How do you choose between adding a long-acting muscarinic antagonist (LAMA) or a leukotriene receptor antagonist (LTRA) in asthma step-up therapy when fractional exhaled nitric oxide (FeNO) and eosinophils are normal?

Choosing Between LAMA and LTRA in Asthma Step-Up Therapy with Normal FeNO and Eosinophils

For patients with uncontrolled asthma and normal FeNO and eosinophil levels, adding a long-acting muscarinic antagonist (LAMA) is preferred over a leukotriene receptor antagonist (LTRA) for step-up therapy due to superior efficacy in improving lung function and reducing exacerbations. 1, 2

Decision Algorithm for Step-Up Therapy

When considering add-on therapy for patients with asthma not adequately controlled on ICS-LABA with normal inflammatory markers:

1. First-line add-on: LAMA (tiotropium)

   • Superior exacerbation reduction (35% lower risk compared to increasing ICS dose) 2
   • Significant improvements in lung function
   • Reduced emergency department visits (74% lower for asthma-related visits) 2
   • Reduced hospitalizations (76% lower for asthma-related admissions) 2
   • Decreased need for rescue medication (SABA) 2

2. Second-line add-on: LTRA (montelukast)

   • Consider if patient has contraindications to LAMA
   • Better suited for patients with specific phenotypes (exercise-induced symptoms)
   • Once-daily dosing (montelukast) improves adherence 3
   • May have fewer respiratory infections in some patients 1

Supporting Evidence

LAMA Efficacy

The 2020 NIH Asthma Management Guidelines specifically recommend adding LAMA to ICS-LABA for patients with uncontrolled persistent asthma (conditional recommendation, moderate certainty of evidence) 1. This triple therapy approach has demonstrated significant benefits in:

• Reducing exacerbation risk
• Improving lung function
• Enhancing asthma control
• Decreasing healthcare resource utilization 2, 4

Recent real-world evidence shows that adding tiotropium to existing therapy significantly decreased exacerbation risk by 35% compared to increasing ICS-LABA dose 2. Additionally, LAMA add-on therapy resulted in:

• 74% reduction in asthma-related ED visits
• 76% reduction in asthma-related hospitalizations
• Fewer SABA refills (56% vs 67%) 2

LTRA Considerations

While LTRAs are listed as alternative (not preferred) therapy in asthma management guidelines 1, they may be appropriate in specific situations:

• Patients who cannot tolerate LAMAs
• Those with concurrent allergic rhinitis
• Patients with exercise-induced bronchoconstriction 1

However, montelukast carries a boxed warning for neuropsychiatric events, including suicidal thinking and behavior 3, which must be considered in the risk-benefit assessment.

Clinical Approach to Decision-Making

When FeNO and eosinophil levels are normal (indicating non-T2 inflammation):

1. Assess current control and adherence:

   • Verify proper inhaler technique
   • Confirm adherence to current therapy
   • Rule out environmental triggers

2. Add tiotropium (LAMA) if patient remains uncontrolled on ICS-LABA:

   • Recommended dose: 5 mcg once daily via Respimat inhaler 5
   • Monitor for anticholinergic side effects (dry mouth, urinary retention)

3. Consider LTRA only if:

   • Patient has contraindications to LAMA
   • Patient has specific phenotype that may benefit (exercise-induced symptoms)
   • Patient has concurrent allergic rhinitis

Monitoring and Follow-up

After initiating add-on therapy:

• Reassess control in 4-6 weeks
• Evaluate lung function (spirometry)
• Monitor for adverse effects
• Adjust therapy as needed

Potential Pitfalls and Caveats

1. LAMA contraindications: Avoid in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction 5

2. LTRA warnings: Be vigilant for neuropsychiatric events with montelukast, including agitation, depression, and suicidal ideation 3

3. Combination devices: Consider patient preference and ability to use multiple inhalers when adding LAMA

4. Non-responders: If no improvement after 3 months of triple therapy, reassess diagnosis and consider referral to specialist for consideration of biologic therapy

The evidence clearly supports LAMA as the preferred add-on therapy for patients with normal inflammatory markers who remain uncontrolled on ICS-LABA, with LTRAs serving as an alternative option in specific clinical scenarios.