Acknowledging the syndemic: a real-life cohort study of major adverse cardiovascular events in COPD

Extract

COPD patients have a high risk of major adverse cardiovascular events (MACE). Hence, COPD and cardiovascular disease may benefit from a syndemic approach. The association between COPD and cardiovascular disease is partially due to shared risk factors such as smoking, ageing, sedentary lifestyle and shared comorbidities [1, 2]. In addition, COPD itself is an independent risk factor for cardiovascular disease. Indeed, when matched for the established cardiovascular risk factors, COPD patients have a 25% higher risk of MACE compared to smokers without COPD [3].

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Male sex and elevated blood eosinophils are associated with major adverse cardiovascular events in COPD, suggesting that patients with these characteristics may particularly benefit from early cardiovascular risk assessment, even in early GOLD stages https://bit.ly/4lF3BkT

To the Editor:

COPD patients have a high risk of major adverse cardiovascular events (MACE). Hence, COPD and cardiovascular disease may benefit from a syndemic approach. The association between COPD and cardiovascular disease is partially due to shared risk factors such as smoking, ageing, sedentary lifestyle and shared comorbidities [1, 2]. In addition, COPD itself is an independent risk factor for cardiovascular disease. Indeed, when matched for the established cardiovascular risk factors, COPD patients have a 25% higher risk of MACE compared to smokers without COPD [3]. This can be partly explained by systemic inflammation and oxidative stress associated with COPD. Moreover, hyperinflation and hypoxia may increase pulmonary vascular resistance, causing right ventricular dysfunction and increase risk of MACE [4, 5]. Recent COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines introduced blood eosinophil count (BEC) as a possible theragnostic biomarker [6]. Because of their link with type 2 inflammation, blood eosinophils can contribute to the development of cardiovascular disease [7, 8]. Neurohumoral activation, which is well recognised in cardiovascular disease and particularly in heart failure, may also contribute to the increased cardiovascular risk observed in COPD patients [9]. Considering the clinical relevance of MACE prevention, this study aimed to identify clinical characteristics associated with MACE in a tertiary care COPD population.

We analysed longitudinal data from COPD patients attending the University Hospital UZ Brussel, a tertiary care centre. The study was approved by the local ethics committee (BUN: 1432023000266). Lung function parameters, clinical data and patient alive/deceased status were extracted from electronic medical records. COPD patients were identified based on a post-bronchodilator forced expiratory volume in 1 s (FEV₁) to forced vital capacity ratio <70% in combination with a smoking history of ≥10 pack-years. Patients with asthma, asthma-COPD overlap, bronchiectasis or interstitial lung disease were excluded.

Patients were eligible if they had a baseline visit between early 2017 and early 2019, with follow-up data available until 2023. We included patients who either returned for follow-up or had died from a known cause before follow-up could occur. MACE was defined according to the four-point criteria, including cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, and hospitalisation for unstable angina or revascularisation procedures [10]. Cause of death was classified as either “cardiovascular” (i.e. one of the MACE endpoints), “respiratory”, “COVID-19”, “cancer-related”, or “other”. Statistical analyses were performed using MedCalc (version 22.013, Mariakerke, Belgium) including Mann–Whitney U-test, Fisher's exact test, Chi-squared test and multivariate logistic regression.

Of the 373 patients, 65% were male and one-third of the patients were active smokers at study entry (median of 45 pack-years). At baseline, 11%, 48%, 33% and 8% of patients were in COPD GOLD grades 1, 2, 3 and 4, respectively. During the median follow-up of 4.5 years (interquartile range 4.3–4.7), 144 patients (39%) died. Mortality rates increased with COPD grade: 26% (11 of 42) in GOLD 1, 37% (67 of 179) in GOLD 2, 43% (53 of 124) in GOLD 3, and 46% (13 of 28) in GOLD 4. Respiratory deaths were more common in GOLD 3–4 (36%) than in GOLD 1–2 (15%, p=0.03), while cancer-related deaths were more frequent in GOLD 1–2 (51% versus 27%, p=0.003). COVID-19 accounted for 8% of deaths in GOLD 1–2 and 2% in GOLD 3–4 (p=0.09). Cardiovascular deaths occurred at similar rates in early and advanced GOLD grades (GOLD 1–2: 11.5% versus GOLD 3–4: 12.1%, p=0.9).

59 patients (16%) experienced at least one MACE during follow-up: 53 patients had one event, five had two, and one had three. The remaining patients formed the control group (n=314). Baseline patient characteristics for both groups are shown in table 1. There were no significant differences in age, smoking history/status, body mass index, FEV₁ or GOLD grade. Notably, there were significantly more men in the MACE group compared to controls (81% versus 62%, p=0.004). Prior MACE at baseline was not associated with increased MACE during follow-up (p=0.13). Patients who experienced MACE were more likely to have a BEC >300 cells·μL⁻¹ at least once during follow-up (65% versus 46%, p=0.008). No significant difference was observed in the number of patients experiencing at least one severe exacerbation between the MACE and control groups (47% versus 41%, p=0.8) (table 1). While inhaled corticosteroids use increased over the course of the follow-up in the entire patient cohort, it was similar between MACE and control groups (baseline: 19% in MACE versus 25% in controls (p=0.4); end of study: 32% in MACE versus 48% in controls (p=0.09)). In addition, stepwise multivariate logistic regression (including all parameters listed in table 1) showed that only male sex (OR 2.07, 95% CI 1.02–4.22; p=0.044) and a BEC >300 cells·μL⁻¹ (OR 2.13, 95% CI 1.16–3.92; p=0.015) were independently associated with the occurrence of MACE during follow-up.

TABLE 1.

Patient characteristics comparing patients with major adverse cardiovascular events (MACE) to controls

	COPD cohort (n=373)	MACE group (n=59)	Control group (n=314)	p-value
Age, years	69 (62–74)	71 (64–78)	69 (62–73)	0.07
Male sex	243 (65)	48 (81)	195 (62)	0.004
Prior history of MACE	84 (23)	18 (31)	66 (21)	0.13
Smoking history, pack-years	45 (33–55)	45 (40–55)	45 (31–55)	0.3
Current smoker	129 (35)	19 (32)	110 (35)	0.8
BMI, kg·m−2	25 (22–28)	26 (22–30)	25 (22–28)	0.2
FEV1, % predicted	55 (41–71)	62 (40–75)	54 (41–70)	0.2
COPD grade at baseline				0.7#
1	42 (11)	8 (14)	34 (11)
2	179 (48)	30 (51)	149 (48)
3	124 (33)	16 (27)	108 (34)
4	28 (8)	5 (8)	23 (7)
ICS treatment at baseline	88 (24)	11 (19)	77 (25)	0.4
≥1 severe exacerbation during follow-up	157 (42)	28 (47)	129 (41)	0.8
BEC >300 cells·µL−1 at least once during follow-up¶	167/342 (49%)	36/55 (65%)	131/287 (46%)	0.008

Data are expressed as median (interquartile range) if continuous and as n (%) if categorical.

p-value: Mann–Whitney U-test or Fisher's exact test, considered significant if p<0.05 (indicated in bold).

ICS: inhaled corticosteroids; FEV₁: forced expiratory volume in 1 s; BMI: body mass index; BEC: blood eosinophil count.

^#: in this case Chi-squared test was used instead of Fisher's exact test.

^¶: BEC was available in 342 out of 373 patients (92% of the cohort): n=55 in MACE group; n=287 in control group.

In the present study, we observed that both elevated BEC and male sex were associated with MACE. A key strength of our study is that all COPD diagnoses were spirometry-based (post-bronchodilator FEV₁ to forced vital capacity <0.70) in contrast to large registry-based studies and population cohorts such as NOVELTY and EXACOS-CV [7, 11]. Literature has established male sex as a risk factor for cardiovascular disease [12] and for COPD [13] in the general population. Our study specifically demonstrates that within the COPD patient population, male sex was associated with a higher occurrence of MACE. A second association with MACE identified by our study was an elevated BEC. Patients with a BEC >300 cells·μL⁻¹ at least once during follow-up were significantly more likely to experience MACE. This association may be explained by the pro-inflammatory role of eosinophils, which release type-2 driven cytotoxic mediators that can affect the cardiovascular system [8, 14]. Although the exact mechanism is not yet fully understood, eosinophilic inflammation could be a potential treatable trait and therapeutic target in the prevention of MACE in COPD.

At least one MACE was observed in 16% of patients during the median follow-up of 4.5 years, comparable to what was seen in large COPD cohorts [15]. MACE and cardiovascular death occurred with similar frequency in both early (GOLD 1–2) and advanced (GOLD 3–4) COPD, supporting the role of COPD itself as an independent cardiovascular risk factor [2, 3, 5] and highlighting the need for systematic cardiovascular screening across all disease stages. Overall mortality was high (39%), reflecting advanced disease and comorbidities typical of a tertiary care COPD population, as opposed to patient populations in clinical trials such as UPLIFT and NOVELTY, which also included asymptomatic patients [7, 16]. Consistent with those trials, mortality increased with GOLD grade.

No difference was seen in severe exacerbation rate between MACE and control groups, contrasting with findings from the EXACOS-CV study [11]. We suspect that this may be partly due to MACE definition differences and the fact that we only reported severe exacerbations. Nevertheless, our findings do suggest that, independently of severe exacerbation frequency, an elevated BEC contributes to MACE. Given that previous research has demonstrated an increased risk of cardiovascular events following acute exacerbations [11], the introduction of biologics for selected COPD patients with frequent exacerbations harbours the hope that cardiovascular events could also be attenuated in these patients, in addition to their effect on exacerbations.

Prior history of MACE at baseline did not predict future events, possibly due to closer follow-up and secondary prevention in those patients. Finally, there was no significant difference between MACE and control groups regarding inhaled corticosteroid use.

Despite smoking being a known risk factor for cardiovascular events, neither current smoking nor pack-years were associated with MACE in this cohort. This may be explained by the absence of systematic data on smoking status at the time of blood sampling and MACE. In addition, baseline eosinophil counts could not be reported due to the lack of routine sampling at study entry. These factors represent limitations of our study.

We conclude that, during a median 4.5-year follow-up of COPD patients in a tertiary centre, MACE occurred in both early and advanced COPD. Male sex and an occurrence of elevated BEC were identified as possible risk factors for MACE, suggesting that patients with these characteristics may particularly benefit from early cardiovascular risk assessment.

Data availability

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.