CME Author: Vicki Brower
Study Authors: Ashraf Fawzy, Nirupama Putcha, et al.
Target Audience and Goal Statement:
Pulmonologists, internists, and family medicine specialists
The goal was to determine whether aspirin could improve respiratory morbidity of patients with chronic obstructive pulmonary disease (COPD).
What effect, if any, does daily aspirin use have on morbidity of patients with COPD?
Study Synopsis and Perspective:
In this study, researchers found that patients with COPD who took aspirin daily experienced reduced disease exacerbations, less shortness of breath, and better quality of life, according to their analysis of the ongoing SPIROMICS study. The association was strongest among study participants reporting symptoms of chronic bronchitis at enrollment, as reported in the journal CHEST.
Previous studies have shown the use of aspirin by patients with COPD is associated with reduced mortality, but the newly published study is among the first to examine the impact of daily aspirin therapy on respiratory morbidity in COPD.
The study reported by Ashraf Fawzy, MD, of Johns Hopkins University in Baltimore, and colleagues, found that at 3 years follow-up, aspirin users were less likely to have acute COPD exacerbations (adjusted incidence rate ratio [IRR] 0.78, 95% CI 0.65-0.94) compared with non-users, with a similar effect seen for moderate acute COPD exacerbations (IRR 0.86, 95% CI 0.63-1.18). Preliminary data from this study were presented last year at the American Thoracic Society annual conference.
“The reduced incidence of total and moderate acute COPD exacerbations among aspirin users was independent of concurrent respiratory or cardiovascular medication use and robust when analyzing the entire follow-up period, limiting the analysis to the first year of follow-up, and across all sensitivity analyses,” the authors reported.
Researchers found that the use of aspirin by COPD patients was also associated with lower total scores on the St. George Respiratory Questionnaire (β -2.2, 95% CI -4.1 to -0.4); reduced odds of moderate-to-severe dyspnea, score ≥2 on the modified Medical Research Council Questionnaire (adjusted OR 0.69, 95% CI 0.51-0.93); and lower COPD Assessment Test scores (β -1.1, 95% CI -1.9 to -0.2).
However, they did not find a difference between aspirin users and non-users in the 6-minute walk distance (β 0.7 meters, 95% CI -14.3 to 15.6).
The analysis included COPD patients in the SPIROMICS study who self-reported daily aspirin use at the beginning of the study, or 45% of the 1,698 study participants. Acute exacerbations of COPD were prospectively determined through quarterly structured telephone questionnaires for up to 3 years, and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring an emergency department visit or hospitalization).
Aspirin users were matched 1:1 with non-users based on propensity score, which resulted in 503 participant-pairs. The association of aspirin use with total, moderate, and severe acute COPD exacerbation was investigated using zero-inflated negative binomial models. Linear or logistic regression were used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance.
The researchers noted that the study’s limitations include the study participants’ self-reporting of daily aspirin use, without dosing information. Information on duration of aspirin use and adherence to therapy before and during the study was also unavailable. And, COPD exacerbations were not confirmed with medical records, which may have led to misclassification of events, they noted.
And despite propensity score matching and other efforts to avoid confounding, the researchers acknowledged that they may not have controlled for all factors that could have impacted their outcomes.
The research team concluded that a randomized study is needed to determine whether daily aspirin use is protective against COPD exacerbations. “Prospective randomized clinical trials of aspirin use are warranted to explore its potential effect in reducing COPD morbidity,” they concluded.
Source Reference: CHEST, Dec. 26, 2018; DOI: 10.1016/j.chest.2018.11.028
Study Highlights: Explanation of Findings
In this study of 1,698 patients, 45% (n=764) of whom reported daily aspirin use, the treated group was found to have a lower incidence of acute exacerbation of COPD, with a similar effect for moderate, but not severe, acute exacerbations of COPD. A subgroup analysis showed that aspirin use was more strongly associated with reduced acute exacerbations among those reporting symptoms of bronchitis at baseline. This is important because patients who reported cough and phlegm at baseline had a significantly stronger association between aspirin use and reduced acute exacerbations of COPD. Researchers noted that future studies, based on this finding, may benefit from oversampling participants with this “bronchitis phenotype.”
Regarding the finding of a trend towards stronger association between aspirin use and acute exacerbation of COPD in patients with mild or moderate disease, researchers noted that this may be because there were a higher proportion of patients with severe disease, or inadequate power to the study. And notably, there was no association of aspirin use with exacerbation of disease based on the presence or burden of emphysema at baseline. Progression of emphysema could not be evaluated in this study, although another recent study indicated that aspirin did attenuate its progression.
Regarding the treatment of COPD, patients typically use combination inhaler therapy for bronchodilation and to decrease pulmonary inflammation. Researchers noted that “the systemic manifestations of COPD, including systemic inflammation, are inadequately addressed by current therapies. “Inhaled corticosteroids have not been shown to reduce circulating inflammatory biomarkers,” they wrote.
The study authors also noted that chronic use of macrolide antibiotics exerts anti-inflammatory and immunomodulatory effects in addition to anti-bacterial properties, but use of these drugs is limited, due to fear of antibiotic resistance and hearing loss. Similarly, they noted that while chronic use of the phosphodiesterase-4 inhibitor roflumilast (Daliresp) also reduced the rate of COPD exacerbations, it did so only in patients with chronic bronchitis and severe disease, and that its use has been limited due to gastrointestinal side-effects. Statins, which are thought to have anti-inflammatory effects, have been ineffective in reducing exacerbation rates among patients with moderate-to-severe COPD.
Exactly how aspirin affects COPD morbidity is a question discussed at some length by the study authors. They noted that aspirin is known to have direct and indirect anti-inflammatory effects, with both systemic and local pulmonary mechanisms of action, which might explain the findings. They also cited “inactivation of platelets and [subsequent] reduced inflammation.” Regarding activated platelets’ role in inflammation, they mentioned that “a urinary metabolite of thromboxane A2, which is secreted by activated platelets, has been shown to be elevated among patients with COPD and represents the pathway irreversibly blocked by aspirin. Persistent systemic elevation of inflammatory markers interleukin-6 and CRP may [also] represent a systemic inflammatory phenotype of COPD which are [also] attenuated by aspirin in other patient populations,” the researchers wrote. Finally, they noted that in a 2017 study, treatment with aspirin was found to reduce pro-inflammatory cytokines in bronchoalveolar lavage samples of 33 healthy volunteers.
Most studies, but not all, to date, indicate that aspirin use in COPD patients is associated with reduced all-cause mortality. Regarding its known effects in reducing morbidity in acute exacerbations, researchers noted that in patients hospitalized with an acute episode, aspirin is associated with lower risk of mechanical ventilation, and a shorter hospital stay. In addition, aspirin use reduces emphysema progression in the general population, they wrote. This study shows, with a number others, that aspirin use reduces exacerbation risk and dyspnea, and improves quality of life.
Salynn Boyles wrote the original story for MedPageToday
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco