1 / 61

Risk vs Benefit Considerations for the Long-Acting Beta-Agonists

Risk vs Benefit Considerations for the Long-Acting Beta-Agonists. Christine A. Sorkness, Pharm.D. Professor of Pharmacy and Medicine University of Wisconsin-Madison. Presentation Objectives. Provide an overview of the clinical pharmacology of the long-acting beta-agonists (LABAs)

jacob
Download Presentation

Risk vs Benefit Considerations for the Long-Acting Beta-Agonists

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Risk vs Benefit Considerations for the Long-Acting Beta-Agonists Christine A. Sorkness, Pharm.D. Professor of Pharmacy and Medicine University of Wisconsin-Madison

  2. Presentation Objectives • Provide an overview of the clinical pharmacology of the long-acting beta-agonists (LABAs) • Discuss the selection of therapeutic outcomes for assessment of risks vs. benefits of the LABAs • Review selected clinical trials which provide insight into the risk/benefit of LABAs • Outline the controversies and remaining questions related to the role of LABAs

  3. Overview of Clinical Pharmacology of theLong-Acting Beta-Agonists

  4. Albuterol HOH2C OH CH3 Salmeterol HO CHCH2NH-C CH3 CH3 H3C CHO OH (RS) Formoterol HN NH O (RS) HOH2C HO O OH OH OCH3 2H2O CH2 CH2 CH2 OH HO CHCH2 NHCH2 CH2 CH2 CH2 CH2 CH2 OCH2 2 Chemical Structures of Albuterol, Salmeterol, and Formoterol Prescribing Information, GlaxoSmithKline. Prescribing Information, Novartis.

  5. Duration of Action** Selectivity Bronchodilation (h) Protection (h) Pharmacologic Profile b2 Potency* b1 b2 Drug Full agonist Partial agonist Full agonist Partial agonist 1 2 0.24 0.5 ++++ ++++ ++++ ++++ Isoproterenol Albuterol Formoterol Salmeterol ++++ + + + 0.5-2 4-8 > 12 > 12 0.5-1 2-4 6-12 6->12 *Relative molar potency to isoproterenol, potency = 1 **Protection refers to the prevention of bronchoconstruction induced by exercise or nonspecific bronchial challenges Comparison of b–Adrenergic Agents Kelly HW and Sorkness CA. Asthma. In: Pharmacotherapy—A Pathophysiologic Approach, Sixth Edition, McGraw Hill 2005.

  6. Characteristic Formoterol Salmeterol Equipotent Bronchodilating Dose Recommended Inspiratory Flow Rate Pregnancy Category Indications Onset of Action • 12 mcg via Foradil Aerolizer • 60 L/min for 2 secs. • C • Twice-daily maintenance • treatment of asthma and • prevention of bronchospasm • in adults and children > 5 yrs EIB prevention Twice daily maintenance treatment of broncho- constriction in COPD • 80% max. bronchodilation • within 5-10 minutes • 50 mcg via Serevent Diskus • 60 L/min for 3 secs. • C • Twice-daily maintenance • treatment of asthma and • prevention of bronchospasm • in adults and children > 4 yrs EIB prevention Twice daily maintenance treatment of bronchospasm associated with COPD • 90% max. bronchodilation • after 1 hr; median time to sig. • BD 30-40 minutes Comparison of Formoterol and Salmeterol

  7. Interaction Between LABA and GCS

  8. What Therapeutic Outcomes Should be Used to Assess the Risks vs. Benefits of the Long-Acting Beta-Agonists?

  9. Lung Function Measures • Longitudinal studies of lung health • “Gold-standard” measure for trial entry • FEV1 60-80% predicted with 15% reversibility • Primary endpoint to measure efficacy of controller therapies • Standardization of procedures for on-site and home measurements

  10. Placebo Placebo (n=56) FEV1 >80% TAA Placebo TAA (n=54) PEF var < 20% Placebo Salmeterol (n=54) 6 weeks Run-in 6 weeks Run-out 16 weeks Treatment Long-Acting b2-Agonist Monotherapy vs. Continued ICS Therapy Lazarus S et al. JAMA 2001; 285:2583-2593 ACRN Group

  11. 500 Run-In Double-Blind Treatment 480 Triamcinolone Salmeterol 460 AM PEF (liters/min) 440 Placebo 420 400 2 6 10 14 18 22 26 Weeks SOCS Primary Outcome: AM Peak FlowIntent-to-treat Analysis Lazarus et al. JAMA 2001; 285:2583-2593 (ACRN Group)

  12. SOCS Secondary Outcomes:Salmeterol versus Triamcinolone Pulmonary Function PM peak flow FEV1 Methacholine PC20 Symptom Control Asthma symptom scores Rescue medication use Quality of life Markers of Inflammation Sputum eosinophils Sputum ECP Sputum tryptase Exhaled nitric oxide P-value* 0.951 0.048 0.042 0.321 0.452 0.331 0.0003 0.005 0.0001 0.059 *significant = p < 0.016

  13. Kaplan-Meier Survival Curves for Treatment Failure and Asthma Exacerbations Lazarus S et.al. JAMA 2001;285:2583-2593 ACRN Group

  14. SOCS: Summary • Patients with persistent asthma well controlled by low doses of ICS cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. • Clear disparity between lung function measures and other outcome measures • Multiple measurements and dimensions of control are needed to adequately assess therapies

  15. Composite Measures of Asthma Control • Days of asthma control • Treatment failure • Asthma exacerbations • Improvement in NAEPP-defined asthma severity classification • “Total Control” • GINA 2002 • Gaining Optimal Asthma Control (GOAL) • Patient surveys of asthma control and quality of life • Asthma Control Questionnaire (ACQ) • Asthma Therapy Assessment Questionnaire (ATAQ) • Asthma Control Test (ACT) • Asthma Quality-of-Life Questionnaire (AQLQ)

  16. How Much Benefit Can be Achieved by the Combination of ICS and LABA?

  17. Low Dose Inhaled Budesonide and Formoterol in Mild Persistent AsthmaThe OPTIMA Randomized Trial O’Byrne PM et al. Am J Respir Crit Care Med 2001;164:1392-9

  18. A Group Patients not on inhaled steriods Design Group A Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

  19. Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma: The OPTIMA Randomized Trial Figure 1.  (A) Kaplan-Meier survival curve for the time to the first severe asthma exacerbation. (B) Proportion (%) of poorly controlled asthma days in Group A (corticosteroid-free patients). BUD 200 = budesonide 100 µg twice daily; F = formoterol 4.5 µg twice daily. Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

  20. Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma: The OPTIMA Randomized Trial Figure 2.   Adjusted mean change from baseline in morning peak expiratory flow in Group A. BUD 200 = budesonide 100 µg twice daily; F = formoterol 4.5 µg twice daily. Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

  21. Addition of Salmeterol to Low-dose Fluticasone vs Higher-dose Fluticasone: An Analysis of Asthma Exacerbations Matz J, Emmett A, Rickard K, Kalberg C. JACI 107:783, 2001

  22. FP/Salm Combination vs FP:Time to First Exacerbation Matz J et al. JACI107:783, 2001

  23. FP/Salm vs FP alone:Effect of Disease Severity on Exacerbation Rates Matz J et al. JACI107:783, 2001

  24. ** 1.0 Budesonide 100mcg/400mcg BID 0.9 Formoterol 12mcg BID 0.8 0.7 ** 0.6 Severe Exacerbations/Patient/yr **p=0.01 0.5 0.4 0.3 0.2 0.1 0.0 BUD 800mcg/day BUD 200mcg/day BUD 200mcg/day+F BUD 800mcg/day+F (n=213) (n=214) (n=215) (n=210) FACET Study: Formoterol and Budesonide in Moderate Asthma Pauwels, et al. N Engl J Med 1997; 337: 1405-1411

  25. Pharmacological Management to Reduce Exacerbations in Adults with Asthma—A Systematic Review and Meta-Analysis Sinn DD et al. JAMA 2004; 292:367-376.

  26. Effects of LABAs on Exacerbations

  27. Effects of ICS & LABA vs Higher-Dose ICS

  28. Can Guideline-defined Asthma Control Be Achieved? The Gaining Optimal Asthma Control Study Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, and Pederson SE for the GOAL Investigators Group. Am J Respir Crit Care Med 2004; 170:836-844.

  29. Total Control Well-Controlled All of: Each Week At least 2 of: None None > 80% predicted daily < 2 days with score > 1 < 2 days + < 4 occasions/wk > 80% predicted daily Daytime Sx Rescue b2 agonist use a.m. PEF All of: All of: Nighttime awakening Exacerbations Emergency Visits Tx-related AEs None None None None enforcing change in asthma Tx None None None None enforcing change in asthma Tx Gaining Optimal Asthma Control (GOAL) Research Question: Is GINA / NIH guideline-based control achievable, and in what proportion of patients, with SFC compared with FP alone? Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

  30. GOAL Study Design • 1 year, R, DB, PG, stratified study • Stratum 1: CS-naïve or CS-free x 6 months • Stratum 2: < 500 mcg BDP daily or equivalent • Stratum 3: > 500 - < 1000 mcg BDP daily or equivalent • > 12 yrs, asthma > 6 months, not well-controlled > 2/4 weeks during run-in, < 10 pack year smoking history, reversibility of >15% • At randomization: either SFC or FP alone via DiskusÒ; dose based on strata • Study Phase I: doses stepped up every 12 weeks until Total Control achieved or maximum dose reached • Study Phase II: dose of Total Control or maximum study dose (SFC 50/500 or FP 500 mcg bid) x 52 weeks Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

  31. BASELINE CHARACTERISTICS Stratum 1 Stratum 2 Stratum 3 SFC FP SFC FP SFC FP N (ITT) m Age (yrs) FEV1, % pred Revers., % 548 36.1 77 23 550 36.4 79 22 585 40.4 78 22 578 40.3 77 22 576 44.1 75 23 579 42.7 76 22 GOAL Study Population Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

  32. GOAL Results

  33. GOAL Results

  34. GOAL Results • Significantly more patients achieved control with SFC vs FP in each stratum • In each stratum, the time to achieve the first individual week of Well-Controlled asthma was significantly lower with SFC than with FP alone (p < 0.001) • More patients achieved control at the same or lower dose of ICS in each stratum for SFC vs FP alone • The majority of patients who achieved Well-Controlled asthma in Phase I, maintained this status when reassessed in the last 8 weeks of the study; additional patients were able to gain control with sustained treatment

  35. The Pediatric Asthma Controller Trial (PACT) A One-Year Prospective Comparison of Three Controller Medications for the Treatment of Mild-Moderate Persistent Asthma in Children

  36. 8 study encounters (5 clinic and 3 2 clinic visits telephone) at 6 - week intervals All participants receive : Morning Evening Evening Diskus Diskus Capsule Albuterol prn ICS fluticasone fluticasone placebo placebo diskus in the morning and evening ICS 50% fluticasone/ salmeterol placebo placebo capsule in the + LABA salmeterol evening LTRA placebo placebo montelukast Study Schematic 48-week treatment period 2-week run-in Randomization

  37. Inclusion Criteria • 6-14 year-old children with mild-moderate persistent asthma • Symptoms or b-agonist rescue use or PEF in the yellow zone on average of at least 3 days/wk during run-in • PC20 methacholine FEV1 12.5 mg/ml • FEV1 80% predicted at screen and  70% predicted at randomization • Nonsmoker within the past year • Naïve to controller medications for specified periods • Otherwise healthy

  38. Primary Outcome • Percent of Asthma Control Days (ACD) during the 12-month treatment period • Using self-reported daily diary data, an ACD was defined as a day without: • Albuterol rescue use (pre-exercise treatment permitted) • Use of non-study asthma medications • Daytime asthma symptoms • Unscheduled health care provider visits for asthma • School absenteeism for asthma

  39. What Potential Safety Concerns Have Been Raised by the Use of Beta-Agonists?

  40. Studies in the early 1990’s suggested that regular use of the ß-agonist fenoterol might produce adverse effects Taylor et al., 1993. Thorax; 48:134-138

  41. M M 6 WKS 4 WKS 16 WKS BAGS (ß-Agonist) TRIAL DESIGN REGULAR ALBUTEROL + “AS NEEDED” M M B M B B M B B M RUN-IN RUN-OUT PLACEBO INHALER+ “AS NEEDED” Drazen JM for the ACRN. NEJM 1996; 335:841.

  42. BAGS: AM Peak Flow Drazen & the ACRN, NEJM, 1996

  43. NH2 Gly Arg 16 Thr 164 Ile Gln 27 Glu Cell membrane Val 34 Met COOH 2-Adrenoceptor (2-AR) Variants Reishaus et al., 1993. AJRCMB; 8:334–339

  44. BAGS Genetic Analysis • No effect seen at the B27 locus • No effect seen in B16 heterozygotes (Arg/Gly) • However, when B16 Arg/Arg patients (1/6 of the population) were compared to B16 Gly/Gly patients, a difference was found in the primary outcome variable - - AM PEF

  45. Reg Arg/Arg PRN Arg/Arg Reg Gly/Gly n=16 n=10 n=34 10 0 Change in AM PEF (L/min) -10 -20 RUN OUT -30 0 5 10 15 20 25 Scheduled vs ‘As Needed’ Albuterol Response by GenotypeBAGS— “Retrospective” Analysis Weeks After Randomization BAGS, Beta-agonist in mild asthma study. Israel E, et al. Am J Respir Crit Care Med. 2000;162:75-80.

  46. The Influence of Beta2-adrenergic Receptor Polymorphisms on Asthma Exacerbations * † * P=0.003 vs Gly/Arg. †P=0.033 vs Gly/Gly. Exacerbations (per patient per year) Taylor DR, et al. Thorax. 2000;55:762-767.

  47. BARGE • Prospective randomized, placebo-controlled, double-blind trial of regular vs minimal albuterol in each genotype • To minimize beta-agonist use patients were provided with ipratropium bromide (IB) for rescue use and instructed only to use albuterol if symptoms were not relieved by IB Israel E, et al. Lancet. 2004;364:1505-1512.

  48. Crossover Randomize 0 6 22 30 46 54 Regularly Scheduled Albuterol Response by GenotypeBARGE-Prospective Analysis 16 weeks placebo or active treatment 6 weeks run-in; all on placebo 8 weeks run-out;all on placebo Screen and genotype 16 weeks active treatment or placebo 8 weeks run-out;all on placebo Baselineweeks 0-2 PretreatmentBaseline 1weeks 3-6 PretreatmentBaseline 2weeks 27-30 BARGE, Beta-Adrenergic Response by GenotypE. Israel E, et al. Lancet. 2004;364:1505-1512.

  49. BARGE: Patient Population • Patients with mild asthma not using controller therapy • Mean age = 31 years • Mean FEV1 = 90% of predicted • Patients were matched in pairs for FEV1 according to whether they had Arg/Arg (n = 37)* or Gly/Gly (n = 41) genotype *4 of the 41 matches withdrew from the study before randomization. BARGE, Beta-Adrenergic Response by GenotypE. Israel E, et al. Lancet. 2004;364:1505-1512.

  50. Albuterol modelled Albuterol raw means Placebo modelled Placebo raw means Gly/Gly Arg/Arg Treatment Washout Treatment Washout 20 20 P=0.029 P=0.0175 10 10 * † Morning PEFR (L/min) Morning PEFR (L/min) 0 0 -10 -10 -20 -20 0 0 5 5 10 10 15 15 20 20 Time (weeks) Time (weeks) BARGE: Change in AM PEF by Genotype BARGE, Beta-Adrenergic Response by GenotypE. Israel E, et al. Lancet. 2004;364:1505-1512.

More Related