Background
Infections represent a great challenge to the medical field everywhere; especially among patients with comorbidities. Morbidity and mortality of infection are greater in the dialysis population compared to the general population [
1‐
4]. In this population, infections explain more than 20 % of hospitalizations and are the second leading cause of death [
5,
4,
6]. Infection-related hospitalizations (IRH) in the hemodialysis population are often associated with hemodialysis catheters, and these have been acknowledged as a major risk factor for bacteremia [
7,
8]. It was estimated that more than 7000 serious complications of catheter-related bacteremia such as sepsis or metastatic infections occur annually in the United States, representing not only a burden on nephrology units, but on the cost of healthcare as well [
9]. Although classic infection prevention strategies such as aseptic protocol, water quality assessment and avoidance of catheters remain essential, we are in dire of new modifiable risk factors.
While mostly used for its antiplatelet activity, acetylsalicylic acid (ASA) has been reported in vitro and in vivo as having an antistaphylococcal activity through its major metabolite, salicylic acid, mitigating α-hemolysin secretion and fibronectin binding [
10]. In a relatively small study, ASA has been associated with a decreased risk of
Staphylococcus aureus bacteremia in hemodialysis patients [
11]. However, preventing one germ may not impact on the overall infection risk as other germs compete at the infection site. A survey of access-related bacteremias in hemodialysis conducted in the province of Quebec showed that
S. aureus accounts for 54 % of isolated germs, followed by
Enterobateria and coagulase negative
Staphylococci with 11 % each [
12]. Moreover, because the dialysis population is at high risk of bleeding events and that ASA may be potentially harmful, the potential benefit of ASA on infections should be clearly established before this new indication justifies its use [
13,
14]. Therefore, this study sought to evaluate the association between ASA and the risk of dialysis-related infections or septicemia in an incident chronic hemodialysis cohort.
Results and discussion
We identified a cohort of 4933 patients initiating chronic hemodialysis during the study period. 446 patients had at least one hospitalization for a dialysis-related infection or a septicemia (cases). Cases were matched to 4126 controls during the study period. The overall median follow-up time was 1.81 years (interquartile range: 0.88-3.10 years). Cases had a median time to first hospitalization of 0.92 years (interquartile range: 0.36-1.95 years). Characteristics for cases and controls are shown in Table
2. Cases were younger (66.5
versus 68.1 years), and had a higher prevalence of diabetes (57.9 %
versus 53.1 %) than controls. In addition, a higher proportion of cases was using anticoagulant drugs than controls (28.9 %
versus 21.2 %). There was no difference with respect to exposure to ASA between cases and controls.
Table 2
Characteristics for cases and controls
Age (years) | 66.5 ± 12.8 | 68.1 ± 10.8 | 0.01 |
Female sex (%) | 42.4 | 40.8 | 0.52 |
Race (%) | | | |
Black | 6.0 | 4.1 | 0.16 |
Caucasian | 84.5 | 86.1 | |
Other | 9.4 | 9.8 | |
BMI (kg/m2) | 27.8 ± 6.3 | 27.4 ± 6.3 | 0.29 |
Smoking (%) | 15.5 | 14.1 | 0.41 |
Co-morbidities (%) | | | |
Cardiovascular disease | 57.9 | 58.2 | 0.87 |
Cerebrovascular disease | 17.7 | 16.3 | 0.46 |
Chronic pulmonary disease | 32.5 | 30.0 | 0.27 |
Chronic liver disease | 2.2 | 3.1 | 0.33 |
Congestive heart failure | 37.4 | 37.8 | 0.89 |
Diabetes | 57.9 | 53.1 | 0.05 |
Hyperlipidemia | 58.3 | 58.7 | 0.87 |
Hypertension | 94.8 | 94.1 | 0.52 |
Malignancy | 17.7 | 16.7 | 0.60 |
Peripheral vascular disease | 37.4 | 36.7 | 0.75 |
ASA daily dose | | | |
Unexposed | 50.7 | 49.3 | 0.79 |
80-324 mg | 35.7 | 37.3 | |
≥ 325 mg | 13.7 | 13.4 | |
Other medication use (%) | | | |
Anticoagulant | 28.9 | 21.2 | >0.001 |
Antiplatelet | 11.0 | 11.8 | 0.63 |
Laboratory data | | | |
Albumin (g/L) | 33.2 ± 6.6 | 33.9 ± 6.5 | 0.09 |
eGFR (ml/min•1.73 m2) | 9.0 ± 3.7 | 9.1 ± 4.0 | 0.65 |
Hemoglobin (g/L) | 10.2 ± 1.8 | 10.5 ± 1.8 | 0.01 |
Adjusted OR for dialysis-related infections and septicemia are presented in Table
3. Regardless of the dose, ASA use was not associated with a reduced risk of dialysis-related infections or septicemia (OR = 1.02 [95 % CI: 0.82-1.26] for <325 mg and OR = 1.17 [95 % CI: 0.87-1.58] for ≥325 mg) compared to unexposed. Among covariates, diabetes (OR = 1.30 [95 % 1.05-1.62]) and concurrent anticoagulant use (OR = 1.61 [95 % CI: 1.29-2.01]) were associated with a higher risk of dialysis-related infection and septicemia.
Table 3
Adjusted odds ratios for dialysis-related infection or septicemia
Age (by 1 year) | 0.87 | 0.62 | , | 1.23 | 0.86 | 0.71 | , | 1.04 |
Race | | | | | | | | |
Black | 1.35 | 0.88 | , | 2.08 | 1.37 | 0.9 | , | 2.08 |
Caucasian | 1.00 | Reference | 1.00 | Reference |
Other | 0.94 | 0.67 | , | 1.32 | 0.95 | 0.7 | , | 1.3 |
BMI (by 5 kg/m2) | 1.05 | 0.97 | , | 1.14 | 1.01 | 0.93 | , | 1.11 |
Smoking | 1.12 | 0.85 | , | 1.47 | 1.1 | 0.84 | , | 1.44 |
Co-morbidities | | | | | | | | |
Cardiovascular disease | 1.11 | 0.90 | , | 1.36 | 1.01 | 0.79 | , | 1.28 |
Cerebrovascular disease | 1.16 | 0.89 | , | 1.50 | 1.1 | 0.84 | , | 1.43 |
Chronic pulmonary disease | 1.18 | 0.96 | , | 1.46 | 1.15 | 0.92 | , | 1.43 |
Chronic liver disease | 0.77 | 0.40 | , | 1.47 | 0.71 | 0.38 | , | 1.32 |
Congestive heart failure | 1.05 | 0.86 | , | 1.29 | 0.91 | 0.73 | , | 1.14 |
Diabetes | 1.31 | 1.07 | , | 1.61 | 1.3 | 1.05 | , | 1.62 |
Hyperlipidemia | 1.07 | 0.87 | , | 1.31 | 0.98 | 0.78 | , | 1.22 |
Hypertension | 1.22 | 0.78 | , | 1.90 | 1.17 | 0.77 | , | 1.77 |
Malignancy | 1.13 | 0.87 | , | 1.46 | 1.17 | 0.91 | , | 1.51 |
Peripheral vascular disease | 1.09 | 0.88 | , | 1.34 | 1.01 | 0.81 | , | 1.24 |
ASA daily dose | | | | | | | | |
Unexposed | 1.00 | Reference | 1.00 | Reference |
80-324 mg | 0.99 | 0.80 | , | 1.24 | 1.02 | 0.82 | , | 1.26 |
≥ 325 mg | 1.06 | 0.78 | , | 1.44 | 1.17 | 0.87 | , | 1.58 |
Other medication use | | | | | | | | |
Anticoagulant | 1.57 | 1.26 | , | 1.96 | 1.61 | 1.29 | , | 2.01 |
Antiplatelet | 0.96 | 0.70 | , | 1.32 | 0.97 | 0.7 | , | 1.33 |
Laboratory data | | | | | | | | |
Albumin (by 10 g/L) | 0.85 | 0.71 | , | 1.02 | 0.93 | 0.79 | , | 1.10 |
eGFR (ml/min•1.73 m2) | 1.00 | 0.97 | , | 1.03 | 1.00 | 0.97 | , | 1.03 |
Hemoglobin (by 10 g/L) | 0.93 | 0.88 | , | 0.99 | 0.94 | 0.89 | , | 1.00 |
The interaction between exposure to ASA and vascular disease (p = 0.72 and p = 0.20), diabetes (p = 0.59 and p = 0.22) or concurrent anticoagulant (p = 0.97 and p = 0.41) use was not statistically significant for low dose and high dose of ASA respectively.
The results of this large multicenter population-based study showed no association between ASA use and dialysis-related infection and septicemia in the chronic hemodialysis population.
Salicylic acid, a major metabolite of ASA, has been shown to reduce the expression of two virulence factors of
S. aureus: α-hemolysin and fibronectin gene promoters [
10]. Few observational studies evaluated the potential antimicrobial effect of ASA use as an adjunctive treatment in infective endocarditis, and found opposing results [
22‐
24]. However, a randomized-control trial in 115 patients showed no beneficial effect and a potential increase in bleeding risk [
25,
19]. To our knowledge, only one prior clinical study evaluated the potential benefit of ASA as an antimicrobial in dialysis patients. Among 872 hemodialysis patients with tunneled catheters, ASA was associated with a 54 % decreased risk of developing a
S. aureus bacteremia [
11]. These different results from our study may be explained by the fact that we considered all bacteria (and not only
S. aureus). Indeed, when all pathogens were considered, bacteremia was not significantly reduced by ASA in the Sedlacek et al. study [
11]. While reducing
S. aureus bacteremia is important as it is associated with high morbidity and mortality, it remains important to evaluate infections from all other pathogens as they may take the place left by
S. aureus reduction. Such a phenomenon was shown in some studies evaluating
S. aureus nasal carriage eradication, where incidence of infections from other germs than S. aureus increased [
26]. Unfortunately, microorganisms information was not available to us while conducting this study.
The dose of ASA may play an important role as earlier studies have reported an antistaphylococcal effect of ASA when using a daily dose of 325 mg, but not with the 80 mg daily dose [
11,
10,
19]. This is probably explained by the fact that the antistaphylococcal effect is mediated by salicylic acid, and is therefore independent of the antiplatelet effect [
10]. However, in the present study, both dose categories were not associated with decreased risk of dialysis-related infections and septicemia.
Consistent with literature, we found that diabetes was associated with an increased risk of infection [
11,
8]. We also found that anticoagulant use was associated with a 61 % increase risk of dialysis-related infection and septicemia. While anticoagulant use is not a known risk factor for infection, it may be a proxy for catheter use in our cohort (anticoagulant may be used for dysfunctional catheters), which is a strong risk factor for infection [
8].
Strengths of this study are its large size leading to high statistical power, the large number of included covariates, and the fact that it is conducted in a universal health care system setting, limiting potential selection bias. However, this study has also some limitations. First, because infections are identified through hospital discharge sheets, our study is limited to cases of serious dialysis-related infections and septicemia requiring hospitalizations.
The use of diagnostic codes does not prevent from underestimating the number of cases. Only the code for the main diagnosis was considered for this study. Infections recorded as secondary diagnoses could have been caused by many reasons, and their inclusion in the study would have introduced an important confounding bias limiting the interpretation of the results. While it is possible that ASA may only reduce less severe infections, we believe that we identified the most clinically important events. Because ASA can be obtained over-the-counter, our study is subject to misclassification bias. However, due to financial incentives and the facts that hemodialysis patients have already numerous medications, it is estimated that the proportion of patients using ASA chronically over-the-counter is low. Despite adjusting for various variables, our study remains prone to residual confounding. Indeed, catheter-related infections are a major cause of infection in this population, but data on catheter use was missing in our database. For reference, 54.4 % of prevalent hemodialysis patients were using a tunneled catheter in 2013 in Quebec [
12]. Because the type of vascular access is not an indication or a contraindication to ASA use, we believe that its use should not differ by vascular access type.
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Competing interests
All authors declare that they have no competing interest.
Authors’ contributions
Co-authors have all contributed to this manuscript and approve its submission. This manuscript is co-authored by HH (conception and design, analysis and interpretation of data, and writing of manuscript), IN (interpretation of data, writing of manuscript and critical appraisal of article), RG (interpretation of data and critical appraisal of article), NE (analysis of data, and critical appraisal of article), L-PL (interpretation of data and critical appraisal of article), and J-PL (conception and design, analysis and interpretation of data, and writing of manuscript). All authors read and approved the final manuscript.