Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie?

Abstract

Aims: We investigated the relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival in a large, heterogeneous clinical cohort.

Methods and results: Physician-reported LVEF on 403 977 echocardiograms from 203 135 patients were linked to all-cause mortality using electronic health records (1998-2018) from US regional healthcare system. Cox proportional hazards regression was used for analyses while adjusting for many patient characteristics including age, sex, and relevant comorbidities. A dataset including 45 531 echocardiograms and 35 976 patients from New Zealand was used to provide independent validation of analyses. During follow-up of the US cohort, 46 258 (23%) patients who had undergone 108 578 (27%) echocardiograms died. Overall, adjusted hazard ratios (HR) for mortality showed a u-shaped relationship for LVEF with a nadir of risk at an LVEF of 60-65%, a HR of 1.71 [95% confidence interval (CI) 1.64-1.77] when ≥70% and a HR of 1.73 (95% CI 1.66-1.80) at LVEF of 35-40%. Similar relationships with a nadir at 60-65% were observed in the validation dataset as well as for each age group and both sexes. The results were similar after further adjustments for conditions associated with an elevated LVEF, including mitral regurgitation, increased wall thickness, and anaemia and when restricted to patients reported to have heart failure at the time of the echocardiogram.

Conclusion: Deviation of LVEF from 60% to 65% is associated with poorer survival regardless of age, sex, or other relevant comorbidities such as heart failure. These results may herald the recognition of a new phenotype characterized by supra-normal LVEF.

Keywords: Cardiac function; Clinical practice; Ejection fraction; Mortality; Survival.

Figure 1

Left ventricular ejection fraction hazard ratios and Kaplan–Meier survival curves in the primary analysis (number of echocardiograms = 403 977). Left ventricular ejection fraction intervals are inclusive of the lower threshold. (A) Error bars represent the 95% confidence interval. (B) Selected left ventricular ejection fraction intervals are shown for clarity. The number at risk includes left ventricular ejection fraction intervals not shown in the figure. LVEF, left ventricular ejection fraction.

Figure 2

Confounder hazard ratios in the primary analysis (number of echocardiograms = 403 977).

Figure 3

Analysis with interactions between age, sex, and left ventricular ejection fraction (number of echocardiograms = 403 977). Left ventricular ejection fraction intervals are inclusive of the lower threshold. The referent group was ‘female, under age 40 years, left ventricular ejection fraction between 60–65%’. LVEF, left ventricular ejection fraction.

Figure 4

Left ventricular ejection fraction adjusted hazard ratios in patients with heart failure (number of echocardiograms = 40 616). Left ventricular ejection fraction intervals are inclusive of the lower threshold. Error bars represent the 95% confidence interval. The referent group was ‘Outpatients with left ventricular ejection fraction of 60–65%’. While 51 192 echocardiograms were performed on patients with heart failure in the primary analysis, only 40 616 echocardiograms are represented in this figure due to excluding echocardiograms missing measurements of end-diastolic volume index or wall thicknesses, for which adjustments were made in the analysis. LVEF, left ventricular ejection fraction.

Take home figure

Deviation of LVEF from 60–65% is associated with poorer survival regardless of age, sex or other relevant comorbidities such as heart failure. These results may herald the recognition of a new phenotype characterized by supra-normal LVEF.