Abstract
Background
COPD frequently coexists with cardiovascular diseases. Cardiovascular death is also a major contributor to mortality in COPD patients. Inhaled corticosteroids (ICS), as the most commonly prescribed inhaled anti-inflammatory medications, have been widely used for management of COPD patients who experience frequent exacerbations. However, whether ICS have a cardiovascular protective effect remains unclear. The purpose of this work was to comprehensively ascertain the risks of cardiovascular deaths related to ICS in COPD patients.
Methods
PubMed, the Cochrane Library and Embase were searched to screen qualifying articles from September to November 2022. An updated search was conducted in October 2025. We identified trials of any ICS for treatment of COPD and reported on cardiovascular deaths. Meta-analyses were conducted to calculate risk ratios with 95% confidence intervals. The primary end-point was cardiovascular mortality.
Findings
35 randomised controlled trials enrolling 74 004 subjects were analysed. Inhaled formulations containing ICS significantly reduced the risk of cardiovascular deaths compared with inhaled formulations without ICS (risk ratio 0.84, 95% CI 0.74–0.95). ICS/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) significantly reduced the risk of cardiovascular deaths compared with dual LAMA/LABA therapy (risk ratio 0.56, 95% CI 0.37–0.86). ICS monotherapy also significantly reduced the risk of cardiovascular deaths compared with placebo (risk ratio 0.81, 95% CI 0.66–0.99). However, ICS/LABA did not significantly reduce the risk of cardiovascular deaths compared to LABA monotherapy (risk ratio 0.98, 95% CI 0.80–1.20).
Conclusions
Inhaled formulations containing ICS are associated with a reduced risk of cardiovascular deaths in patients with COPD.
Shareable abstract
In patients with COPD, inhaled formulations containing ICS are associated with a reduced risk of cardiovascular deaths. https://bit.ly/4q9m5eH
Introduction
COPD imposes a significant public health challenge worldwide due to its high prevalence and mortality [1]. Airways inflammation triggered by the inhalation of cigarette smoke or other harmful airborne particles (e.g. air pollution and biomass fuel) is a key driver of COPD progression and exacerbations [1]. During this inflammatory process, inflammatory mediators such as fibrinogen, C-reactive protein, interleukin (IL)-6 and IL-8 are released and enter the systemic circulation, thereby promoting the occurrence and development of cardiovascular diseases (CVDs), including atherosclerosis, coronary heart disease and myocardial infarction (MI) [1–3]. Consequently, CVD frequently coexists with COPD. Cardiovascular death is also a major contributor to mortality in COPD patients [3].
Management of COPD currently relies primarily on inhaled medications, including long-acting muscarinic receptor antagonists (LAMAs), long-acting β2 adrenoceptor agonists (LABAs) and inhaled corticosteroid (ICS) [2]. In particular, due to the potent local anti-inflammatory effects of ICS, multiple randomised controlled trials (RCTs) have demonstrated that adding ICS to long-acting bronchodilators significantly reduces the risk of acute exacerbations in patients with COPD compared with long-acting bronchodilator monotherapy (e.g., ICS/LABA/LAMA versus LABA/LAMA or ICS/LABA versus LABA) [4–9]. Interestingly, Sin et al. [10] also reported that ICSs can reduce serum C-reactive protein levels in COPD, which suggested that ICSs may lower the risk of CVD through suppression of systemic inflammatory responses. However, the current evidence regarding the impact of ICSs on cardiovascular outcomes in COPD patients remains quite limited. Here, we performed a meta-analysis of RCTs to comprehensively ascertain the risk of cardiovascular mortality associated with ICS therapy in COPD patients.
Methods
Our work was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and prospectively registered in PROSPERO (CRD42022375421) [11].
Search strategy
On 5 September 2022, an independent review of Embase, the Cochrane Library and PubMed was performed to identify eligible RCTs. The search included the following keywords: “ICS”, “inhaled corticosteroids”, “budesonide”, “fluticasone”, “beclomethasone”, “ciclesonide”, “mometasone” and “chronic obstructive pulmonary disease”. An updated search was conducted in October 2025. Detailed search strategies and procedures are shown in table S1.
Primary and secondary end-points
Cardiovascular mortality was the primary end-point, which was defined as any death with a reported cardiovascular cause, including acute MI, heart failure, sudden cardiac death, cardiovascular haemorrhage, cardiovascular procedures, stroke and other cardiovascular causes [12]. A major cardiovascular event (MACE) was a secondary outcome and was defined as cardiovascular death, nonfatal stroke or non-fatal MI, whichever came first. The definition of stroke included cerebrovascular accident, cerebral infarction, haemorrhagic stroke, embolic cerebral infarction, ischaemic cerebral infarction, transient ischaemic attack, ischaemic stroke and cerebellar infarction [12].
Eligibility criteria
Trials that met the following criteria were included in our analysis: 1) RCTs, 2) stable COPD (according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition [1]), 3) ICS monotherapy (including budesonide, fluticasone propionate, fluticasone furoate, beclomethasone, ciclesonide and mometasone; other ICS formulations that are occasionally seen in trials but not clinically used were not included in the study), ICS/LABA or triple therapy as the interventional drug, 4) inhaled therapy without ICS (including placebo) as controls, 5) trials providing data on cardiovascular deaths (studies that provided data only on the secondary end-points, but not the primary end-point, were excluded from the analysis).
Data extraction and quality assessment
In this work, two reviewers (M.-J. Yang and X.-M. Ying) independently extracted data on cardiovascular deaths, MI, stroke and MACEs. Any discrepancies were settled through discussion. If necessary, a third reviewer was consulted. To obtain information on cardiovascular deaths, MACEs, MI and stroke for each trial, we reviewed the reported secondary outcomes, adverse event listings, online supplementary data and records on ClinicalTrials.gov. The quality of each trial was assessed using the Cochrane risk of bias tool [13]. Moreover, the GRADE (grading of recommendations assessment, development and evaluation) approach was used to rate the quality of evidence.
Subgroup analyses
Several pre-defined subgroup analyses were performed based on the length of follow-up (≤3, 6 and ≥12 months), the type of medication combined with ICS, baseline MACE rates in the control group, the severity of COPD (GOLD grade II versus GOLD grades III–IV), specific formulations of ICS (fluticasone, budesonide, beclomethasone dipropionate and mometasone furoate), blood eosinophil levels, ICS use during a run-in period, baseline exacerbations in the previous year, history of asthma, exclusion of participants with exacerbations at enrolment, and dose of ICS (high/medium/low dose, as defined in supplementary appendix; dose equivalency is provided in table S2) [14].
Data analyses
Review Manager version 5.4 and R software version 4.3.3. was used to calculate risk ratios and their associated 95% confidence intervals for the primary and other outcomes. Random and fixed-effects models were both used to pool the extracted data. Considering that cardiovascular death, MACEs, MI and stroke were relatively rare in the included RCTs, Peto odds ratios with 95% confidence were also calculated [15]. Statistical heterogeneity was assessed using the I2 statistic. I2 values ≥50% were considered to represent significant heterogeneity. Potential publication bias was assessed by visual estimation (funnel plot) and Egger and Begg tests were also used for further quantitative assessment. All reported p-values are two-sided with significance set at less than 0.05. Sensitivity analyses were performed by using a random-effects model and also by excluding RCTs with a high risk of bias. Trial sequential analysis (TSA) was also performed using TSA software (version 0.9.5.10) to detect the possibility of type 1 and type 2 errors.
Results
Eligible trials
A total of 35 eligible trials reported data on cardiovascular deaths (figure 1) [4–6, 8, 9, 16–45]. These RCTs enrolled 74 004 participants, of whom 43 818 received ICS-based therapy and 30 186 received non-ICS therapy. Of these, 10 RCTs (n=15 413) assessed ICS only versus placebo, 16 RCTs (n=23 750) assessed ICS/LABA versus LABA only and four RCTs (n=14 156) assessed ICS/LAMA/LABA versus LAMA/LABA. Seven RCTs were followed-up for 3 months, 14 for 6 months, 11 for 12 months and three for 36 months. The characteristics of the included trials are summarised in table 1.
FIGURE 1.
Flow of study selection. ICS: inhaled corticosteroid; RCT: randomised controlled trial.
TABLE 1.
Summary characteristics of included randomised controlled trials (RCTs)
| Characteristic | Number of RCTs | Percentage (%) |
|---|---|---|
| Published year | ||
| <2000 | 1 | 2.9 |
| 2000–2004 | 3 | 8.6 |
| 2005–2009 | 7 | 20 |
| 2010–2014 | 7 | 20 |
| 2015–2020 | 17 | 48.6 |
| Follow-up duration | ||
| About 12 weeks | 7 | 20 |
| About 24 weeks | 14 | 40 |
| About 52 weeks | 10 | 28.6 |
| About 108 weeks | 1 | 2.9 |
| About 216 weeks | 3 | 8.6 |
| Type of intervention | ||
| LAMA/LABA/ICS | 4 | 11.4 |
| LABA/ICS | 29 | 82.9 |
| ICS only | 11 | 31.4 |
| Evaluated outcome | ||
| Cardiovascular deaths | 35 | 100.0 |
| MACE | 35 | 100.0 |
| Myocardial infarction | 30 | 85.7 |
| Stroke | 23 | 65.7 |
| Male | ||
| ≤50% | 0 | 0 |
| 50–75% | 21 | 60 |
| >75% | 14 | 40 |
| Mean age | ||
| ≤65 years | 21 | 60 |
| >65 years | 13 | 37.1 |
| Current smoker | ||
| ≤25% | 0 | 0 |
| 25–50% | 22 | 62.9 |
| >50% | 10 | 28.6 |
| Unclear | 3 | 8.6 |
| Grade FEV1 | ||
| GOLD 1 (≥80% pred) | 1 | 2.9 |
| GOLD 2 (50–79% pred) | 13 | 37.1 |
| GOLD 3 (30–49% pred) | 19 | 54.3 |
| GOLD 4 (<30% pred) | 0 | 0 |
| Unclear | 2 | 5.7 |
| Cardiovascular risk factors# | ||
| <10% | 0 | 0 |
| 10–20% | 0 | 0 |
| 21–30% | 1 | 2.9 |
| 31–40% | 0 | 0 |
| 41–50% | 0 | 0 |
| ≥50% | 2 | 5.7 |
| Unclear | 32 | 91.4 |
FEV1: forced expiratory volume in 1 s; GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroids; LABA: long-acting β2-agonists; LAMA: long-acting muscarinic antagonist; MACE: major adverse cardiovascular event. #: Cardiovascular risk factors percentage is defined as the proportion of patients with a history of diseases such as angina, myocardial infarction, stroke, diabetes, hypertension or hyperlipidaemia in the total population.
Risk of bias
The quality assessment of the included trials is shown in figure S1a and b. One trial was considered to have a high risk for performance bias. One RCT was considered to have a high risk for detection bias. One trial was considered to have a high risk for attrition bias. 15 RCTs were considered to have a low risk of bias in all aspects. All of the included studies reported data on withdrawal rates.
Primary outcomes
Our findings showed that ICS-based therapy significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy (35 RCTs; 1.08% versus 1.61% for control; risk ratio 0.84, 95% CI 0.74–0.95; I2=0%) (table 2).
TABLE 2.
Results of meta-analysis of inhaled corticosteroid (ICS)-based therapy versus non-ICS therapy for cardiovascular mortality according to type of comparison, different levels of baseline major adverse cardiovascular event (MACE) rates, the duration of treatment, COPD severity, blood eosinophil levels, baseline exacerbations of participants in the previous year, ICS withdrawal during a run-in period, co-existing asthma and whether participants with exacerbations were excluded at enrolment
| Groups and subgroups | Number of studies | Participants | ICS (events/total, %) |
No-ICS (events/total, %) |
Risk ratio (M-H, fixed, 95% CI) |
p-value | I2 (%) | GRADE evidence | p-value for interaction |
|---|---|---|---|---|---|---|---|---|---|
| Risk of cardiovascular death for ICS-based therapy versus non-ICS therapy | |||||||||
| ICS therapy versus non-ICS therapy (all) | 35 | 74 004 | 474/43 818 (1.08) | 486/30 186 (1.61) | 0.84 (0.74–0.95) | 0.006 | 0 | Low | |
| Stratified analysis by type of comparison | 0.06 | ||||||||
| LAMA/LABA/ICS versus LAMA/LABA | 4 | 14 156 | 43/9193 (0.47) | 40/4963 (0.81) | 0.56 (0.37–0.86) | 0.007 | 0 | Moderate | |
| ICS only versus placebo | 10 | 15 413 | 173/7828 (2.21) | 211/7585 (2.78) | 0.81 (0.67–0.99) | 0.04 | 0 | Low | |
| ICS/LABA versus LABA only | 16 | 23 750 | 182/12 898 (1.41) | 180/10 852 (1.66) | 0.98 (0.80–1.20) | 0.83 | 0 | Low | |
| Stratified analysis by baseline MACE rates in controls# | 0.14 | ||||||||
| Baseline MACE rate ≥1% per year | 13 | 52 738 | 455/31 671 (1.44) | 457/21 067 (2.17) | 0.86 (0.76–0.98) | 0.02 | 8 | Moderate | |
| Baseline MACE rate <1% per year | 22 | 21 266 | 19/12 147 (0.16) | 29/9119 (0.32) | 0.57 (0.34–0.97) | 0.04 | 0 | Low | |
| Stratified analysis by different duration | 0.72 | ||||||||
| ≤3 months | 7 | 5643 | 12/2815 (0.43) | 19/2828 (0.67) | 0.67 (0.34–1.30) | 0.24 | 0 | Moderate | |
| About 6 months | 14 | 14 181 | 16/8594 (0.19) | 16/5587 (0.29) | 0.74 (0.39–1.39) | 0.34 | 0 | High | |
| ≥12 months | 14 | 54 180 | 446/32 409 (1.38) | 451/21 771 (2.07) | 0.85 (0.75–0.97) | 0.01 | 14 | Low | |
| Stratified analysis by COPD severity | 0.99 | ||||||||
| Moderate COPD | 13 | 28 206 | 221/14 972 (1.48) | 263/13 234 (1.99) | 0.83 (0.70–0.99) | 0.04 | 0 | Moderate | |
| Severe COPD | 20 | 45 064 | 250/28 560 (0.88) | 222/16 504 (1.35) | 0.83 (0.70–1.00) | 0.05 | 0 | Low | |
| Stratified analysis by ICS dose | 0.28 | ||||||||
| Low-dose ICSs | 5 | 7327 | 14/3405 (0.41) | 27/3922 (0.69) | 0.59 (0.32–1.10) | 0.10 | 0 | High | |
| Medium-dose ICSs | 15 | 45 434 | 281/27 369 (1.03) | 293/18 066 (1.62) | 0.79 (0.67–0.93) | 0.004 | 0 | Moderate | |
| High-dose ICSs | 23 | 26 213 | 179/13 044 (1.37) | 195/13 169 (1.48) | 0.92 (0.75–1.12) | 0.40 | 0 | High | |
| Stratified analysis by ICS type | 0.55 | ||||||||
| Fluticasone propionate | 19 | 23 828 | 174/11 853 (1.47) | 193/11 975 (1.61) | 0.90 (0.74–1.10) | 0.31 | 0 | Moderate | |
| Fluticasone furoate | 8 | 32 424 | 255/19 713 (1.29) | 265/12 711 (2.08) | 0.82 (0.69–0.97) | 0.02 | 0 | Moderate | |
| Budesonide | 7 | 16 556 | 44/11 535 (0.38) | 28/5021 (0.56) | 0.65 (0.42–1.02) | 0.06 | 10 | Moderate | |
| Mometasone | 1 | 1196 | 1/717 (0.14) | 0/479 (0.00) | 2.01 (0.08–49.13) | 0.67 | – | – | |
| Stratified analysis by whether the ICS is withdrawn during a run-in period | 0.94 | ||||||||
| ICS withdrawal | 21 | 36 614 | 192/21 729 (0.88) | 196/14 885 (1.32) | 0.84 (0.69–1.02) | 0.07 | 0 | Low | |
| ICS continuation | 12 | 35 655 | 281/21 213 (1.32) | 286/14 442 (1.98) | 0.85 (0.72–1.00) | 0.05 | 0 | Moderate | |
| Stratified analysis by whether participants with a history of asthma were excluded | 0.51 | ||||||||
| Yes | 33 | 72 963 | 461/43 297 (1.06) | 474/29 666 (1.60) | 0.83 (0.73–0.95) | 0.005 | 0 | Low | |
| No | 2 | 1041 | 13/521 (2.50) | 12/520 (2.31) | 1.08 (0.50–2.30) | 0.85 | 48 | Moderate | |
| Stratified analysis by blood eosinophil levels | 0.02 | ||||||||
| ≥150 cells·mm−3 | 3 | 12 766 | 33/9377 (0.35) | 24/3389 (0.71) | 0.47 (0.28–0.78) | 0.004 | 0 | High | |
| Unclear | 32 | 61 238 | 441/34 441 (1.28) | 462/26 797 (1.72) | 0.87 (0.76–0.99) | 0.03 | 0 | Low | |
| Stratified analysis by baseline exacerbations of participants in the previous year | 0.67 | ||||||||
| ≥1 | 15 | 40 250 | 236/25 575 (0.92) | 200/14 675 (1.36) | 0.86 (0.72–1.04) | 0.12 | 0 | Moderate | |
| <1 | 11 | 26 987 | 213/14 673 (1.45) | 249/12 314 (2.02) | 0.84 (0.70–1.01) | 0.06 | 0 | Moderate | |
| Stratified analysis by whether participants with exacerbations were excluded at enrolment | 0.25 | ||||||||
| Participants with AEs were excluded | 30 | 62 111 | 424/35 474 (1.20) | 448/26 637 (1.68) | 0.86 (0.75–0.98) | 0.03 | 0 | Low | |
| Participants with AEs were included | 5 | 11 893 | 50/8344 (0.60) | 38/3549 (1.07) | 0.67 (0.44–1.00) | 0.05 | 18 | High | |
AE: acute exacerbation; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; GRADE: grading of recommendations assessment, development and evaluation; M-H: Mantel–Haenszel. #: Controls included LAMA only, LABA only, ICS/LABA and placebo.
When stratified by type of comparison, ICS/LAMA/LABA (i.e. triple therapy) significantly reduced the risk of cardiovascular deaths compared with dual LAMA/LABA therapy (four RCTs; 0.47% versus 0.81% for control; risk ratio 0.56, 95% CI 0.37–0.86; I2=0%) (figure 2 and table 2). ICS monotherapy also significantly reduced the risk of cardiovascular deaths compared with placebo (10 RCTs; 2.21% versus 2.78% for placebo; risk ratio 0.81, 95% CI 0.67–0.99; I2=0%) (figure 2 and table 2). However, ICS/LABA did not significantly modify the risk of cardiovascular deaths compared to LABA monotherapy (16 RCTs; 1.41% versus 1.66% for control; risk ratio 0.98, 95% CI 0.80–1.20; I2=0%) (figure 2 and table 2).
FIGURE 2.
Meta-analysis of included randomised controlled trials (RCTs) of inhaled corticosteroid (ICS)-based therapy versus non-ICS therapy for cardiovascular death according to type of comparison. Horizontal lines indicate 95% confidence intervals. Sizes of boxes are proportional to study weight. The I2 value indicates the percentage of variability across the pooled estimates attributable to statistical heterogeneity and the p-value is a test of heterogeneity across all studies. The other p-value represents the pooled estimates for all studies. df: degrees of freedom; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; M-H: Mantel–Haenszel.
When stratified by the daily dose of ICS, medium-dose ICS (15 RCTs; 1.03% versus 1.62% for control; risk ratio 0.79, 95% CI 0.67–0.93; I2=0%) significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy, while low doses and high doses did not significantly modify the risk of cardiovascular deaths (figure S5, table 2).
When stratified by ICS formulation, fluticasone furoate (eight RCTs; 1.29% versus 2.08% for control; risk ratio 0.82, 95% CI 0.69–0.97) (figure S7) significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy, while fluticasone propionate and budesonide did not significantly modify the risk of cardiovascular deaths (figure S7, table 2).
When stratified by duration of follow-up, the pooled results showed that ICS-based therapy significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy in populations who continued the treatment for at least 12 months (14 RCTs; 1.38% versus 2.07% for control; risk ratio 0.85, 95% CI 0.75–0.97) (figure S4), but did not significantly modify the risk of cardiovascular deaths in populations who were on treatment for 6 or less than 3 months (I2=0%) (table 2).
When stratified by the severity of airflow limitation, the pooled results showed that ICS-based therapy significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy in populations with moderate COPD (13 RCTs; 1.48% versus 1.99% for control; risk ratio 0.83, 95% CI 0.70–0.99; I2=0%), but did not significantly modify the risk of cardiovascular deaths in populations with severe COPD (figure S6).
When stratified by blood eosinophil levels, the pooled results showed that ICS-based therapy significantly reduced the risk of cardiovascular deaths compared with non-ICS therapy in populations with a blood eosinophil count ≥150 cells·mm−3 (three RCTs; 0.35% versus 0.71% for control; risk ratio 0.47, 95% CI 0.28–0.78; I2=0%) (table 2). However, there are insufficient data to investigate the effect in populations with a blood eosinophil count <150 cells·mm−3.
Secondary outcomes
ICS therapy significantly reduced the risk of MACEs compared to non-ICS therapy (35 RCTs; 2.01% versus 2.56% for control; risk ratio 0.89, 95% CI 0.81–0.98) in COPD patients. However, no significant difference was detected in the risk for MI (30 RCTs; 0.52% versus 0.63% for control; risk ratio 0.90, 95% CI 0.73–1.11; I2=0%) or stroke (23 RCTs; 0.59% versus 0.59% for control; risk ratio 1.05, 95% CI 0.84–1.32; I2=0%) (table 3). When stratified by the concomitant drug that was combined with ICS, no significant differences were detected in the comparison between ICS/LAMA/LABA and LAMA/LABA for stroke, MI or MACE, the comparison between ICS/LABA and LABA only for MACE, MI and stroke, and the comparison between ICS only and placebo for MACE, MI and stroke (table 3).
TABLE 3.
Results of meta-analysis of inhaled corticosteroid (ICS)-based therapy versus non-ICS therapy for a major adverse cardiovascular event (MACE), stroke and myocardial infarction (MI) according to different levels of baseline MACE event rates, the duration of treatment, ICS dose and formulation and COPD severity
| Groups and subgroups | Number of studies | Participants | ICS (events/total, %) | No-ICS (events/total, %) | Risk ratio (M-H, fixed) (95% CI) | p-value | I2 (%) | GRADE evidence | p-value for interaction |
|---|---|---|---|---|---|---|---|---|---|
| Secondary end-points – MACE | |||||||||
| Risk of MACE for ICS-based therapy versus non-ICS therapy | |||||||||
| ICS-based therapy versus non-ICS therapy | 35 | 74 004 | 880/43 818 (2.01) | 772/30 186 (2.56) | 0.89 (0.81–0.98) | 0.02 | 0 | Low | |
| Stratified analysis by type of comparison | 0.55 | ||||||||
| ICS/LAMA/LABA versus LAMA/LABA | 4 | 14 156 | 146/9193 (1.59) | 89/4963 (1.79) | 0.84 (0.65–1.09) | 0.19 | 0 | Moderate | |
| ICS/LABA versus LABA only | 16 | 23 750 | 307/12 898 (2.38) | 295/10 852 (2.72) | 0.98 (0.84–1.15) | 0.83 | 0 | Low | |
| ICS only versus placebo | 10 | 15 413 | 269/7828 (3.44) | 296/7585 (3.90) | 0.90 (0.77–1.06) | 0.20 | 0 | Moderate | |
| Risk of MACE for ICS-based therapy versus non-ICS therapy according to baseline MACE rates in controls# | 0.56 | ||||||||
| Baseline MACE rate ≥1% per year | 13 | 52 738 | 810/31 671 (2.56) | 709/21 067 (3.37) | 0.90 (0.81–0.99) | 0.04 | 0 | Low | |
| Baseline MACE rate <1% per year | 22 | 21 266 | 70/12 147 (0.58) | 63/9119 (0.69) | 0.81 (0.58–1.14) | 0.22 | 0 | Low | |
| Risk of MACE for ICS-based therapy versus non-ICS therapy according to different durations of treatment | 0.63 | ||||||||
| ≤3 months | 7 | 5643 | 17/2815 (0.60) | 26/2828 (0.92) | 0.67 (0.38–1.21) | 0.19 | 0 | Moderate | |
| About 6 months | 14 | 14 181 | 57/8594 (0.66) | 41/5587 (0.73) | 0.91 (0.61–1.36) | 0.63 | 0 | Low | |
| ≥12 months | 14 | 54 180 | 806/32 409 (2.49) | 705/21 771 (3.24) | 0.90 (0.81–0.99) | 0.04 | 0 | Moderate | |
| Risk of MACE for ICS-based therapy versus non-ICS therapy according to COPD severity | 0.72 | ||||||||
| Moderate COPD | 13 | 28 206 | 415/14 972 (2.77) | 447/13 234 (3.38) | 0.90 (0.79–1.03) | 0.12 | 0 | Low | |
| Severe COPD | 20 | 45 064 | 460/28 560 (1.61) | 321/16 504 (1.94) | 0.87 (0.75–1.01) | 0.06 | 0 | Low | |
| Secondary end-points – MI | |||||||||
| Risk of MI for ICS-based therapy versus non-ICS therapy | |||||||||
| ICS-based therapy versus non-ICS therapy | 30 | 63 263 | 200/38 440 (0.52) | 156/24 823 (0.63) | 0.90 (0.73–1.11) | 0.31 | 0 | Moderate | |
| Stratified analysis by type of comparison | 0.28 | ||||||||
| ICS/LAMA/LABA versus LAMA/LABA | 4 | 14 156 | 48/9193 (0.52) | 34/4963 (0.69) | 0.74 (0.48–1.15) | 0.18 | 0 | High | |
| ICS/LABA versus LABA only | 15 | 23 750 | 66/11 365 (0.58) | 61/9331 (0.65) | 0.99 (0.70–1.39) | 0.94 | 0 | Moderate | |
| ICS only versus placebo | 8 | 15 413 | 53/6171 (0.86) | 43/5940 (0.72) | 1.19 (0.80–1.77) | 0.38 | 0 | Moderate | |
| Secondary end-points – stroke | |||||||||
| Risk of stroke for ICS-based therapy versus non-ICS therapy | |||||||||
| ICS-based therapy versus non-ICS therapy | 23 | 57 795 | 206/35 180 (0.59) | 133/22 615 (0.59) | 1.05 (0.84–1.32) | 0.65 | 0 | Low | |
| Stratified analysis by type of comparison | 0.14 | ||||||||
| ICS/LAMA/LABA versus LAMA/LABA | 2 | 12 599 | 56/8409 (0.67) | 16/4190 (0.38) | 1.74 (1.00–3.04) | 0.05 | 0 | High | |
| ICS/LABA versus LABA only | 10 | 16 688 | 56/9072 (0.62) | 55/7616 (0.72) | 0.90 (0.62–1.30) | 0.56 | 0 | Low | |
| ICS only versus placebo | 5 | 10 511 | 43/5377 (0.80) | 42/5134 (0.82) | 1.02 (0.67–1.55) | 0.94 | 0 | Moderate | |
GRADE: grading of recommendations assessment, development and evaluation; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; M-H: Mantel–Haenszel. #: Controls included LAMA only, LABA only, ICS/LABA and placebo
Sensitivity analyses
The results of sensitivity analyses for cardiovascular death were robust when using the Mantel–Haenszel method to calculate odds ratio or risk ratio under both random-effects and fixed-effects models, as well as when excluding RCTs with a high risk of bias. Given the relative rarity of cardiovascular death in the included RCTs, the Peto odds ratio was also employed to estimate the associated risk. The effect estimates obtained were similar in both direction and magnitude to those derived from the Mantel-Haenszel method for risk ratio (tables S5–S8). Furthermore, additional sensitivity analyses were conducted using the leave-one-out approach and by excluding studies that did not employ blinding procedures. The results remained consistent with those of the main analysis (figures S2–S3).
Discussion
In this meta-analysis of 35 high-quality RCTs that included 74 004 patients with COPD, we showed for the first time in RCTs that inhaled formulations containing ICS are associated with a significantly reduced risk of cardiovascular death compared with inhaled formulations without ICS. When stratified by type of comparison, ICS/LAMA/LABA significantly reduced the risk of cardiovascular death compared with dual LAMA/LABA therapy. ICS monotherapy also significantly lowered cardiovascular death risk relative to placebo. However, ICS/LABA did not significantly modify the risk of cardiovascular deaths compared to LABA monotherapy, although the direction of the effect is similar to that of the overall effect of inhaled formulations containing ICS. In addition, some factors, such as baseline eosinophil levels, duration of ICS use, history of asthma and COPD severity, may also play an important role in the degree and duration of cardiovascular protection generated by ICS, but these factors may need to be further verified in future studies due to limited sample size.
Our results are in keeping with a recent population-based cohort study that reported improved survival of patients with COPD with ICS therapy, especially among those with either established CVD or at a high risk of a cardiovascular event [46]. We extend these results by showing in high-quality RCTs that ICS therapy reduced the risk of cardiovascular deaths by ∼16% in patients with COPD. In subgroup analyses, we found that triple therapy (ICS/LAMALABA) resulted in an approximately 44% reduction in cardiovascular deaths compared to double bronchodilator therapy (i.e. LAMA/LABA); ICS mono-therapy resulted in an approximately 19% reduction in cardiovascular death compared to placebo. Interestingly, we did not detect a significant effect when ICS/LABA was compared to LABA only. However, this analysis may have been limited because of small sample size.
Our results showed that triple therapy resulted in an approximate 44% reduction in cardiovascular deaths compared to dual LAMA/LABA therapy. These results may explain why the ETHOS trial found that triple therapy significantly reduced the risk of all-cause death in COPD patients compared with dual LAMA/LABA therapy [47]. These results also partially explain why dual LAMA/LABA therapy significantly increases the risk of MACEs in COPD patients compared to ICS/LABA [48]. The latest GOLD guidelines have recommended dual LAMA/LABA therapy and triple therapy as the cornerstone in the management of moderate-to-severe COPD, but the guidelines do not recommend how best to select these inhaled agents for high-risk cardiovascular populations, our results will fill these gaps and provide an important reference for clinicians facing these issues [1].
We are aware of two published meta-analyses that have explored the effects of ICS on cardiovascular endpoints. In 2018, Jing et al. [49] reported that ICS does not modify cardiovascular risk in COPD patients. However, this work included outcomes such as arrhythmias, hypertension, valvular heart disease, aneurysms and pulmonary embolism, while serious outcomes such as cardiovascular mortality was excluded, which may have diluted the risk estimates. In addition, their work did not incorporate recently published high-quality RCTs [8, 9, 22, 28, 37–39]. By focusing on the most serious outcome, cardiovascular mortality and by including high quality RCTs, our study had sufficient statistical power to demonstrate a salutary effect of ICS on cardiovascular mortality in a large number of patients with COPD. Another meta-analysis found a cardiovascular benefit of ICS in observational studies, but failed to demonstrate a cardiovascular protective effect of ICS in RCTs [50]. However, this review also did not include more recent (large) RCTs, which reduced the power of the meta-analysis [8, 9, 22, 24–39].
The underlying mechanisms by which ICS reduces the risk of cardiovascular deaths are unclear. One possibility is that inhaled corticosteroids have significant anti-inflammatory effects both systemically and locally that may modulate the risk of cardiovascular mortality [51]. Another possibility is that because the risk of cardiovascular deaths is highest during acute exacerbations of COPD, by reducing the risk of exacerbations and especially those requiring systemic corticosteroids, ICS may confer cardiovascular benefits to patients with moderate-to-severe COPD [31].
Our results found that the cardiovascular protective effect of ICS was driven primarily by reducing the risk of cardiovascular death in patients with COPD, rather than by reducing CVDs such as MI and stroke. The most likely explanation is that the majority of participants, such as approximately 90% of participants in the SUMMIT study and 60% of participants in the ETHOS study, had underlying CVD at the time of enrolment. In this context, using the incidence of CVD as an end-point may be insensitive in detecting the protective effect of ICS, potentially masking the cardiovascular protective effects of ICS. In contrast, cardiovascular death is a likely a more sensitive and specific end-point given that the majority of patients enrolled in large COPD therapeutic clinical trials had a history of CVD. The choice of end-points may also explain why, in the SUMMIT trial, the investigators found that ICS monotherapy reduced the risk of cardiovascular death by 21% relative to placebo (n=97, 2.3% versus n=122, 3.0%), but failed to demonstrate a cardiovascular protective effect of ICS on a set of composite cardiovascular end-points that included cardiovascular death and CVDs such as MI, stroke, unstable angina and transient ischaemic attacks [30]. The use of a composite end-point requires validation in COPD as therapies such as ICS may have differential impact on different cardiovascular outcomes.
Interestingly, we observed that triple therapy was associated with a marginally significant increase in risk of stroke compared with LAMA/LABA (risk ratio 1.74, 95% CI 1.00–3.04). Although the effect lies at the threshold of statistical significance, its potential clinical implications warrant careful consideration. On one hand, evidence from prior studies suggests that glucocorticoids may promote thrombosis by elevating coagulation factor levels and suppressing fibrinolytic activity [52, 53]. On the other hand, this finding is based on only two RCTs with limited sample sizes and without adjustment for multiple comparisons, raising the possibility that the observed association could be due to chance. Given these limitations, this result should be interpreted as an exploratory signal and requires confirmation in larger, prospectively designed studies.
Limitations and strengths
Our study also has several limitations, detailed discussion of which is described below. First, most of the trials included in this meta-analysis was not powered on cardiovascular deaths. Further, criteria for determining cardiovascular deaths varied among the included RCTs, leading to possible misclassification of cardiovascular deaths. However, any misclassification bias arising from above problem would be nondifferential, resulting in a dilution of risk estimates. Second, baseline cardiovascular risk may vary among subjects in these included RCTs and individual cardiovascular risk could not be determined during the review. Third, some studies were excluded due to insufficient information, which may have resulted in selection bias. In the future, researchers should carefully record cardiovascular baseline conditions in trials related COPD, as CVD is a very common comorbidity in COPD patients in the real world.
Despite certain limitations, our findings have clinical implications. First, this paper is the largest systematic review and meta-analysis to date designed to comprehensively assess the risk of cardiovascular deaths associated with ICS therapy among patients with COPD (35 RCTs enrolling 74 004 subjects were analysed). Second, CVDs are a common comorbidity in COPD patients, affecting 28–70% of patients, and is one of the leading causes of death in patients with COPD [54]. We investigated the effects of ICS on the risks of cardiovascular death among patients with COPD, which is a clinically important end-point. We show for the first time that ICS therapy significantly reduces the risk of cardiovascular death compared with non-ICS therapy among published RCTs. In a subgroup analysis, we show that the benefits of ICS therapy on cardiovascular mortality are observed only in those treated with low or medium doses and in patients who had an elevated baseline risk of cardiovascular events. This finding may also explain why ICS, despite a very modest effect on lung function and risk of exacerbations, appears to have a relatively large effect on mortality, especially in combination with LAMA and/or LABA [35, 50]. Third, the latest GOLD guidelines have recommended dual LAMA/LABA therapy and triple therapy as cornerstones in the management of moderate-to-severe COPD [1], but the guidelines do not recommend how best to select these inhaled agents for high-risk cardiovascular populations; our results will fill these gaps and provide an important reference for clinicians facing these issues.
Conclusions
In summary, the current body of evidence indicates that inhaled formulations containing ICS are associated with a significantly reduced risk of cardiovascular death compared with inhaled formulations without ICS. Although the exact mechanisms by which this occurs are largely unknown, these data suggest that low or moderate doses of ICSs should be considered in COPD patients who have elevated risk of cardiovascular events.
Points for clinical practice
Inhaled formulations containing ICS are associated with a reduced risk of cardiovascular death among patients with COPD.
These data suggest that inhaled formulations containing ICS should be considered in COPD patients who have an elevated risk of cardiovascular events.
Acknowledgements
The authors are indebted to all members of Department of Respiratory and Critical Care Medicine of The First Affiliated Hospital of Chongqing Medical University.
Footnotes
The systematic review protocol was registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) with identifier: CRD42022375421.
Provenance: Submitted article, peer reviewed.
Author contributions: All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. Conceived and designed the paper: M-J. Yang, S-L. Guo, D.D. Sin. Performed the study: M-J. Yang, X-X. Jin. Analysed the data: Y. Zhang, X-M. Ying, W. He. Contributed reagents/materials/analysis tools: X-M. Ying, W. He. Wrote the first draft of the manuscript: M-J. Yang, S-L. Guo, D.D. Sin.
Conflict of interest: D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim. The other authors declare no conflicts of interest.
Support statement: Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau): 2025MSXM006. Chongqing Sports Science Research Project: B202339. National Natural Science Foundation of China: 82500055. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
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Supplementary material
ERR-0254-2025.SUPPLEMENT
Data availability
Data sharing is not applicable as no datasets were generated and/or analysed for this study.
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Supplementary Materials
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Supplementary material
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Data Availability Statement
Data sharing is not applicable as no datasets were generated and/or analysed for this study.