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 Childrens 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 therapya step downcan 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 patients 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 Corticosteroids Lemanske and CARE Network NEJM 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 ICS Primary Outcome: Probability of BEST Response Based on Composite Outcome* LTRA *Covariate adjusted model LABA step-up was more than 1.5 times as likely to produce the best response (p = 0.002) (p = 0.004)

14. Accompanying editorial von 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 OByrne) LABAs should be used only in patients for whom other controller medications alone do not provide adequate (not optimal) control (Drazen and OByrne) 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 1 st 12 weeks compared to last 2 weeks of run-in Secondary outcomes: –PEF over last 12 weeks –Evening PEF –Daily symptoms –SABA use –FEV 1 at clinic visits –Asthma control (GOAL definitions) –Exacerbations: severe, moderate, mild

21. Primary efficacy analysis

22. Symptom-free days over 1 st 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) Other outcomes

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.