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Original Research Articles: Original Clinical Research Report

Association Between Aspirin Use and Sepsis Outcomes: A National Cohort Study

Hsu, Wan-Ting MS*; Porta, Lorenzo MD; Chang, I-Jing MD, MS; Dao, Quynh-Lan MD§; Tehrani, Babak M. MD, MS§; Hsu, Tzu-Chun BS; Lee, Chien-Chang MD, ScD‡,¶

Author Information
doi: 10.1213/ANE.0000000000005943

Abstract

KEY POINTS

  • Question: Can aspirin improve sepsis outcomes?
  • Findings: Among sepsis patients, aspirin use within 90 days before a sepsis admission was associated with reduced 90-day mortality (odds ratio 0.90) compared to nonuse.
  • Meaning: Aspirin therapy before hospital admission may improve short-term survival outcomes for patients with sepsis.

Sepsis is a growing cause of death in hospitalized patients worldwide.1,2 The Centers for Disease Control and Prevention (CDC) recently reported a 31% increase in sepsis-related deaths in the United States from 1999 to 2014.1 Despite advances in critical care, organ support and infection control remain the cornerstones of sepsis management.3 Although sepsis-related mortality has decreased over the past decade, the globally increasing prevalence of antimicrobial-resistant bacteria raises new challenges.4–8

One drug with therapeutic potential in sepsis is aspirin (acetylsalicylic acid [ASA]). Aspirin has anti-inflammatory and antiplatelet activities, directly inhibits bacterial growth,9–11 and has been proposed as an antisepsis agent.10–12 Low doses of ASA (75–81 mg/d) trigger the synthesis of lipoxins, which have anti-inflammatory and inflammation-resolving effects. ASA-triggered 15-epi-lipoxin A4 (ATL) alters nitric oxide production and inhibits superoxide production by neutrophils and neutrophil-endothelial interactions.10,11 ASA also modulates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which induces genes involved in inflammation (tumor necrosis factor-alpha [TNF-alpha], interleukin 6 [IL-6], and cyclooxygenase [COX]), cell cycle control (cyclin-D1), and coagulation (tissue factor).10,11 Additionally, in vitro studies find that ASA reduces Staphylococcus aureus virulence.10

Aspirin also modulates platelet activity. During systemic inflammation, platelets release chemokines, prostaglandins, and small molecules, which promote a proinflammatory state, leukocyte migration, and thrombotic microangiopathy.9,13 In animal models of endotoxemia and polymicrobial sepsis, platelet ADP inhibitors, such as clopidogrel or monoclonal antibodies directed against the activated platelet glycoprotein IIb/IIIa complex, prolong survival.14–16 Organ sequestration of activated platelets contributes to the thrombocytopenia commonly seen in sepsis patients.9,10 In animal models, aspirin treatment before endotoxin exposure improved survival.10 Animals that received aspirin had decreased platelet accumulation in the lungs and liver.10

Clinical evidence is mixed regarding the benefit of aspirin in sepsis. In clinical studies, aspirin reduces serum levels of inflammatory markers, sepsis-related multiorgan failure (MOF), and mortality.14,17–19 A recent retrospective multicenter study found an association between aspirin use and improved survival in patients with the coronavirus disease 2019 (COVID-19).13 However, 1 randomized clinical trial found that aspirin use, compared with placebo, did not decrease the risk of developing acute respiratory distress syndrome (ARDS).20 Like previous studies, this study only evaluated sepsis outcomes in patients who received aspirin after sepsis onset. Additionally, prior studies have been limited by small sample size.20

Table 1. - Comparison of Baseline Characteristics Among Aspirin Users and Nonusers
Variable Aspirin nonusers n = 39,081 Aspirin users n = 12,776 P value
Demographics
 Male sex (%) 23,110 (59.13) 7419 (58.07) .0930
 Age (mean ± SD) 65.35 ± 19.55 74.42 ± 11.96 <.0001
Living area
 Urban area 15,724 (40.24) 4488 (35.13) <.0001
 Metro area 10,206 (26.12) 3351 (26.23)
 Suburban area 8656 (22.15) 3319 (25.98)
 Countryside area 4493 (11.50) 1618 (12.66)
Pre-existing comorbidities
 Hypertension 21,764 (55.69) 10,892 (85.25) <.0001
 Chronic pulmonary disease 19,323 (49.44) 7865 (61.56) <.0001
 Congestive heart failure 9282 (23.75) 5500 (43.05) <.0001
 Hemiplegic stroke 3895 (9.97) 2220 (17.38) <.0001
 Complicated diabetes 7878 (20.16) 4564 (35.72) <.0001
 Chronic kidney disease 7340 (18.78) 3520 (27.55) <.0001
 Chronic liver disease 12,746 (32.61) 3996 (31.28) .0171
 Alcohol-related disease 1436 (3.67) 216 (1.69) <.0001
 Any tumor 8297 (21.23) 2372 (18.57) <.0001
 Metastatic cancer 1972 (5.05) 409 (3.20) <.0001
 Peripheral vascular disorder 3545 (9.07) 2062 (16.14) <.0001
 Coagulopathy 1673 (4.28) 341 (2.67) <.0001
 Dementia 5184 (13.26) 2539 (19.87) <.0001
 Psychosis 3688 (9.44) 1296 (10.14) .0033
 HIV/AIDS 70 (0.18) 10 (0.08) .0522
 Charlson comorbidity index 6.35 ± 3.42 7.63 ± 3.16 <.0001
Health care utilization
 Number of OPD visit 30.44 ± 25.71 41.90 ± 29.49 <.0001
 Number of emergency department visit 0.66 ± 2.23 0.80 ± 2.48 <.0001
 Number of hospitalizations 1.32 ± 2.35 1.42 ± 2.08 <.0001
Comedication
 NSAIDs 14,171 (36.26) 5880 (46.02) <.0001
 Systemic immunosuppressive agents and biologics 411 (1.05) 78 (0.61) .0001
 Systemic corticosteroids 8314 (21.27) 3110 (24.34) <.0001
 Beta-blockers 5556 (14.22) 3367 (26.35) <.0001
 Statins 2345 (6.00) 1952 (15.28) <.0001
 Other antiplatelets 5546 (14.19) 3964 (31.03) <.0001
Abbreviations: AIDS, acute respiratory distress syndrome; HIV, human immunodeficiency virus; NSAID, nonsteroidal anti-inflammatory drug; OPD, outpatient department; SD, standard deviation.

To clarify the effect of prehospital aspirin use on patients with sepsis, we conducted a retrospective population-based cohort study to investigate whether preadmission use of aspirin was associated with decreased sepsis mortality or sepsis-related organ dysfunction.

METHODS

The study was approved by the institutional review board of the National Taiwan University Hospital. Informed consent from patients was waived as all patients were anonymous.

Study Design

We performed a population-based cohort study using Taiwan’s National Health Insurance Research Database (NHIRD). The National Health Insurance (NHI) program is a compulsory, government-run insurance plan that covers 99.9% of Taiwan’s population. The 1 million participants in the NHIRD were randomly selected from the 23 million Taiwanese residents using a systematic multistage sampling approach to reflect the age, sex, and regional distributions of the general population of Taiwan in 2000. The NHIRD contains records of patient demographics, inpatient and outpatient procedures, expenditures, hospital characteristics, prescription information (including the drug prescribed, route of administration, quantity, and the number of days supplied), and mortality. The NHIRD is particularly suited for studying the pharmacoepidemiology of aspirin because, unlike most western countries, aspirin is exclusively prescribed by physicians in Taiwan and is not available over-the-counter. Thus, all aspirin prescriptions can be retrieved from the NHIRD.

Study Cohort

The study cohort consisted of participants from the NHIRD who were longitudinally followed from 2001 to 2011. Patients aged 18 years or older with an emergency department (ED) visit or a hospitalization for sepsis were eligible for inclusion. Sepsis was identified by a previously published code abstraction strategy that combined International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for (1) bacterial or fungal infection and (2) at least 1 organ/system dysfunction (Supplemental Digital Content 1, eAppendices 1 and 2, https://links.lww.com/AA/D846).21 This method is consistent with the Sepsis-3 definition of sepsis and permits patient populations to be extracted with accuracy similar to manual physician review.22 In our study, we included patients with a single diagnosis of sepsis or septicemia, a modification that differed from the original Sepsis-3 algorithm. In accordance with the Sepsis-3 concept, we defined septic shock as the presence of both diagnostic codes for (1) shock or hypotension and (2) vasopressor use.23 The date of ED visit or hospital admission for sepsis was defined as the index date. We subsequently followed all patients from the index date until termination of health insurance, death, or the end date of the study period. Patients with sepsis were identified within this cohort as described previously.25

Drug Exposure and Covariates

Patients with a record of a prescription for aspirin for at least 7 days in the 1-year period before the index date were classified as aspirin users. “Current use” referred to patients who had a 7 day or longer prescription for aspirin that either included the index date or ended within 90 days before the index date. “Past use” referred to patients with a prescription of aspirin between 91 and 365 days before the index date. Patients without any pharmacy dispensing records for aspirin (or any antiplatelet medications) in the period 1 year before the index date were defined as nonusers. Covariate information (demographics, comorbidities, sources of infection, extent of health care utilization, and comedications) up to 1 year before the index sepsis admission was collected for each patient. Detailed covariate information is listed in Table 1.

Statistical Analysis

The primary end point was all-cause mortality 90 days after the index date among current users, past users, and nonusers. Secondary end points were septic shock, acute respiratory failure, and acute renal failure among aspirin users and nonusers. Continuous variables were recorded as means and standard deviations (SDs), and categorical variables were presented as frequencies and percentages. For univariate comparison of variables between aspirin users and nonusers, we used χ2 tests for categorical variables and analysis of variance for continuous variables.

Propensity Score

To balance covariates among current users, past users, and nonusers, we used a 3-way propensity score (PS) model. The PS, estimated by multinomial logistic regression, is a scalar summary of all observed confounders.24 Based on literature review,21,25 covariates related to aspirin prescription and sepsis outcomes were treated as potential confounders and were included in the PS model (Table 1). Given the differences in baseline characteristics between aspirin users and nonusers, the inverse probability of treatment weighting (IPTW) method was used to control confounding. IPTW is an alternative to PS matching to statistically balance confounding variables in nonrandomized studies.26 The IPTW approach weights individuals based on their PS, where patients with a high likelihood of treatment are weighted lower to create weighted individual samples.24,26 Unlike PS matching, IPTW avoids the loss of unmatched treated patients.26,27 To directly compare the treatment groups, we used a 3-way IPTW analysis developed by Yoshida et al.28,29 To demonstrate covariate balance, we plotted the PS distribution graph before and after IPTW for current use versus nonuse, past use versus nonuse, and current use versus past use. Standardized differences of covariates were also plotted to quantify the covariate imbalance of the 3 groups before and after 3-way IPTW. Standardized differences below 10% were considered balanced.

Analysis of Association

The association between aspirin use and the outcomes of interest, 90-day mortality and sepsis-related acute organ dysfunction, was assessed using the univariate logistic regression models in the IPTW cohort. Odds ratios (ORs) with 95% confidence intervals (CIs) and their P value were reported. Kaplan-Meier survival curves weighted by IPTW were plotted to visualize the impact of aspirin use on sepsis outcomes. Because the proportional hazards assumption did not always hold for this study, we quantified differences in survival using the nonparametric restricted mean survival time (RMST) method.30 The RMST calculates the average survival time of all patients within a specific follow-up period without the proportional hazards assumption or any other model assumptions. Larger areas under the curve represent higher RMSTs and, thus, better treatment outcomes. RMST is being increasingly used as an alternative to COX survival analysis in various fields, including oncology, cardiology, and infectious disease.30–32 We calculated absolute RMST differences with 95% CIs for current use versus nonuse, past use versus nonuse, and current use versus past use in the IPTW cohort.30

Subgroup Analysis

We conducted subgroup analysis comparing aspirin use to nonuse in age (18–65 years and >65 years), sex, Charlson comorbidity score (0–2, 3–4, and ≥ 5), and 2 major indications of aspirin use, stroke and angina.

All analyses were conducted with SAS 9.4 for Windows (SAS Institute Inc) or R 3.6.2 (Survminer, survival, survRM2, forestplot, and ggplot2 packages, The R Foundation for Statistical Computing). A P value of ≤.05 was considered significant.

RESULTS

Patient Enrollment and Patient Characteristics

We identified a total of 52,982 patients with sepsis from the NHIRD during the study period. We excluded 1125 patients who had concomitant use of aspirin and other antiplatelets or switched between aspirin and other antiplatelets. The final cohort included for analysis consisted of 51,857 patients. A total of 12,776 were aspirin users, and 39,081 had not used antiplatelet medications preadmission (nonusers). Detailed patient inclusion and exclusion criteria are summarized in Supplemental Digital Content 1, eFigure 1, https://links.lww.com/AA/D846. Compared to nonusers, aspirin users were older, had a higher burden of pre-existing comorbidities, used more health care resources, and were prescribed more medications (Table 1).

Balance of Baseline Covariates After IPTW

Supplemental Digital Content 1, eFigure 2, https://links.lww.com/AA/D846 shows the PS distribution before and after IPTW for current aspirin use versus nonuse, past use versus nonuse, and current use versus past use. IPTW successfully balanced baseline covariates among the groups, since standardized differences after IPTW were <10% for all covariates (Supplemental Digital Content 1, eFigure 3, https://links.lww.com/AA/D846).

Association Between Aspirin Use and Sepsis Mortality

Table 2 shows the adjusted association between preadmission use of aspirin and 90-day all-cause mortality. After IPTW, past use was associated with lower odds of 90-day mortality (IPTW OR, 0.96; 95% CI, 0.93–0.99; P = .002) compared with nonuse. Current use of aspirin had lower odds of 90-day sepsis mortality when compared with both nonuse (IPTW OR, 0.90; 95% CI, 0.88–0.93; P < .0001) and past use (IPTW OR, 0.93%; 95% CI, 0.91–0.99; P < .0001) (Table 2; Figure). In the IPTW cohort, current aspirin users had improved survival at 90 days, followed by past users, and then nonusers (log-rank test, P = .026).

Table 2. - Crude and IPTW Effect Measure for the Association Between Use of Aspirin and Sepsis Mortality
Variable Crude OR (95% confidence intervals) P value IPTW OR (95% confidence intervals) P value
Current use versus nonuse 1.00 (0.96–1.08) .53 0.90 (0.88–0.93) <.0001
Past use versus nonuse 1.07 (1.02–1.12) .01 0.96 (0.93–0.99) .002
Current use versus past use 0.92 (0.85–1.00) .06 0.93 (0.91–0.96) <.0001
Abbreviations: IPTW, inverse probability of treatment weighting; OR, odds ratio.

F1
Figure.:
Kaplan-Meier survival curves comparing aspirin current users versus past users versus nonusers in the IPTW cohort. IPTW indicates inverse probability of treatment weighting.
Table 3. - RMST Difference After IPTW Analysis
Variable IPTW RMST difference (95% confidence intervals) P value
Current use versus nonuse 1.37 (0.50–2.24) .002
Past use versus nonuse 0.80 (0.04–1.57) .04
Current use versus past use 0.82 (−0.47 to 2.12) .21
Abbreviations: IPTW, inverse probability treatment weighting; RMST, restricted mean survival time.

Table 4. - Crude and IPTW Weighted Effect Measure for the Association Between Aspirin Use and Different End Points
End point Crude OR (95% confidence interval) P value IPTW OR (95% confidence interval) P value
Septic shock, n = 12,080 1.04 (0.99–1.10) .129 1.00 (0.97–1.03) .245
Respiratory failure, n = 34,328 1.24 (1.18–1.30) <.0001 1.02 (1.00–1.05) .104
Acute renal failure, n = 8491 1.27 (1.19–1.35) <.0001 0.99 (0.96–1.03) .601
Abbreviations: IPTW, inverse probability treatment weighting; OR, odds ratio.

To verify the robustness of our results and generate a clinically interpretable outcome, we compared the RMST of current aspirin users, past users, and nonusers in the IPTW cohort (Table 3). On IPTW RMST analysis, the mean survival time for current users within 90 days of follow-up was 73.12 days compared to 71.75 days for nonusers. Thus, when compared to nonuse, current use of aspirin was associated with an increased mean survival time (1.37 days; 95% CI, 0.50–2.24; P = .002). We also observed improved survival with past use of aspirin (IPTW RMST difference 0.80 days; 95% CI, 0.04–1.57; P = .04) as compared with nonuse.

Subgroup Analysis

On subgroup analysis, we found an association between aspirin use (as compared with nonuse) and decreased 90-day mortality regardless of age, sex, indication for aspirin (angina or stroke), and burden of comorbidities (Supplemental Digital Content 1, eFigure 4, https://links.lww.com/AA/D846). Patients with intermediate (Charlson 2–4) or high (Charlson ≥5) scores saw greater benefit from aspirin use than patients with fewer comorbidities (Supplemental Digital Content 1, eFigure 4, https://links.lww.com/AA/D846).

Sepsis-Related Organ Dysfunction

We further investigated the relationship between aspirin use (compared with nonuse) and organ system dysfunction (Table 4). After IPTW adjustment, we found no association between the use of aspirin and septic shock (IPTW OR, 1.00; 95% CI, 0.97–1.03; P = .245), respiratory failure (IPTW OR, 1.02; 95% CI, 1.00–1.05; P = .104), or acute renal failure (IPTW OR, 0.99; 95% CI, 0.96–1.03; P = .601).

DISCUSSION

In this 10-year retrospective review of the NHIRD of Taiwan, we observed an association between preadmission use of aspirin and mortality in patients with sepsis. When compared with patients not taking aspirin or those who had been on aspirin but not during the 90 days before hospital admission, patients who were taking aspirin during the 90 days immediately before hospital admission had a lower mortality and longer mean survival time. The association was more pronounced in patients with more comorbidities, but aspirin use was not associated with changes in the incidence of organ dysfunction during sepsis.

Our results are consistent with previous studies finding that pretreatment with low-dose aspirin is associated with better outcomes in community-acquired pneumonia, Saureus bacteremia, ARDS, COVID-19, and other critical illnesses.13,17,33,34 A 2020 meta-analysis also found that preadmission use of aspirin was associated with decreased incidence of ARDS.35 Nonetheless, a 2016 multicenter randomized clinical trial on patients in the ED at increased risk of developing ARDS found that, compared with placebo, aspirin administration before ARDS onset did not significantly reduce the incidence of ARDS at 7 days.20 Similarly, when comparing aspirin current users versus past users versus nonusers in the 3-way IPTW cohort (Figure), we found no survival difference among the 3 groups within 7 days of the 90-day follow-up.

Several plausible mechanisms for the association we observed between aspirin and sepsis survival have been proposed. At low doses, aspirin inhibits cyclooxygenase-1 (COX-1), downregulating arachidonic acid, and subsequent platelet aggregation.10 At higher doses, aspirin inhibits the COX-2 and NF-κB pathways, both of which play key roles in mediating inflammation.10 As platelets play a role in the activation, amplification, and regulation of inflammation, inhibiting platelets may dampen severe systemic inflammatory responses.

Additionally, aspirin may have direct antimicrobial properties. In a rabbit model of Saureus endocarditis, ASA given before and during antimicrobial therapy significantly reduced vegetation burden.36 In rat models of Enterococcus faecalis and Streptococcus gallolyticus endocarditis, dual therapy with aspirin and ticlopidine had similar effects.37 In addition, in vitro studies found that ASA activates stress response regulon sigma fact β and reduces Saureus virulence.38,39 Finally, evidence that inhibiting platelets with low-dose ASA could reduce biofilm formation and subsequent resistance to antimicrobials suggests another potential mechanism for the association we observed.40

This study has several strengths and weaknesses. One key strength is a large sample size of sepsis patients. Our large population-based database allows for 3-way IPTW with PSs between 3 types of users with well-balanced covariates. The novel 3-way IPTW we adopted in this study allows simultaneous rather than pairwise comparison among 3 groups. The use of RMST is also a strength, as RMST analyses are not bound by specific assumptions. In contrast, hazard ratios rely on the proportional hazards assumption,31,32 which may not be valid in our study. RMST provides clinically meaningful summary measures without the proportional hazards assumption. In addition, RMST analysis allows for quantification of mean absolute survival differences to evaluate clinical and economic impact.

Our study has limitations. First, several clinical variables reflecting lifestyle, such as body mass index and smoking, were not collected in the database. Therefore, we used proxy variables, such as diagnoses of morbid obesity, hyperlipidemia, hypertension, ischemic heart disease, and chronic obstructive pulmonary disease, to adjust for obesity and smoking-related comorbidities. Second, it is possible that healthy user bias may have contributed to our results. It is possible that patients who take aspirin may also have a higher health awareness, use more health care resources, and live a healthier overall lifestyle than nonusers. However, we addressed this possible confounding effect by including insurance premium categories (a proxy for socioeconomic status) and frequency of health care utilization. Finally, our study was retrospective. We cannot make inferences as to causality, and it is, thus, possible that unrecognized confounders may have affected our results, but our design allowed for robust statistical analysis in a large patient cohort. Further prospective studies are needed to confirm our findings.

CONCLUSIONS

In conclusion, in this large population-based cohort study, we describe an association between chronic presepsis aspirin therapy and reduced sepsis. This effect was larger in patients with more comorbidities but not related to organ system dysfunction. Patients who are at increased risk for sepsis and are using aspirin for secondary prevention of cardiovascular disease may be at lower risk of sepsis-related mortality. Further studies are needed to confirm our findings.

ACKNOWLEDGMENT

We thank Professor Sonia Hernandez-Diaz for comments and suggestions on our study design and manuscript, Professor Lee-Jen Wei for statistical advice, Dr Michael A. Liu and Dr Douglas Oro for their constructive comments on the manuscript, the staff of the Core Labs at the Department of Medical Research, National Taiwan University Hospital for technical support, and Medical Wizdom LLC, USA, for technical assistance in statistical analysis.

DISCLOSURES

Name: Wan-Ting Hsu, MS.

Contribution: This author helped with conceptualization writing, reviewing, and editing, and statistical analysis.

Name: Lorenzo Porta, MD.

Contribution: This author helped with writing–reviewing, and editing.

Name: I-Jing Chang MD, MS.

Contribution: This author helped with writing—reviewing and editing.

Name: Quynh-Lan Dao, MD.

Contribution: This author helped with writing, reviewing, and editing.

Name: Babak M. Tehrani, MD, MS.

Contribution: This author helped with writing, reviewing, and editing.

Name: Tzu-Chun Hsu, BS.

Contribution: This author helped with writing, reviewing and editing, and statistical analysis.

Name: Chien-Chang Lee, MD, ScD.

Contribution: This author helped with supervision, writing, reviewing and editing, and statistical analysis plan.

This manuscript was handled by: Avery Tung, MD, FCCM.

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