Step-down or Step-off: How do we consider the warning about LABA from the FDA?

1. Step-down or Step-off:How do we consider the warning about LABA from the FDA? Robert C. Strunk, MD Strominger Professor of Pediatrics Washington University School of Medicine St. Louis Children’s Hospital Division of Allergy, Immunology, and Pulmonary Medicine

2. Disclosures • Employment • Washington University School of Medicine • Research Interests • NHLBI • Financial Interests • None • Chair, Pediatric Adjudication Committee, GSK study of safety and benefit of FP/salmeterol vs. FP

3. Areas to be discussed • Importance of stepping down on therapy when control achieved • How to step down from ICS/LABA • What is needed to help clinicians in decision making

4. Focus on LABA • LABA are effective in achieving improved control when added to ICS • ICS dose reduction greater when done in the context of LABA • How to step down from ICS/LABA • Step-off LABA • Step-down on ICS dosing • What is the evidence for step-off LABA to retain control

5. Why Step Down Asthma Care? • Minimization of Risks • Cost • Simplicity of regimen • To better define disease severity/phenotype • The NAEPP/EPR3 Guideline say so • The FDA says so

6. Why Step Down Asthma Care? • The NAEPP/EPR3 Guideline Say So • The Expert Panel recommends that, once asthma is well controlled and the control is achieved and maintained for at least 3 months, a reduction in pharmacologic therapy—a step down—can be considered. This will be helpful to identify the minimum therapy for maintaining good control of asthma (Evidence D). • Reduction in therapy should be gradual and closely monitored, because asthma can deteriorate at a highly variable rate and intensity. • Guidelines for the rate of reduction and intervals for evaluation have not been validated, and clinical judgment of the individual patient’s response to therapy is important. • The opinion of the Expert Panel is that the dose of ICS may be reduced about 25–50 percent every 3 months to the lowest dose possible that is required to maintain control.

7. Why Step Down Asthma Care? • The FDA Says So • LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. • LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. • Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid. • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications.

8. How to Step Down from Combination Therapy? • Potential Strategies • Last med added, first med stopped • Reduce or discontinue the medication with the most concern for side effects/risks • Reduce ICS first (to minimize ICS risks)? • Eliminate (or reduce) LABA first (to minimize LABA risks)? • Replace one medication with another? • Change from ICS to LTRA?

9. How to Step Down from Combination Therapy? • Potential Strategies • Last med added, first med stopped • Reduce or discontinue the medication with the most concern for side effects/risks • Reduce ICS first (to minimize ICS risks)? • Eliminate (or reduce) LABA first (to minimize LABA risks)? • Replace one medication with another? • Change from ICS to LTRA?

10. Why Step Down Combination Therapy? • Potential Strategies • Last med added, first med stopped • Reduce or discontinue the medication with the most concern for side effects/risks • Reduce ICS first (to minimize ICS risks)? • Eliminate (or reduce) LABA first (to minimize LABA risks)? • Replace one medication with another? • Change from ICS to LTRA?

11. How the issue of step-off emerged in editorials after a recent article

12. Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled CorticosteroidsLemanske and CARE NetworkNEJM 2010;362:975 • Step-up therapies: +LABA, + LTRA, double ICS • LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up • However, many children had a best response to ICS or LTRA step-up

13. LABA step-up was more than 1.5 times as likely to produce the best response (p = 0.002) (p = 0.004) *Covariate adjusted model Primary Outcome: Probability of BEST Response Based on Composite Outcome* LABA ICS LTRA

14. Accompanying editorialvon Mutius and Drazen • Choice for a given patient should be based on three things: surety of safety, price, and convenience, in that order • Given lingering about safety of LABA, first choice would be either increasing dose of ICS or adding LTRA • Onus lies with the treating practitioner to follow patients closely and to be sure that there is improvement with therapeutic step-up • If there is no improvement, the patient should be switched to an alternative medication and again closely monitored.

15. Other Recent Opinions • Concern about safety, most notably death, needs to be addressed by large safety studies (Drazen and O’Byrne) • LABAs should be used only in patients for whom other controller medications alone do not provide adequate (not optimal) control (Drazen and O’Byrne) • If step-up is done by adding LABA to ICS, LABA should be withdrawn, of possible, once stability is achieved (FDA 2/2010)

16. Step-Off: Remove LABA • What is the evidence that it can be done without compromising control? • Who should be considered for step-off?

17. Overview of literature • 5 articles report RCTs of patients with stable asthma controlled on ICS/LABA • Intervention: • step-off to same dose of ICS without LABA • Controls: • ICS of same dose with continued LABA • lower dose of ICS with continued LABA

18. Respiratory Medicine 2008;102:1124

19. Patients • 18 years or older, N=476 • Eligibility • Asthma controlled on dose of 1000 mcg CFC beclomethasone or equivalent and a LABA • Stable for at least 4 weeks • During 8-week run-in period on open-label fluticasone 250/salmeterol 50 (SFC250), had “well-controlled” asthma

20. Methods • Randomized to SFC 250, SFC 100, FP250 • Primary end-point variation in mean AM PEF over 1st 12 weeks compared to last 2 weeks of run-in • Secondary outcomes: • PEF over last 12 weeks • Evening PEF • Daily symptoms • SABA use • FEV1at clinic visits • Asthma control (GOAL definitions) • Exacerbations: severe, moderate, mild

21. Primary efficacy analysis

22. Other outcomes • Symptom-free days over 1st 12 weeks (change from baseline) • SFC 250: 90.2% to 89.4% • SFC 100: 94.8% to 93.2% • FP 250: 91.2% to 85.8% (p=0.012) • Rescue-free days over weeks 5-12 (change from baseline) • SFC 250: 89.6% to 89.0% • SFC 100: 95.7% to 93.6% • FP 250: 93.6% to 88.2% (p=0.014) • Moderate exacerbations (prednisone) similar in groups • SFC 250: 5.8% • SFC 100: 7.7% • FP 250: 10.4% (p=NS)

23. Overall Conclusion • The better option for reducing treatment in controlled asthma patient on an ICS/LABA conbination was to reduce the ICS dose and to maintain the LABA • All published studies come to same conclusion

24. Problems with all published studies • Poor control on ICS alone not systematically demonstrated before addition of LABA • Group data only presented: Variability in response to step-off not described • Patient characteristics that might be associated with variability in response to step-off not part of any study

25. Conclusions • Therapeutic nihilism is desired by patients and should be a goal of all medical care • Patients should continually be re-assessed for degree of asthma control • A discussion of therapeutic strategies, including step-down of care, in the setting of well-controlled asthma is essential

26. Conclusions • Less (robust) data available to guide step-down approaches than to guide step-up approaches • Step-down of ICS within fixed dose inhaler of ICS/LABA may be effective • Step-off LABAs might put patients at risk for losing asthma control • Substituting LTRA+ICS for LABA+ICS has not been studied • All patients need close follow-up to evaluate adequacy of step-down/step-off

27. References • Koenig et al. Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are “Stepped-Down”. J Asthma 2008;45:681-687. • Bateman et al. Asthma control can be maintained with fluticasone propionate/salmeterol in a single inhaler is stepped down. JACI 2006;117:563-570. • Godard et al. Maintaining asthma control in persistent asthma: Comparison of three strategies in a 6-month double-blind randomized study. Resp Med 2008;102:1124-1131. • Berger et al. Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: Randomized controlled trial comparing once- and twice-daily dosing in patients with asthma. Allergy Asthma Proc 2010;31:49-59. • Reddel et al. Down-titration from high-dose combination therapy in asthma: Removal of long-acting beta2-agonist. Resp Med 2010;104:1110-1120.