Methods

The study population was derived from Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), a multicenter, randomized clinical trial of exercise training plus usual care versus usual care alone in patients with stable HF who were receiving state-of-the-art medical care. Exercise training consisted of 36 supervised sessions followed by home-based training. Eligible patients had New York Heart Association (NYHA) class II to IV HF for ≥3 months and left ventricular ejection fractions ≤35% within 6 months of enrollment. Patients were ineligible if they recently had major cardiovascular events or had conditions that could interfere with exercise training. A total of 2,331 patients were enrolled from April 2003 to February 2007 and were followed for up to 4 years at 82 sites in the United States (n = 67), Canada (n = 9), and France (n = 6). The primary end point, a composite of all-cause mortality or hospitalization, occurred in 65% of patients assigned to exercise training versus 68% of patients assigned to usual care (hazard ratio 0.93, 95% confidence interval 0.84 to 1.02, p = 0.13).

Some patient characteristics were collected only at baseline but did not necessarily represent characteristics of patients within the year before death (e.g., blood pressure, co-morbid conditions, the ejection fraction). However, several important variables were collected routinely, including NYHA class, medications, and Kansas City Cardiomyopathy Questionnaire scores. For these variables, we determined patient characteristics at the start of the year before death. We calculated age at 1 year before death.

In addition to demographic, clinical, and laboratory characteristics, the trial collected a wide range of data on medical resource use quarterly for the first 2 years and annually thereafter, including all-cause hospitalizations, emergency department and urgent care visits, outpatient visits and procedures, and other institutional care. Dates for outpatient care, outpatient procedures, and care provided at nonacute care facilities were not collected, so we limited our analysis to inpatient admissions, inpatient days, and inpatient costs (for which specific dates were available).

Inpatient costs were based primarily on event-level billing data, which were collected centrally for >80% of all hospitalizations reported during follow-up. Using these data, we estimated comprehensive costs of inpatient care by converting department-level charges to costs using cost-to-charge ratios generated from each hospital’s annual Medicare cost report. For remaining admissions for which bills were not available, we calculated inpatient costs by multiplying estimates of the median daily cost for each of 47 reasons for admission by length of stay for corresponding hospitalizations. We also assigned costs for physicians’ inpatient services and procedures throughout the follow-up period. Additional details about the costing methods have been described previously. We valued all costs in 2008 United States dollars.

Mode of death was adjudicated by the trial’s end point committee, which was blinded to treatment assignment. Mode of death was assigned on the basis of the definitions below and using information from case report forms reporting death, including site investigator summaries of events, copies of pertinent hospital discharge or death summaries, and diagnostic studies (e.g., computed tomographic scans, electrocardiography, operative reports), and a summary of interviews conducted by the study site coordinator of family members or witnesses describing out-of-hospital deaths. These sources of information were reviewed by 2 members of the end point committee, who had to independently agree on the mode of death. Mode of death was otherwise assigned by consensus of the entire committee.

Modes of death included SCD, HF, other cardiovascular causes, and noncardiovascular causes. Each mode was defined prospectively before the study. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient, including patients who were comatose and then died after attempted resuscitation. Patients in this category had recent human contact before the event. Patients who died but were out of human contact for prolonged or unknown periods were classified as unknown. Death from HF was defined as death from worsening or intractable HF, which generally occurred during hospitalization but could have occurred at home during hospice care. Terminal arrhythmias associated with HF deaths were classified as HF deaths. Other cardiovascular deaths were defined as being caused by a cardiovascular cause other than SCD or HF. HF secondary to a recent myocardial infarction was classified as other cardiovascular death.

We excluded patients who died of unknown causes. To ensure that differences in available follow-up time did not influence descriptive estimates or comparisons of resource use or costs, we limited the analysis to patients who had ≥1 year of follow-up before death. We combined patients from the 2 treatment groups for analysis.

We describe patient characteristics using means with SDs for continuous variables and frequencies for categorical variables. We compared baseline characteristics using Kruskal-Wallis tests for continuous variables and chi-square tests for categorical variables. We report proportions of patients hospitalized. To describe counts of medical resources and costs, we report means with SDs and medians with interquartile ranges.

We performed unadjusted and adjusted comparisons of medical resource use and costs incurred in the year before death using generalized linear regression models. To model counts of resource use throughout the year before death, we applied negative binomial distributions and log links. To model associations between cause of death and inpatient costs, we applied a generalized linear model specified with gamma variances and log links. Patients without admissions in the last year of life were assigned a cost of $1, because we modeled only inpatient costs. In unadjusted analyses, we included only covariates representing the cause of death.

We expected that differences in inpatient resource use and costs could differ across modes of death because of differences in disease severity or other factors. Therefore, we extended the regression models to include covariates. Before conducting multivariate regression analyses, we centered all continuous covariates on corresponding mean values and computed variance inflation factors to check for collinearity between covariates (factors for all covariates <2). We limited selection of covariates to those that were significant in bivariate analyses at p <0.10, because the samples were relatively small. These variables included NYHA class at 1 year before death and the following baseline variables: systolic blood pressure, implantable cardioverter-defibrillator (ICD), biventricular pacemaker, blood urea nitrogen level, serum creatinine level, serum sodium level, the left ventricular ejection fraction, and treatment with angiotensin-converting enzyme inhibitors and β blockers.

Results

During the follow-up period, 387 of 2,331 patients (16%) died, of whom 48 died of unknown causes. Of the remaining 339 patients with adjudicated reasons for death, 231 (68.1%) had ≥12 months of follow-up before death. Approximately equal numbers of patients died of HF (n = 80) and SCD (n = 72). Another 34 patients died of other cardiovascular causes, and 45 died of noncardiovascular causes. On the basis of the hospitalization dates and death dates available, 16.7% of patients with SCD and 58.5% of patients dying from non-SCD causes were in the hospital at the time of death.

Table 1 lists patient characteristics at the time of randomization for information collected only at baseline or 1 year before death for information collected repeatedly throughout the trial. Although patients who experienced SCD were approximately 5 years younger than patients who died of other causes (61 vs 66 years, p = 0.06), they were similar with regard to gender and race.

Medical histories were similar across groups, with the exception of patients who died of SCD or noncardiovascular causes, who were more likely to have chronic obstructive pulmonary disease (p = 0.02). Patients who experienced SCD were less likely to have ICDs or biventricular pacemakers before randomization. Several measures representing severity of HF indicated less severe HF in patients with SCD, including significantly lower blood urea nitrogen levels, higher peak oxygen consumption, higher left ventricular ejection fractions, and fewer patients with NYHA class IV HF. Long-term medication use was similar across groups, except that β-blocker use was significantly higher in patients with SCD (92% vs 69% to 85%, p = 0.004).

Approximately 6 of 10 patients who died of SCD were hospitalized in the previous year, compared with >9 of 10 patients who died of other causes (p <0.01, Table 2 ). Patients with SCD had an average of 1.4 hospitalizations, whereas patients who died of other causes had twice as many (2.4 to 3.5, p <0.01). The relative difference was larger with respect to the number of inpatient days in the last year of life, with 11.8 inpatient days for patients who experienced SCD and about 3 times as many for patients who died of other causes (32.3 to 42.8 days, p <0.01). The sharpest increase in inpatient days occurred in the last 2 months of life ( Figure 1 ).

Table 2

Inpatient resource use and costs within 12 months of death

Variable	Mode of Death
	SCD (n = 72)	HF (n = 80)	Other Cardiovascular (n = 34)	Noncardiovascular (n = 45)
Hospitalized at least once	45 (63%)	76 (95%) ⁎	31 (91%) ⁎	42 (93%) ⁎
Number of hospitalizations
Mean ± SD	1.4 ± 1.6	3.5 ± 2.2 ⁎	2.4 ± 1.9 ⁎	3.3 ± 2.2 ⁎
Median (IQR)	1.0 (0.0–2.0)	3.0 (2.0–5.0)	2.0 (1.0–4.0)	3.0 (2.0–4.0)
Number of inpatient days
Mean ± SD	11.8 ± 19.5	32.3 ± 28.5 ⁎	42.8 ± 55.0 ⁎	36.0 ± 37.1 ⁎
Median (IQR)	6.5 (0.0–12.5)	26.5 (14.0–42.0)	20.0 (5.0–60.0)	27.0 (11.0–50.0)
Inpatient costs ($)
Mean ± SD	23,328 ± 48,003	70,224 ± 85,154 ⁎	119,374 ± 159,398 ⁎	76,313 ± 96,019 ⁎
Median (IQR)	7,832 (0–23,750)	46,756 (19,694–81,751)	39,226 (8,064–195,002)	46,955 (17,043–91,272)

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