Chronic heart failure and mortality in patients with community-acquired Staphylococcus aureus bacteremia: a population-based cohort study

This cohort study was conducted using routinely recorded data from population-based medical registries in Northern Denmark between 1 January 2000 and 31 December 2011 (catchment population ~ 1.8 million inhabitants). Tax-supported, unfettered healthcare is provided for the entire Danish population through a national health insurance program [10, 11]. Northern Denmark is served by two University hospitals and a dwindling number of regional hospitals (22 regional hospitals in 2000 and 7 regional hospitals in 2011). All Danish residents are assigned a unique identification number which allows unambiguous linkage of registry data at the individual level [10, 11].

Using the databases of the departments of clinical microbiology within the area, we identified all patients hospitalized with CA-SAB from 1995 onwards. We included patients ≥15 years with ≥1 positive blood cultures with S.aureus as the sole isolate (information on blood culture practice and susceptibility testing is provided in Additional file 1: Identification and susceptibility testing of S. aureus isolates). Because recurrence of SAB may affect prognosis [12], we limited the study to patients with incident SAB, defined as no prior SAB diagnosis within at least 5 years of the current hospitalization.

CA-SAB was defined as SAB in patients, in whom one or more positive blood cultures had been obtained within the first two days of admission. Patients with a first blood cultured obtained >2 days after admission were excluded, because we consider these infections to be hospital-acquired. Patients with CA-SAB and healthcare contacts recently preceding the current admission were sub-classified as healthcare-associated SAB (HCA-SAB) if one or more of the following criteria were met: ≥1 hospital admission, ≥1 contacts to hospital outpatient surgical clinics (including minor surgery), or ≥1 contacts to clinics of hematology, oncology or nephrology, all within a 30-day window of the current admission.

Data on recent health care contacts were retrieved using the Danish National Patient Registry (DNPR) [13]. This register holds data on all citizens and permanent residents admitted to Danish hospitals since 1977 and all visits to hospital outpatient clinics since 1995. Each record includes the dates of hospital admission and discharge, up to 20 discharge diagnoses, and information on surgical procedures.

Patients diagnosed with CHF at any time before the current admission were identified from the DNPR [13]. We defined CHF as a previous hospital discharge diagnosis or outpatient diagnosis of congestive heart failure, pulmonary edema with mention of heart failure, left ventricular failure, unspecified heart failure, cardiomyopathy, or hypertensive heart disease with congestive heart failure (with or without hypertensive renal disease or renal failure). CHF patients were further classified according to presence of CHF-related conditions: 1) cardiomyopathy (with or without any of the following diagnoses), 2) valvular heart disease (with or without any of the other diagnoses except cardiomyopathy), 3) previous myocardial infarction (with or without atrial fibrillation), 4) atrial fibrillation only, and 5) none of the above concomitant conditions. All diagnostic codes are provided in Additional file 2: Codes for diagnoses, procedures, medication, and blood tests.

Severity of CHF is not included in the diagnostic codes in the DNPR. Thus, as a proxy for CHF severity, patients were categorized according to daily dosage of redeemed prescriptions of loop-diuretics: non-users (no loop-diuretics), low dose (≤40 mg/day), medium dose (41–80 mg/day), high dose (81–159 mg/day), and very high dose (≥160 mg/day). We computed mean loop-diuretic dosages by dividing the number of dispensed tablets by a dispensing time interval of 180 days, as described previously [14, 15]. Loop-diuretic dosages have been shown to correlate positively with worsened New York Heart Association functional class and mortality risk, but not with glomerular filtration rate in CHF patients [15]. Data on filled prescriptions were retrieved from the Aarhus University Prescription Database (AUPD) [16], which holds data on redeemed prescriptions in the study area according to the Anatomical Therapeutic Chemical (ATC) classification system (ATC codes are provided in Additional file 2: Codes for diagnoses, procedures, medication, and blood tests). We calculated duration of CHF as the time elapsed between the first diagnosis of CHF and the sampling date of the first positive blood culture.

Data on sex, age, and marital status was retrieved from the Danish Civil Registration System, which is updated electronically on a daily basis and keeps track of demographic data and changes in vital status and migration for all Danish residents since 1968 [10, 11]. We computed a modified Charlson Comorbidity Index (m-CCI) using all available diagnoses registered in the DNPR up to 10 years before the current hospitalization excluding CHF from the index (the exposure variable of interest). The CCI is a validated comorbidity scoring system covering both the number and severity of 19 major disease categories [17, 18]. Patients were classified as having a low (score = 0), intermediate (score = 1–2), or a high comorbidity level (score >2). We further collated data on a number of conditions not included in the m-CCI, counting hypertension, drug- and alcohol-related conditions and dialysis (within 30 days of the current admission). Using the AUPD [16], we obtained data on the following filled prescriptions: Any previous use of antihypertensive treatment, statins (and other lipid lowering agents), anticoagulants, and use of immunosuppressant drugs, and antibiotics within 30 days of the SAB-related hospitalization (ATC codes are provided in Additional file 2: Codes for diagnoses, procedures, medication, and blood tests). The LABKA Database (CSC Scandihealth, Denmark) keeps laboratory test results from patients in Northern Denmark for the entire study period including the exact time of blood sample collection [19]. Using this database, we obtained information on white blood count levels on the date the first positive blood culture was drawn (laboratory codes are available in Additional file 2: Codes for diagnoses, procedures, medication, and blood tests). Data on all-cause mortality was retrieved from the Danish Civil Registration System [10, 11].

All patients were followed from the date the first positive blood culture was drawn until death, emigration or 90 days, whichever came first. Patient characteristics (including demographics, comorbidity, and preadmission medication use) were tabulated according to CHF status. We computed the 90-day mortality risk using the Kaplan-Meier method (1 – survival function) and graphically displayed 90-day mortality for patients with and without CHF. Ninety-day mortality rates for patients with vs. without CHF were compared using a Cox proportional hazards model estimating hazard ratios as a measure of mortality rate ratios (MMRs) with corresponding 95 % confidence intervals (CIs). CHF exposure was further subcategorized according to CHF-related conditions, CHF severity and CHF duration. To examine whether mortality differed among subsets of CHF patients, we stratified the analyses by sex, age category (15–39, 40–59, 60–79, 80+ years), and m-CCI level (“low”, “intermediate”, and “high”). All MRRs were adjusted for age, sex, conditions included in the m-CCI, hypertension, alcohol related conditions, marital status (as a marker of socioeconomic status) and preadmission use of antibiotic therapy (within 30 days). The assumption of proportional hazards in the Cox models was assessed graphically and found appropriate. We conducted all statistical analyses using Stata 11.2 for Windows (Stata Corp, College Station, TX).

During the study period 2638 patients aged ≥15 years were hospitalized with incident CA-SAB, of which 390 (14.8 %) had CHF (Table 1). Median age was 77 (interquartile range (IQR), 70–82) and 67 (IQR, 54–78) years for patients with and without CHF, respectively. There were slightly more men among patients with CHF compared to patients without CHF (64.9 % vs. 60.6 %). Forty-eight percent of patients with CHF were classified as HCA vs. 41.4 % among patients without CHF. Methicillin-resistant S.aureus (MRSA) was rarely observed (0.5 % of all patients). Patients with CHF had considerably more hospital-diagnosed comorbidity than patients without CHF, including diabetes (31.0 % vs. 12.8 %), chronic pulmonary disease (30.8 % vs. 10.8 %), renal disease (33.3 % vs. 13.6 %), and hypertension (49.5 % vs. 20.4 %). Compared to patients without CHF, patients with CHF were more likely to have filled prescriptions for angiotensin-converting-enzyme inhibitors, beta blockers, acetylsalicylic acid, and statins.

Ninety-day cumulative mortality was 44.6 % in patients with CHF and 30.4 % in patients without CHF, respectively (Table 2 and Fig. 1). This yielded an unadjusted MRR of 1.60 (95 % CI, 1.36–1.89), and an adjusted MRR of 1.24 (1.04–1.48). Compared to 30.4 % among patients without CHF, 90-day mortality was 30.8 % among patients with concomitant cardiomyopathy (aMRR = 1.04 (95 % CI, 0.63–1.72)), 60 % among patients with a history of valve disease (aMRR = 1.73 (95 % CI, 1.26–2.38)), 41.2 % among patients with previous myocardial infarction (aMRR = 1.17 (95 % CI, 0.83–1.65)), and 41.0 % among CHF patients with none of the above concomitant conditions (aMRR = 1.12 (0.83–1.50)).

Compared to patients without CHF, an increased risk of death within 90 days was observed among patients with dosages of 81–159 mg/day (aMRR = 1.55 (95%CI, 1.11–2.14)) and ≥160 mg/day (1.62 (95 % CI, 1.21–2.18)), whereas no association was noted among patients with daily intakes of loop-diuretics ≤80 mg/day (Table 2). Ninety-day mortality was 50 % among patients with CHF of <3 years as compared to 30.4 % among patients with no CHF, corresponding to an aMRR of 1.43 (95 % CI, 1.14–1.78). Longer duration of CHF did not appear to be associated with a poor outcome: Thus, compared with patients with no history of CHF, the aMRR was 1.01 (95 % CI, 0.71–1.46) for ≥3- < 6 years of CHF, 1.22 (95 % CI, 0.84-1.78) for ≥6- < 10 years of CHF and 0.97 (95 % CI, 0.61–1.54) for ≥10 years of CHF history. We observed no consistent pattern or major differences in 90-day mortality according to sex, age, or m-CCI level (Table 3).