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The association of aspirin use with severity of acute exacerbation of chronic obstructive pulmonary disease: a retrospective cohort study

The association of aspirin use with severity of acute exacerbation of chronic obstructive... www.nature.com/npjpcrm BRIEF COMMUNICATION OPEN The association of aspirin use with severity of acute exacerbation of chronic obstructive pulmonary disease: a retrospective cohort study 1 1 1 1 Tadahiro Goto , Mohammad Kamal Faridi , Carlos A. Camargo and Kohei Hasegawa Little is known about the effect of long-term aspirin use on acute severity of COPD. We hypothesized that, in patients hospitalized for acute exacerbation of COPD (AECOPD), long-term aspirin use is associated with lower risks of disease severity (in-hospital death, mechanical ventilation use, and hospital length-of-stay). We conducted a retrospective cohort study using large population-based data from 2012 through 2013. Among 206,686 patients (aged ≥40 years) hospitalized for AECOPD, aspirin users had lower in- hospital mortality (1.0 vs. 1.4%; OR 0.60 [95% CI 0.50–0.72]; P < 0.001) and lower risk of invasive mechanical ventilation use (1.7 vs. 2.6%; OR 0.64 [95% CI 0.55–0.73]; P < 0.001) compared to non-users, while there was no significant difference in risks of non- invasive positive pressure ventilation use. Length-of-stay was shorter in aspirin users compared to non-users (P < 0.001). In sum, in patients with AECOPD, aspirin use was associated with lower rates of in-hospital mortality and invasive mechanical ventilation use, and shorter length-of-stay. npj Primary Care Respiratory Medicine (2018) 28:7 ; doi:10.1038/s41533-018-0074-x Increasing evidence suggests a potential benefit of antiplatelet regression or negative binomial regression models with general- therapy on chronic outcomes in patients with chronic obstructive ized estimating equations to account for patient clustering within 1,2 pulmonary disease (COPD). For example, a recent analysis of an hospitals. We adjusted for age, sex, race/ethnicity, payer, median ongoing prospective cohort study revealed that antiplatelet household income, 27 Elixhauser comorbidity measures (including therapy was associated with a lower 1-year mortality among heart failure, arrhythmias, and valvular diseases), hospitalization individuals with COPD. However, little is known about the effect year, and hospital state. We repeated the analyses with (1) of aspirin use on acute outcomes (including mortality) in patients excluding patients who had any of the cardiovascular comorbid- hospitalized for acute exacerbation of COPD (AECOPD). ities that are commonly treated with aspirin (coronary artery To examine the association of aspirin use with severity of diseases [codes, 410–414] and ischemic stroke [codes, 433–434]) AECOPD, we conducted a retrospective cohort study using data and (2) excluding these potential aspirin users and patients with from the State Inpatient Databases (SID) of seven US states heart failure. All analyses were performed using STATA 14.1 (Arkansas, Florida, Iowa, Nebraska, New York, Utah, and Washing- (StataCorp, College Station, TX). ton) from 2012 and 2013. Additional details of the SID may be Overall, we identified 206,686 patients with hospitalization for found elsewhere. The institutional review board of Massachusetts AECOPD in the seven US states. Of these, 13,826 patients (7%) General Hospital approved this study. were aspirin users. Aspirin users were older, and more likely to We identified all hospitalizations made by patients aged ≥40 have Medicare comorbidities, compared to non-users (all P < years with a primary discharge diagnosis of COPD (ICD-9-CM 0.001; Table 1). Aspirin users had a significantly lower in-hospital codes: 491.21, 491.22, 491.8, 491.9, 492.8, 493.20, 493.21, 493.22, mortality compared to non-users (1.0 vs. 1.4%; adjusted OR 0.60 and 496), or those with a primary diagnosis of respiratory failure [95% CI 0.50–0.72] P < 0.001; Table 2). Additionally, aspirin users (codes: 518.81, 518.82, 518.84, and 799.1) and a secondary had a significantly lower rate of invasive mechanical ventilation diagnosis of COPD. We included only the first hospitalization use (1.7 vs. 2.6%; adjusted OR 0.64 [95% CI 0.55–0.73] P < 0.001), for AECOPD for each patient during the study period. Then, we while there was no significant difference in the rate of NIPPV use further identified aspirin users by using the ICD-9-CM code for (7.6 vs. 7.2%; adjusted OR 1.05 [95% CI 0.98–1.12] P = 0.20). long-term (current) use of aspirin (V58.66) in any diagnostic field at Hospital LOS was significantly shorter in aspirin users compared to the hospitalization. non-users (median, 3 days vs. 4 days), corresponding to −7% The outcome measures were in-hospital death (SID does not change in the adjusted model (95% CI −5to −9%, P < 0.001). In include the information on the cause of death), the use of the sensitivity analysis excluding the patients with history of mechanical ventilation (invasive mechanical ventilation [ICD-9-CM coronary artery diseases, ischemic stroke, and/or heart failure, the procedure code 96.04] and non-invasive positive pressure point estimates of these associations did not change materially. ventilation [NIPPV, code 96.30] assessed separately), and hospital Consistent with our findings, previous cohort studies have length-of-stay (LOS). To examine the association between aspirin reported that, among patients with COPD, the use of antiplatelet use and each outcome, we fit unadjusted and adjusted logistic therapy is associated with a lower long-term mortality. Department of Emergency Medicine, Massachusetts General Hospital, 125 Nashua Street, Suite 920, Boston, MA 02114, USA Correspondence: Tadahiro Goto (tag695@mail.harvard.edu) Received: 8 October 2017 Revised: 25 January 2018 Accepted: 26 January 2018 Published in partnership with Primary Care Respiratory Society UK Aspirin use and severity of COPD exacerbation T Goto et al. Table 1. Characteristics of patients hospitalized for acute exacerbation of chronic pulmonary obstructive disease, according to aspirin use Aspirin users Non-users Characteristics n = 13,826 n = 192,860 P-value Age, year, median (interquartile range) 73 (65–81) 70 (59–79) <0.001 Female sex 7229 (52) 112,549 (58) <0.001 Race/ethnicity <0.001 Non-Hispanic white 11,528 (86) 139,497 (75) Non-Hispanic black 867 (6) 19,134 (10) Hispanics 716 (5) 18,996 (10) Others 366 (3) 7250 (4) Payer <0.001 Medicare 10,835 (78) 135,143 (70) Medicaid 902 (7) 21,012 (11) Private 1474 (11) 22,843 (12) Self-pay 238 (2) 7738 (4) Others 377 (3) 6116 (3) Quartiles for median household income <0.001 1 (lowest) 3958 (29) 61,225 (33) 2 4147 (31) 52,084 (28) 3 3144 (23) 43,354 (23) 4 (highest) 2333 (17) 30,680 (16) Number of comorbidities <0.001 0–1 433 (3) 14,728 (8) 2–3 4173 (30) 74,140 (38) ≥4 9220 (67) 103,992 (54) Selected comorbidities Coronary artery diseases 6974 (50) 55,723 (29) <0.001 Ischemic stroke 273 (3) 1821 (1) <0.001 Hospital state <0.001 Arkansas 1006 (7) 13,008 (7) Florida 6085 (44) 90,530 (47) Iowa 594 (4) 9431 (5) Nebraska 114 (1) 5512 (3) New York 3695 (27) 58,240 (30) Utah 76 (1) 2757 (1) Washington 2256 (16) 13,382 (7) Note: Data were shown as n (%) unless otherwise specified Additionally, an observational study of 1343 patients hospitalized mechanism may be supported by the observed attenuated for AECOPD in the UK reported that antiplatelet users (aspirin or associations between aspirin use and severity of AECOPD in clopidogrel) have a non-significantly lower odds of in-hospital patients without cardiovascular diseases. mortality. Our population-based study from seven US states, with Our inferences may be limited by the low sensitivity of ICD-9-CM a much larger sample size, extends these findings by demonstrat- code for long-term (current) aspirin use. However, the results ing the significant association of long-term aspirin use with lower were consistent in the sensitivity analysis excluding potential acute severity and mortality of AECOPD. aspirin users that addressed the under-coding among patients The nature of aspirin-acute severity association in COPD who should have been treated with antiplatelets. Additionally, our warrants further investigation. The increased platelet activation inferences might not be generalizable to patients with less-than- in patients with AECOPD contributes to microvascular thrombosis severe AECOPD. Nevertheless, our data remain highly relevant for that leads to organ ischemia and tissue damage. The use of 700,000 patients hospitalized yearly in the US, a population with aspirin may impede the inflammatory pathways secondary to the high morbidity. activated state of platelets and prevent microvascular thrombus In sum, by using a large population-based data set, we found formation by inhibiting the surface expression of adhesion 8 that long-term aspirin users have lower rates of in-hospital molecules. These mechanisms for potential benefits of aspirin mortality and invasive mechanical ventilation use, and shorter have also been indicated in other acute conditions accompanying LOS. Although causal inferences remain premature, in conjunction systemic inflammation, such as sepsis and acute respiratory 1,2,6 with the prior studies, aspirin—a widely used and inexpensive distress syndrome. Furthermore, the aspirin use potentially medication—may be a potential therapeutic option for patients reduced the risk of cardiovascular diseases-related death, mechanical ventilation use, and longer LOS. This potential with COPD. npj Primary Care Respiratory Medicine (2018) 7 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; Aspirin use and severity of COPD exacerbation T Goto et al. Table 2. Unadjusted and adjusted associations between aspirin use and severity of acute exacerbation of chronic obstructive pulmonary disease Outcomes Aspirin users Non-users Unadjusted association P-value Adjusted association P-value (95% CI) (95% CI) Main analysis In-hospital death 1.0% (0.8–1.1%) 1.4% (1.4–1.5%) 0.67 (0.56–0.80) <0.001 0.60 (0.50–0.72) <0.001 Invasive mechanical ventilation 1.7% (1.5–1.9%) 2.6% (2.5–2.6%) 0.64 (0.56–0.74) <0.001 0.64 (0.55–0.73) <0.001 NIPPV use 7.6% (7.2–8.1%) 7.2% (7.1–7.3%) 1.06 (0.99–1.13) 0.06 1.05 (0.98–1.12) 0.20 Hospital LOS, days, median (IQR) 3(2–5) 4 (2–6) −6% (−4to −7%) <0.001 −7% (−5to −9%) <0.001 Sensitivity analysis 1 In-hospital death 1.0% (0.8–1.3%) 1.3% (1.1–1.3%) 0.85 (0.67–1.09) 0.20 0.72 (0.56–0.93) 0.01 Invasive mechanical ventilation 1.8% (1.5–2.1%) 2.4% (2.3–2.5%) 0.74 (0.61–0.89) 0.002 0.71 (0.59–0.87) 0.001 NIPPV use 8.0% (7.3–8.7%) 7.1% (7.0–7.2%) 1.15 (1.05–1.27) 0.002 1.10 (0.99–1.21) 0.053 Hospital LOS, days, median (IQR) 3(2–5) 3 (2–5) −2% (0 to −5%) 0.10 −5% (−2to −8%) <0.001 Sensitivity analysis 2 In-hospital death 0.8% (0.6–1.1%) 1.0% (1.0–1.1%) 0.81 (0.59–1.11) 0.19 0.66 (0.47–0.92) 0.02 Invasive mechanical ventilation 1.8% (1.5–2.2%) 2.4% (2.3–2.5%) 0.79 (0.64–0.97) 0.02 0.77 (0.62–0.95) 0.02 NIPPV use 7.2% (6.5–7.9%) 6.2% (6.1–6.4%) 1.20 (1.08–1.34) 0.001 1.15 (1.03–1.29) 0.02 Hospital LOS, days, median (IQR) 3(2–5) 3 (2–5) −1% (−4to −2%) 0.52 −4% (−7to −1%) 0.02 CI confidence interval, NIPPV non-invasive positive pressure ventilation, IQR interquartile range Odds ratio of aspirin use for each outcome in comparison with non-aspirin use, by using logistic regression model with generalized estimating equation to account for patient clustering within hospitals Percent change in hospital LOS, by using negative binomial model with generalized estimating equation to account for patient clustering within hospitals Among patients without coronary artery diseases or ischemic stroke, 6753 patients were aspirin users and 136,325 patients were non-users Among patients without coronary artery diseases, ischemic stroke, or heart failure, 5257 patients were aspirin users and 114,425 patients were non-users DATA AVAILABILITY 4. Yale New Haven Health Services Corporation/Center for Outcomes Research & Evaluation. 2014 measures updates and specifications report hospital-level The State Inpatient Databases can be purchased from the website 30-day risk-standardized readmission measures, http://altarum.org/sites/ of Healthcare Cost and Utilization Project (https://www.hcup-us. default/files/uploaded-publication-files/Rdmsn_Msr_Updts_HWR_0714_0.pdf ahrq.gov). (2014). 5. Bassett, J. C. et al. Gender, race, and variation in the evaluation of microscopic hematuria among Medicare beneficiaries. J. Gen. Intern. Med. 30, ACKNOWLEDGEMENTS 440–447 (2015). This study was supported by the grant R01 HS-023305 (Camargo) from the Agency 6. Pavasini, R. et al. Antiplatelet treatment reduces all-cause mortality in COPD for Healthcare Research and Quality (Rockville, MD). patients: a systematic review and meta-analysis. Chron. Obstruct. Pulmon. Dis. 13, 509–514 (2016). 7. Maclay, J. D. et al. Increased platelet activation in patients with stable and acute AUTHOR CONTRIBUTIONS exacerbation of COPD. Thorax 66, 769–774 (2011). T.G. takes responsibility for the paper as a whole. T.G., M.K.F., and K.H. conceived the 8. Gando, S. Microvascular thrombosis and multiple organ dysfunction syndrome. study. C.A.C. obtained research funding. C.A.C. and K.H. supervised the conduct of the Crit. Care Med. 38, S35–S42 (2010). study. C.A.C. and K.H. provided statistical advice. T.G. and M.K.F. analyzed the data. T. 9. Toner, P., McAuley, D.F. & Shyamsundar, M. Aspirin as a potential G. drafted the manuscript, and all authors contributed substantially to its revision. treatment in sepsis or acute respiratory distress syndrome. Crit. Care 19, 374 The content is solely the responsibility of the authors and does not necessarily (2015). represent the official views of the Agency for Healthcare Research and Quality. 10. Ford, E. S. Hospital discharges, readmissions, and ED visits for COPD or bronch- iectasis among US adults: findings from the nationwide inpatient sample 2001- 2012 and Nationwide Emergency Department Sample 2006-2011. Chest 147, ADDITIONAL INFORMATION 989–998 (2015). Competing interests: The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims Attribution 4.0 International License, which permits use, sharing, in published maps and institutional affiliations. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party REFERENCES material in this article are included in the article’s Creative Commons license, unless 1. Harrison, M. T. et al. Thrombocytosis is associated with increased short and long indicated otherwise in a credit line to the material. If material is not included in the term mortality after exacerbation of chronic obstructive pulmonary disease: a article’s Creative Commons license and your intended use is not permitted by statutory role for antiplatelet therapy? Thorax 69, 609–615 (2014). regulation or exceeds the permitted use, you will need to obtain permission directly 2. Ekstrom, M. P., Hermansson, A. B. & Strom, K. E. Effects of cardiovascular drugs on from the copyright holder. To view a copy of this license, visit http://creativecommons. mortality in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care org/licenses/by/4.0/. Med. 187, 715–720 (2013). 3. Overview of the State Inpatient Databases (SID). Healthcare cost and utilization project. Agency for healthcare research and quality, http://www.hcup-us.ahrq. © The Author(s) 2018 gov/sidoverview.jsp (2017). Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2018) 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Primary Care Respiratory Medicine Springer Journals

The association of aspirin use with severity of acute exacerbation of chronic obstructive pulmonary disease: a retrospective cohort study

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Medicine & Public Health; Medicine/Public Health, general; Primary Care Medicine; Internal Medicine; Pneumology/Respiratory System; Thoracic Surgery
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Abstract

www.nature.com/npjpcrm BRIEF COMMUNICATION OPEN The association of aspirin use with severity of acute exacerbation of chronic obstructive pulmonary disease: a retrospective cohort study 1 1 1 1 Tadahiro Goto , Mohammad Kamal Faridi , Carlos A. Camargo and Kohei Hasegawa Little is known about the effect of long-term aspirin use on acute severity of COPD. We hypothesized that, in patients hospitalized for acute exacerbation of COPD (AECOPD), long-term aspirin use is associated with lower risks of disease severity (in-hospital death, mechanical ventilation use, and hospital length-of-stay). We conducted a retrospective cohort study using large population-based data from 2012 through 2013. Among 206,686 patients (aged ≥40 years) hospitalized for AECOPD, aspirin users had lower in- hospital mortality (1.0 vs. 1.4%; OR 0.60 [95% CI 0.50–0.72]; P < 0.001) and lower risk of invasive mechanical ventilation use (1.7 vs. 2.6%; OR 0.64 [95% CI 0.55–0.73]; P < 0.001) compared to non-users, while there was no significant difference in risks of non- invasive positive pressure ventilation use. Length-of-stay was shorter in aspirin users compared to non-users (P < 0.001). In sum, in patients with AECOPD, aspirin use was associated with lower rates of in-hospital mortality and invasive mechanical ventilation use, and shorter length-of-stay. npj Primary Care Respiratory Medicine (2018) 28:7 ; doi:10.1038/s41533-018-0074-x Increasing evidence suggests a potential benefit of antiplatelet regression or negative binomial regression models with general- therapy on chronic outcomes in patients with chronic obstructive ized estimating equations to account for patient clustering within 1,2 pulmonary disease (COPD). For example, a recent analysis of an hospitals. We adjusted for age, sex, race/ethnicity, payer, median ongoing prospective cohort study revealed that antiplatelet household income, 27 Elixhauser comorbidity measures (including therapy was associated with a lower 1-year mortality among heart failure, arrhythmias, and valvular diseases), hospitalization individuals with COPD. However, little is known about the effect year, and hospital state. We repeated the analyses with (1) of aspirin use on acute outcomes (including mortality) in patients excluding patients who had any of the cardiovascular comorbid- hospitalized for acute exacerbation of COPD (AECOPD). ities that are commonly treated with aspirin (coronary artery To examine the association of aspirin use with severity of diseases [codes, 410–414] and ischemic stroke [codes, 433–434]) AECOPD, we conducted a retrospective cohort study using data and (2) excluding these potential aspirin users and patients with from the State Inpatient Databases (SID) of seven US states heart failure. All analyses were performed using STATA 14.1 (Arkansas, Florida, Iowa, Nebraska, New York, Utah, and Washing- (StataCorp, College Station, TX). ton) from 2012 and 2013. Additional details of the SID may be Overall, we identified 206,686 patients with hospitalization for found elsewhere. The institutional review board of Massachusetts AECOPD in the seven US states. Of these, 13,826 patients (7%) General Hospital approved this study. were aspirin users. Aspirin users were older, and more likely to We identified all hospitalizations made by patients aged ≥40 have Medicare comorbidities, compared to non-users (all P < years with a primary discharge diagnosis of COPD (ICD-9-CM 0.001; Table 1). Aspirin users had a significantly lower in-hospital codes: 491.21, 491.22, 491.8, 491.9, 492.8, 493.20, 493.21, 493.22, mortality compared to non-users (1.0 vs. 1.4%; adjusted OR 0.60 and 496), or those with a primary diagnosis of respiratory failure [95% CI 0.50–0.72] P < 0.001; Table 2). Additionally, aspirin users (codes: 518.81, 518.82, 518.84, and 799.1) and a secondary had a significantly lower rate of invasive mechanical ventilation diagnosis of COPD. We included only the first hospitalization use (1.7 vs. 2.6%; adjusted OR 0.64 [95% CI 0.55–0.73] P < 0.001), for AECOPD for each patient during the study period. Then, we while there was no significant difference in the rate of NIPPV use further identified aspirin users by using the ICD-9-CM code for (7.6 vs. 7.2%; adjusted OR 1.05 [95% CI 0.98–1.12] P = 0.20). long-term (current) use of aspirin (V58.66) in any diagnostic field at Hospital LOS was significantly shorter in aspirin users compared to the hospitalization. non-users (median, 3 days vs. 4 days), corresponding to −7% The outcome measures were in-hospital death (SID does not change in the adjusted model (95% CI −5to −9%, P < 0.001). In include the information on the cause of death), the use of the sensitivity analysis excluding the patients with history of mechanical ventilation (invasive mechanical ventilation [ICD-9-CM coronary artery diseases, ischemic stroke, and/or heart failure, the procedure code 96.04] and non-invasive positive pressure point estimates of these associations did not change materially. ventilation [NIPPV, code 96.30] assessed separately), and hospital Consistent with our findings, previous cohort studies have length-of-stay (LOS). To examine the association between aspirin reported that, among patients with COPD, the use of antiplatelet use and each outcome, we fit unadjusted and adjusted logistic therapy is associated with a lower long-term mortality. Department of Emergency Medicine, Massachusetts General Hospital, 125 Nashua Street, Suite 920, Boston, MA 02114, USA Correspondence: Tadahiro Goto (tag695@mail.harvard.edu) Received: 8 October 2017 Revised: 25 January 2018 Accepted: 26 January 2018 Published in partnership with Primary Care Respiratory Society UK Aspirin use and severity of COPD exacerbation T Goto et al. Table 1. Characteristics of patients hospitalized for acute exacerbation of chronic pulmonary obstructive disease, according to aspirin use Aspirin users Non-users Characteristics n = 13,826 n = 192,860 P-value Age, year, median (interquartile range) 73 (65–81) 70 (59–79) <0.001 Female sex 7229 (52) 112,549 (58) <0.001 Race/ethnicity <0.001 Non-Hispanic white 11,528 (86) 139,497 (75) Non-Hispanic black 867 (6) 19,134 (10) Hispanics 716 (5) 18,996 (10) Others 366 (3) 7250 (4) Payer <0.001 Medicare 10,835 (78) 135,143 (70) Medicaid 902 (7) 21,012 (11) Private 1474 (11) 22,843 (12) Self-pay 238 (2) 7738 (4) Others 377 (3) 6116 (3) Quartiles for median household income <0.001 1 (lowest) 3958 (29) 61,225 (33) 2 4147 (31) 52,084 (28) 3 3144 (23) 43,354 (23) 4 (highest) 2333 (17) 30,680 (16) Number of comorbidities <0.001 0–1 433 (3) 14,728 (8) 2–3 4173 (30) 74,140 (38) ≥4 9220 (67) 103,992 (54) Selected comorbidities Coronary artery diseases 6974 (50) 55,723 (29) <0.001 Ischemic stroke 273 (3) 1821 (1) <0.001 Hospital state <0.001 Arkansas 1006 (7) 13,008 (7) Florida 6085 (44) 90,530 (47) Iowa 594 (4) 9431 (5) Nebraska 114 (1) 5512 (3) New York 3695 (27) 58,240 (30) Utah 76 (1) 2757 (1) Washington 2256 (16) 13,382 (7) Note: Data were shown as n (%) unless otherwise specified Additionally, an observational study of 1343 patients hospitalized mechanism may be supported by the observed attenuated for AECOPD in the UK reported that antiplatelet users (aspirin or associations between aspirin use and severity of AECOPD in clopidogrel) have a non-significantly lower odds of in-hospital patients without cardiovascular diseases. mortality. Our population-based study from seven US states, with Our inferences may be limited by the low sensitivity of ICD-9-CM a much larger sample size, extends these findings by demonstrat- code for long-term (current) aspirin use. However, the results ing the significant association of long-term aspirin use with lower were consistent in the sensitivity analysis excluding potential acute severity and mortality of AECOPD. aspirin users that addressed the under-coding among patients The nature of aspirin-acute severity association in COPD who should have been treated with antiplatelets. Additionally, our warrants further investigation. The increased platelet activation inferences might not be generalizable to patients with less-than- in patients with AECOPD contributes to microvascular thrombosis severe AECOPD. Nevertheless, our data remain highly relevant for that leads to organ ischemia and tissue damage. The use of 700,000 patients hospitalized yearly in the US, a population with aspirin may impede the inflammatory pathways secondary to the high morbidity. activated state of platelets and prevent microvascular thrombus In sum, by using a large population-based data set, we found formation by inhibiting the surface expression of adhesion 8 that long-term aspirin users have lower rates of in-hospital molecules. These mechanisms for potential benefits of aspirin mortality and invasive mechanical ventilation use, and shorter have also been indicated in other acute conditions accompanying LOS. Although causal inferences remain premature, in conjunction systemic inflammation, such as sepsis and acute respiratory 1,2,6 with the prior studies, aspirin—a widely used and inexpensive distress syndrome. Furthermore, the aspirin use potentially medication—may be a potential therapeutic option for patients reduced the risk of cardiovascular diseases-related death, mechanical ventilation use, and longer LOS. This potential with COPD. npj Primary Care Respiratory Medicine (2018) 7 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; Aspirin use and severity of COPD exacerbation T Goto et al. Table 2. Unadjusted and adjusted associations between aspirin use and severity of acute exacerbation of chronic obstructive pulmonary disease Outcomes Aspirin users Non-users Unadjusted association P-value Adjusted association P-value (95% CI) (95% CI) Main analysis In-hospital death 1.0% (0.8–1.1%) 1.4% (1.4–1.5%) 0.67 (0.56–0.80) <0.001 0.60 (0.50–0.72) <0.001 Invasive mechanical ventilation 1.7% (1.5–1.9%) 2.6% (2.5–2.6%) 0.64 (0.56–0.74) <0.001 0.64 (0.55–0.73) <0.001 NIPPV use 7.6% (7.2–8.1%) 7.2% (7.1–7.3%) 1.06 (0.99–1.13) 0.06 1.05 (0.98–1.12) 0.20 Hospital LOS, days, median (IQR) 3(2–5) 4 (2–6) −6% (−4to −7%) <0.001 −7% (−5to −9%) <0.001 Sensitivity analysis 1 In-hospital death 1.0% (0.8–1.3%) 1.3% (1.1–1.3%) 0.85 (0.67–1.09) 0.20 0.72 (0.56–0.93) 0.01 Invasive mechanical ventilation 1.8% (1.5–2.1%) 2.4% (2.3–2.5%) 0.74 (0.61–0.89) 0.002 0.71 (0.59–0.87) 0.001 NIPPV use 8.0% (7.3–8.7%) 7.1% (7.0–7.2%) 1.15 (1.05–1.27) 0.002 1.10 (0.99–1.21) 0.053 Hospital LOS, days, median (IQR) 3(2–5) 3 (2–5) −2% (0 to −5%) 0.10 −5% (−2to −8%) <0.001 Sensitivity analysis 2 In-hospital death 0.8% (0.6–1.1%) 1.0% (1.0–1.1%) 0.81 (0.59–1.11) 0.19 0.66 (0.47–0.92) 0.02 Invasive mechanical ventilation 1.8% (1.5–2.2%) 2.4% (2.3–2.5%) 0.79 (0.64–0.97) 0.02 0.77 (0.62–0.95) 0.02 NIPPV use 7.2% (6.5–7.9%) 6.2% (6.1–6.4%) 1.20 (1.08–1.34) 0.001 1.15 (1.03–1.29) 0.02 Hospital LOS, days, median (IQR) 3(2–5) 3 (2–5) −1% (−4to −2%) 0.52 −4% (−7to −1%) 0.02 CI confidence interval, NIPPV non-invasive positive pressure ventilation, IQR interquartile range Odds ratio of aspirin use for each outcome in comparison with non-aspirin use, by using logistic regression model with generalized estimating equation to account for patient clustering within hospitals Percent change in hospital LOS, by using negative binomial model with generalized estimating equation to account for patient clustering within hospitals Among patients without coronary artery diseases or ischemic stroke, 6753 patients were aspirin users and 136,325 patients were non-users Among patients without coronary artery diseases, ischemic stroke, or heart failure, 5257 patients were aspirin users and 114,425 patients were non-users DATA AVAILABILITY 4. Yale New Haven Health Services Corporation/Center for Outcomes Research & Evaluation. 2014 measures updates and specifications report hospital-level The State Inpatient Databases can be purchased from the website 30-day risk-standardized readmission measures, http://altarum.org/sites/ of Healthcare Cost and Utilization Project (https://www.hcup-us. default/files/uploaded-publication-files/Rdmsn_Msr_Updts_HWR_0714_0.pdf ahrq.gov). (2014). 5. Bassett, J. C. et al. Gender, race, and variation in the evaluation of microscopic hematuria among Medicare beneficiaries. J. Gen. Intern. Med. 30, ACKNOWLEDGEMENTS 440–447 (2015). This study was supported by the grant R01 HS-023305 (Camargo) from the Agency 6. Pavasini, R. et al. Antiplatelet treatment reduces all-cause mortality in COPD for Healthcare Research and Quality (Rockville, MD). patients: a systematic review and meta-analysis. Chron. Obstruct. Pulmon. Dis. 13, 509–514 (2016). 7. Maclay, J. D. et al. Increased platelet activation in patients with stable and acute AUTHOR CONTRIBUTIONS exacerbation of COPD. Thorax 66, 769–774 (2011). T.G. takes responsibility for the paper as a whole. T.G., M.K.F., and K.H. conceived the 8. Gando, S. Microvascular thrombosis and multiple organ dysfunction syndrome. study. C.A.C. obtained research funding. C.A.C. and K.H. supervised the conduct of the Crit. Care Med. 38, S35–S42 (2010). study. C.A.C. and K.H. provided statistical advice. T.G. and M.K.F. analyzed the data. T. 9. Toner, P., McAuley, D.F. & Shyamsundar, M. Aspirin as a potential G. drafted the manuscript, and all authors contributed substantially to its revision. treatment in sepsis or acute respiratory distress syndrome. Crit. Care 19, 374 The content is solely the responsibility of the authors and does not necessarily (2015). represent the official views of the Agency for Healthcare Research and Quality. 10. Ford, E. S. Hospital discharges, readmissions, and ED visits for COPD or bronch- iectasis among US adults: findings from the nationwide inpatient sample 2001- 2012 and Nationwide Emergency Department Sample 2006-2011. Chest 147, ADDITIONAL INFORMATION 989–998 (2015). Competing interests: The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims Attribution 4.0 International License, which permits use, sharing, in published maps and institutional affiliations. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party REFERENCES material in this article are included in the article’s Creative Commons license, unless 1. Harrison, M. T. et al. Thrombocytosis is associated with increased short and long indicated otherwise in a credit line to the material. If material is not included in the term mortality after exacerbation of chronic obstructive pulmonary disease: a article’s Creative Commons license and your intended use is not permitted by statutory role for antiplatelet therapy? Thorax 69, 609–615 (2014). regulation or exceeds the permitted use, you will need to obtain permission directly 2. Ekstrom, M. P., Hermansson, A. B. & Strom, K. E. Effects of cardiovascular drugs on from the copyright holder. To view a copy of this license, visit http://creativecommons. mortality in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care org/licenses/by/4.0/. Med. 187, 715–720 (2013). 3. Overview of the State Inpatient Databases (SID). Healthcare cost and utilization project. Agency for healthcare research and quality, http://www.hcup-us.ahrq. © The Author(s) 2018 gov/sidoverview.jsp (2017). 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