For a patient with mixed asthma and Chronic Obstructive Pulmonary Disease (COPD) experiencing frequent COPD exacerbations leading to hospitalization and having high blood eosinophils, would they be treated with a single inhaler containing Long-Acting Muscarinic Antagonist (LAMA), Long-Acting Beta-Agonist (LABA), and Inhaled Corticosteroid (ICS), or with their existing Inhaled Corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA) plus a Methylxanthine (MART) therapy and a separate Long-Acting Muscarinic Antagonist (LAMA)?

Treatment Recommendation for Mixed Asthma-COPD with Frequent Exacerbations and High Eosinophils

For a patient with mixed asthma-COPD, frequent COPD exacerbations requiring hospitalization, and high blood eosinophils, you should prescribe a single-inhaler triple therapy (LAMA/LABA/ICS) rather than ICS/LABA MART plus separate LAMA. 1

Rationale for Single-Inhaler Triple Therapy

The Canadian Thoracic Society guidelines strongly prefer single-inhaler triple therapy (SITT) over multiple-inhaler combinations due to superior adherence, reduced inhalation technique errors, and simplified treatment regimen 1. This is particularly critical for your patient given their history of hospitalizations, which indicates poor disease control that demands optimal medication delivery and adherence.

Key Patient Characteristics That Mandate Triple Therapy

Your patient meets all three criteria for triple therapy initiation 1:

• High exacerbation risk: ≥1 severe exacerbation requiring hospitalization in the past year 1
• Moderate-to-high symptom burden: Implied by frequent exacerbations leading to hospitalization 1
• Impaired lung function: Typical in patients with this exacerbation pattern 1

Why High Eosinophils Matter

Patients with blood eosinophils ≥300 cells/μL have a stronger likelihood of reduced exacerbations when treated with ICS-containing regimens 2. The Canadian Thoracic Society consensus indicates this subgroup particularly benefits from triple therapy 2. Additionally, withdrawing ICS from triple therapy in patients with high eosinophils (≥300 cells/μL) increases the risk of moderate-to-severe exacerbations 1.

Why Not ICS/LABA MART Plus LAMA?

MART Therapy Is Not Indicated for COPD

MART (Maintenance and Reliever Therapy) is an asthma-specific strategy, not a COPD treatment approach. The evidence base for triple therapy in COPD is built on fixed-dose combinations, not MART regimens 3. Your patient's presentation with "frequent COPD exacerbations" suggests COPD is the dominant phenotype requiring management.

Multiple-Inhaler Approach Is Inferior

While multiple-inhaler triple therapy (ICS/LABA plus separate LAMA) can achieve the same medication combination, it is associated with 1, 4:

• Reduced adherence compared to single-inhaler therapy 1
• Increased inhalation technique errors when using devices with different mechanisms 2
• Higher rates of exacerbations when multiple devices require different inhalation techniques 2

The INTREPID study demonstrated that single-inhaler triple therapy resulted in significantly more patients showing improvements in health status and lung function compared to multiple-inhaler triple therapy 2.

Mortality and Morbidity Benefits

Triple therapy in a single inhaler reduces mortality compared to dual therapy (LAMA/LABA) in patients meeting your patient's profile 1. The IMPACT and ETHOS trials, which enrolled patients with frequent/severe exacerbations (≥2 moderate or ≥1 severe requiring hospitalization), demonstrated this mortality benefit 2. The Canadian Thoracic Society notes that adjudicated causes of death suggest triple therapy may reduce mortality not only by preventing exacerbations but also by improving cardiovascular outcomes 2.

Exacerbation Reduction

Triple therapy reduces 3:

• Annual rate of moderate-to-severe exacerbations to 0.91 versus 1.21 for LAMA/LABA alone 1
• Rate of severe exacerbations to 0.13 per year versus 0.19 per year for LAMA/LABA (hazard ratio 0.66) 1

Specific Single-Inhaler Options

Available single-inhaler triple therapy combinations include 1:

• Fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg once daily (demonstrated 25% reduction in annual moderate/severe exacerbations in IMPACT trial) 1
• Budesonide/glycopyrronium/formoterol fumarate (reduced annual rate of moderate/severe exacerbations by 24% with demonstrated mortality benefit at moderate ICS dose) 1

Safety Considerations

Pneumonia Risk

Triple therapy is associated with increased pneumonia risk (3.3% versus 1.9% with LAMA/LABA alone, OR 1.74) 3. However, the number needed to treat to prevent one moderate-to-severe exacerbation is 4, while the number needed to harm to cause one pneumonia is 33 1. The overall clinical benefit of mortality reduction outweighs the pneumonia risk 2.

Monitor closely for pneumonia, particularly given your patient's risk factors of hospitalization history and likely severe airflow limitation 1, 4.

ICS Dosing

Use moderate doses of ICS—budesonide 320 mcg has demonstrated mortality benefit without requiring higher doses 1, 4. Higher ICS doses increase adverse effects without proportional benefit 4.

Common Pitfalls to Avoid

• Do not use ICS monotherapy in this patient—it is explicitly not recommended for stable COPD 1
• Do not add theophylline to LAMA/LABA therapy due to low certainty of benefits and high risk of adverse effects and drug interactions 1
• Do not prescribe LABA without ICS in patients with asthma component, as LABA alone increases risk of asthma-related deaths 5, 6
• Do not use multiple inhalers when single-inhaler options are available and appropriate 2, 1

Ongoing Management

Continue the single-inhaler triple therapy long-term 1. Do not step down from triple therapy to dual therapy in this high-risk patient with elevated eosinophils, as ICS withdrawal increases exacerbation risk 1. Ensure proper inhaler technique at every visit, as errors in inhaler handling lead to increased emergency department admissions, hospitalizations, and systemic corticosteroid requirements 2.