Methods

Patients were first identified using the Duke Echocardiography Laboratory Database, which is a prospectively maintained digital archive of all clinical echocardiograms performed in the Duke University Health System (Durham, North Carolina) since 1995 that is linked to a corresponding searchable reporting database. This database also contains information on HR obtained at the time of the echocardiogram. Additional information on heart rhythm was obtained from a linked repository of electrocardiograms performed at Duke University Medical Center. Baseline clinical variables, including demographics, laboratory data, medications, and International Classification of Disease, Ninth Revision, Clinical Modification codes, for each patient were also obtained from the searchable, online Duke Enterprise Data Unified Content Explorer research portal. Follow-up data were obtained from electronic medical records and the Duke Databank of Cardiovascular Disease, a databank of all patients who underwent a cardiac catheterization and/or cardiac surgery at Duke University Medical Center since 1969. Additional mortality data were obtained through a search of the Social Security Death Master File. Institutional cost data were obtained from the medical center’s cost accounting system (Allscripts EPSi, Chicago, IL), to provide direct and indirect costs for inpatient and outpatient care inclusive of laboratory testing, medical procedures, and imaging. We also obtained professional billing records representing payments for all inpatient and outpatient services performed within 1 year of the index echocardiogram for each patient. The Institutional Review Board of the Duke University Health System approved this study.

For this analysis, we identified patients aged 18 years or older who underwent an echocardiogram as either an inpatient or outpatient for HF from August 1, 2008, to July 31, 2010, and a recent linked electrocardiogram (i.e., within 6 months before the echocardiogram). Patients were included if they were assigned an International Classification of Disease, Ninth Revision, Clinical Modification code for HF for any encounter within the 12 months before the echocardiogram. If a patient had >1 echocardiogram performed during the study period, then we used the first as the index echocardiogram.

We excluded patients with a preserved left ventricular EF (LVEF; >40%) as reported clinically by either quantitative or qualitative assessment. This definition was chosen to be consistent with recent guideline definitions of HFrEF. Using data from the recent electrocardiograms, patients with a paced rhythm or recent atrial fibrillation were excluded. If a patient had ≥1 electrocardiogram performed on the same day, each was reviewed for a paced rhythm or atrial fibrillation. We also limited the analysis to patients with expected follow-up at Duke University Medical Center, as defined by ≥2 outpatient visits within the medical center in the 18 months preceding the echocardiogram.

Heart rates used in the analysis were from a clinical assessment of HR performed at the beginning of the echocardiogram with the patient typically resting in the supine position. In the event this was missing, we used the HR measure from the most recent electrocardiogram performed within 6 months of the baseline echocardiogram.

We first described baseline characteristics of the study population stratified by HR at rest (<70 and ≥70 beats/min). This cutoff was chosen to be consistent with the design of the Systolic Heart Failure Treatment with Ivabradine Trial, which included patients with chronic, symptomatic HFrEF, HR ≥70 beats/min, and background medical therapy that included a maximally tolerated dose of beta-blocker therapy or a contraindication or intolerance to beta-blocker therapy. We reported frequencies and proportions for categorical variables and medians with 25th and 75th percentiles for continuous variables. We compared the 2 groups using the chi-square tests for categorical variables and Wilcoxon tests for continuous variables.

We then described and compared 1-year outcomes of interest by group, including a composite of all-cause mortality or hospitalization, all-cause mortality, all-cause hospitalization, and average medical costs per day alive. We used Cox proportional hazard models to compare time-to-event (i.e., mortality and/or hospitalization) end points, adjusting for potential confounding variables. Candidate variables were selected for use in the multivariable models based on clinical judgment. For adjusted comparisons of costs, we used a generalized linear model specified with a log link and gamma error distribution.

Analyses were repeated using continuous HR; linearity was assessed and suggested no violation. Results are reported per 10 beats/min increase in HR. Interactions were assessed between HR ≥70 beats/min and echocardiogram performed during a hospitalization (vs outpatient) as well as beta blocker use. In a sensitivity analysis, we restricted the cohort to those patients potentially eligible for ivabradine, that is, an LVEF ≤35%. Given the smaller cohort, we performed adjusted analysis using a parsimonious model and the full model used in the previous analyses.

We used 2-tailed α = 0.05 to establish statistical significance and reported 95% confidence intervals. All analyses were performed using SAS software, version 9.2 or higher (SAS Institute, Cary, North Carolina).

Results

Of 5,265 unique patients with HF undergoing an echocardiogram at Duke University Medical Center during the study period, 3,413 patients (65%) were initially excluded for a preserved LVEF ( Figure 1 ). The remaining were excluded for a recent paced rhythm, recent atrial fibrillation, or a missing electrocardiogram, 868 (16%), or for <2 recent outpatient visits at Duke University Medical Center, 260 (4.9%). Finally, a total of 724 unique patients met the study criteria of which 2 additional patients were excluded from the outcomes analysis because of incomplete cost data; rendering a final sample size of 722.

Flow diagram of the study design. This figure displays the initial study population, through exclusions, to the final study population. DUMC = Duke University Medical Center; ECG = electrocardiogram.

Baseline characteristics of the study population stratified by HR at rest (<70 or ≥70 beats/min) are reported in Table 1 . The median HR for the study population was 81 beats/min (25th and 75th percentiles 69 to 96) and 582 patients (81%) were on a β blocker. Patients with an HR ≥70 beats/min were younger (median age 61 vs 66 years, p <0.001), were less likely to have coronary artery disease (64% vs 75%, p = 0.007), and were more likely to have an LVEF <20% (17% vs 5.1%, p <0.001) compared to those without. The echocardiogram was also more likely to be performed while hospitalized (63% vs 37%, p <0.001) for patients with an HR ≥70 beats/min compared to those without. The use of a β blocker was greater in patients with an HR ≥70 beats/min compared to those without (82% vs 76%, p = 0.051).

The association between an HR ≥70 beats/min and 1-year outcomes including costs per day alive are listed in Table 2 and Figure 2 and Figure 3 . An HR ≥70 beats/min was associated with increased 1-year all-cause mortality or all-cause hospitalization in both unadjusted, hazard ratio 1.67 (95% CI 1.32 to 2.09, p <0.001) and adjusted analyses, hazard ratio 1.37 (95% CI 1.07 to 1.75, p = 0.012). We found similar results for individual components of the 1-year outcome. An HR ≥70 beats/min was also associated with increased medical costs per day alive in both unadjusted, cost ratio 3.37 (95% CI 2.81 to 4.96, p <0.001), and adjusted analyses, cost ratio 2.03 (95% CI 1.53 to 2.69, p <0.001). We also repeated the analysis considering HR as a continuous variable. A 10 beats/min increase in HR was associated with increased 1-year all-cause mortality or all-cause hospitalization in both unadjusted, hazard ratio 1.15 (95% CI 1.10 to 1.20, p <0.001) and adjusted analyses, hazard ratio 1.11 (95% CI 1.05 to 1.17, p <0.001). Increasing HR was also associated with increased medical costs per day alive in both unadjusted, cost ratio 1.42 (95% CI 1.33 to 1.51, p <0.001), and adjusted analyses, cost ratio 1.32 (95% CI 1.24 to 1.40, p <0.001).

Table 2

Association between heart rate ≥70 beats/min and 1-year outcomes

1-Year Outcomes	Unadjusted		Adjusted ∗
	HR (95% CI)	p-value	HR (95% CI)	p-value
Mortality or Hospitalization	1.67 (1.32 to 2.09)	<.001	1.37 (1.07 to 1.75)	.012
Mortality	2.32 (1.51 to 3.58)	<.001	1.78 (1.13 to 2.80)	.013
All-Cause Hospitalization	1.54 (1.20 to 1.98)	.001	1.32 (1.01 to 1.72)	.043
	Cost Ratio (95% CI)	p-value	Cost Ratio (95% CI)	p-value
Average Medical Cost per Day Alive	3.37 (2.81 to 4.96)	<.001	2.03 (1.53 to 2.69)	<.001

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