What is the recommended single inhaler triple therapy regimen for patients with Chronic Obstructive Pulmonary Disease (COPD) requiring an Inhaled Corticosteroid (ICS), Long-Acting Beta2-Adrenergic Agonist (LABA), and Long-Acting Muscarinic Antagonist (LAMA)?

Single Inhaler Triple Therapy in COPD

Single inhaler triple therapy (SITT) with LAMA/LABA/ICS is the recommended treatment for symptomatic COPD patients at high risk of exacerbations, and should be preferentially administered as a single inhaler rather than multiple inhalers. 1

Patient Selection for Triple Therapy

Triple therapy is indicated for patients meeting ALL of the following criteria:

• High exacerbation risk: ≥2 moderate exacerbations (requiring antibiotics/oral corticosteroids) OR ≥1 severe exacerbation (requiring hospitalization/ED visit) in the past year 1, 2
• Moderate to high symptom burden: CAT score ≥10 OR mMRC score ≥2 1, 2
• Impaired lung function: FEV1 <80% predicted 1, 2

Mortality and Morbidity Benefits

Triple therapy reduces mortality compared to dual LAMA/LABA therapy in high-risk patients, which is the most critical outcome. 2 The evidence demonstrates:

• Exacerbation reduction: Annual rate of 0.91 exacerbations/year with triple therapy versus 1.21 with LAMA/LABA and 1.07 with ICS/LABA 1, 2
• Severe exacerbation reduction: 0.13 versus 0.19 severe exacerbations/year compared to LAMA/LABA (rate ratio 0.66,95% CI 0.56-0.78) 1, 2
• Additional benefits: Improvements in dyspnea, health status, and lung function 2

The IMPACT and ETHOS trials provide the strongest evidence supporting these benefits, with both demonstrating superiority of single-inhaler triple therapy over dual therapy regimens. 1

Single Inhaler Versus Multiple Inhalers

Triple therapy should preferably be administered as a single inhaler (SITT) rather than multiple inhalers. 1 The rationale includes:

• Improved adherence with single-inhaler formulations 2
• Reduced inhalation technique errors 2
• Evidence demonstrates incremental benefit with single-inhaler triple therapy compared to multiple-inhaler triple therapy 1

The guidelines acknowledge that some patients may prefer separate inhalers, but SITT remains the preferred approach. 1

Available Single Inhaler Triple Therapy Combinations

Current fixed-dose triple combinations include:

• Fluticasone furoate/umeclidinium/vilanterol 3, 4, 5
• Budesonide/formoterol/glycopyrronium 3, 4
• Beclometasone dipropionate/formoterol/glycopyrronium 3, 4

ICS Dosing Considerations

Moderate doses of ICS are sufficient; high doses are not necessary and increase adverse effects. 1 The ETHOS trial demonstrated:

• No significant difference in exacerbation reduction between 320 mg and 160 mg budesonide doses (rate ratio 1.00,95% CI 0.91-1.10) 1
• Moderate doses (e.g., budesonide 320 μg) demonstrate mortality benefit without requiring higher doses 2

Biomarker-Guided Therapy

Blood eosinophils ≥300 cells/μL identify patients who particularly benefit from ICS-containing triple therapy. 2 This is especially important when considering:

• Stepping down from triple therapy: Withdrawing ICS in patients with eosinophils ≥300 cells/μL increases risk of moderate-severe exacerbations 1, 2
• ICS withdrawal may also lower health status and lung function 1

Safety Profile

The pneumonia risk with ICS-containing regimens must be balanced against benefits:

• Number needed to treat: 4 patients to prevent one moderate-to-severe exacerbation 2
• Number needed to harm: 33 patients to cause one pneumonia 2
• The benefit-risk ratio favors triple therapy in appropriate high-risk patients 2

Monitor closely in patients who are current smokers, aged ≥55 years, have history of exacerbations or pneumonia, BMI <25 kg/m², or severe airflow limitation. 2

Notably, pneumonia risk may vary by ICS type, with some evidence suggesting lower risk with beclometasone dipropionate or budesonide compared to fluticasone furoate. 6

When NOT to Use Triple Therapy

Do not step down from triple therapy to dual therapy in high-risk patients (weak recommendation). 1 Specifically:

• Patients with CAT ≥10 and/or FEV1 <80% predicted should continue triple therapy 1
• Patients with low exacerbation risk (≤1 moderate exacerbation/year without hospitalization) should start with LAMA/LABA dual therapy instead 1

Treatment Algorithm

For low-risk patients (≤1 moderate exacerbation/year, no hospitalizations):

• Low symptoms (CAT <10): Start LAMA or LABA monotherapy 1
• Moderate-high symptoms (CAT ≥10, FEV1 <80%): Start LAMA/LABA dual therapy 1

For high-risk patients (≥2 moderate or ≥1 severe exacerbation/year):

• With moderate-high symptoms (CAT ≥10, FEV1 <80%): Start LAMA/LABA/ICS triple therapy as initial maintenance therapy 1, 2

Special Considerations

Concomitant asthma: ICS/LABA combination therapy is preferred over LAMA/LABA in patients with COPD and concomitant asthma. 1 However, triple therapy remains appropriate if exacerbation risk is high. 4

ICS monotherapy has no role in COPD: ICS should only be used in combination with long-acting bronchodilators. 1