• COPD

Recognize and reduce cardiopulmonary risks

An increasing number of studies have shown that patients with chronic obstructive pulmonary disease (COPD) have an increased cardiovascular risk and that COPD exacerbations promote serious cardiac complications. A review published in Advances in Therapy in 2024 will summarize the evidence, including recent treatment studies that have examined various inhaled combination treatments for cardiovascular and other outcomes.

COPD ist durch eine Obstruktion der Atemwege und/oder ein nicht reversibles Lungenemphysem gekennzeichnet. Ausgangspunkt ist stets eine chronische Inflammation der Bronchien: überschiessende Entzündungsreaktionen können zu einer irreversiblen Schädigung der Lungenstruktur bis zur Zerstörung der Lunge führen. Meistens leiden COPD-Patienten unter einer oder mehreren Komorbiditäten, wobei kardiovaskuläre Erkrankungen (CVD) am häufigsten vorkommen [1]. Dass COPD mit einem deutlich erhöhten kardiovaskulären Risiko einhergeht, bestätigte sich auch in einer grossen retrospektiven kanadischen Kohortenstudie, deren Ergebnisse 2023 veröffentlicht wurden [2]. Von ~5,8 Millionen ≥40-jährigen Erwachsenen ohne nachgewiesene CVD hatten 152 125 eine COPD. Nach Adjustierung bezüglich anderer kardiovaskulärer Risikofaktoren, Komorbiditäten und weiterer Variablen stellte sich heraus, dass die MACE**-Rate bei COPD-Betroffenen um 25% höher war im Vergleich zu Personen ohne COPD (HR=1,25; 95%-KI: 1,23–1,27). Dies sei vergleichbar mit der Rate bei Diabetesbetroffenen, so die Studienautoren [3]. Daher wird bei COPD zu einer angemessenen kardiovaskulären Primärprävention geraten. 

** MACE=majoradverse cardiac event (serious cardiac complication)

This topic was addressed by Professor Dave Singh, Clinical Pharmacology and Respiratory Medicine, University of Manchester (UK) and colleagues in a review published in 2024 [3]. Her focus is on explaining how symptoms and exacerbations influence the cardiovascular risk in COPD and how this can be counteracted by therapeutic measures.

Comorbidities, blood eosinophilia and poor lung function increase the risk of an exacerbation in COPD [4]. Symptoms such as increased dyspnea and frequent productive coughing are predictors of the risk of a later exacerbation. In a retrospective observational cohort study, about half of the patients with a score of ≥3 on the MRC (Medical Research Council) dyspnea scale experienced an exacerbation in the following 12 months [36]. In a prospective observational study, COPD patients with frequent productive cough at baseline were twice as likely to be hospitalized due to an exacerbation within the following 12 months and had a 39% increased risk of a serious adverse cardiovascular or respiratory event during the three-year follow-up period [37,38].

Exacerbations increase the risk of CVD

Descriptions by patients such as “worsening, cold, restriction, more spray use” should alert treating physicians, as these are often indications of an exacerbation [4]. Study data show that exacerbations increase the risk of cardiovascular events and that this risk can persist for up to a year [5,6]. In a retrospective cohort study in Canada, 43.4% of 1,42,787 COPD patients (mean age 68.1 years) suffered at least one exacerbation within an observation period of 64 months. The adjusted hazard risk (HR) for death from any cause or hospitalization due to acute coronary syndrome, heart failure, arrhythmia or cerebral ischemia was 15.86 (95% CI: 15.17-16.58) 1-7 days after an exacerbation and remained elevated for up to 1 year [7]. Across different cohorts, there was a significantly increased risk of major cardiovascular events$ or death within the first 7 days after a severe exacerbation (adjusted HR& 15.84 to 48.57) and this persisted for over a year, or up to 6 months after a moderate exacerbation [7–9]. These findings are also supported by a post-hoc analysis of the IMPACT study, which reported that the overall risk of cardiovascular events was higher in moderate and severe exacerbations and remained elevated up to 30 days after the exacerbation, even in patients with low cardiovascular risk [10].

$ Acute coronary syndrome, cardiac arrhythmia, heart failure and ischemic stroke

& HR 15.84; 95%-CI 15.26-16.45 to HR 48.57; 95%-CI 36.88-63.96

ETHOS study: Randomization according to eosinophil count
In the ETHOS (Efficacy and safety of Triple Therapy in Obstructive lung disease) study, triple therapy was investigated over a period of 52 weeks. The total of >8500 included patients were randomized stratified according to the following criteria:
– History of exacerbations (1 or ≥2 moderate or severe exacerbations)
– FEV1 after bronchodilation (25 to 50% or 50 to <65% target)
– Eosinophil count in the blood (<150 or ≥150 cells/mm3)
– Country of recruitment
to [4,26]

Multidisciplinary risk-adapted drug treatment

The latest GOLD update advocates a multidisciplinary approach to COPD management [11,12]. Cooperation between primary care physicians and specialists from respiratory and cardiology departments is to be strengthened.

Recent real-world data suggest that initiating triple therapy within 30 days of an exacerbation is better at reducing the risk of a future exacerbation compared to delayed intervention (31-180 or 181-365 days) [34,35]. Singh et al. discuss various treatment studies in their review and point out that when interpreting the results of treatment studies, the patient characteristics of the collectives studied must be taken into account [3]. For example, in the FLAME study, dual therapy with LAMA/LABA was associated with a reduction in exacerbations compared to a dual inhaled corticosteroid (ICS)/LABA combination, while in the IMPACT and ETHOS studies, dual therapy with ICS/LABA showed a more significant reduction in exacerbations compared to the LAMA/LABA combination [13–15]. These differences may be explained by the fact that patients with a higher risk of exacerbations were included in IMPACT and ETHOS than in FLAME, according to Singh et al. [3,13–16].

Which inhalation therapy for which patients?

Singh et al. cite evidence showing how inhaled therapies can provide cardiopulmonary protection [3,16]. Accordingly, ICS can reduce inflammation in the lungs and bronchodilators reduce airway resistance and hyperinflation, thereby improving inspiratory capacity (Fig. 1) [10, 17-19]. Both ICS and bronchodilators can improve ventilation and perfusion matching, resulting in reduced hypoxemia [21,22]. These components of triple therapy have shown a reduction in exacerbations in various studies, with the overall benefit of ICS appearing to be greatest in patients at high risk of exacerbations [23,24].

FULFIL and IMPACT: Triple therapy with fluticasone furoate/umeclidinium/vilanterol was investigated in the 24-week FULFIL study and the 52-week IMPACT study. The FULFIL study found a significant reduction in the rate of moderate or severe exacerbations with triple therapy compared to ICS/LABA, and the IMPACT study met its primary endpoint of reducing moderate or severe exacerbations with triple therapy compared to LAMA/LABA and ICS/LABA [14,15].

ETHOS and KRONOS: The efficacy of a different triple therapy (budesonide/glycopyrrolate/formoterol fumarate) compared with the corresponding dual therapies was investigated in the 24-week KRONOS and 52-week ETHOS studies [15,26,27]. In the KRONOS study, triple therapy showed a significant reduction in the rate of moderate or severe exacerbations compared to LAMA/LABA [27]. 74.4% of the population had no documented moderate or severe exacerbations in the 12 months prior to the study [27]. Further effects of this triple therapy on the rate of exacerbations were demonstrated in the ETHOS study, which met its primary endpoint of reducing the risk of moderate or severe exacerbations compared to LAMA/LABA and ICS/LABA [15].

TRILOGY, TRINITY and TRIBUTE: Similarly, in the three 52-week studies TRILOGY, TRINITY and TRIBUTE, a significant reduction in the rate of moderate or severe exacerbations was observed with triple therapy (beclomethasone dipropionate/glycopyrronium/formoterol fumarate) compared to ICS/LABA or LAMA- or LAMA/LABA [28–30].

Post-hoc analyses of the IMPACT and ETHOS studies showed a greater reduction in the risk of exacerbation with triple therapy in patients with an eosinophil count of ≥100 cells/μl [31–33].

Literature:

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  37. Hughes R, et al: Frequent productive cough: symptom burden and future exacerbation risk among patients with asthma and/or COPD in the NOVELTY study. Respir Med 2022; 200: 106921.
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FAMILY PHYSICIAN PRACTICE 2024; 19(5): 48-49

Autoren
  • Mirjam Peter, M.Sc.
Publikation
  • HAUSARZT PRAXIS
  • CARDIOVASC
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