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. Author manuscript; available in PMC: 2016 Apr 1.
Published in final edited form as: Crit Care Med. 2015 Apr;43(4):801–807. doi: 10.1097/CCM.0000000000000789

Prehospital Aspirin Use Is Associated with Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Patients: A Propensity-Adjusted Analysis

W Chen 1,2, DR Janz 3, JA Bastarache 1, AK May 4, HR O'Neal Jr 3, GR Bernard 1, LB Ware 1,5
PMCID: PMC4359645  NIHMSID: NIHMS635472  PMID: 25559436

Abstract

Objectives

Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). In our prior study of 575 patients at high risk for ARDS, concurrent statin and aspirin use was associated with reduced ARDS. However, the largest study (n=3855) to date found no significant benefit of prehospital aspirin in a lower risk population when adjusted for the propensity for aspirin use. We aimed to determine whether prehospital aspirin use is associated with decreased ARDS in patients at high risk for ARDS after adjusting for the propensity to receive aspirin.

Design

Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis (VALID) study.

Patients

A total of 1149 critically ill patients (age ≥ 40) admitted to the medical or surgical intensive care units of an academic tertiary care hospital including 575 previously reported patients as well as additional patients who were enrolled after completion of the prior statin and aspirin study.

Intervention

None

Measurements and Results

Of 1149 patients, 368 (32%) developed ARDS during the first four ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower incidence of ARDS (27% vs. 34%, p=0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis and APACHE II, prehospital aspirin use was associated with a decreased risk of ARDS (OR 0.66, 95% CI 0.46-0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (OR 0.60, 95% CI 0.41-0.90).

Conclusions

In this selected cohort of critically ill patients, prehospital aspirin use was independently associated with a decreased risk of ARDS even after adjusting for the propensity of pre-hospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical ARDS.

Introduction

Despite advances in critical care, the acute respiratory distress syndrome (ARDS) remains a life-threatening condition associated with a hospital mortality of 25 to 40% (1-3). Although numerous promising therapies have been effective in the prevention of ARDS in experimental models, successful translation to clinical application is still lacking (4-7).

Growing evidence suggests that platelets play a crucial role in the pathogenesis of ARDS. The possible mechanisms by which platelets contribute to ARDS include activation of endothelial cells by release of pro-inflammatory mediators (8-10), and adherence of platelets to lung capillary endothelial cells leading to activation of attached leukocytes (11). Preclinical studies have shown that the platelet inhibitor aspirin can prevent or treat ARDS by decreasing neutrophil activation, TNF-alpha expression in pulmonary intravascular macrophages, plasma thromboxane B2 levels, and platelet sequestration in the lungs (12-17).

In a multicenter clinical study, Harr et al. showed that prehospital antiplatelet therapy (predominantly aspirin) was associated with a decreased risk of lung dysfunction and multiple organ failure in high-risk blunt trauma patients who received blood transfusions (18). Our group reported in a prior study of 575 patients in the Validating Acute Lung Injury Markers for Diagnosis (VALID) cohort, that concurrent statin and aspirin use, but not aspirin alone, was associated with reduced risk of ARDS (19). However, this study was likely underpowered to show an independent association between prehospital aspirin use and reduced risk of ARDS, given the large proportion of patients who were receiving both prehospital statin and prehospital aspirin therapy. By contrast, the largest clinical study to date found no significant association of prehospital aspirin use and risk of ARDS when adjusted for a propensity score that quantified the propensity to receive aspirin therapy (20). However, the overall incidence of ARDS in that study was low.

To further characterize the possible benefit of prehospital aspirin use in ARDS, we performed a new cross-sectional analysis of the entire prospectively collected VALID cohort with approximately 2500 critically ill patients enrolled during a six-year interval. This analysis included the previously studied 575 patients as well as patients who were enrolled in the VALID cohort after our previous study was published (19). The aim of the study was to investigate the association between prehospital aspirin therapy and development of ARDS in a heterogeneous group of critically ill patients at high risk for ARDS as well as in the subgroup of patients with sepsis, adjusting for propensity to receive aspirin.

Materials and Methods

Description of the VALID cohort

We studied patients who were prospectively enrolled from January 23, 2006 to February 18, 2012 in the VALID study. The VALID study was designed to identify and validate plasma biomarkers for diagnosis and prognosis of ARDS. The Vanderbilt University Institutional Review Board approved the study protocol, and written informed consent was obtained from the patient or their surrogate when possible. Because the study carries minimal risk to the study participants, the Institutional Review Board also granted a waiver of informed consent.

Patients eligible for the VALID study were those age ≥ 18 yrs admitted to the medical, surgical, cardiovascular, and trauma ICUs who remained in the ICU for at least 2 days. Detailed exclusion criteria for patients in VALID were described previously (19). Clinical data, including demographics, prehospital medications, medical history, and admission diagnoses were collected on admission; variables such as hemodynamics, ventilator variables, laboratory values, and in-hospital medications were collected daily during the first four days after enrollment. Prehospital medications including aspirin, statins, angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs) and clopidogrel were recorded. For prehospital medication use, the medical record was manually reviewed by the research coordinator for mention of the relevant medication (such as aspirin or an aspirin-containing medicine) in the admission history and physical(s), the list of prehospital medicines (routinely collected for all admitted patients) and any other physician or ancillary health personnel notes around the time of admission. This was done prospectively, at the time that patients were enrolled into the VALID study. For in hospital medication use including aspirin use, manual review of the medical record was supplemented with query of the Vanderbilt electronic medication administration record for specific medications of interest including all doses of aspirin or aspirin-containing medicines received by the patient during the hospitalization of interest. The diagnoses of sepsis, organ dysfunction, and ARDS were made by study investigators, in accordance with published consensus definitions (21-23). Acute lung injury or ARDS during the first five days in hospital was defined by the American European Consensus Conference definitions. For ARDS ascertainment, two-physician review of chest radiographs and clinical data was done. When arterial blood gas data was not available for a given day, then the SpO2/FiO2 ratio was used to assess the level of hypoxemia (24). In keeping with the recent Berlin definition of ARDS (25) the diagnosis of acute lung injury or ARDS is subsequently referred to as ARDS herein. Outcome data, including duration of mechanical ventilation, duration of ICU stay, duration of hospital stay, and hospital mortality were collected.

Study population

During the six-year study period, 2,503 patients enrolled into the VALID study were considered for inclusion in the current study (Figure 1). We excluded patients who transferred from other hospitals without thorough medical information and excluded patients with an ICU stay less than 48 hours. Patients admitted to the trauma ICU were excluded since overall, this younger group of patients were less likely to be taking prehospital aspirin and preadmission medication histories were often not available. To avoid the confounding effects of cardiovascular diseases that might be associated with both higher rates of aspirin use and lower rates of ARDS, we excluded patients admitted to the cardiovascular ICU and patients with an acute cardiac diagnosis. We also excluded patients admitted for elective surgery because antiplatelet agents are frequently discontinued before surgery and medication history may be inaccurate. Finally, we excluded patients < 40 yrs of age because prehospital aspirin was rarely prescribed in that age group.

Figure 1.

Figure 1

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Study flow diagram. VALID, Validating Acute Lung Injury Marker for Diagnosis; ICU, intensive care unit

Statistical analysis

As the majority of continuous variables are not normally distributed, data are expressed as median values and interquartile range (IQR). Categorical variables are expressed as counts and percentage. Comparison of two groups with continuous variables was conducted using Wilcoxon's rank-sum test. Comparison of categorical variables between two groups was performed with a chi-square test or Fisher's exact test. A propensity score was created for the probability of receiving pre-hospital aspirin therapy. The a priori selected variables included in the propensity score model were age, hypertension, diabetes mellitus, chronic kidney disease, end-stage renal disease, peripheral vascular disease, congestive heart failure, coronary artery disease, cerebral vascular disease, and prehospital statin use. Propensity adjustment, rather than matching, was used to increase the power of our analysis and avoid misclassification of patients. We used the Hosmer and Lemeshow goodness-of-fit test to perform score diagnostics for the propensity score (p=0.27) and for the ARDS regression model (p=0.33). Multivariate logistic regression models with a priori selected variables were developed for diagnosis of ARDS and in hospital mortality. IBM SPSS Statistics (version 21.0, Chicago, IL) was used for statistical analysis; a two-sided significance level of 0.05 was used for statistical inference.

Results

A total of 1149 VALID patients met the inclusion and exclusion criteria and were included in the current study (Figure 1). Of these, 368 (32%) patients developed ARDS during the first four days of ICU admission. The majority of the patients who developed ARDS (84%) developed it on the first ICU day (Figure 2). Table 1 includes a comparison of baseline characteristics and clinical outcomes between patients with and without ARDS. Baseline demographic characteristics were not associated with development of ARDS. Patients with ARDS were significantly less likely to have a history of hypertension. Patients with ARDS also had higher APACHE II scores at the time of ICU admission and had longer hospital and ICU length of stays.

Figure 2.

Figure 2

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Timing of onset of ARDS during the first four days of ICU admission among the 368 patients in the cohort who developed ARDS. There were 309 patients who developed ARDS on Day 1, 30 on Day 2, 20 on Day 3 and 9 on Day 4.

Table 1. Comparison of demographic data and outcomes between patients with and without ARDS.

ARDS (n=368) Non-ARDS (n=781) p-value
Age (years) 59 (52, 69) 61 (52, 68) 0.801
Male 192 (52%) 439 (53%) 0.204
Caucasian 320 (87%) 682 (87%) 0.925
Current smoker 114 (31%) 235 (30%) 0.783
Diabetes 109 (30%) 265 (34%) 0.157
Hypertension 184 (50%) 456 (58%) 0.009
Chronic kidney disease 70 (19%) 179 (22%) 0.312
On dialysis 13 (3.5%) 45 (5.8%) 0.114
Prehospital Aspirin 77 (21%) 210 (27%) 0.034
APACHE II score 29 (24, 34) 25 (20, 31) <0.001
Length of ICU stay (days) 8 (5, 14) 5 (3, 9) <0.001
Time on Ventilator (days) 5 (2, 9) 2 (0, 5) <0.001
Shock 224 (61%) 341 (44%) <0.001
Hospital stay (days) 15 (9, 23) 11 (7, 20) <0.001
Hospital mortality 119 (32%) 129 (17%) <0.001
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Data is median (IQR) or n (%) as indicated.

Of the 1149 enrolled patients, a total of 287 (25%) patients were receiving any aspirin-containing medication before hospitalization. Patients taking aspirin were more likely to have diabetes mellitus, hypertension, chronic kidney disease, cerebrovascular disease, peripheral vascular disease, coronary artery disease, and congestive heart failure (Table 2). In an unadjusted analysis, patients who took prehospital aspirin had a significantly lower rate of ARDS (27%) than patients not receiving prehospital aspirin therapy (33%, p=0.034) (Figure 3). By contrast, patients who took prehospital statins (29% vs. 33%, p=0.158) or ACE inhibitors (28% vs. 33%, p=0.129) did not have a significantly lower rate of ARDS than patients who did not take those medications. Patients who took both aspirin and statins had a lower incidence of ARDS than patients who received neither (23% vs. 34%, p=0.008). Of the 287 patients with prehospital aspirin use, 92 (31%) patients were taking high dose aspirin (325mg per day) and 184 patients (64%) were taking low dose aspirin (81mg per day). In 11 patients the dose was not available. The incidence of ARDS did not differ significantly by aspirin dose (25% in the higher dose vs. 27% in the lower dose, p=0.773). Of 287 patients receiving prehospital aspirin, 150 (52.3%) patients continued to receive aspirin during the first three days of ICU stay; among these 150 patients, 11% (n=17) received aspirin for one day, 18% (n=27) received aspirin for two days and 71% (n=106) received aspirin for 3 days. Of 287 patients receiving prehospital aspirin, the incidence of ARDS was not different between patients who discontinued aspirin use during hospitalization compared to patients who continued aspirin use (22% vs. 31%, p=0.083). Comparing the ARDS incidence among pre-hospital aspirin users with in-hospital one-day, two-day and three-day aspirin use, there was no significant difference (29.4%, 37%, 30.2% respectively, p=0.284).

Table 2. Comparison of demographic data and outcomes between patients with prehospital aspirin use and without aspirin use.

Aspirin users (n=287) Non-Aspirin users (n=862) p-value
Age (years) 67 (61, 74) 58 (50, 65) 0.801
Male 167 (58.2%) 464 (53.8%) 0.218
Caucasian 253 (88.2%) 749 (86.9%) 0.611
Current smoker 69 (24%) 280 (32.5%) 0.008
Diabetes 123 (42.9%) 251 (29.1%) <0.001
Hypertension 224 (78%) 416 (48.3%) <0.001
Chronic kidney disease 87 (30.3%) 153 (17.7%) <0.001
On dialysis 18 (6.3%) 40 (4.6%) 0.278
Chronic liver disease 7 (2.4%) 127 (14.7%) <0.001
Cerebral vascular disease 20 (7%) 27 (3.1%) 0.006
Peripheral vascular disease 45 (15.7%) 57 (6.6%) <0.001
Coronary artery disease 147 (51.2%) 169 (19.6%) <0.001
Congestive heart failure 67 (23.3%) 104 (12.1%) <0.001
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Data is median (IQR) or n (%) as indicated.

Figure 3. Incidence of ARDS in patients with and without prehospital aspirin, statin or combined aspirin and statin use.

Figure 3

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To control for the potential confounding associated with baseline differences in prehospital aspirin users and non-users, we used a propensity score to adjust for propensity to receive aspirin in the pre-hospital setting. In a multivariate logistic regression model that included age, gender, race, sepsis and APACHE II score along with the aspirin propensity score, prehospital aspirin use was significantly associated with a lower rate of ARDS (OR 0.659, 95% CI 0.46 - 0.94, p=0.023)(Table 3).

Table 3. Logistic regression analysis of prehospital aspirin use and development of ARDS in all enrolled patients (n=1149).

Model Odd ratio 95% Confidence Interval p-value
Unadjusted 0.719 0.535 – 0.968 0.030
Adjusted for propensity 0.745 0.532 – 1.043 0.086
Adjusted for propensity and selected variables* 0.659 0.469 – 0.944 0.023
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*

Selected variables included age, gender, race, sepsis and APACHE II score

Among the 1149 patients, 725 (63%) patients were diagnosed with sepsis during the first 4 days of ICU admission. To determine whether prehospital aspirin use had a stronger association with a lower rate of ARDS in sepsis patients, we repeated the same regression models as above in the 725 patients with sepsis (Table 4). Prehospital aspirin use was significantly associated with a lower rate of ARDS in sepsis patients either adjusted by propensity score (OR 0.62, 95% CI 0.41- 0.92, p=0.018) or adjusted by propensity score and selected variables (OR 0.61, 95% CI 0.41- 0.90, p=0.014).

Table 4. Logistic regression analysis of prehospital aspirin use and development of ARDS in sepsis patients (n=725).

Model Odd ratio 95% Confidence Interval p value
Unadjusted 0.589 0.416 – 0.835 0.003
Adjusted for propensity 0.602 0.418 – 0.902 0.018
Adjusted for propensity and selected variables* 0.608 0.408 – 0.905 0.014
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*

Selected variables included age, gender, race, sepsis and APACHE II score

Of the 1149 patients in the cohort, 248 (21.6%) patients died before discharge from the hospital. In a multivariate logistic regression model, first-day APACHE II score, and presence of any sepsis, ARDS or shock during the first four days of ICU admission were significantly associated with in-hospital mortality (Table 5). Prehospital aspirin use, adjusted by propensity score, had a trend towards association with lower in-hospital mortality that did not reach statistical significance (OR 0.697, 95% CI 0.47-1.03, p=0.075).

Table 5. Multivariate logistic regression model for mortality (aspirin adjusted by propensity) in 1149 patients.

Odds ratio 95% C.I P value
Aspirin* 0.697 0.468 – 1.037 0.075
Sepsis 1.445 1.014 – 2.068 0.043
ARDS 1.768 1.296 – 2.418 <0.001
APACHE II (per one point increase) 1.044 1.025– 1.064 <0.001
Age (per one year increase) 1.013 0.994 – 1.032 0.186
Shock 1.445 1.058 – 1.974 0.021
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*

Aspirin was adjusted by propensity score

Discussion

In this expanded cohort, prehospital aspirin use was significantly associated with a lower incidence of ARDS during the first four days of ICU stay even when controlling for potential confounding factors and adjusting for the propensity to receive aspirin. In addition, the association was even stronger in patients with sepsis. By contrast, prehospital statin use was not significantly associated with a lower incidence of ARDS although the subgroup that received both aspirin and statins had the lowest overall incidence of ARDS.

The finding that prehospital aspirin use is associated with a decreased risk of ARDS in critically ill patients is consistent with the known beneficial effects of aspirin in both clinical and experimental acute lung injury (13, 26, 27). In addition, aspirin also has potent effects on treatment and prevention of sepsis via anti-platelet and anti-inflammatory effects in preclinical and clinical studies (28-30). This could, in part, explain why the association between prehospital aspirin use and ARDS is stronger in the sepsis subgroup in our study.

The current findings can be compared to prior studies of the association between prehospital aspirin use and ARDS. In the largest prior study, Kor et al. reported that there was no significant association between prehospital aspirin therapy and in hospital development of ARDS after adjusting for the propensity to receive aspirin therapy (20). However, the patient population was substantially different compared to the current study, with a much lower overall incidence of ARDS (240/3855, 6.2%) due to inclusion of a large number of patients who were not critically ill. The smaller number of ARDS cases in that study may have limited the power to detect a significant association between aspirin use and risk of ARDS. Of note, the unadjusted OR (0.65) and propensity-adjusted OR (0.70) for development of ARDS in prehospital aspirin users in the Kor study were almost identical to the current findings. Also of note, the Kor study included 947 (24.5%) patients admitted with high-risk trauma. In our study, we excluded patients with severe traumatic injuries for two reasons. First, the trauma patients enrolled in VALID were predominantly young adults, and few of them had prehospital aspirin use. Second, most of the patients admitted to the trauma ICU were unconscious and had no surrogate immediately available, making the prehospital medication history unreliable. Given the very low likelihood of prehospital aspirin use in the trauma subgroup, inclusion of this group in the analysis might have obscured any aspirin-related signal.

In our prior analysis of a smaller group of patients enrolled in the VALID cohort (who were also part of the current study), we found a significant association between prehospital statin use or prehospital statin and aspirin use and lower risk of ARDS, but there was no significant association of aspirin alone with ARDS. There are several possible explanations for the different results in this larger group of patients from the VALID cohort. First, it is likely that the prior study was underpowered to detect an aspirin effect. Second, based on the current findings, it is possible that the prior association between statin use and reduced risk of ARDS was confounded by aspirin use, an effect that is only fully apparent in this larger cohort. Either way, the discordant results between our prior study and our current study underscore the need for prospective clinical trials to more definitively answer these questions. Discouragingly, a large NIH-funded multicenter randomized clinical trial of statins for the treatment of ARDS was recently stopped for futility.

Currently, there is an ongoing multicenter, randomized clinical trial for evaluation of aspirin for prevention of ARDS (NCT01504867). In this study, the first dose of study drug (aspirin vs. placebo) is administered within the first 24 h after presentation to the hospital with a goal of preventing the subsequent development of ARDS in the hospital (31). However, it should be noted that in the current observational study, the majority of the patients (84%) had already developed ARDS on the first ICU day. As such, any medication prescribed only from the beginning of hospitalization may be too late to prevent the majority of occurrences of ARDS, highlighting the difficulties that are encountered in designing prevention studies for ARDS.

This study has both strengths and limitations. Major strengths include the large number of patients and large number of ARDS cases as well as the meticulous prospective phenotyping for ARDS in the VALID cohort. The use of a propensity score for aspirin use in the primary analysis also strengthens the study. A limitation of the study is that the information about prehospital aspirin use was derived from the medical record or from the patients themselves, and may not be completely accurate. Second, since aspirin use is indicated for a variety of medical conditions, there may still be factors that influence aspirin use that confound the association between aspirin use and ARDS even after propensity adjustment. Third, we were likely underpowered to demonstrate a dose effect of aspirin. Tuinman et al. showed that high-dose aspirin is superior to low-dose in preventing ALI in animal study (15). In our study, high-dose aspirin users had slightly lower incidence (25%) of ARDS than low-dose users (27.2%), but this finding was not statistically significant (p=0.773). Fourth, it is possible that competing risk of death could confound the primary outcome of ARDS development. However, since the vast majority of patients in the study developed ARDS on the first ICU day (Figure 2), and patients were excluded if they stayed in the ICU for less than 48 hours, the risk of confounding by competing risk of death is substantially mitigated. Finally, it should be noted that all patients in the current study were enrolled in a single center. Although the VALID study enrolls a very heterogeneous population of critically ill patients with few exclusions to enrollment, the findings may not be generalizable to other centers that care for a different population.

In summary, in critically ill patients after adjusting for a propensity score for prehospital aspirin use, we found that aspirin use was significantly associated with a lower incidence ARDS of during the first four days of ICU stay. Furthermore, this association was stronger in patients with sepsis compared to other critically ill patients. These findings lend support to the need for prospective clinical trials to determine whether aspirin can prevent development of ARDS in at-risk patients.

Acknowledgments

Funding: NIH HL103836, HL112656-02, T32 HL087738, UL1 RR024975, American Heart Association Clinical Research Award and an American Heart Association Established Investigator Award

Copyright form disclosures: Dr. Chen received support for article research from the National Institutes of Health (NIH). Dr. Bastarache received support for article research from the NIH and the American Heart Association. Dr. Ware received support for article research from the NIH. Her institution received grant support from the NIH.

Footnotes

Conflict of Interest: All authors declared no conflict of interest

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