Changes in Left Ventricular Ejection Fraction Predict Survival and Hospitalization in Heart Failure With Reduced Ejection Fraction

Abstract

Background: Left ventricular remodeling, as commonly measured by left ventricular ejection fraction (LVEF), is associated with clinical outcomes. Although change in LVEF over time should reflect response to therapy and clinical course, serial measurement of LVEF is inconsistently performed in observational settings, and the incremental prognostic value of change in LVEF has not been well characterized.

Methods and results: The β-Blocker Evaluation of Survival Trial measured LVEF by radionuclide ventriculography at baseline and at 3 and 12 months after randomization. We built a series of multivariable models with 16 clinical parameters plus change in LVEF for predicting 4 major clinical end points, including the trial's primary end point of all-cause mortality. Among 2484 patients with at least 1 follow-up LVEF, change in LVEF was the second most significant predictor (behind baseline creatinine) of all-cause mortality (adjusted hazard ratio for improvement in LVEF by ≥5 U responder versus nonresponder [95% confidence intervals] for all-cause mortality=0.62 [0.52-0.73]). Other end points, including heart failure hospitalization or the composite of all-cause mortality and heart failure hospitalization, yielded similar results. LVEF change ≥5 U was associated with a modest increase in discrimination when added to traditional predictors and was predictive of outcomes in both the bucindolol and placebo treatment groups. LVEF change as a predictor of outcomes was affected by sex and race, with evidence that LVEF improvement is associated with less survival benefit in African Americans and women.

Conclusions: Serial evaluation for LVEF change predicts both survival and heart failure hospitalization and provides a dynamic/real-time measure of prognosis in heart failure with reduced LVEF.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000560.

Keywords: creatinine; heart failure; hospitalization; outcomes research; prognosis.

© 2016 American Heart Association, Inc.

Figures

Figure 1. Flowchart of Patients

Figure 2. Change in 12-Month LVEF and Risk of ACM

2a indicates absolute changes with treatment at 12-month; worsened, ≤−5 units; unchanged, −4 to 4 units, and improved ≥5 units. 2b indicates LVEF at 12-months. 2c indicates a histogram of absolute units change in histogram and linear plot of hazard ratio of ACM based upon absolute units change in LVEF compared to unchanged LVEF; the dotted black line indicates local polynomial smoothing of the ACM hazard ratio; dotted blue lines, 95% Confidence Interval (CI) band of ACM hazard ratio with local polynomial smoothing.

Figure 2. Change in 12-Month LVEF and Risk of ACM

2a indicates absolute changes with treatment at 12-month; worsened, ≤−5 units; unchanged, −4 to 4 units, and improved ≥5 units. 2b indicates LVEF at 12-months. 2c indicates a histogram of absolute units change in histogram and linear plot of hazard ratio of ACM based upon absolute units change in LVEF compared to unchanged LVEF; the dotted black line indicates local polynomial smoothing of the ACM hazard ratio; dotted blue lines, 95% Confidence Interval (CI) band of ACM hazard ratio with local polynomial smoothing.

Figure 2. Change in 12-Month LVEF and Risk of ACM

2a indicates absolute changes with treatment at 12-month; worsened, ≤−5 units; unchanged, −4 to 4 units, and improved ≥5 units. 2b indicates LVEF at 12-months. 2c indicates a histogram of absolute units change in histogram and linear plot of hazard ratio of ACM based upon absolute units change in LVEF compared to unchanged LVEF; the dotted black line indicates local polynomial smoothing of the ACM hazard ratio; dotted blue lines, 95% Confidence Interval (CI) band of ACM hazard ratio with local polynomial smoothing.

Figure 3. Hazard Ratio of Outcome Based Upon Predictors of ACM, CVM, HF Hospitalization, and ACM or HF Hospitalization

3a indicates ACM; 3b, CVM; 3c, HFH, HF Hospitalization; and 3d, ACM or HFH. The predictors included the presence versus absence of disease in binary fashion unless noted otherwise: age (continuous: years (yr)/10); atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure duration (continuous variable in months (mon)/25); creatinine (continuous: mg/dL); diabetes; LVEF, baseline left ventricular ejection fraction 2p indicates the chi squared p-value.

Figure 3. Hazard Ratio of Outcome Based Upon Predictors of ACM, CVM, HF Hospitalization, and ACM or HF Hospitalization

3a indicates ACM; 3b, CVM; 3c, HFH, HF Hospitalization; and 3d, ACM or HFH. The predictors included the presence versus absence of disease in binary fashion unless noted otherwise: age (continuous: years (yr)/10); atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure duration (continuous variable in months (mon)/25); creatinine (continuous: mg/dL); diabetes; LVEF, baseline left ventricular ejection fraction 2p indicates the chi squared p-value.

Figure 3. Hazard Ratio of Outcome Based Upon Predictors of ACM, CVM, HF Hospitalization, and ACM or HF Hospitalization

3a indicates ACM; 3b, CVM; 3c, HFH, HF Hospitalization; and 3d, ACM or HFH. The predictors included the presence versus absence of disease in binary fashion unless noted otherwise: age (continuous: years (yr)/10); atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure duration (continuous variable in months (mon)/25); creatinine (continuous: mg/dL); diabetes; LVEF, baseline left ventricular ejection fraction 2p indicates the chi squared p-value.

Figure 3. Hazard Ratio of Outcome Based Upon Predictors of ACM, CVM, HF Hospitalization, and ACM or HF Hospitalization

3a indicates ACM; 3b, CVM; 3c, HFH, HF Hospitalization; and 3d, ACM or HFH. The predictors included the presence versus absence of disease in binary fashion unless noted otherwise: age (continuous: years (yr)/10); atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure duration (continuous variable in months (mon)/25); creatinine (continuous: mg/dL); diabetes; LVEF, baseline left ventricular ejection fraction 2p indicates the chi squared p-value.

Figure 4. Risk of Event for ≥5 Units LVEF 12-Month Change Stratified by Subgroup

Hazard Ratio with 95% confidence intervals are shown for subgroups 4a. treatment group (bucindolol and placebo), 4b. race (African-American, AA and Non-African-American, Non-AA), and 4c. sex.1 indicates Cox model test for significance of treatment × LVEF response indicator interaction;2, Cox model test for significance of race × LVEF response indicator interaction;3, Cox model test for significance of sex × LVEF response indicator interaction; ACM, all-cause mortality; CVM, cardiovascular mortality; and HFH, heart failure hospitalization.

Figure 4. Risk of Event for ≥5 Units LVEF 12-Month Change Stratified by Subgroup

Hazard Ratio with 95% confidence intervals are shown for subgroups 4a. treatment group (bucindolol and placebo), 4b. race (African-American, AA and Non-African-American, Non-AA), and 4c. sex.1 indicates Cox model test for significance of treatment × LVEF response indicator interaction;2, Cox model test for significance of race × LVEF response indicator interaction;3, Cox model test for significance of sex × LVEF response indicator interaction; ACM, all-cause mortality; CVM, cardiovascular mortality; and HFH, heart failure hospitalization.

Figure 4. Risk of Event for ≥5 Units LVEF 12-Month Change Stratified by Subgroup

Hazard Ratio with 95% confidence intervals are shown for subgroups 4a. treatment group (bucindolol and placebo), 4b. race (African-American, AA and Non-African-American, Non-AA), and 4c. sex.1 indicates Cox model test for significance of treatment × LVEF response indicator interaction;2, Cox model test for significance of race × LVEF response indicator interaction;3, Cox model test for significance of sex × LVEF response indicator interaction; ACM, all-cause mortality; CVM, cardiovascular mortality; and HFH, heart failure hospitalization.