Reducing COPD exacerbations and mortality: A multidisciplinary perspective

Prof. David Price
Observational and Pragmatic Research Institue
Prof. David Berg
Division of Cardiovascular Medicine, Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts, US
Prof. Bartolome Celli
Harvard Medical School
Boston, Massachusetts, US
11 Nov 2021
Reducing COPD exacerbations and mortality: A multidisciplinary perspective

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased mortality not only from respiratory failure, but also from cardiovascular (CV) events. At the European Respiratory Society (ERS) International Congress 2021, experts discussed a multidisciplinary approach to better protect patients with COPD from exacerbations and mortality. Professor David Price of the Observational and Pragmatic Research Institute, Singapore, outlined the burden of exacerbations and mortality in COPD. Dr David Berg of the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, US, offered a cardiologist’s insight into COPD and CV risk. Professor Bartolome Celli of Harvard Medical School, Boston, Massachusetts, US, explored the role of triple therapy in reducing mortality risk in patients with COPD.

COPD exacerbations occur long before diagnosis

COPD, characterized by an accelerated decline in lung function and exacerbations, is often diagnosed late in life, usually in individuals aged >65 years, when recovery of lung function is difficult. [Eur Respir J 2014;44:324-31; N Engl J Med 2010;363:1128-1138; N Engl J Med 2015;373:111-122.]

According to UK databases, 58 percent of patients with COPD sought medical consultation for lower respiratory symptoms in the 6–10 years preceding diagnosis. “Many of those were associated with what we would now probably consider exacerbations,” said Price. “Exacerbations prior to diagnosis actually predict exacerbations after.” Early diagnosis of COPD in these patients could provide an opportunity for moving COPD treatment upstream to improve outcomes. [Lancet Respir 2014;2:267-276]

Predictors of exacerbations

Most patients with COPD will experience an exacerbation. In the ECLIPSE longitudinal study, up to 77 percent of patients experienced at least one exacerbation within 3 years. [N Engl J Med 2010;363:1128-1138] Notably, the frequency of subsequent exacerbations increased following a severe exacerbation. [Thorax 2012;67:957-963]

Significant predictors of having ≥2 exacerbations in the subsequent year included a history of exacerbation(s) in the previous year (one exacerbation: odds ratio [OR], 2.42; 95 percent confidence interval [CI], 2.18 to 2.69) (two exacerbations: OR, 4.39; 95 percent CI, 3.89 to 4.95) (three exacerbations: OR, 7.28; 95 percent CI, 6.25 to 8.48) (≥4 exacerbations: OR, 17.83; 95 percent CI, 15.12 to 21.03), eosinophilia in noncurrent smokers (OR, 1.29; 95 percent CI, 1.10 to 1.51), and comorbidities (asthma: OR, 1.34; 95 percent CI, 1.23 to 1.46) (nonallergic rhinitis: OR, 1.35; 95 percent CI, 1.15 to 1.59) (nasal polyps: OR, 1.39; 95 percent CI, 1.09 to 1.78) (ischaemic heart disease: OR, 1.12; 95 percent CI, 1.01 to 1.25) (anxiety or depression: OR, 1.11; 95 percent CI, 1.02 to 1.22) (gastro-oesophageal reflux disease: OR, 1.18; 95 percent CI, 1.05 to 1.34). “Strikingly, COPD assessment test score [CAT; per 10 units] was also a significant predictor [OR, 1.28; 95 percent CI, 1.15 to 1.42],” said Price. [Int J Chron Obstruct Pulmon Dis 2015;10:2439-2450]

KRONOS: Triple therapy reduces exacerbations vs LAMA/LABA

In the phase III KRONOS trial in symptomatic patients with moderate to very severe COPD (n=1,902), triple therapy with a fixed-dose combination (FDC) of inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting beta-agonist (LABA) (ie, budesonide/glycopyrrolate/formoterol [BUD/GLY/FORM 320/18/9.6 μg]) led to a significantly lower rate of moderate or severe exacerbations than the dual FDC of LAMA/LABA (ie, GLY/FORM 18/9.6 μg). [Lancet Respir Med 2018;6:747-758]

Compared with GLY/FORM, BUD/GLY/FORM 320/18/9.6 μg significantly reduced rates of moderate or severe exacerbations by 52 percent (hazard ratio [HR], 0.48; 95 percent CI, 0.37 to 0.64; p<0.0001) and severe exacerbations by 64 percent (HR, 0.36; 95 percent CI, 0.18 to 0.70; p=0.0026). Importantly, >70 percent of patients in the KRONOS trial did not have moderate or severe exacerbations in the preceding year, supporting the use of BUD/GLY/FORM 320/18/ 9.6 μg in patients with high exacerbation risk as well as low exacerbation risk. [Lancet Respir Med 2018;6:747-758; ERS 2021, session 169]

“Preventing exacerbations has an impact on the rate of lung function decline,” said Celli. In the KRONOS trial, BUD/GLY/FORM 320/18/9.6 μg was also associated with a significant improvement in lung function, as measured by change from baseline in morning predose trough forced expiratory volume in 1 second (FEV1) over 24 weeks, vs GLY/FORM (least square mean, 22 mL; p=0.0139).

ETHOS: Triple therapy reduces all-cause mortality vs LAMA/LABA

Exacerbations are associated with increased mortality. “One out of five patients with COPD died within 1 year after the first severe exacerbation. Within 3.6 years, only half of the patients were still alive,” said Price. [PLoS One 2014;9:e114866; Thorax 2012;67:957-963]

“Preventing exacerbations may reduce mortality in COPD patients,” said Celli.

In addition to reducing exacerbations in the KRONOS trial, the triple FDC of BUD/GLY/FORM 320/18/9.6 μg was also shown to significantly reduce all-cause mortality (including on- and off-treatment deaths) by 49 percent (HR, 0.51; 95 percent CI, 0.33 to 0.80; unadjusted p=0.0035) vs LAMA/LABA (ie, GLY/FORM 18/9.6 μg) in the phase III ETHOS trial in symptomatic patients with moderate to very severe COPD and ≥1 exacerbation in the past year (n=8,509).  (Figure) However, the reduction in all-cause mortality vs ICS/LABA (ie, BUD/FORM 320/9.6 μg) was not statistically significant (HR, 0.72; 95 percent CI, 0.44 to 1.16; p=0.1721). [Am J Respir Crit Care Med 2021;203:553-564]


In the ETHOS trial, CV events accounted for fewer deaths in the BUD/GLY/FORM 320/18/9.6 μg vs GLY/FORM arm (11 vs 29 CV deaths). “The combined effects of preventing exacerbations and improving lung function may be why patients with a history of exacerbations were less likely to die if they received triple therapy vs dual therapy,” highlighted Celli.

CVD and COPD: A toxic relationship

COPD exacerbations are linked to death not only from respiratory failure, but also from CV events. In a post hoc analysis of the SUMMIT trial (n=16,485), within the first 30 days after an acute exacerbation, patients had a four- to ten-fold higher risk of subsequent CV events, including CV death, MI, stroke, unstable angina and transient ischaemic attack (all exacerbations: HR, 3.8; 95 percent CI, 2.7 to 5.5) (exacerbation requiring hospitalization: HR, 9.9; 95 percent CI, 6.6 to 14.9). “The risk of CV events was elevated for up to 1 year after an acute exacerbation of COPD,” said Berg. [Am J Respir Crit Care Med 2018;198:51-57]

“Systemic inflammation associated with COPD may increase patients’ CV risk. Other potential mechanistic links include right ventricular dysfunction and shared risk factors, such as smoking and advanced age,” he suggested. [Cardiol Clin 2012;30:243-256]

“Treating CV disease may improve COPD outcomes and vice versa,” concluded Berg. “Close collaboration between pulmonologists and cardiologists may be critical to improving outcomes for both conditions.”

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