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COPD exacerbations and MACE: More than a chance encounter?

Cardiovascular death occurs in approximately 30% of chronic obstructive pulmonary disease (COPD) patients, and although many comorbidities have been linked to COPD, interactions with the cardiovascular system are of particular interest. Research over the past two decades has established a strong and perhaps independent association between COPD and cardiovascular disease (CVD), which is partly, but not entirely, explained by shared risk factors including age, environmental pollutants, sedentary lifestyle and—most importantly—smoking. Biologically plausible links between COPD and CVD have been described for both periods of stable disease and during acute exacerbations. Potential mechanisms for increased cardiovascular events around the time of acute exacerbations are incompletely understood but include heightened systemic inflammation with associated oxidative stress resulting in endothelial dysfunction, vascular reactivity and even atherosclerotic plaque rupture. Donaldson et al. showed an approximately twofold increased risk for myocardial infarction (MI) for the 5 days after an acute exacerbation of COPD (AECOPD), as well as an increased risk for stroke even beyond 30 days. These findings were corroborated by Kunisaki et al. using data from the SUMMIT (Study to Understand Mortality and Morbidity) trial designed to assess the role of inhaled treatments on all-cause mortality in COPD patients with heightened CVD risk. In that report, the hazard ratio for CVD events in the first 30 days after AECOPD was 3.8 (2.7–5.5), and the risk remained elevated for up to 1 year. In a recent publication in Respirology, Reilev et al. published the results of their large population-based study that extends the generalizability of these findings. In a case-crossover study using the Danish nationwide health registries (1997–2014), the authors estimated the association between AECOPD and subsequent acute MI, stroke and CVD related death, as well as their composite, overall major adverse cardiac events (MACE). Patients aged at least 50 years with their first MI or stroke during the study period were included. Exacerbations were defined a priori based on filling a short-duration course of oral corticosteroids or being hospitalized due to COPD. The overall risk of MACE following an acute exacerbation was increased almost fourfold (odds ratio, OR: 3.7), with slightly higher risks for the MI and CVD death MACE components than for stroke and the highest risk following exacerbations requiring hospitalization. The study has several strengths, including its very large sample size and population-based sample, which adds to the generalizability of prior reports. The use of the Danish health registry minimizes selection bias compared with randomized trials and provides realworld estimates of attributable risk in a nationwide sample. The exacerbation definition the authors used has also been shown to be highly predictive of adjudicated events, and the case-crossover design elegantly controls for most time-invariant confounders. Despite these advantages, there are some limitations to consider. First, the authors required that all included patients have both a MACE and an acute exacerbation during the study period, making the population more severely ill than often encountered in clinical practice, particularly in primary care. The design may have also excluded patients with the ‘super-exacerbator’ phenotype for whom the risk of CVD events is unclear. Second, although the authors highlight the fact that their exacerbation definition is robust and has been validated in other studies, our current clinical definition and the one supported by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document is inherently flawed as these events are heterogeneous. Unlike for MI, we have no gold standard for the diagnosis, and the included events may have been due to infectious bronchitis, pneumonia, diastolic heart failure, subclinical coronary ischaemia or even pulmonary thromboembolism. This may also have led to conclusions based on reverse causality, where events believed to be acute exacerbations were in fact early manifestations of acute CVD events. Finally, it is also possible that cardiac events, including mild elevations in troponin, were captured and coded based on greater clinical vigilance during hospitalized acute exacerbations, which could lead to overestimation of risk. Adjudication by an uninvolved third party may have aided in the classification of clinical events. Multiple studies now suggest a strong association between exacerbations of COPD and MACE. Although a definitive cause-and-effect relationship cannot be proven, it seems prudent to view COPD exacerbations as an opportunity to stratify patients for their overall CVD risk, including consideration of non-invasive cardiac testing, and to initiate treatment where appropriate. It is also wise to treat the periand postexacerbation periods as a time of particular risk and to be vigilant for the signs and symptoms of cardiovascular events, particularly given the lack of specificity of our exacerbation definition. Vulnerabilities in our current management paradigm also include risk assessment and prognostication based largely, if not solely, on the underlying pulmonary disease without a broader appreciation of exacerbations as a sentinel effect in the natural history of COPD. It is time to develop a calculated, systematic approach to the prevention of adverse cardiovascular outcomes in COPD