Integrating Disease Burden and Cost-Effectiveness for Value-Based Prioritisation of COPD Interventions: A Narrative Review

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Disease burden and economic value are typically evaluated separately, limiting integrated assessment for value-based healthcare and resource allocation. This review integrated COPD burden-reduction potential with the incremental cost-effectiveness ratio (ICER) to prioritise interventions by health impact and economic value.

Methods

This narrative review was conducted with reference to the Scale for the Assessment of Narrative Review Articles (SANRA). PubMed, Embase, and the Cochrane Library were searched from inception to August 2026 for evidence on COPD burden, healthcare costs, and intervention economic outcomes. Reporting completeness and methodological quality were assessed using CHEERS 2022, the CHEC-list, and AMSTAR 2, as appropriate. Interventions were synthesised within an integrated disability-adjusted life years (DALYs)-ICER framework.

Results

Eighty publications contributed to the synthesis. Acute exacerbations, pulmonary complications, and major comorbidities were the principal drivers of COPD burden and healthcare costs. Smoking cessation and pulmonary rehabilitation showed the most favourable combination of burden-reduction and economic value. Influenza and pneumococcal vaccination showed favourable profiles, although their classification remains provisional because COPD-specific economic evidence is limited. Triple inhaled therapy showed context-dependent economic value across healthcare settings, while long-term azithromycin and long-term oxygen therapy combined with home mechanical ventilation were economically favourable primarily in selected high-risk populations. Ensifentrine and mepolizumab in type 2 COPD demonstrated clinically meaningful benefits but less favourable economic value at the prices evaluated in their source settings. ICS-containing therapy in low-eosinophil, non-exacerbating patients, household air pollution control, and comorbidity-directed interventions could not be formally classified because applicable COPD-specific economic evidence was insufficient.

Conclusion

Integrating burden-reduction potential with ICER-based cost-effectiveness provides a conceptual framework for prioritising COPD interventions by health impact and economic value, while highlighting priorities for COPD-specific economic evaluation and future validation.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, heterogeneous lung condition characterised by chronic respiratory symptoms and persistent, often progressive airflow obstruction resulting from airway and/or alveolar abnormalities.¹ It typically presents with dyspnoea, cough, and sputum production, while recurrent exacerbations contribute substantially to reduced life expectancy, increased mortality, and escalating healthcare costs.² Despite advances in prevention and treatment, the global burden of COPD continues to rise, particularly in low- and middle-income countries (LMICs), where population ageing, persistent tobacco exposure, and increasing air pollution are expected to further exacerbate its impact.³ Globally, COPD affects an estimated 391.9 million people aged 30–79 years, corresponding to a prevalence of 10.3%.⁴ According to the Global Burden of Disease Study 2019, COPD accounted for 3.3 million deaths and 74.4 million disability-adjusted life years (DALYs) in 2019.³

COPD is currently the third leading cause of death worldwide, underscoring its substantial and growing public health burden.^3,5,6 Between 2019 and 2021, annual COPD-related deaths increased from 3.3 million to 3.5 million, accounting for approximately 5% of all deaths worldwide in 2021.⁷ This considerable clinical burden is accompanied by substantial economic consequences, including direct medical costs, hospitalisation expenses, and productivity losses.⁸ Acute exacerbations are particularly important drivers of this burden, as they accelerate lung-function decline, increase mortality, and account for a substantial proportion of direct healthcare costs, while comorbidities such as cardiovascular disease and lung cancer further increase healthcare utilisation and expenditure.^9–12

The global burden of COPD is projected to increase further in the coming decades. Recent estimates suggest that the number of people living with COPD could reach approximately 600 million by 2050, representing a 23% increase from 2020.^13,14 This growing prevalence is expected to place increasing pressure on healthcare systems and healthcare expenditure worldwide. In high-income countries, COPD already accounts for a substantial proportion of respiratory disease-related healthcare expenditure.¹³ In the United States, annual direct medical costs attributable to COPD are projected to approach USD 40 billion in the coming decades, while modelling studies in China indicate an even greater societal burden when both direct medical costs and productivity losses are considered.^2,9,15–17 Collectively, these trends underscore the urgent need not only to reduce the clinical burden of COPD but also to improve the efficiency of healthcare resource allocation.

However, current evidence provides limited guidance on how COPD interventions should be prioritised. Existing research has generally developed along two separate pathways. Burden-of-disease studies quantify the population health impact of COPD using measures such as DALYs but rarely evaluate which interventions can most efficiently reduce this burden. Conversely, economic evaluations assess individual interventions using measures such as the incremental cost-effectiveness ratio (ICER), but usually do not consider the magnitude of the population health burden addressed. As a result, decision-makers are often unable to distinguish between interventions that provide substantial population health gains at acceptable cost and those that are cost-effective only within selected patient groups or healthcare contexts.

Integrating these complementary perspectives may provide a more informative basis for COPD resource prioritisation. DALYs capture the magnitude of health loss attributable to disease, whereas ICERs estimate the additional resources required to achieve health gains. Considering these measures together may allow interventions to be evaluated according to both their potential to reduce COPD-related burden and their economic efficiency, thereby supporting value-based healthcare decision-making.

Therefore, this narrative review aimed to (i) characterise the principal determinants of COPD-related healthcare costs, including acute exacerbations, complications and comorbidities; (ii) evaluate preventive, non-pharmacological and pharmacological interventions by integrating burden-reduction potential with cost-effectiveness evidence; and (iii) develop a practical DALY-ICER prioritisation framework to inform value-based reimbursement strategies for COPD. Particular attention was given to LMICs, where COPD burden is increasing rapidly and locally generated economic evidence remains limited. To our knowledge, this review represents an early attempt to integrate disease burden and economic efficiency into a unified framework for prioritising COPD interventions.

Methods

Search Strategy and Study Selection

This narrative review was conducted with reference to the Scale for the Assessment of Narrative Review Articles (SANRA) and was not prospectively registered.¹⁸ A structured literature search was conducted in PubMed, Embase, and the Cochrane Library from database inception to August 2026. Search terms combined controlled vocabulary and free-text keywords covering COPD, disease burden, healthcare costs, economic evaluation, comorbidities, complications, and treatment strategies. Reference lists of eligible studies and relevant reviews were also screened to identify additional publications.

Studies were eligible if they reported epidemiological, clinical, or economic evidence relevant to COPD, including DALYs, quality-adjusted life years (QALYs), ICERs, healthcare costs, or the cost-effectiveness of preventive or therapeutic interventions. Eligible evidence included original economic evaluations, modelling studies, observational studies, randomised controlled trials, systematic reviews, and meta-analyses. Editorials, conference abstracts, case reports, and studies without relevant burden- or economic-related outcomes were excluded. Only English-language publications were considered.

A total of 80 publications contributed to the evidence synthesis. Four additional references describing methodological guidance (SANRA, CHEERS 2022, CHEC-list, AMSTAR 2) were cited for contextual purposes only, resulting in 84 references overall. Given the substantial heterogeneity in study design, economic perspective, outcome measures, currencies and time horizons, findings were synthesised narratively rather than quantitatively.

Quality Appraisal and Definition of Review-Specific Evidence Categories

Although formal risk-of-bias synthesis is beyond the scope of a narrative review, structured quality appraisal was undertaken to support interpretation of the economic evidence. Among the 80 publications contributing to the evidence synthesis, only studies eligible for assessment using the predefined appraisal instruments underwent structured assessment. Burden-of-disease studies, descriptive cost studies, clinical studies, systematic reviews included only to support the clinical or burden-reduction narrative, guidelines and consensus statements were not eligible for these appraisal instruments. Secondary or narrative economic evidence that contributed directly to the economic synthesis but did not meet the criteria for formal CHEERS, CHEC-list or AMSTAR 2 appraisal was described separately in Supplementary Table S1C. Four additional references cited solely for methodological purposes were not part of the substantive evidence base. Reporting completeness of full economic evaluations was assessed using the CHEERS 2022 checklist, methodological quality using the CHEC-list, and the methodological quality of eligible systematic reviews using AMSTAR.^19–21 Detailed appraisal results for full economic evaluations are provided in Supplementary Table S1A, while AMSTAR 2 assessments of eligible systematic reviews are presented in Supplementary Table S1B. Literature screening, study selection, and quality appraisal were conducted by a single reviewer using predefined eligibility criteria and structured assessment tools. The appraisal informed interpretation of the evidence but was not used to determine study eligibility.

Interventions were assigned review-specific evidence categories (High, Moderate or Low) according to methodological quality, reporting completeness, consistency of findings and the availability of supporting clinical evidence. High evidence required consistent findings from at least two independent methodologically adequate economic evaluations or one high-quality systematic review. Moderate evidence represented one methodologically adequate economic evaluation supported by consistent clinical evidence or concordant modelling studies. Low evidence reflected limited or methodologically weaker evidence, including isolated modelling studies without external validation or studies with important methodological limitations.

Because CHEERS 2022 evaluates reporting quality rather than methodological validity, reporting completeness alone was not considered evidence of methodological robustness. The predefined 80% CHEERS threshold was therefore used as a descriptive convention rather than a validated methodological benchmark. Where the certainty of burden evidence and economic evidence differed, the lower category determined the final review-specific evidence category. These review-specific categories were developed solely for this review and should not be interpreted as equivalent to GRADE certainty ratings.

Operational Definition of the Integrated DALY-ICER Framework

To integrate population health impact with economic efficiency, this review developed a conceptual prioritisation framework integrating evidence on COPD burden-reduction potential with ICER-based assessments of cost-effectiveness. DALYs quantify health loss attributable to disease, whereas ICERs estimate the additional cost required to achieve health gains. Their combined interpretation therefore provides a broader basis for prioritisation than either measure alone.

The framework comprises two independent assessment axes (Figure 1 and Table 1). The first evaluates burden-reduction potential according to evidence that an intervention reduces mortality, DALYs or clinically important COPD exacerbations. Interventions were classified as having High, Moderate or Limited burden-reduction potential using predefined criteria. Exposure-directed public-health measures for which intervention-avertable COPD burden cannot be directly graded, such as household air-pollution control, were evaluated separately. Smoking cessation was graded within the burden-reduction axis because direct COPD-specific evidence demonstrated reductions in clinically important outcomes.

Figure 1.

Conceptual prioritisation framework for COPD interventions based on disease burden reduction potential and cost-effectiveness.

Notes: Fifteen COPD interventions were evaluated across two dimensions. The left panel indicates the potential of each intervention to reduce COPD-related burden, categorised qualitatively as High, Moderate or Limited according to the predefined review criteria. The right panel represents cost-effectiveness relative to the willingness-to-pay threshold of the source setting. Economic results are interpreted within their original healthcare context rather than against a universal threshold. For triple inhaled therapy, results varied across healthcare settings, comparators and acquisition prices; favourable economic value was reported in several analyses, whereas at least one recent analysis reported an ICER above the source-setting threshold at current prices. Interventions labelled “Not classifiable” lacked an applicable COPD-specific economic evaluation; household air-pollution control was additionally not graded on the intervention-avertable burden axis. The review-specific evidence category reflects the authors’ structured appraisal of the supporting evidence as High, Moderate or Low. Interventions are classified into four conceptual categories: Q1, high or moderate burden-reduction potential with broadly favourable economic value; Q2, meaningful burden reduction with an ICER above the source-setting threshold at the evaluated price; Q3, economic value dependent on an explicitly defined subgroup, eligibility criterion, comparator or healthcare context; and Q4, limited burden reduction with applicable COPD-specific economic evidence demonstrating an unfavourable value profile. No intervention–population combination was robustly assigned to Q4. Influenza and pneumococcal vaccination remain provisional Q1 assignments because the available economic evidence was derived from broader adult populations rather than COPD-specific cohorts. Hatched bar = context-dependent: for triple inhaled therapy, reported ICERs span from cost-saving or below the willingness-to-pay threshold to far above it, depending on country, comparator and drug price (eg FF/UMEC/VI at THB 1,899,408 per QALY against a THB 160,000 per QALY threshold in Thailand, 2026).

Abbreviations: COPD, chronic obstructive pulmonary disease; ICER, incremental cost-effectiveness ratio; ICS, inhaled corticosteroid; Q, quadrant; WTP, willingness-to-pay.

Table 1.

Conceptual DALY-ICER-Informed Prioritisation Matrix for COPD Interventions and Illustrative Reimbursement Considerations

Quadrant	Potential to Reduce COPD-Related Burden	Cost-Effectiveness (ICER Against the Willingness-to-Pay Threshold of the Source Setting)	Representative COPD Interventions	Illustrative Reimbursement Consideration
Q1	High or moderate	Cost-saving or dominant, or ICER clearly below the threshold, with the result applying across the eligible COPD population, eligibility being defined by the intervention’s routine clinical indication rather than by additional risk enrichment introduced solely to achieve a favourable economic result	Smoking cessation; pulmonary rehabilitation; influenza and pneumococcal vaccination (provisional; indirect economic evidence)	May be considered for high-priority coverage and broader implementation, subject to local budget impact, affordability, feasibility and equity considerations
Q2	High or moderate	ICER above the threshold at the price analysed	Ensifentrine at launch price; mepolizumab in type 2 COPD at the evaluated price	Conditional coverage contingent on price negotiation, managed-entry or outcome-based risk-sharing agreements; re-appraisal after price revision
Q3	High, moderate or limited within the subgroup evaluated	ICER below the source-setting threshold or dominance in an explicitly defined subgroup, treatment-eligible population or comparator-specific decision problem; economic value may vary across healthcare settings because of differences in acquisition prices, comparators and willingness-to-pay thresholds	Triple inhaled therapy in exacerbation-prone/high-risk patients; long-term low-dose azithromycin in patients with an exacerbation history; home oxygen plus home mechanical ventilation in persistent hypercapnia; integrated disease management in exacerbation-prone patients; COPD screening/case-finding (questionnaire plus portable spirometry)	Consider reimbursement within clearly defined treatment-eligible populations, with eligibility criteria and local economic conditions—including comparator, acquisition price and willingness-to-pay threshold—incorporated into coverage decisions
Q4	Limited	ICER above the threshold, or an unfavourable ICER in the subgroup concerned	No intervention–population combination in this review was robustly assigned to Q4 under the predefined criteria	Deprioritise only when both limited burden-reduction potential and applicable COPD-specific economic evidence demonstrate an unfavourable value profile; otherwise retain as Not classifiable pending further evidence
Not classifiable	High, moderate or limited, or not gradable on the intervention-avertable burden axis	No applicable COPD-specific cost-utility or cost-effectiveness analysis reporting QALYs, DALYs or ICERs was identified	ICS-containing therapy in low-eosinophil, non-exacerbating patients; household air-pollution control (also not graded on the burden axis); COVID-19 booster vaccination; selective beta-blockade	Do not infer lack of clinical value or cost-effectiveness from missing evidence; commission COPD-specific economic evaluation before assigning a quadrant, with provisional funding decisions based on clinical need, burden, equity, budget impact and local implementation considerations

Notes: quadrant assignment follows the axis criteria pre-specified in the Methods and is applied consistently with Table 2 and the main text. Q1 includes interventions with high or moderate burden-reduction potential and favourable economic value across the intervention’s routine eligible COPD population; influenza and pneumococcal vaccination remain provisional because the available economic evidence was derived from broader adult populations rather than COPD-specific cohorts. Q2 is reserved for interventions with meaningful burden reduction but an ICER above the source-setting willingness-to-pay threshold at the analysed price. Q3 applies when favourable cost-effectiveness depends on an explicitly defined subgroup, treatment-eligible population, comparator-specific decision problem or healthcare context, including differences in acquisition prices and willingness-to-pay thresholds. No intervention–population combination in this review was robustly assigned to Q4: assignment requires both limited burden-reduction potential and applicable COPD-specific economic evidence demonstrating an unfavourable value profile. Interventions lacking an applicable COPD-specific economic evaluation are recorded as Not classifiable rather than being placed in Q4; this designation indicates an evidence gap, not absence of clinical value. Dominant denotes an intervention that is both less costly and more effective than its comparator. Because willingness-to-pay thresholds differ between countries, each intervention is classified against the threshold applied in its source study. The grading and quadrant assignment of each intervention are given in Table 2, and the underlying numerical results in Table 3.

Abbreviations: COPD, chronic obstructive pulmonary disease; DALY, disability-adjusted life year; ICER, incremental cost-effectiveness ratio; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; QALY, quality-adjusted life year.

The second axis evaluates economic efficiency according to the reported ICER relative to the willingness-to-pay threshold adopted in each original economic evaluation. Interventions were classified as cost-saving or dominant, below the willingness-to-pay threshold, above the threshold, or Not classifiable when no COPD-specific economic evaluation was identified. Because willingness-to-pay thresholds vary across healthcare systems, cost-effectiveness was interpreted within the context of each source study rather than against a universal benchmark.

Combining these two axes generated four conceptual prioritisation categories (Q1-Q4) (Table 1). Q1 represents interventions with high or moderate burden-reduction potential and favourable economic value; Q2 includes interventions with meaningful health benefits but less favourable cost-effectiveness; Q3 comprises interventions with favourable economic value in an explicitly defined subgroup, treatment-eligible population, comparator-specific decision problem, or healthcare context; and Q4 includes interventions with limited burden-reduction potential together with applicable COPD-specific economic evidence demonstrating an unfavourable value profile. Interventions lacking COPD-specific economic evaluations remained Not classifiable, indicating insufficient economic evidence rather than lack of clinical effectiveness. These predefined operational rules were applied consistently throughout Tables 1–3 and Figure 1 to ensure transparent and reproducible interpretation of the available evidence.

Table 2.

Potential to Reduce COPD-Related Burden, Cost-Effectiveness, Review-Specific Evidence Category and Quadrant Assignment of COPD Management Strategies

Intervention or Strategy	Potential to Reduce COPD-Related Burdena	Cost-Effectiveness Against the Willingness-to-Pay Threshold of the Source Setting	Review-Specific Evidence Categoryb	Quadrant
Smoking cessation4,22–25	High	Cost-saving or dominant in one lifetime model; EUR 2400 per QALY gained for intensive counselling plus pharmacotherapy in another. Intervention costs were included in both analyses	High	Q1
Pulmonary rehabilitation4,26–30	High	Cost-saving or dominant: a UK evaluation reported 0.065 QALYs gained, approximately 8% reduction in hospitalisation and GBP 245 lower expenditure per patient; a US lifetime model after AECOPD hospitalisation found rehabilitation dominant, with 0.53 additional QALYs and approximately USD 5721 saved per patient.	Moderate	Q1
Influenza vaccination31–33	Moderate	Cost-effective versus no vaccination against country-specific willingness-to-pay thresholds in a Southeast Asian systematic review; economic evidence was indirect because the evaluated adult populations were not restricted to COPD.	Moderate	Q1 (provisional)
Pneumococcal vaccination31–33	Moderate	Cost-effective versus no vaccination against country-specific willingness-to-pay thresholds in a Southeast Asian systematic review; PPSV23 showed greater economic value than PCV13. Economic evidence was indirect because the evaluated adult populations were not restricted to COPD.	Moderate	Q1 (provisional)
Ensifentrine34–36	Moderate	Added to maintenance therapy, ensifentrine was projected to reduce moderate-to-severe exacerbations and increase QALYs, but the estimated ICER at launch price exceeded conventional US willingness-to-pay thresholds.	Moderate	Q2
Mepolizumab in type 2 COPD37	Moderate	A Colombian lifetime Markov analysis comparing mepolizumab plus triple therapy with triple therapy alone estimated an ICER of USD 45,192/QALY, above the source-setting willingness-to-pay threshold of USD 5180/QALY. Cost-effectiveness was highly dependent on acquisition price.	Moderate	Q2
Triple inhaled therapy38–47	High	Context-dependent. Several analyses in Spain, China, Colombia and Chile reported ICERs below source-setting thresholds or dominance in treatment-eligible populations or specific comparator settings. However, a 2026 Thai analysis found FF/UMEC/VI not cost-effective versus multiple-inhaler triple therapy at current prices (THB 1,899,408/QALY versus a THB 160,000/QALY threshold), while BUD/GLY/FOR was dominated. Economic value therefore varies by comparator, patient eligibility, acquisition price and healthcare setting.	High	Q3
Long-term low-dose azithromycin48	Moderate	CAD 43,200/QALY for ≥1 exacerbation in previous 12 months; CAD 8862/QALY for frequent exacerbators; dominated in patients without prior exacerbations.	Moderate	Q3
Oxygen therapy plus home mechanical ventilation4,49–52	Moderate	In patients with persistent hypercapnia after an exacerbation, adding home mechanical ventilation increased annual costs by GBP 512 but improved quality-adjusted survival, yielding an ICER of GBP 10,259 per QALY, below the GBP 30,000 per QALY threshold.	Moderate	Q3
Integrated disease management53	Moderate	Dominant over usual care in high-risk, exacerbation-prone patients in Canadian primary care, generating additional QALYs while reducing costs; one-year net monetary benefit was CAD 5360 per patient at a CAD 50,000 per QALY threshold.	Moderate	Q3
COPD screening (questionnaire plus portable spirometry) and case-finding54,55	Moderate	A Chinese microsimulation estimated ICERs of USD 8034–13,209 per QALY, below the national threshold of USD 38,441 per QALY. Subsequent systematic reviews generally supported the economic value of screening and case-finding, although results varied by target population, screening strategy and healthcare setting.	Moderate	Q3
ICS-containing therapy in low-eosinophil, non-exacerbating patients4,56	Limited	Not classifiable: no subgroup-specific COPD cost–utility or cost-effectiveness analysis reporting QALYs, DALYs or ICERs was identified. Clinical evidence suggests limited incremental exacerbation benefit in patients with blood eosinophils <100 cells/μL and no exacerbation history, while treatment acquisition costs and ICS-associated pneumonia risk remain.	Low	Not classifiable
Household air-pollution control50,56,57	Not directly classifiable	Not classifiable: no COPD-specific economic evaluation incorporating stove, fuel, infrastructure or implementation costs was identified. COPD-specific intervention-avertable burden has not been quantified.	Low	Not classifiable
COVID-19 booster vaccination31,33	Limited	Not classifiable for COPD: reported as cost-effective in general adult populations, but no COPD-specific economic evaluation was identified and reductions in COPD exacerbations, mortality or DALYs have not been demonstrated.	Low	Not classifiable
Selective beta-blockade4,58	Moderate	Not classifiable: selective beta-blockade is clinically appropriate for established cardiovascular disease, but no COPD-cohort cost-utility analysis reporting QALYs, DALYs or ICERs was identified.	Low	Not classifiable

Notes: the two graded columns are the axes of the prioritisation matrix defined in Table 1. The burden-reduction axis has three ordered levels. The economic-efficiency axis has three ordered levels, together with a separate not-classifiable status for interventions lacking an applicable economic evaluation. The same terms are used in the text, in Tables 1 to 3 and in Figure 1. Cost-effectiveness is graded against the willingness-to-pay threshold applied in the source setting rather than against a single global benchmark. An intervention for which no cost-utility or cost-effectiveness analysis conducted in a COPD population was identified is recorded as not classifiable rather than as costless, and this rule is applied uniformly to pharmacological, non-pharmacological and population-level public-health measures alike. Influenza, pneumococcal and COVID-19 vaccination are listed as separate rows because the economic evaluation identified was conducted in adults including, but not restricted to, patients with COPD and reported the three vaccines together; their economic evidence is accordingly labelled indirect, the influenza and pneumococcal assignments are provisional, and COVID-19 booster vaccination, whose review-specific evidence category is Low, is not assigned to a quadrant. The corresponding numerical results, comparators and populations are given in Table 3, and Figure 1 presents the same grades graphically. Superscript numerals and the numbers in the final column are the reference numbers of the source studies in the reference list of this manuscript. ^aPotential to reduce COPD-related burden follows the mutually exclusive criteria pre-specified in the Methods, the levels being tested in the order High, Moderate, Limited and the first level whose conditions are met being assigned. High: the intervention acts on a dominant source of COPD burden (acute exacerbations, tobacco smoking, household air pollution or cardiopulmonary comorbidity), exposure-directed public-health measures being excluded from this axis altogether as stated below, and a reduction in mortality, in DALYs or in moderate-to-severe exacerbations has been directly observed for the intervention itself in at least two independent studies or in one high-quality systematic review or meta-analysis. Moderate: such a reduction, or a QALY gain, has been demonstrated in at least one controlled clinical study or population-based cohort, or in an externally validated model or a model whose effectiveness estimates are taken from randomised trials or population-based cohorts, while the population-level DALY impact remains uncertain. Limited: the evidence rests only on surrogate outcomes, indirect comparison, modelling not anchored in trial- or cohort-derived effect estimates, or results that the source studies themselves describe as substantially uncertain. Whether a result comes from a single study or a single setting is deliberately not a criterion on this axis, because almost every published economic evaluation in COPD is a single-country analysis; the number of independent sources separates High from Moderate and the nature of the evidence separates Moderate from Limited. Exposure-directed public-health measures, for which no trial of the intervention in a COPD population exists, are not graded on this axis; they are recorded as not directly classifiable for intervention-avertable burden, with the burden attributable to the exposure stated separately, and only where a high-quality comparative risk assessment quantifies the COPD-relevant attributable burden and an exposure–response relationship for COPD is established. Attributable burden is never presented as a burden-reduction grade. A grade refers to the burden an intervention has been shown to be capable of averting, not to the burden attributable to the risk factor at which it is directed, and not to the clinical severity of the condition in an individual patient. ^bThe review-specific evidence category follows the definitions pre-specified in the Methods (High: at least two independent economic evaluations judged methodologically adequate on the CHEC-list and reporting at least 80% of applicable CHEERS 2022 items, or one high-quality systematic review; Moderate: one such evaluation with consistent clinical evidence, or several modelling studies of intermediate quality; Low: a single modelling study that was neither externally validated nor supported by consistent clinical evidence, or important methodological limitations; evaluation in a single healthcare setting is not by itself a reason to assign this category). The 80% cut-off is an author-defined descriptive convention and not a validated threshold; CHEERS 2022 was used to assess completeness of reporting and the CHEC-list to assess methodological quality. Where the certainty of the burden evidence and of the economic evidence differ, the lower of the two determines the category shown. These categories are descriptive and are not equivalent to a formal GRADE certainty rating.

Abbreviations: CHEC-list, Consensus Health Economic Criteria list; CHEERS, Consolidated Health Economic Evaluation Reporting Standards; COPD, chronic obstructive pulmonary disease; DALY, disability-adjusted life year; EUR, euro; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ICER, incremental cost-effectiveness ratio; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LMIC, low- and middle-income country; QALY, quality-adjusted life year; Q1 to Q4, quadrants of the prioritisation matrix defined in Table 1; UMEC/VI, umeclidinium/vilanterol.

Table 3.

Cost-Effectiveness Evidence Underlying the DALY-ICER Classification of COPD Interventions, by Comparator and Target Population

Intervention (Setting)	Comparator	Target Population	Reported Economic Result	WTP Threshold in Source Study	Burden-Reduction Evidence	Quadrant
Smoking cessation: counselling ± pharmacotherapy (Netherlands, dynamic population model)24	Usual care	Patients with COPD who smoke	EUR 16,900/QALY (minimal counselling); EUR 8200/QALY (intensive counselling); EUR 2400/QALY (intensive counselling + pharmacotherapy); the latter dominated intensive counselling alone	Source-setting thresholds	Reduced smoking exposure; mortality and exacerbation benefits supported by COPD-specific evidence4,22,23 (High)	Q1
Smoking cessation (England, lifetime Markov model; societal perspective)25	Continued smoking	Patients with COPD who smoke	Dominant: GBP 1824 saved per patient with 0.68 additional QALYs and 1.27 additional life-years	Not applicable (dominant)	Life-years and QALYs gained; COPD mortality benefit supported by cohort evidence23 (High)	Q1
Pulmonary rehabilitation (UK)29	Usual care	Patients completing pulmonary rehabilitation	0.065 QALYs gained; approximately 8% reduction in hospitalisation and GBP 245 lower expenditure	UK threshold in source	Reduced admissions and disability; clinical benefit supported by multiple studies4,26–28 (Moderate)	Q1
Pulmonary rehabilitation after AECOPD hospitalisation (USA, lifetime model)30	Usual care	Patients discharged after AECOPD hospitalisation	Dominant: 0.53 additional QALYs and approximately USD 5721 saved per patient	Not applicable (dominant)	Post-hospital rehabilitation improves outcomes and is associated with lower mortality4,26–28 (Moderate)	Q1
Influenza vaccination (Southeast Asia systematic review)33	No vaccination	Adults in source studies; populations not restricted to COPD	Cost-effective versus no vaccination; quadrivalent vaccine economically favoured over trivalent vaccine in included analyses	Country-specific thresholds	COPD-specific exacerbations, deaths or DALYs averted were not quantified; clinical rationale supported by COPD vaccination evidence31,32 (Moderate)	Q1 (provisional)
Pneumococcal vaccination (Southeast Asia systematic review)33	No vaccination	Adults in source studies; populations not restricted to COPD	Cost-effective versus no vaccination; PPSV23 showed greater economic value than PCV13	Country-specific thresholds	COPD-specific exacerbations, deaths or DALYs averted were not quantified; economic evidence is indirect31,32 (Moderate)	Q1 (provisional)
Ensifentrine added to maintenance therapy (USA value assessment)36	Existing maintenance therapy	Moderate-to-severe symptomatic COPD	ICER exceeded conventional US willingness-to-pay thresholds at launch price	Conventional US thresholds used in source appraisal	Modelled QALY gain and fewer moderate-to-severe exacerbations34,35 (Moderate)	Q2
Mepolizumab plus triple therapy37	Triple therapy alone	COPD with type 2/eosinophilic inflammation	USD 45,192/QALY; probability of cost-effectiveness 0% under base-case assumptions	USD 5180/QALY	14% relative reduction in exacerbation risk (RR 0.86, 95% CI 0.77–0.95) based on clinical evidence incorporated into the model	Q2
Single-inhaler triple therapy, FF/UMEC/VI (Spain, IMPACT)39	FF/VI (ICS/LABA)	Exacerbation-prone/high-risk COPD	EUR 6887/QALY	EUR 30,000/QALY	Fewer moderate-to-severe exacerbations (High)	Q3
Single-inhaler triple therapy, FF/UMEC/VI (Spain, IMPACT)39	UMEC/VI (LAMA/LABA)	Exacerbation-prone/high-risk COPD	Dominant in the source analysis	Not applicable (dominant)	Fewer moderate-to-severe exacerbations (High)	Q3
Triple therapy, FF/UMEC/VI (China)40	Budesonide/formoterol (ICS/LABA)	Moderate-to-severe COPD	CNY 33,006.80/QALY	CNY 72,447/QALY	QALY gain and fewer exacerbations (High)	Q3
Triple therapy, FF/UMEC/VI (China)41	UMEC/VI (LAMA/LABA)	Moderate-to-severe COPD	Cost-effective versus UMEC/VI in the source analysis	Source-setting threshold	Clinical benefit concentrated in patients with greater expected exacerbation reduction (High)	Q3
Triple therapy, BGF (Spain, ETHOS-based model)42	LAMA/LABA	Moderate-to-severe COPD	EUR 3461.19/QALY	EUR 25,000/QALY	QALY gain; favourable value in a treatment-eligible COPD population (High)	Q3
Single-inhaler versus multiple-inhaler triple therapy (UK and Germany)43,44	Multiple-inhaler triple therapy	Patients already indicated for triple therapy	Single-inhaler therapy was dominant in selected analyses	Not applicable (dominant)	Adherence-mediated health gains; device comparison within an already selected triple-therapy population (High)	Q3
Single-inhaler triple therapy47	Multiple-inhaler triple therapy (SAL/FP + TIO)	GOLD group E patients inadequately controlled on dual therapy	FF/UMEC/VI, THB 1,899,408/QALY; BUD/GLY/FOR was dominated by MITT	THB 160,000/QALY	FF/UMEC/VI produced a small QALY gain; economic value was strongly price-dependent	Q3
Single-inhaler triple therapy, FF/UMEC/VI45	BUD/GLY/FOR	Moderate-to-very severe COPD	Dominant; approximately 0.51 additional QALYs and USD 1038 saved per patient	USD 5180/QALY	QALY gains and modelled reductions in exacerbation-related burden	Q3
Single-inhaler versus multiple-inhaler triple therapy46	Multiple-inhaler triple therapy	Moderate-to-severe COPD	USD 438.41/QALY in the base case; dominant over 5- and 10-year horizons	Source-setting threshold	0.261 additional QALYs and approximately 4.38% fewer severe exacerbations per patient-year	Q3
Long-term low-dose azithromycin (Canada)48	Usual care	Patients with a documented exacerbation history	CAD 43,200/QALY for ≥1 exacerbation in previous 12 months; CAD 8862/QALY for frequent exacerbators; dominated in patients without prior exacerbations	Source-setting thresholds	11.86 to 10.95 modelled exacerbations per patient over 20 years among patients with ≥1 moderate or severe exacerbation in the previous 12 months; benefit increased with baseline exacerbation risk (Moderate)	Q3
Home oxygen plus home mechanical ventilation (UK)51	Home oxygen alone	Persistent hypercapnia after an exacerbation	GBP 10,259/QALY; GBP 512 additional annual cost per patient	GBP 30,000/QALY	Improved quality-adjusted survival and delayed readmission (Moderate)	Q3
Home mechanical ventilation52	Facility-based mechanical ventilation	Adults with COPD requiring mechanical ventilation	Dominant; lower cumulative cost and slightly greater cumulative QALYs over 10 years	Not required for a dominant result	Similar or improved utility with home-based delivery; comparator differs from the post-exacerbation HOT–HMV decision problem	Q3
Integrated disease management (Canada)53	Usual care	High-risk, exacerbation-prone patients in primary care	Dominant; 1-year net monetary benefit CAD 5360 per patient at the stated threshold	CAD 50,000/QALY	Additional QALYs with reduced healthcare use in a high-risk population (Moderate)	Q3
Two-step COPD screening: questionnaire + portable spirometry (China)54	No systematic screening	Adults aged 35–80 years	USD 8034–13,209/QALY across modelled strategies; annual two-step screening was the most economically efficient strategy	USD 38,441/QALY	Modelled prevention of 0.39–8.10% of COPD deaths and 0.58–2.70% of exacerbations (Moderate)	Q3
COPD screening and case-finding55	No screening/usual care or alternative case-finding strategies	General or higher-risk adult populations across included studies	Systematic reviews generally supported favourable economic value for COPD screening and case-finding, with substantial heterogeneity according to screening method, population and setting	Study- and country-specific thresholds	Earlier diagnosis and modelled reductions in COPD-related morbidity and mortality; population-level impact remains context-dependent	Q3
ICS-containing therapy in low-eosinophil, non-exacerbating patients4,56	Non-ICS maintenance therapy	Blood eosinophils <100 cells/µL and no exacerbation history	Not classifiable: no subgroup-specific COPD cost-utility/cost-effectiveness analysis reporting QALYs, DALYs or ICERs was identified	Not applicable	Limited expected incremental exacerbation benefit; treatment cost and ICS-associated pneumonia risk remain (Limited)	Not classifiable
Household air-pollution control/clean household fuel50,56,57	Continued polluting-fuel exposure	Exposure-affected populations; no defined COPD economic cohort	Not classifiable: no COPD-specific economic evaluation incorporating stove, fuel, infrastructure or implementation costs was identified	Not applicable	COPD-specific intervention-avertable burden has not been quantified; not graded on the burden axis	Not classifiable
COVID-19 booster vaccination (Southeast Asia review)31,33	No booster	General adult populations; no COPD-specific economic cohort	Reported cost-effective in general adults, but no COPD-specific economic evaluation was identified	Country-specific thresholds in source review	No demonstrated COPD-specific reduction in exacerbations, mortality or DALYs (Limited)	Not classifiable
Selective beta-blockade for established cardiovascular disease4,58	Standard cardiovascular care	Patients with COPD and an established cardiovascular indication	Not classifiable: no COPD-cohort cost-utility analysis reporting QALYs, DALYs or ICERs was identified	Not applicable	Clinically appropriate for established cardiovascular disease; COPD-specific economic evidence unavailable (Moderate)	Not classifiable

Notes: Rows correspond to the intervention-comparator-population decision problems that support the classifications in Table 1 and Table 2. Q1 denotes high- or moderate-burden-reduction interventions with favourable economic value across the routine eligible population; influenza and pneumococcal vaccination are provisional Q1 assignments because the available economic evidence was derived from broader adult populations rather than COPD-specific cohorts. Q2 denotes meaningful burden reduction with an ICER above the source-setting willingness-to-pay threshold at the analysed price. Q3 denotes favourable cost-effectiveness that depends on an explicitly defined subgroup, treatment-eligible population, comparator-specific decision problem or healthcare context, including differences in acquisition prices and willingness-to-pay thresholds. No intervention-population combination in this review was robustly assigned to Q4. Interventions without an applicable COPD-specific economic evaluation are recorded as Not classifiable rather than Q4. Dominant indicates lower cost and greater effectiveness than the comparator. Values are reported in the original currencies and were not converted or inflation-adjusted. Reference numbers correspond to the manuscript reference list.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BGF, budesonide/glycopyrronium/formoterol; CAD, Canadian dollar; CNY, Chinese yuan renminbi; COPD, chronic obstructive pulmonary disease; DALY, disability-adjusted life year; EUR, euro; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol; FF/VI, fluticasone furoate/vilanterol; GBP, pound sterling; ICER, incremental cost-effectiveness ratio; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; QALY, quality-adjusted life year; UMEC/VI, umeclidinium/vilanterol; USD, United States dollar; WTP, willingness to pay.

Results

Overview of the Evidence

A total of 80 publications were synthesised to characterise the economic burden of COPD and evaluate interventions using the integrated DALY-ICER framework. Rather than presenting individual studies sequentially, the evidence was organised into four thematic groups. Groups 1–3 examine the principal drivers of COPD-related healthcare expenditure, including acute exacerbations, complications and comorbidities, whereas Group 4 evaluates preventive, non-pharmacological and pharmacological interventions according to their burden-reduction potential and economic efficiency. Detailed economic results, including reported ICERs, willingness-to-pay thresholds and reimbursement classifications, are summarised in Tables 1–3, with the overall framework illustrated in Figure 1.

Overview: Scale and Composition of the COPD Cost Burden

COPD imposes a substantial and growing economic burden worldwide, which increases progressively with disease severity. Model-based projections estimate cumulative direct medical costs of approximately USD 3.1 trillion in China between 2020 and 2039, equivalent to an average annual direct medical expenditure of approximately USD 155 billion, with total societal costs approaching USD 173 billion when productivity losses are included.¹⁶ In the United States, COPD accounted for approximately USD 31.3 billion in respiratory healthcare expenditure in 2019, and cumulative global direct medical costs are projected to reach USD 24.35 trillion by 2050.^2,8,13, Figure 2 summarises representative estimates of the economic burden of COPD across China and the United States. These findings indicate that COPD represents an increasingly important challenge for healthcare systems worldwide.

Figure 2.

Economic burden of chronic obstructive pulmonary disease: (A) Annual COPD-related costs in the United States and China. The United States value represents the projected annual direct medical cost. Chinese annual estimates were derived by dividing the published cumulative 2020–2039 projections by the 20-year study period and are indicated by hatched bars to distinguish them from directly reported annual estimates. (B) Projected cumulative global direct medical costs of COPD through 2050, reaching USD 24.35 trillion.

Across healthcare settings, healthcare expenditure is driven primarily by acute exacerbations, hospitalisation and major comorbidities. Hospital admissions account for the largest proportion of direct medical costs, while disease progression further increases expenditure through recurrent exacerbations, long-term pharmacological treatment, oxygen therapy and management of cardiovascular disease, lung cancer and other chronic comorbidities.^9–12,17 Approximately 90% of patients have at least one comorbidity, and these conditions account for a substantial proportion of excess healthcare expenditure beyond COPD itself.^11,59 Given the high burden of comorbidities among patients with COPD, Figure 3 summarises the prevalence of the major comorbidities associated with COPD, and Table 4 presents the annual healthcare costs of COPD alone and COPD with major comorbidities or complications.

Figure 3.

Reported prevalence of the major comorbidities of chronic obstructive pulmonary disease. Horizontal lines represent the prevalence ranges reported in the included studies, with end caps indicating the reported limits and open circles marking the midpoint of each range for visual reference only. Grey diamonds denote comorbidities for which only a single estimate was available. Differences in prevalence primarily reflect variation in study populations and diagnostic definitions; values are therefore not directly comparable across comorbidities.

Table 4.

Reported Healthcare Costs Associated with COPD Alone and with Selected Comorbidities or Complications

Comorbidity or Complication	Setting	Annual Cost, COPD Alone	Annual Cost, COPD Plus the Condition	Incremental (Excess) Cost	Principal Finding of the Source Study
Acute exacerbation	United States60	USD 26,544 per patient	USD 38,564 per patient	USD 12,020 per patient (+45%; ≈1.45 times comparator)	Unadjusted year-2 all-cause costs were higher after one severe baseline exacerbation than after no baseline exacerbation; recurrent/severe exacerbations predicted greater future costs.
Chronic respiratory failure	United States61	Not reported as an annual comparator	Not reported as an annual comparator	Not estimable from the cited study	Among patients hospitalised with severe COPD exacerbation, median hospital cost was USD 7100 and median stay was 9 days; the study did not provide COPD-alone versus chronic-respiratory-failure annual costs.
Pulmonary hypertension	United States62	USD 18,412 per patient-year	USD 51,435 per patient-year	USD 33,023 per patient-year (+179%; ≈2.79 times COPD alone)	PH-COPD was associated with almost threefold higher annual all-cause costs; hospitalisations accounted for 56.8% of total costs.
Cardiovascular disease	United States58	USD 12,400 per patient	USD 29,200 per patient	USD 16,800 per patient (+135%; ≈2.35 times COPD alone)	All-cause costs; COPD-specific costs rose by only 38%
Lung cancer	Turkey63	Not reported for COPD alone	Not reported for COPD plus lung cancer	Not estimable from the cited evidence	No COPD-specific comparative cost study was identified. Annual direct lung-cancer costs alone were EUR 10,167 for NSCLC and EUR 8772 for SCLC.
Metabolic disorders	United States58	USD 8671 per patient-year	USD 11,819 per patient-year	USD 3148 per patient-year (+36%; ≈1.36 times COPD alone)	In the systematic review, diabetes was among the comorbidities associated with the highest excess costs; complicated diabetes produced substantially greater excess costs.
Psychological comorbidities	Canada64	Not reported as a condition-specific comparator	Not reported as COPD plus a psychological condition	CAD 731 per patient-year attributable to psychiatric disorders	Psychiatric disorders were a major contributor to excess COPD-associated costs; the cited population study reported attributable excess cost rather than a COPD-alone versus COPD-plus-condition pair.
Bronchiectasis	South Korea65	USD 4453.40 per patient	USD 5984.08 per patient	USD 1530.68 per patient (+34%; ≈1.34 times COPD alone)	COPD with bronchiectasis was associated with more exacerbations, more hospitalisation days, and significantly higher medical costs than COPD without bronchiectasis.

Notes: Costs are presented in the original currency and price year reported by each study and have not been converted or inflation-adjusted; comparisons between rows should therefore be regarded as indicative rather than quantitative. Ratios represent total cost ratios rather than fold increases above the comparator. Superscript numerals indicate the corresponding references. For acute exacerbations, the displayed values are unadjusted year-2 all-cause costs according to baseline exacerbation category (no exacerbation versus one severe exacerbation), rather than contemporaneous costs of an acute event. For chronic respiratory failure and lung cancer, the cited evidence did not provide directly comparable annual COPD-alone and COPD-plus-condition costs; these cells are therefore reported as not estimable rather than extrapolated. For psychological comorbidities, the Canadian study reported condition-attributable excess cost but not a paired COPD-alone/COPD-plus-condition annual total.

Abbreviations: CAD, Canadian dollar; COPD, chronic obstructive pulmonary disease; EUR, euro; NSCLC, non-small cell lung cancer; PH-COPD, pulmonary hypertension associated with COPD; SCLC, small cell lung cancer; USD, United States dollar.

The distribution of economic costs closely parallels the distribution of disease burden. COPD accounted for 74.4 million DALYs globally in 2019, reflecting substantial health loss from both premature mortality and disability. Acute exacerbations and major cardiopulmonary comorbidities further contribute to mortality, disability and healthcare utilisation.³ Consequently, interventions targeting these dominant sources of burden may offer substantial opportunities to reduce both health loss and healthcare expenditure. This relationship forms the conceptual basis of the integrated DALY-ICER framework applied throughout this review.

Group 1. Acute Exacerbations as the Principal Driver of COPD Costs

Acute exacerbation of COPD (AECOPD) is defined as an acute worsening of dyspnoea and/or cough with sputum production, with symptom deterioration typically occurring within 14 days and often accompanied by tachypnoea and/or tachycardia.⁵⁶ The incidence and clinical burden of AECOPD vary across countries and healthcare settings. In the United States, approximately 29–47% of patients with COPD experience at least one exacerbation annually, making exacerbations the leading cause of COPD-related healthcare utilisation and expenditure.⁶⁰ Across healthcare systems, exacerbations account for the largest proportion of direct medical costs through emergency department visits, hospitalisations and post-discharge care, while simultaneously accelerating disease progression, increasing mortality and contributing substantially to disability.^{56,60,66–68} In the United States, hospitalisations for AECOPD account for approximately 50–75% of total COPD-related medical costs.⁶⁸ Beyond the immediate costs of acute care, recurrent exacerbations result in repeated healthcare utilisation, accelerated lung function decline and sustained increases in long-term treatment costs.

The economic impact of AECOPD is largely determined by exacerbation frequency and severity. Patients with recurrent exacerbations incur disproportionately higher healthcare costs because of repeated hospital admissions, prolonged inpatient stays and increased use of pharmacological and supportive therapies. Hospitalisation is consistently the largest component of direct COPD-related medical costs across both high- and middle-income countries, with severe exacerbations accounting for the greatest share of expenditure.^{9,56,60,66–69} Despite the substantial economic burden of exacerbations worldwide, the distribution of healthcare costs varies considerably between countries. In China, the median cost of hospitalisation for AECOPD is CNY 11,598, with medications accounting for 36–88% of total costs depending on hospital level.⁶⁹ In Vietnam, medications comprise 53.9% of total AECOPD-related costs, and this proportion increases with disease severity.⁷⁰ By contrast, a study from Greece identified personnel costs as the principal cost driver, accounting for 54.5% of total hospitalisation costs. Medication costs contributed only 4% of total costs, of which antibiotics, oral corticosteroids and short-acting bronchodilators accounted for 67%, 16% and 13%, respectively.⁷¹ These findings highlight substantial international variation in the composition of exacerbation-related healthcare costs while consistently identifying exacerbation prevention as an important target for reducing healthcare utilisation and expenditure.

Beyond increasing healthcare costs, exacerbations substantially increase COPD-related mortality and disability. Severe exacerbations requiring hospitalisation are associated with high short- and long-term mortality, while recurrent events accelerate lung function decline, worsen health status and increase the risk of subsequent exacerbations.^70–73 This vicious cycle places patients with a frequent-exacerbation phenotype at disproportionate risk of COPD-related disability-adjusted life years (DALYs) and healthcare expenditure.

From the perspective of the integrated DALY-ICER framework, interventions that effectively prevent exacerbations are expected to produce the greatest reductions in both disease burden and healthcare costs. Consequently, exacerbation prevention represents a major target of value-based COPD management and provides the rationale for prioritising smoking cessation, pulmonary rehabilitation and selected pharmacological therapies discussed later in this review. Although acute exacerbations are the largest immediate driver of COPD-related healthcare expenditure, they represent only one component of the overall disease burden. Progressive pulmonary complications further increase long-term healthcare utilisation, prolong hospitalisation, accelerate functional decline and contribute substantially to mortality. Understanding these downstream consequences is therefore essential for identifying interventions that reduce both COPD-related disease burden and long-term healthcare costs within the integrated DALY-ICER framework.

Group 2. Pulmonary Complications as Drivers of Long-Term Healthcare Costs

Pulmonary complications substantially amplify the long-term clinical and economic burden of COPD beyond that attributable to acute exacerbations alone. Progressive respiratory failure, pulmonary hypertension and recurrent respiratory infections are associated with increased healthcare utilisation, prolonged hospitalisation and greater dependence on long-term supportive therapies. Collectively, these complications drive sustained increases in direct medical costs while accelerating disability and premature mortality.^62,72–74

Among these complications, chronic respiratory failure is associated with particularly high healthcare costs because of recurrent hospital admissions, long-term oxygen therapy, ventilatory support and complex multidisciplinary care.^{61,62,72–74} A prospective cohort study by Connors et al involving 1016 patients from five hospitals reported that patients with AECOPD complicated by hypercapnic respiratory failure incurred a median hospitalisation cost of USD 7100 and had a median hospital stay of 9 days.⁶¹ Pulmonary hypertension further increases healthcare expenditure and worsens clinical outcomes. In a US study, the mean annual healthcare cost for patients with COPD-associated pulmonary hypertension was USD 51,435, compared with USD 18,412 for patients with COPD alone, representing an excess annual cost of USD 33,023, primarily attributable to more frequent hospitalisations and greater healthcare resource utilisation.⁶² Recurrent pulmonary infections further compound disease progression by increasing exacerbation frequency, delaying recovery and increasing the likelihood of subsequent hospitalisation. In the cohort reported by Connors et al, infection was the leading precipitating factor, accounting for 51.3% of acute respiratory failure episodes.^61,72 Together, these pulmonary complications create a self-reinforcing cycle in which progressive respiratory impairment drives increasing healthcare utilisation, escalating medical costs and worsening clinical outcomes.

Within the integrated DALY-ICER framework, pulmonary complications should be regarded primarily as markers of disease progression and indicators of high-risk patients rather than direct intervention targets. Their greatest value lies in identifying individuals who are most likely to benefit from interventions that prevent disease progression, reduce exacerbation frequency and delay the onset of advanced respiratory impairment. Although pulmonary complications substantially increase healthcare costs during advanced disease, coexisting chronic comorbidities contribute an additional and often independent source of healthcare expenditure throughout the course of COPD. Their combined impact further complicates disease management and highlights the importance of integrated, value-based strategies for optimising healthcare resource allocation.

Group 3. Comorbidities as Multipliers of COPD Disease Burden and Healthcare Costs

Comorbidities are among the strongest determinants of healthcare utilisation and economic burden in COPD, contributing independently to hospitalisation, treatment complexity and mortality throughout the disease course. Approximately 90% of patients with COPD have at least one chronic comorbidity, and multimorbidity is associated with substantially higher healthcare expenditure than COPD alone.^49,59 Rather than representing isolated conditions, comorbidities interact with COPD to accelerate functional decline, increase exacerbation frequency and prolong healthcare utilisation.

Cardiovascular diseases are among the most prevalent and economically important comorbidities in patients with COPD. The reported prevalence of cardiovascular disease among patients with COPD ranges from 20% to 70% and includes heart failure, ischaemic heart disease, arrhythmias, peripheral vascular disease and hypertension.⁵⁶ These conditions are consistently associated with increased hospital admissions, prolonged hospitalisation and higher mortality. Cardiovascular events frequently occur during or following acute exacerbations, thereby further increasing healthcare utilisation, direct medical costs, and the risk of COPD-related disability.^{50,58,59,64,75–77} A US study reported that patients with both COPD and cardiovascular disease incurred annual direct healthcare costs that were 135% higher than those of patients with COPD alone. Annual all-cause healthcare costs increased by approximately USD 16,800 per patient, whereas COPD-specific healthcare costs increased by only about 38%, highlighting that cardiovascular comorbidity contributes substantially to the overall economic burden beyond COPD itself.⁵⁸ A recent population-based Canadian study further demonstrated the dominant contribution of cardiovascular disease to excess healthcare costs among patients with COPD. Cardiovascular disease accounted for CAD 1375 per patient-year in excess healthcare costs, exceeding the costs directly attributable to COPD itself (CAD 904 per patient-year). These findings identify cardiovascular disease as the single largest contributor to excess healthcare expenditure among patients with COPD.⁶⁴

Lung cancer is another major comorbidity that substantially increases the clinical and economic burden of COPD. A meta-analysis of 31 observational studies involving 829,490 patients with COPD reported a pooled prevalence of lung cancer of 5.08%.⁷⁸ Conversely, COPD is highly prevalent among patients with lung cancer, affecting approximately 40–70% of cases, and represents an important non-cancer cause of mortality in this population.³⁸ Patients with coexisting COPD and lung cancer experience substantially greater healthcare utilisation because of complex diagnostic pathways, multimodal treatment and poorer clinical outcomes. To date, no studies have specifically quantified the healthcare costs attributable to COPD with coexisting lung cancer. However, a study from Turkey reported that the annual direct medical costs of non-small cell lung cancer were EUR 10,167 per patient, compared with EUR 8772 for small cell lung cancer.⁶³ Although these estimates were not specific to patients with COPD, they illustrate the considerable economic burden associated with lung cancer treatment. Consequently, the coexistence of COPD and lung cancer is likely to result in substantially greater healthcare expenditure and poorer survival than either disease alone.

Metabolic disorders, particularly diabetes mellitus and osteoporosis, further amplify the long-term clinical and economic burden of COPD by increasing treatment complexity, medication use and the risk of hospitalisation. Up to 40% of patients with COPD have one or more metabolic syndrome-related conditions, with diabetes mellitus being the most common.⁷⁹ The prevalence of metabolic syndrome itself exceeds 30% among patients with COPD and is associated with poorer clinical outcomes.⁵⁶ Patients with COPD and type 2 diabetes are at increased risk of infections, severe exacerbations and hospitalisation, resulting in poorer prognosis and greater healthcare costs than those without diabetes.⁸⁰ COPD is also associated with a 2.8-fold increased risk of osteoporosis, with an estimated prevalence of 7–15% among patients with stable disease.⁴⁹ Although metabolic disorders contribute less directly to COPD-related mortality than cardiovascular disease or lung cancer, they substantially impair quality of life, increase frailty and disability, and drive cumulative healthcare utilisation and long-term medical costs.^79,80

Psychological comorbidities, particularly anxiety and depression, also contribute substantially to the overall burden of COPD. These conditions are associated with poorer treatment adherence, reduced participation in pulmonary rehabilitation, more frequent exacerbations and increased healthcare utilisation, thereby increasing both direct and indirect healthcare costs.^79,81 Bronchiectasis is another clinically important comorbidity, affecting approximately 30% of patients with COPD.⁵⁶ Patients with coexisting COPD and bronchiectasis have poorer lung function, require more intensive antibiotic therapy following acute exacerbations and experience more frequent moderate-to-severe exacerbations than those with COPD alone.^65,82 Consequently, the coexistence of bronchiectasis is associated with significantly higher treatment costs and greater healthcare resource utilisation.⁶⁵ Other comorbid conditions, including gastro-oesophageal reflux disease (GERD) and obstructive sleep apnoea (OSA), further contribute to disease burden. GERD is associated with an increased risk of respiratory symptoms and acute exacerbations, whereas OSA contributes to more severe nocturnal hypoxaemia, intermittent oxygen desaturation and hypercapnia, leading to poorer clinical outcomes and greater healthcare utilisation.^56,83,84 Collectively, these comorbidities increase treatment complexity and reinforce the need for integrated multidisciplinary management to reduce disease burden and optimise healthcare resource utilisation.

Therefore, these findings indicate that the economic impact of comorbidities extends beyond the management of individual diseases. Instead, multimorbidity amplifies COPD-related disability, recurrent hospitalisation and long-term healthcare expenditure, making integrated disease management an essential component of value-based care. Within the integrated DALY-ICER framework, comorbidities primarily function as indicators of patients with disproportionately high disease burden rather than as independent reimbursement targets. Their presence identifies patient populations most likely to benefit from interventions that reduce exacerbations, improve functional status and prevent disease progression, thereby increasing the overall health gains achievable through targeted resource allocation.

The evidence presented in Groups 1–3 demonstrates that acute exacerbations, pulmonary complications and multimorbidity collectively account for most COPD-related health loss and healthcare expenditure. These observations provide the clinical and economic rationale for evaluating interventions according to both their capacity to reduce disease burden and their economic value. The following section therefore applies the integrated DALY-ICER framework to preventive, non-pharmacological and pharmacological interventions to identify priorities for value-based COPD management.

Group 4. Prioritising COPD Interventions Using the Integrated DALY-ICER Framework

The evidence presented in Groups 1–3 demonstrates that acute exacerbations, pulmonary complications and major comorbidities collectively account for most COPD-related health loss and healthcare expenditure. Interventions should therefore be prioritised not only according to clinical efficacy but also according to their capacity to reduce population health loss and deliver economic value. The predefined classification rules described in the Methods were applied consistently across all interventions, and the resulting burden grades, reported economic results and quadrant assignments are summarised in Tables 1–3 and Figure 1. Because willingness-to-pay thresholds differ between healthcare systems, each economic result is interpreted against the threshold adopted in its source setting rather than against a single global benchmark.

Q1 Interventions: High or Moderate Burden Reduction with Favourable Cost-Effectiveness

Smoking cessation demonstrated the strongest combination of population health benefit and economic value among all interventions evaluated, slowing lung-function decline, reducing exacerbation frequency and lowering premature mortality.^4,22,56 In a nationwide Korean cohort, cessation after diagnosis was associated with adjusted hazard ratios of 0.83 for all-cause mortality and 0.56 for cardiovascular mortality.²³ In a Dutch dynamic population model, the ICERs were EUR 16,900 per QALY for minimal counselling, EUR 8200 per QALY for intensive counselling and EUR 2400 per QALY for intensive counselling combined with pharmacotherapy; the last strategy dominated intensive counselling alone.²⁴ An English societal-perspective Markov model found cessation to be dominant, saving GBP 1824 per patient while generating 1.27 additional life-years and 0.68 QALYs.²⁵ Given its broad applicability, relatively low implementation requirements and substantial long-term health gains, smoking cessation represents the highest-priority intervention within the framework.

Pulmonary rehabilitation consistently improves exercise capacity and health-related quality of life and reduces hospitalisation and disability; observational evidence also suggests a mortality benefit, particularly when rehabilitation is initiated after hospitalisation.^4,26–28 A UK evaluation reported a gain of 0.065 QALYs per completed programme, approximately 8% reduction in hospitalisation and GBP245 lower expenditure.²⁹ Following hospitalisation for AECOPD, a US lifetime model found rehabilitation to be dominant, producing 0.53 additional QALYs while saving approximately USD 5721 per patient.³⁰ These findings support classification as a Q1 intervention suitable for widespread implementation.

Influenza and pneumococcal vaccination may reduce infection-related exacerbations and hospitalisation, a clinically relevant target because respiratory infections precipitate a substantial proportion of COPD exacerbations; vaccination coverage in COPD populations nevertheless remains low.^31,32 A systematic review from Southeast Asia found both vaccines cost-effective compared with no vaccination against country-specific willingness-to-pay thresholds, with quadrivalent influenza vaccine outperforming trivalent vaccine and PPSV23 showing greater economic value than PCV13.³³ However, these evaluations were conducted in broader adult populations rather than in COPD-specific cohorts and did not quantify exacerbations or DALYs averted in COPD. Their Q1 assignments are therefore provisional pending disease-specific economic evidence.

Collectively, Q1 interventions combine broad applicability, substantial reductions in COPD-related burden and consistently favourable economic value, making them the strongest candidates for routine reimbursement and implementation.

Q2 Interventions: Meaningful Clinical Benefit with Less Favourable Economic Value

Ensifentrine, an inhaled selective phosphodiesterase 3/4 inhibitor approved in 2024 for maintenance treatment, produced clinically meaningful improvements in lung function, respiratory symptoms and quality of life.^34,35 A US value assessment projected fewer moderate-to-severe exacerbations and additional QALYs when ensifentrine was added to existing maintenance therapy, but at the launch price the estimated ICER exceeded conventional willingness-to-pay thresholds.³⁶ Its economic value therefore remains highly dependent on acquisition cost, and the Q2 assignment identifies price negotiation rather than exclusion as the appropriate reimbursement response. Its position may change as real-world effectiveness data accumulate and acquisition prices evolve.

A similar pattern was observed for mepolizumab in patients with COPD and type 2 inflammation. A 2026 Colombian lifetime Markov analysis comparing mepolizumab plus triple therapy with triple therapy alone estimated a 14% relative reduction in exacerbation risk but an ICER of USD 45,192 per QALY, substantially exceeding the Colombian willingness-to-pay threshold of USD 5180 per QALY. Under base-case assumptions, the probability of cost-effectiveness was 0%.³⁷ These findings suggest that mepolizumab may provide clinically meaningful benefit in a biomarker-defined COPD population, but its economic value at the evaluated price is unfavourable in the source setting.

Q3 Interventions: Favourable Economic Value in Selected Populations or Contexts

Several interventions demonstrated favourable economic value only when targeted to carefully selected patient populations.

Triple inhaled therapy consistently improved clinical outcomes, whereas its economic value varied substantially according to the healthcare setting, comparator, acquisition price and characteristics of the treatment-eligible population.³⁸ In Spain, fluticasone furoate/umeclidinium/vilanterol yielded an ICER of EUR 6887 per QALY against ICS/LABA, below the EUR 30,000 per QALY threshold, and was dominant over dual bronchodilation;³⁹ in China, the corresponding ICER against budesonide/formoterol was CNY 33,006.80 per QALY, below the CNY 72,447 threshold.⁴⁰ A separate Chinese analysis likewise found FF/UMEC/VI to be cost-effective compared with UMEC/VI.⁴¹ In a Spanish ETHOS-based model, budesonide/glycopyrronium/formoterol yielded an ICER of EUR 3461.19 per QALY versus LAMA/LABA, well below the EUR 25,000 threshold.⁴² Among patients already indicated for triple therapy, single-inhaler regimens were dominant over multiple-inhaler regimens in UK and German analyses; this represents an adherence-mediated device comparison rather than a question of initial treatment indication.^43,44

More recent economic evaluations further demonstrate this context dependence. In Colombia, FF/UMEC/VI was dominant over budesonide/glycopyrronium/formoterol in a microsimulation analysis, providing additional QALYs at lower overall cost.⁴⁵ In Chile, FF/UMEC/VI was cost-effective compared with multiple-inhaler triple therapy, with an ICER of approximately USD 438 per QALY in the base case.⁴⁶ By contrast, a Thai economic evaluation found that FF/UMEC/VI was not cost-effective compared with multiple-inhaler triple therapy at current prices, with an ICER of approximately THB 1.90 million per QALY against a THB 160,000 per QALY threshold; budesonide/glycopyrrolate/formoterol was dominated by the multiple-inhaler comparator.⁴⁷ These findings indicate that the economic value of triple therapy cannot be generalised across healthcare systems and is sensitive to comparator choice, local prices and patient eligibility. These findings support context-specific reimbursement for clinically eligible patients, with consideration of exacerbation risk, comparator, acquisition price and local willingness-to-pay thresholds.

Long-term low-dose azithromycin reduced exacerbations among patients with recurrent events but raises concerns regarding antimicrobial resistance. In a Canadian 20-year model, among patients with at least one moderate or severe exacerbation in the previous 12 months, azithromycin reduced the modelled number of exacerbations from 11.86 to 10.95 per patient and yielded an ICER of CAD 43,200 per QALY gained. Among frequent exacerbators, defined as at least two moderate or one severe exacerbation in the previous 12 months, the ICER decreased to CAD 8862 per QALY gained. In patients with no exacerbation history, azithromycin was dominated, with higher costs and lower QALYs than usual care.⁴⁸ These findings indicate that economic value improves with increasing baseline exacerbation risk, supporting classification within Q3.

Long-term oxygen therapy combined with home mechanical ventilation delayed readmission and improved quality-adjusted survival in patients with persistent hypercapnia after an exacerbation.^4,49,50 In a UK evaluation, adding home mechanical ventilation increased costs by GBP 512 per patient per year but improved quality-adjusted survival, giving an ICER of GBP 10,259 per QALY, well below the GBP 30,000 per QALY threshold.⁵¹ Given the substantial equipment and follow-up costs, reimbursement is most appropriately targeted to predefined high-risk groups. A 2026 Czech cost-utility analysis also found home mechanical ventilation to be dominant over facility-based mechanical ventilation, with lower cumulative costs and slightly higher QALYs over a 10-year horizon.⁵² However, because the comparator and clinical decision context differed from those of post-exacerbation long-term oxygen therapy combined with home mechanical ventilation (HOT-HMV) studies, this finding provides additional supportive rather than directly comparable economic evidence.

Integrated disease management reduced healthcare utilisation and improved patient outcomes, although economic benefit varied with programme design, healthcare system and patient characteristics. Among high-risk, exacerbation-prone patients in Canadian primary care, integrated disease management was dominant over usual care, generating additional QALYs while reducing costs, with a one-year net monetary benefit of CAD 5360 per patient against a CAD 50,000 per QALY threshold.⁵³ Implementation is therefore best directed at patients at increased risk of recurrent exacerbations rather than applied routinely.

COPD screening demonstrated generally favourable but context-dependent economic value. A Chinese microsimulation of adults aged 35–80 years estimated ICERs of USD 8034–13,209 per QALY across modelled strategies, all below the national willingness-to-pay threshold of USD 38,441 per QALY, with annual two-step screening using a questionnaire followed by portable spirometry identified as the most economically efficient strategy.⁵⁴ Subsequent systematic reviews further supported the potential economic value of COPD screening and case-finding across multiple healthcare settings, although substantial heterogeneity was observed in target populations, screening tools, comparators and economic assumptions.⁵⁵ These findings support targeted implementation, particularly in populations at increased risk of undiagnosed COPD, rather than a uniform population-wide screening strategy.

Overall, Q3 interventions demonstrate favourable economic value only within defined patient populations, treatment contexts or comparator-specific decision problems, illustrating the importance of both patient stratification and local economic context in value-based healthcare.

Q4 Interventions: Limited Burden Reduction with Unfavourable Economic Value

No intervention-population combination included in this review could be robustly assigned to Q4 under the predefined operational criteria. Although some interventions may have limited expected incremental clinical benefit in specific patient subgroups, assignment to Q4 requires applicable economic evidence demonstrating an unfavourable value profile rather than the absence of such evidence.

Not Classifiable: Insufficient COPD-Specific Economic Evidence

Several clinically important interventions could not be formally classified.

ICS-containing maintenance therapy in patients with blood eosinophil counts below 100 cells/μL and no exacerbation history represents a clinically relevant low-expected-benefit context. In this population, the expected incremental reduction in exacerbations is limited, while treatment acquisition costs and the risk of ICS-associated pneumonia remain. However, no subgroup-specific COPD cost-utility or cost-effectiveness analysis reporting QALYs, DALYs or ICERs was identified. Accordingly, this intervention-population combination was classified as Not classifiable. This designation reflects insufficient applicable economic evidence and should not be interpreted as evidence that ICS-containing therapy is universally cost-ineffective.

Reducing household air pollution remains an important public health strategy, particularly in low- and middle-income countries, where biomass-fuel exposure is an important contributor to COPD among never-smokers.^50,56 Household air pollution affected 2.67 billion people in 2021 and was associated with an estimated 111 million DALYs across all attributable diseases globally, approximately 3.9% of total global DALYs.⁵⁷ However, the COPD-specific burden avertable through a defined clean-fuel intervention has not been quantified, and no economic evaluation incorporating stove, fuel, infrastructure or implementation costs was identified. This strategy is therefore not graded on the intervention-avertable burden axis and remains not classifiable.

COVID-19 booster vaccination was reported to be cost-effective in general adult populations in the Southeast Asian review,³³ but reductions in exacerbations, mortality or DALYs have not been demonstrated in a COPD population, and no COPD-specific economic evaluation was identified.^31,33 Selective beta-blockade remains clinically appropriate in patients with established cardiovascular disease, yet no cost-utility analysis in a COPD cohort reporting QALYs, DALYs or ICERs was identified.^4,58 No eligible COPD-specific cost-utility evaluation was likewise identified for metabolic or CPAP-based management of relevant comorbidities, although the strength of clinical evidence differs across these interventions.^49,50

Importantly, Not classifiable does not imply a lack of clinical effectiveness. It records an absence of applicable COPD-specific economic evidence rather than a low position on the economic axis, and these interventions therefore represent priorities for future health-economic research rather than lower-priority clinical care.

Summary of Group 4

Application of the integrated DALY-ICER framework revealed clear differences in reimbursement priority across COPD interventions. Smoking cessation and pulmonary rehabilitation provided the most favourable combination of burden reduction and economic value and support broad implementation. Ensifentrine achieved meaningful clinical benefit at an unfavourable launch price, identifying price negotiation rather than exclusion as the appropriate response. Triple inhaled therapy, long-term azithromycin, home oxygen with mechanical ventilation, integrated disease management and screening showed favourable economic value in selected populations, treatment contexts or comparator-specific decision problems. ICS-containing therapy in low-eosinophil, non-exacerbating patients, household air pollution control, COVID-19 booster vaccination and selective beta-blockade remained Not classifiable because applicable COPD-specific economic evaluations were unavailable. Integrating disease burden with cost-effectiveness therefore supports more transparent and evidence-based prioritisation of COPD interventions while making the limits of the available evidence explicit.

Discussion

Summary of Principal Findings

This review addresses an important gap in the COPD literature by integrating disease burden reduction and economic efficiency within a unified DALY-ICER framework for intervention prioritisation. Unlike conventional reviews, which generally evaluate either disease burden or cost-effectiveness separately, the proposed framework combines these complementary dimensions to provide a more transparent conceptual basis for value-based clinical and reimbursement discussions. By considering burden-reduction evidence alongside ICER-based economic evidence, this review proposes a structured approach for evaluating COPD interventions from both clinical and reimbursement perspectives.

The findings indicate that recurrent acute exacerbations remain the principal driver of COPD-related healthcare expenditure and disease burden, with pulmonary complications and major comorbidities further amplifying long-term healthcare utilisation, disability and premature mortality. Hospitalisation consistently accounted for the largest proportion of direct medical costs across healthcare systems, although the relative contribution of individual cost components varied according to healthcare delivery models and resource availability. These observations reinforce the importance of preventing exacerbations and delaying disease progression as the most effective strategies for simultaneously reducing health loss and healthcare expenditure.

Application of the integrated DALY-ICER framework demonstrated clear differences in reimbursement priority across interventions. Smoking cessation and pulmonary rehabilitation consistently achieved the most favourable combination of burden reduction and economic value and therefore occupied the highest-priority positions within the framework. Influenza and pneumococcal vaccination also demonstrated favourable clinical and economic profiles, although their classification remains provisional because COPD-specific economic evaluations are limited. In contrast, several pharmacological interventions achieved favourable economic value primarily within carefully selected high-risk populations rather than when applied universally. Triple inhaled therapy, long-term azithromycin and long-term oxygen therapy combined with home mechanical ventilation all illustrated the importance of patient stratification in value-based COPD care, whereas ensifentrine highlighted a different challenge by demonstrating meaningful clinical benefit despite less favourable economic value at current pricing.

Another important finding is the substantial evidence gap surrounding several clinically important interventions and intervention-population combinations. Applicable COPD-specific economic evaluations remain scarce for several clinically important strategies, including ICS-containing therapy in low-eosinophil, non-exacerbating patients, household air-pollution control and many comorbidity-directed interventions. Economic evidence is beginning to emerge for selected newer therapies, including biologic treatment in biomarker-defined COPD populations, but remains limited and highly setting-dependent. Consequently, these interventions could not be confidently positioned within the economic dimension of the DALY-ICER framework. Importantly, this reflects limitations of the available evidence rather than limited clinical effectiveness and identifies priorities for future health-economic research.

Comparison with Existing Literature

Previous reviews have generally examined either the burden of COPD or the cost-effectiveness of individual interventions but have rarely integrated these complementary perspectives into a unified decision framework. Global economic analyses have consistently demonstrated that COPD imposes an increasing financial burden driven by population ageing, continued tobacco exposure and environmental risk factors, while systematic reviews have identified cardiovascular disease, metabolic disorders and lung cancer as major contributors to healthcare utilisation and costs. National economic studies have similarly documented substantial variation in COPD-related expenditure across healthcare systems.^8,12–15 However, these studies primarily described disease burden and resource use without addressing how competing interventions should be prioritised for reimbursement.

Conversely, numerous pharmacoeconomic evaluations have reported favourable ICERs for individual interventions, including targeted screening, triple therapy and home mechanical ventilation.^39,40,51,54 Although these studies provide valuable evidence regarding the economic performance of specific interventions, they were designed to evaluate isolated treatment strategies rather than to compare interventions across the entire COPD care pathway. The present review extends this evidence by integrating burden reduction and economic efficiency within a common analytical framework, thereby enabling preventive, non-pharmacological and pharmacological interventions to be evaluated using consistent decision criteria.

Our findings also help explain apparent inconsistencies among published economic evaluations. Differences in reported ICERs for the same intervention are largely attributable to variations in healthcare costs, willingness-to-pay thresholds, patient characteristics and model assumptions rather than conflicting evidence regarding clinical effectiveness. Economic evaluations should therefore be interpreted within the context of the healthcare systems in which they were conducted rather than extrapolated directly across countries.

Recent evidence further reinforces this point. Economic evaluations of single-inhaler triple therapy published across Thailand, Chile and Colombia produced markedly different conclusions despite evaluating closely related COPD treatment strategies. Favourable or dominant results were reported in Chile and Colombia, whereas a Thai analysis found single-inhaler triple therapy not cost-effective at prevailing prices. These differences illustrate that cost-effectiveness is determined not only by clinical effectiveness but also by comparator choice, acquisition price, healthcare resource costs and source-setting willingness-to-pay thresholds. Accordingly, cross-country differences in ICERs should not be interpreted as contradictory evidence but as an expected consequence of context-specific economic evaluation.

Contribution of the Integrated DALY-ICER Framework

The principal contribution of this review is the development of a conceptual framework that integrates burden-reduction evidence with ICER-based assessments of cost-effectiveness to inform discussion of intervention priorities. Neither DALYs nor ICERs alone provide a sufficient basis for healthcare decision-making. DALYs quantify the magnitude of population health loss but provide no indication of economic efficiency, whereas ICERs evaluate value for money without considering the underlying burden of disease. Integrating these complementary perspectives enables interventions to be prioritised according to both expected health gains and economic value, thereby supporting more transparent and consistent resource allocation.

Within this framework, four reimbursement scenarios emerge. Interventions that achieve substantial burden reduction together with favourable cost-effectiveness are appropriate candidates for broad reimbursement. Interventions demonstrating important clinical benefits but less favourable affordability may warrant price negotiation or managed-entry agreements. Therapies whose value depends on patient characteristics are best supported through phenotype- or risk-based reimbursement strategies. Finally, interventions lacking COPD-specific economic evaluations should be prioritised for future economic research while continuing to be guided by established clinical evidence and guideline recommendations.

Importantly, the proposed framework is intended to complement rather than replace existing health technology assessment processes. Budget impact, healthcare equity, implementation feasibility, affordability and local policy priorities remain essential considerations when translating economic evidence into reimbursement decisions. Accordingly, the proposed framework should be regarded as a conceptual decision-support structure rather than a validated or prescriptive reimbursement algorithm.

Implications for Clinical Practice and Health Policy

For clinicians, the proposed framework facilitates identification of interventions expected to deliver the greatest overall health gains while avoiding unnecessary treatment escalation in patients with lower expected benefit. These findings reinforce current precision-medicine approaches in COPD by aligning treatment intensity with disease burden, exacerbation risk and expected economic value, thereby supporting more efficient use of healthcare resources.

For healthcare payers and policy-makers, the framework provides a transparent structure for considering value-based reimbursement alongside other decision criteria. Broad access should be prioritised for interventions that consistently demonstrate favourable economic value and substantial burden reduction, whereas therapies with context-dependent or subgroup-specific value are better linked to clearly defined eligibility criteria, price negotiation or managed-entry agreements. For interventions lacking robust COPD-specific economic evidence, investment in high-quality pharmacoeconomic research should accompany clinical implementation rather than delaying access solely because economic data remain incomplete.

Future research should prospectively evaluate the performance of the DALY-ICER framework in real-world reimbursement decisions and further strengthen the model by incorporating additional dimensions such as budget impact, health equity, implementation feasibility and patient-reported outcomes. Such refinements may improve the applicability of value-based decision-making across diverse healthcare systems and enhance the practical utility of the framework for clinicians, healthcare payers and policy-makers.

Future Directions

Future Research Priorities

This review identifies several important evidence gaps that should guide future research. First, although substantial evidence supports the clinical effectiveness of many COPD interventions, COPD-specific economic evaluations remain unavailable for several clinically important strategies, including household air pollution control, management of major comorbidities and a number of emerging therapies. Future studies should integrate clinical effectiveness with robust pharmacoeconomic analyses to determine the position of these interventions within the DALY-ICER framework.

Second, most economic evaluations included in this review were conducted in high-income countries. Because healthcare costs, willingness-to-pay thresholds and resource availability differ substantially across healthcare systems, the transferability of ICER estimates remains limited. Additional economic evaluations from low- and middle-income countries are therefore essential to support context-specific reimbursement decisions and improve the global applicability of value-based COPD care.

Finally, future economic evaluations should extend beyond conventional cost-effectiveness analyses by incorporating broader dimensions relevant to healthcare decision-making, including budget impact, implementation feasibility, health equity and long-term sustainability. Integrating these considerations would provide a more comprehensive assessment of intervention value and strengthen the practical relevance of future reimbursement decisions.

Implications for Healthcare Payment Policy

The integrated DALY-ICER framework provides a practical approach for aligning reimbursement decisions with both disease burden and economic value. Rather than adopting uniform reimbursement strategies, healthcare systems may consider differentiated funding approaches according to the strength of available clinical and economic evidence.

Interventions demonstrating substantial burden reduction together with consistently favourable economic value, such as smoking cessation and pulmonary rehabilitation, should receive high reimbursement priority. Therapies whose value depends primarily on patient characteristics, including triple therapy, long-term azithromycin and home mechanical ventilation, are more appropriately supported through phenotype- or risk-based reimbursement strategies. Emerging therapies demonstrating meaningful clinical benefit but uncertain affordability, such as ensifentrine, may warrant price negotiation, managed-entry agreements or additional real-world economic evaluation before routine reimbursement is considered.

Importantly, reimbursement decisions should not rely exclusively on ICER estimates. Budget impact, affordability, healthcare infrastructure, implementation capacity and health equity all influence the translation of economic evidence into policy. Accordingly, the DALY-ICER framework should be regarded as a structured decision-support tool that complements, rather than replaces, existing health technology assessment processes.

Future Development of the Integrated DALY-ICER Framework

The proposed framework should be regarded as an evolving model rather than a final decision algorithm. Future work should prospectively validate its performance using real-world clinical and economic data from diverse healthcare systems and evaluate its consistency across different reimbursement environments.

Further methodological development could strengthen the framework by incorporating additional value dimensions, including patient-reported outcomes, implementation costs, health equity, budget impact and other components commonly considered within multi-criteria decision analysis (MCDA). Such refinements would enable more comprehensive assessment of healthcare value while maintaining the transparency and practical applicability of the current framework.

Ultimately, integrating disease burden, economic efficiency and broader healthcare value into a unified decision framework may provide a more robust foundation for value-based COPD care and reimbursement policy across diverse healthcare settings.

Limitations

This review has several limitations that should be considered when interpreting its findings.

First, this was a narrative rather than a systematic review or meta-analysis. Although the literature search followed a structured and transparent approach, and the included studies were appraised using the CHEERS 2022 checklist, the CHEC-list and AMSTAR 2 where appropriate, these assessments were intended to support qualitative interpretation rather than generate formal certainty ratings or quantitative risk-of-bias estimates. Consequently, the review-specific evidence categories should be regarded as descriptive classifications rather than validated measures of evidence certainty.

Second, most estimates of disease burden and economic outcomes were derived from decision-analytic or Markov models rather than prospective clinical studies. Reported DALYs, QALYs and ICERs therefore depend on assumptions regarding transition probabilities, disability weights, model structure, time horizons and willingness-to-pay thresholds adopted in the original studies. Consequently, the reported estimates should be interpreted within the context of these modelling assumptions.

Third, substantial heterogeneity existed across the included economic evaluations. Costs were reported using different currencies, reference years, healthcare systems and methodological perspectives, precluding direct quantitative comparison between studies. Furthermore, most evidence originated from high-income countries, limiting the generalisability of the findings to low- and middle-income settings, where the burden of COPD continues to increase and healthcare resources are often more constrained.

Fourth, the proposed DALY-ICER framework should be regarded as a transparent decision-support tool rather than a formal health technology assessment model. It does not explicitly incorporate several important determinants of reimbursement decisions, including budget impact, health equity, implementation feasibility and opportunity costs. In addition, the classification of subgroup-targeted interventions depends on the clinical eligibility criteria and economic assumptions adopted in the underlying studies.

Fifth, the burden-reduction axis was constructed using the most appropriate outcome available for each intervention, including mortality, acute exacerbations, QALYs or attributable DALYs. Because intervention-avertable DALYs have not yet been quantified for most COPD interventions, attributable disease burden, avertable burden and individual clinical benefit could only be integrated qualitatively rather than through a common quantitative metric.

Finally, important evidence gaps remain for several clinically relevant interventions. COPD-specific economic evaluations were unavailable for household air pollution control, most comorbidity-directed interventions and several emerging therapies, preventing their formal classification within the DALY-ICER framework. In addition, the economic evidence supporting influenza and pneumococcal vaccination was derived primarily from studies conducted in broader adult populations rather than exclusively in patients with COPD, making these classifications provisional, whereas COVID-19 vaccination could not be formally classified because COPD-specific economic evidence remains unavailable.

The review was restricted to English-language publications and was not prospectively registered. Given the narrative review design, literature screening, study selection and quality appraisal were conducted by a single reviewer using predefined eligibility criteria and structured appraisal tools. Although independent duplicate assessment was not performed, transparent reporting and predefined methodological procedures were used to enhance consistency and reproducibility. Nevertheless, some degree of reviewer-related bias remains possible, and the findings should be interpreted within the context of these methodological limitations. Future studies incorporating independent duplicate assessment, prospective protocol registration, and validation of the DALY-ICER framework using real-world data from diverse healthcare systems will further strengthen the methodological robustness, external validity, generalisability and practical applicability of this framework.

Conclusion

COPD continues to impose a substantial global health and economic burden, driven predominantly by recurrent acute exacerbations, progressive pulmonary complications and multimorbidity. These findings indicate that interventions capable of preventing exacerbations, delaying disease progression and reducing long-term disability may offer substantial opportunities to improve both population health and healthcare efficiency.

By integrating evidence on burden-reduction potential with ICER-based assessments of cost-effectiveness, this review proposes a conceptual framework for comparing COPD interventions across complementary clinical and economic dimensions. Within this framework, smoking cessation and pulmonary rehabilitation consistently demonstrated the strongest combination of clinical benefit and cost-effectiveness, supporting broad implementation. Influenza and pneumococcal vaccination also showed favourable value but require additional COPD-specific economic evidence to strengthen their classification. In contrast, several pharmacological and advanced respiratory interventions were economically attractive primarily when targeted to carefully selected high-risk populations, highlighting the importance of patient stratification within value-based COPD care. Importantly, interventions classified as Not classifiable should not be interpreted as lacking clinical effectiveness; rather, they represent areas where COPD-specific economic evidence remains insufficient to support reliable positioning within the proposed framework.

Overall, the proposed framework is intended to support transparent prioritisation discussions rather than to prescribe reimbursement decisions, which additionally require consideration of budget impact, affordability, healthcare equity, implementation feasibility and local healthcare priorities. Future validation using prospective real-world clinical and economic data across diverse healthcare systems will be important to assess the framework’s robustness, generalisability and potential utility.

These conclusions should be interpreted in light of the narrative, non-systematic design of the review and the heterogeneity of the underlying evidence.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abbreviations

AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CAD, Canadian dollar; CAP, community-acquired pneumonia; CAT, COPD Assessment Test; CNY, Chinese yuan renminbi; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; DALYs, disability-adjusted life years; EUR, euro; EI, emphysema index; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; GERD, gastro-oesophageal reflux disease; GBP, pound sterling; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HAP, household air pollution; HMV, home mechanical ventilation; HOT, home oxygen therapy; ICS, inhaled corticosteroid; ICER, incremental cost-effectiveness ratio; IDM, integrated disease management; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LMICs, low- and middle-income countries; mMRC, modified Medical Research Council (dyspnoea scale); NIV, non-invasive ventilation; OSA, obstructive sleep apnoea; PH-COPD, pulmonary hypertension associated with COPD; PM, particulate matter; PR, pulmonary rehabilitation; QALY, quality-adjusted life year; WTP, willingness to pay; 6-MWT, 6-Minute Walk Test; AMSTAR 2, A MeaSurement Tool to Assess systematic Reviews version 2; CHEC-list, Consensus Health Economic Criteria list; CHEERS, Consolidated Health Economic Evaluation Reporting Standards; GRADE, Grading of Recommendations Assessment, Development and Evaluation; SANRA, Scale for the Assessment of Narrative Review Articles; SUPPORT, Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments; USD, United States dollar; YLD, years lived with disability; YLL, years of life lost.

Data Sharing Statement

No original datasets were generated or analysed during the current study. All data reviewed are available in the cited published literature.

Ethics Approval and Informed Consent

Not applicable. This article is a review based on previously published literature and does not involve primary data collection from human subjects or animals.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.