Diastolic Volume Figure 3B. Predicted Probability of a Categorical Mortality Outcome Based on Drug/Device Effect on End-Diastolic Volume. The solid lines represent the likelihood of a categorical mortality outcome based on an intervention’s trial-level effect on end-diastolic volume compared with placebo. The dashed lines signify the corresponding 95% confidence interval. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. EDV = End-Diastolic Volume

Figure 4

Figure 4A. Quantitative Relationship Between Drug/Device Effects on End-Systolic Volume and Mortality. Each data point represents a placebo-corrected change in ESV from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. Remodeling data derived from analysis of 40 RCTs of 16 interventions, including 5037 total patients. RCT = Randomized Controlled Trial; ESV = End-Systolic Volume Figure 4B. Predicted Probability of a Favorable Mortality Outcome Based on Drug/Device Effect on End-Systolic Volume. The solid line represents the likelihood of a favorable mortality outcome based on an intervention’s trial-level effect on end-systolic volume compared with placebo. The dashed lines signify the corresponding 95% confidence interval. There was insufficient remodeling data for ESV to model the probability for neutral or adverse outcomes individually. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. ESV = End-Systolic Volume

Figure 4

Figure 4A. Quantitative Relationship Between Drug/Device Effects on End-Systolic Volume and Mortality. Each data point represents a placebo-corrected change in ESV from an individual remodeling trial plotted against the mortality OR for the specific therapy. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. Remodeling data derived from analysis of 40 RCTs of 16 interventions, including 5037 total patients. RCT = Randomized Controlled Trial; ESV = End-Systolic Volume Figure 4B. Predicted Probability of a Favorable Mortality Outcome Based on Drug/Device Effect on End-Systolic Volume. The solid line represents the likelihood of a favorable mortality outcome based on an intervention’s trial-level effect on end-systolic volume compared with placebo. The dashed lines signify the corresponding 95% confidence interval. There was insufficient remodeling data for ESV to model the probability for neutral or adverse outcomes individually. Color-coded mortality effect based on data from mortality trials listed in Table 1. Definition of mortality effect for a given intervention as described in Figure 2A legend. ESV = End-Systolic Volume