30th June 2024, A/Prof Chee L Khoo
We are all aware of the exacerbations in patients with chronic obstructive pulmonary disease (COPD) especially when they are discharged from hospital back to primary care. We tend to forget that each time a patient with COPD have flare up or chest infection, that represent an exacerbation of COPD. Now, you may think it’s just a matter of semantics and coding but it’s more than that. Frequent exacerbations may warrant an up titration of the management of COPD. COPD and cardiovascular disease often co-exist in the same patient. COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. How are COPD exacerbations related to increase cardiovascular events?
We often concentrate on improving the quality of life in our patients with COPD but although cardiovascular disease (CVD) is the most important comorbidity in patients with COPD, it is often ignored. Several studies have demonstrated an association between COPD exacerbations and CVD, but they possess limitations (1-4) For instance, some studies, such as the SUMMIT (Study to Understand Mortality and Morbidity Trial) trial, exclusively included patients with COPD with CVD or high CVD risk (3).
Yang et al recently published the temporal relationship between COPD exacerbations and cardiovascular events (5). They used up to 15 years of prospective longitudinal follow‐up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study to explore that relationship. The COPDGene study is a prospective, multicenter, longitudinal cohort investigation exploring the epidemiology, genetics, and natural history of COPD across 21 centers in the US.
Participants were 45 – 80 years with a minimum of 10 pack‐years of cigarette smoking history. Subjects were recruited to represent the full range of spirometric abnormalities as well as normal spirometry, and then were classified by the GOLD spirometric grading system. In addition, they recruited subjects with preserved ratio impaired spirometry (PRISm), defined as a postbronchodilator FEV1/FVC ratio ≥0.70 but with FEV1 <80% predicted.
They gather data on incident COPD‐related events, comorbidities, and death. COPD‐related events and comorbidities encompassed self‐reported COPD exacerbations (defined as acute worsening of respiratory symptoms necessitating treatment with systemic steroids and/or antibiotics), severe exacerbations (defined as any exacerbation requiring an emergency room visit and/or hospital admission), and CVD events (a composite end point including coronary artery disease, stroke, heart attack indicating myocardial infarction, coronary artery angioplasty, coronary artery bypass graft surgery, and peripheral artery disease).
Enrolled subjects were contacted every 6 via phone or online survey to prospectively gather data on incident COPD‐related events, comorbidities, and death. The target population was divided into 2 groups: frequent exacerbators (≥1 exacerbation per year) and infrequent exacerbators (<1 exacerbation per year). Severe exacerbations (defined as any exacerbation requiring an emergency room visit and/or hospital admission).
Results
The study population were divided based on their spirometry results (GOLD 1- 4 + PRISm) and further classified into groups with or without CVD. Amongst the 5063 study participants, the mean age was 61 years for those without CVD and 65 years with CVD. 70-80% were non-hispanic white. There were more men (63%) in those with CVD.
The mean follow up was 9.6 years. Approximately 22% of the participants had CVD at baseline. 48% of the non-CVD group were still smoking while only 35% of those CVD were still smoking.
Regardless of CVD presence at study enrolment, frequent exacerbators demonstrated a higher cumulative incidence of the composite CVD end point than infrequent exacerbators (without CVD: HR, 1.79 and those with CVD: HR, 1.84).
Even after adjusting for covariates including age, sex, race, body mass index, current smoking status, FEV1% predicted, pack‐years, hypertension, dyslipidaemia, and diabetes, frequent exacerbators still exhibited higher HRs than the infrequent group (without CVD: HR, 1.81, with CVD: HR, 1.92).
Amongst participants with moderate to severe COPD (GOLD 2-4), the hazard ratios between those without and those with CVD were similar (1.77 vs 1.80). Amongst the same group of moderate to severe COPD, severe exacerbations were associated with higher composite CVD endpoints. Those without CVD were worse off with HR of 2.30 vs HR of 1.97 in those with known CVD.
In the mild COPD (GOLD 1) population, frequent exacerbators exhibited a trend toward increased cardiovascular events, but the results were not statistically significant (without CVD: HR, 1.86, with CVD: HR, 1.64)
In summary, many patients with COPD have underlying CVD. There is an association between exacerbations of COPD and subsequent cardiovascular events. There is also an association between the severity of the exacerbations and subsequent cardiovascular events. The associations is particularly strong in those with moderate to severe COPD. We often underdiagnose the presence of cardiovascular disease in patients with COPD. Guidelines largely focus on individual cardiovascular or individual respiratory disease. As GPs we are in an ideal position to manage both.
References:
- Vestbo J, Anderson JA, Brook RD, Calverley PM, Celli BR, Crim C, Martinez F, Yates J, Newby DE, SUMMIT Investigators . Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double‐blind randomised controlled trial. Lancet. 2016;387:1817–1826.
- Rothnie KJ, Connell O, Mullerova H, Smeeth L, Pearce N, Douglas I, Quint JK. Myocardial infarction and ischemic stroke after exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2018;15:935–946.
- Kunisaki KM, Dransfield MT, Anderson JA, Brook RD, Calverley PMA, Celli BR, Crim C, Hartley BF, Martinez FJ, Newby DE, et al. Exacerbations of chronic obstructive pulmonary disease and cardiac events. A post hoc cohort analysis from the SUMMIT randomized clinical trial. Am J Respir Crit Care Med. 2018;198:51–57.
- Dransfield MT, Criner GJ, Halpin DMG, Han MK, Hartley B, Kalhan R, Lange P, Lipson DA, Martinez FJ, Midwinter D, et al. Time‐dependent risk of cardiovascular events following an exacerbation in patients with chronic obstructive pulmonary disease: post hoc analysis from the IMPACT trial. J Am Heart Assoc. 2022;11:e024350.
- Yang HM, Ryu MH, Carey VJ, Kinney GL, Hokanson JE, Dransfield MT, Hersh CP, Silverman EK; COPDGene Investigators †. Chronic Obstructive Pulmonary Disease Exacerbations Increase the Risk of Subsequent Cardiovascular Events: A Longitudinal Analysis of the COPDGene Study. J Am Heart Assoc. 2024 Jun 4;13(11):e033882. doi: 10.1161/JAHA.123.033882. Epub 2024 May 31. PMID: 38818936.