What is the preferred treatment between Breztri (budesonide, glycopyrrolate, and formoterol) and Trelegy (fluticasone furoate, umeclidinium, and vilanterol) for a patient with chronic obstructive pulmonary disease (COPD) and a history of exacerbations?

Breztri vs Trelegy for COPD with Exacerbation History

Both Breztri (budesonide/glycopyrrolate/formoterol) and Trelegy (fluticasone furoate/umeclidinium/vilanterol) are equally effective triple therapy options for COPD patients with exacerbation history, with no clinically meaningful differences in mortality, exacerbation reduction, lung function, or safety outcomes. 1, 2

Evidence Supporting Equivalence

The most recent and comprehensive meta-analysis directly comparing these agents found no significant differences across critical outcomes 1:

• Exacerbation rates: No significant difference (p > 0.05) between BDP/FOR/GLY, BUD/GLY/FOR (Breztri), and FF/UMEC/VI (Trelegy) 1
• Lung function (trough FEV1): Comparable improvements across all triple FDCs 1, 2
• Symptom control (TDI, SGRQ): No significant differences in dyspnea or quality of life measures 1, 2
• Safety profile: Similar rates of serious adverse events, cardiovascular events, pneumonia, and all-cause mortality 1, 2

A 2021 network meta-analysis of 37,741 patients over 52 weeks confirmed that BUD/GLY/FOR (Breztri) showed comparable efficacy to FF/UMEC/VI (Trelegy) across all measured outcomes including exacerbations, lung function, symptoms, and health-related quality of life 2.

Guideline-Based Indications for Triple Therapy

Both medications are appropriate for patients meeting these criteria 3, 4, 5:

• FEV1 <50% predicted with history of ≥2 moderate exacerbations or ≥1 severe exacerbation requiring hospitalization in the previous year 3
• Persistent symptoms or exacerbations despite optimal dual bronchodilator therapy (LAMA/LABA) 3, 5
• GOLD Group D patients (high symptom burden + high exacerbation risk) 3, 5

The Canadian Thoracic Society strongly recommends LAMA/LABA/ICS triple combination therapy over dual therapy for patients with high exacerbation risk, moderate to high symptom burden, and impaired lung function, based on moderate certainty evidence showing greater reduction in mortality 4, 5.

Practical Considerations for Selection

Dosing Frequency

• Breztri: Twice-daily administration (BID) 1
• Trelegy: Once-daily administration (QD) 6, 1, 7

Single-inhaler triple therapy may improve adherence compared to multiple inhalers, and once-daily dosing with a simple device may further increase adherence 5, 7.

ICS Dose and Mortality Benefit

The ETHOS study demonstrated that the moderate dose of budesonide (320 μg in Breztri) showed a mortality benefit 5. Higher ICS doses are not typically necessary for optimal benefit in COPD 5.

Pneumonia Risk

Both regimens carry similar pneumonia risk 1, 2. The incidence of pneumonia is slightly higher with ICS-containing regimens, but the benefit-risk ratio favors triple therapy in appropriate patients, with a number needed to treat of 4 to prevent one moderate-to-severe exacerbation versus a number needed to harm of 33 for pneumonia 5.

Monitor patients with these risk factors more closely 5:

• Current smokers
• Age ≥55 years
• Prior exacerbations or pneumonia
• BMI <25 kg/m²
• Severe airflow limitation

Clinical Decision Algorithm

Choose either medication based on:

1. Patient preference for dosing frequency: Once-daily (Trelegy) versus twice-daily (Breztri) 1, 7
2. Insurance formulary coverage: Select the option with better coverage/lower cost
3. Prior ICS exposure: If patient has tolerated budesonide previously, Breztri may be preferred; if fluticasone furoate, then Trelegy 1, 2

Do not switch between these agents once stable on either medication, as they provide equivalent outcomes and switching introduces unnecessary risk of technique errors and non-adherence 1, 2.

Common Pitfalls to Avoid

• Do not add a second LAMA to either triple therapy regimen—both already contain a LAMA component (glycopyrrolate in Breztri, umeclidinium in Trelegy) 4
• Do not step down from triple therapy during or immediately after an exacerbation, as ICS withdrawal increases recurrent exacerbation risk, particularly in patients with eosinophils ≥300 cells/μL 4
• Do not use theophylline as add-on therapy to triple therapy due to low certainty of benefit and high risk of adverse events and drug interactions 5
• Monitor for oral candidiasis, hoarseness, and dysphonia with both ICS-containing regimens 5

When Triple Therapy Fails

If patients continue to exacerbate despite triple therapy, consider 3, 4:

• Roflumilast: For FEV1 <50% predicted with chronic bronchitis phenotype and ≥1 hospitalization for exacerbation in the previous year 3
• Macrolide maintenance therapy (azithromycin): For former smokers with frequent exacerbations, considering QT prolongation risk and bacterial resistance 3, 4
• Pulmonary rehabilitation: Schedule within 3 weeks after any exacerbation to reduce readmissions 4