Current Triple Therapy for COPD
The current recommended triple therapy for COPD consists of a long-acting muscarinic antagonist (LAMA), a long-acting beta-2 agonist (LABA), and an inhaled corticosteroid (ICS), administered preferably as a single-inhaler triple therapy (SITT). 1
Specific Patient Population for Triple Therapy
Triple therapy LAMA/LABA/ICS is specifically indicated for patients who meet all of the following criteria: 1, 2
- High risk of exacerbations: ≥2 moderate exacerbations (requiring antibiotics and/or oral corticosteroids) OR ≥1 severe exacerbation (requiring hospitalization or emergency department visit) in the past year 1
- Moderate to high symptom burden: mMRC ≥2 OR CAT score ≥10 1, 2
- Impaired lung function: FEV1 <80% predicted 1, 2
Why Triple Therapy Over Dual Therapy
The 2023 Canadian Thoracic Society guidelines make a strong recommendation for triple therapy over LAMA/LABA dual therapy specifically because it reduces mortality, representing a major advancement in COPD management. 1 The IMPACT and ETHOS trials demonstrated hazard ratios for all-cause mortality of 0.64 (95% CI, 0.42-0.97) and 0.54 (95% CI, 0.34-0.87) respectively, with independent adjudication confirming lower rates of both respiratory and cardiovascular death. 1
Beyond mortality reduction, triple therapy provides: 1
- Reduced annual exacerbation rate (0.91 per year versus 1.21 for LAMA/LABA) 2
- Reduced severe exacerbation rate (0.13 per year versus 0.19 for LAMA/LABA, hazard ratio 0.66) 2
- Improved dyspnea, health status, and lung function 1
Delivery Method: Single Inhaler Preferred
Triple therapy should preferably be administered as a single-inhaler triple therapy (SITT) rather than multiple separate inhalers. 1 This approach improves adherence and reduces errors in inhaler technique. 1, 2, 3
Available Fixed-Dose Triple Combinations
Current fixed-dose triple combination inhalers include: 4, 5, 6
- Fluticasone furoate/umeclidinium/vilanterol
- Beclomethasone dipropionate/glycopyrronium/formoterol fumarate
- Budesonide/glycopyrronium/formoterol fumarate (320/18/9.6 µg)
The ETHOS study demonstrated mortality benefit with the moderate budesonide dose (320 µg), indicating higher ICS doses are not necessary for optimal benefit. 1, 2
Biomarker Considerations
Patients with blood eosinophils ≥300 cells/μL derive particular benefit from the ICS component of triple therapy. 2 ICS should not be withdrawn from triple therapy in high-risk patients, especially those with eosinophils ≥300 cells/μL, as this increases the risk of moderate to severe exacerbations. 2
Safety Profile and Monitoring
The incidence of pneumonia is slightly higher with ICS-containing regimens, but the benefit-risk ratio strongly favors triple therapy in appropriate patients (number needed to treat of 4 to prevent one moderate-to-severe exacerbation versus number needed to harm of 33 for pneumonia). 2, 3
Monitor closely for pneumonia in patients with these risk factors: 2, 3
- Current smokers
- Age ≥55 years
- History of prior exacerbations or pneumonia
- BMI <25 kg/m²
- Severe airflow limitation
Treatment Algorithm
For patients with low exacerbation risk and mild symptoms (CAT <10, mMRC 1): Start with single long-acting bronchodilator (LAMA or LABA). 2
For patients with low exacerbation risk and moderate-to-severe symptoms (CAT ≥10, mMRC ≥2): Start with LAMA/LABA dual therapy. 1, 2
For patients with high exacerbation risk and moderate-to-severe symptoms (CAT ≥10, mMRC ≥2) and FEV1 <80%: Start directly with triple therapy LAMA/LABA/ICS—do not delay by stepping up from dual therapy. 2, 3
Critical Pitfall to Avoid
Do not add theophylline to patients already on LAMA/LABA therapy. 2, 3 The Canadian Thoracic Society specifically recommends against this due to low certainty of benefit and high risk of adverse effects and drug interactions. 2, 3
Important Limitation
Triple therapy is not indicated for patients with concomitant asthma-COPD overlap—these patients should receive ICS/LABA combination therapy based on their asthma component. 1 The use of LABA without ICS is contraindicated in asthma. 7