What is the role of Vilanterol (long-acting beta2-adrenergic agonist (LABA)) umevlidinum (long-acting muscarinic antagonist (LAMA)) fluticasone (inhaled corticosteroid (ICS)) in the management of moderate to severe asthma?

Role of Vilanterol/Umeclidinium/Fluticasone in Moderate to Severe Asthma

Current Guideline Position

The triple combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is not currently recommended in standard asthma guidelines, as LAMA addition to ICS-LABA is conditionally recommended against as a first-line step-up strategy in patients ≥12 years with uncontrolled persistent asthma. 1

The 2020 NIH guidelines explicitly state that in individuals aged 12 years and older with uncontrolled persistent asthma, adding LAMA to ICS is conditionally recommended against, as opposed to adding LABA to ICS (conditional recommendation against, moderate certainty of evidence). 1

When LAMA May Be Considered

If LABA is not used or cannot be tolerated, the guidelines conditionally recommend adding LAMA to ICS controller therapy in patients ≥12 years with uncontrolled persistent asthma, as opposed to continuing the same dose of ICS alone (conditional recommendation, moderate certainty of evidence). 1

For patients already on ICS-LABA with inadequate control, the guidelines conditionally recommend adding LAMA to ICS-LABA (creating triple therapy), as opposed to continuing the same dose of ICS-LABA (conditional recommendation, moderate certainty of evidence). 1

FDA-Approved Dosing for FF/VI (Without UMEC)

For asthma management with the ICS/LABA combination alone:

• Adults ≥18 years: FF/VI 100/25 mcg once daily, with option to increase to 200/25 mcg once daily if inadequate response. Maximum dose is 200/25 mcg once daily. 2

• Adolescents 12-17 years: FF/VI 100/25 mcg once daily. 2

• Children 5-11 years: FF/VI 50/25 mcg once daily. 2

The FDA label emphasizes that LABA monotherapy without ICS increases risk of asthma-related death, but when used in fixed-dose combination with ICS, large trials show no significant increase in serious asthma-related events compared to ICS alone. 2

Evidence for Triple Therapy (FF/UMEC/VI)

Recent research demonstrates that FF/UMEC/VI may provide additional benefits in select populations:

• A 52-week Japanese study (n=111) showed favorable long-term safety with FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg in patients inadequately controlled on ICS/LABA. 3

• The CAPTAIN study demonstrated that FF/UMEC/VI improved lung function (trough FEV1 increase of 105 mL for 100/62.5/25 mcg vs FF/VI 100/25 mcg) and asthma control measures versus FF/VI alone in patients with inadequately controlled asthma despite ICS/LABA. 4

Preferred Stepwise Approach

For moderate to severe persistent asthma in patients ≥12 years:

1. Step 3: Low-dose ICS + LABA (preferred) OR medium-dose ICS alone. 1, 5

2. Step 4: Medium-dose ICS + LABA (preferred). 1, 5

3. Step 5: High-dose ICS + LABA. 1, 5

4. Step 6: High-dose ICS + LABA + oral corticosteroid. 1, 5

ICS-formoterol as single maintenance and reliever therapy (SMART) is conditionally recommended in individuals ≥12 years with moderate to severe persistent asthma, as opposed to higher-dose ICS-LABA as daily controller plus SABA for quick-relief (conditional recommendation, high certainty of evidence). 1

Evidence for FF/VI Efficacy

FF/VI 100/25 mcg once daily demonstrated:

• Reduced time to first severe exacerbation (HR 0.795,95% CI 0.642-0.985) and 25% reduction in annualized severe exacerbation rate versus FF alone in a 24-78 week study (n=2019). 6

• Lower SABA use (1.47 vs 1.64 canisters per patient-year) and 13% lower risk of overall exacerbations, 22% lower risk of severe exacerbations versus budesonide/formoterol in real-world US data (n=37,062 matched patients). 7

Critical Safety Considerations

Never allow LABA monotherapy – LABAs must always be combined with ICS due to increased risk of severe exacerbations and asthma-related deaths when used alone (black box warning). 1, 2

Maximum LABA dosing: Daily use of LABA should not exceed 100 mcg salmeterol or 24 mcg formoterol equivalent; vilanterol 25 mcg once daily is within safe limits. 1

Mouth rinsing: Patients should rinse mouth with water without swallowing after each use to reduce risk of oropharyngeal candidiasis. 2

Common Pitfalls

• Do not initiate triple therapy (FF/UMEC/VI) before optimizing ICS-LABA therapy – guidelines recommend against adding LAMA to ICS as opposed to adding LABA to ICS. 1

• Do not use for acute symptom relief – FF/VI and FF/UMEC/VI are maintenance therapies only; SABA should be used for acute symptoms. 2

• Reassess control every 2-6 weeks after initiating or adjusting therapy, and step down to minimum effective dose once control is sustained for ≥3 months. 1, 5

• SABA use >2 days/week (excluding exercise prevention) indicates inadequate control requiring treatment intensification. 1, 5