Update on Asthma & COPD. Stephen C. Lazarus, M.D. Division of Pulmonary & Critical Care Medicine University of California San Francisco

Transcription

1 Update on Asthma & COPD Stephen C. Lazarus, M.D. Division of Pulmonary & Critical Care Medicine University of California San Francisco Advances in Primary Care Medicine October 27, 29 Disclosures No Pharma Consulting, Research, Lectures NHLBI - Asthma Clinical Research Network NHLBI - COPD Clinical Research Network NAEPP Coordinating Committee

2 Asthma Key Points - 1 New NHLBI/NAEPP Guidelines 27 (EPR 3 - a systematic review) Emphasis is on Severity, Control, Responsiveness Too many patients have poor asthma control Good Control is possible (and is associated with fewer exacerbations and improved QofL) Assessment of Control includes Impairment and Risk

3 Key Points - 2 Not all mild persistent asthma requires daily medication Prn (rescue) use of ICS/LABA may be a useful strategy Smoking cigarettes alters the response to inhaled and oral steroids EPR 3: Primary Themes Comprehensive, systematic review of the scientific evidence for the treatment of asthma Treatment recommendations based on the concepts of: Severity Control Responsiveness Includes the domains of current impairment and future risk EPR 3 provides standardized definitions of these important concepts NHLBI Expert Panel Report 3: Guidelines for the diagnosis and management of asthma - full report 27. Available at:

4 The Burden of Asthma in the United States Telephone Survey: 42, households called; 38, participated (91%) 3,2 asthmatics identified; 2,5 interviewed Severity Classification: Short-term symptoms Mild Intermittent Mild Persistent Moderate/Severe Persistent Long-term symptoms Functional Global asthma Impact burden Fuhlbrigge et al., AJRCCM 168:144-9, 22 Current State of Asthma Care AIRE AIRCEE AIRJ AIRIAP AIA AILA

5 Activity Limitation Asia Pacific Japan W Europe 7 C&E Europe USA 6 % of patients Social activities Career choice Housekeeping Lifestyle Normal Sleeping Sports physical activity Rabe et al. Eur Respir J 2; Lai et al. J Allergy Clin Immunol 23; Adachi et al. Arerugi 22; School and Work Absence Asia Pacific Japan C&E Europe W Europe USA % of patients School loss Work absence Due to asthma in the previous year Rabe et al. Eur Respir J 2; Lai et al. JACI 23; Adachi et al. Arerugi 22;

6 Health-Care Utilization Hospitalized in past year Hospital emergency room visits in past year Unscheduled emergency visits in past year Asia Pacific Japan W Europe C&E Europe USA % of patients 4 5 Rabe et al. Eur Respir J 2; Lai et al. J Allergy Clin Immunol 23; Adachi et al. Arerugi 22; % of patients Estimates of Control Self-assessment of control among patients with severe persistent symptoms Complete control 6 Well control USA Europe Asia Pacific Japan C&E Europe Rabe et al. Eur Respir J 2; Lai et al. J Allergy Clin Immunol 23; Adachi et al. Arerugi 22;

7 Patterns of Asthma Control (US Managed Care Plans) N=63,324, Claims Data x 12 months 5 Percent Uncomtrolled Age 5-17 Age Age 4-55 Males Females Stempel et al. J Allergy Clin Immunol 115: 935-9, 25 Patterns of Asthma Control (US Managed Care Plans) N=63,324, Claims Data x 36 months QuickTime and a decompressor are needed to see this picture. Stempel et al. J Allergy Clin Immunol 115: 935-9, 25

8 Patterns of Asthma Control (US Managed Care Plans) N=63,324, Claims Data x 36 months 8 73% Percent of Patients % Controlled Uncontrolled Stempel et al. J Allergy Clin Immunol 115: 935-9, 25 Can Guideline-defined Control be Achieved? The GOAL Study N=3,421 with uncontrolled asthma Phase I Phase II SM/FP 5/5 or FP 5 SM/FP 5/1 or FP 1 Step 1 SM/FP 5/25 or FP 25 Step 2 Step 3 Total control Total control Visit Week Bateman et al., AJRCCM 17: , 24

9 Most Patients Achieved a Well- 9 Controlled Week 8 7 % of patients Well controlled: 6-7% Total control: 3-4% 2 1 FP SFC Bateman et al., AJRCCM 17: , 24 GOAL: Quality of life at baseline Baseline 6 Severe impairment Moderate / some impairment Minimal or no impairment % of patients <2 2 -<3 3 -<4 4 -<5 5 -<6 6 -<7 7 Overall AQLQ score (all strata) Bateman et al., AJRCCM 17: , 24

10 Impact on Quality of Life Baseline Fluticasone FP/SM 6 Severe impairment Moderate / some impairment Minimal or no impairment % Patients <2 2 -<3 3 -<4 4 -<5 5 -<6 6 -<7 7 Overall AQLQ score (all strata, week 52) Bateman et al., AJRCCM 17: , 24 Exacerbation rates by Control Status FP.7 Salmeterol/FP.6 Mean exacerbation rate per patient per year Not Controlled Well Controlled Totally Controlled *Requiring either oral steroids or hospitalization/er visit Exacerbation rates based on summary information, no statistical testing performed Bateman et al., AJRCCM 17: , 24

11 Assessment of Impairment Questionnaires that evaluate the degree of present asthma control: Asthma Therapy Assessment Questionaire (ATAQ) Asthma Control Questionnaire (ACQ) Asthma Control Test (ACT) Key Elements Patient s recall of symptoms Physical activity Quality of life Need for rescue medication in past 2 to 4 weeks Pulmonary Function NHLBI Expert Panel Report 3: Guidelines for the diagnosis and management of asthma - full report 27. Available at: Tool for Assessing Asthma Control Nathan et al. JACI 113:59-65, 24

12 Assessment of Risk Risk of exacerbation assessed by asking probing questions pertaining to: Occurrence of exacerbations Use of medications (e.g., oral corticosteroids) Need for urgent care and ED visits Low FEV1 Risk of exacerbation also assessed by measurement of: FEV1 Other measures? (e.g., FENO, Sputum Eosinophils, BHR) Risk of drug specific side effects assessed by questioning NHLBI Expert Panel Report 3: Guidelines for the diagnosis and management of asthma - full report 27. Available at: Should all patients with asthma be treated regularly with an inhaled corticosteroid? The IMPACT Study

13 IMPACT Protocol Design N = 225 Placebo Budesonide Zafirlukast Placebo (therapy only as needed) Week Visit All patients were taught to initiate short courses of oral or inhaled corticosteroids by a Symptombased Action Plan* *Coté et al., AJRCCM 1997; 155: 159 Change in AM Peak Flow Baseline to End Treatment Change in AM PEF (%) 1 5 Bud P=.94 Zaf PRN Boushey et al N Engl J Med 352: , 25

14 Change in FEV 1 (% Change baseline to end treatment) Pre Albuterol FEV 1 * Post Albuterol FEV FEV1 (%) 2-2 FEV 1 (%) Bud Zaf PRN -5 Bud Zaf PRN *P =.5 P =.292 Boushey et al N Engl J Med 352: , 25 Asthma Exacerbation Rates (symptoms warranting course of oral CS) 47.8 wks Controller.48 wks Controller Boushey et al N Engl J Med 352: , 25

15 IMPACT: Summary In adults with long-standing, mild persistent asthma, who were given medication and a symptom-based action plan, twice daily treatment with budesonide, with zafirlukast, and with placebo over one year did not differ with regard to asthma exacerbations, asthma-specific quality of life, or the rate of loss of lung function over 1 year. Boushey et al N Engl J Med 352: , 25 IMPACT: Conclusion The criteria for mild persistent asthma may define a condition so mild that the decision as to whether to take regular daily therapy or to take only short courses of inhaled or oral corticosteroid therapy on an as needed basis may be left to the patient s own assessment of the importance of the subjective improvements experienced, and of the cost, inconvenience, and perceived risks of the treatment. Boushey et al N Engl J Med 352: , 25

16 FACET: Changes Associated with Exacerbations Tattersfield et al. Am J Respir Crit Care Med 16: , 1999 Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma Prn BDP/S Regular BDP Regular BDP/S Prn S Papi et al. N Engl J Med 27;356:24-52.

17 Is High-Dose Fixed ICS dosing Necessary? Sx-Guided Management as an Alternate Approach Budesonide/Formoterol Combination Therapy as Both Maintenance and Reliever Medication in Asthma Purpose: to compare three treatments: Bud/FM 8/4.5 2X/d + prn Terbutaline Bud 32 2x/d + prn Terbutaline Bud/FM 8/4.5 2x/d + prn Bud/FM 8/4.5 Outcomes: Time to first exacerbation; number of exacerbations Symptoms, nocturnal awakenings, AM PEF, FEV1 Subjects: 276 adults and children with moderately severe asthma (mean FEV1 = 73% predicted) O Byrne P, et al. Am J Resp Crit Care Med 25; 171: Time to First Exacerbation O Byrne P, et al. Am J Resp Crit Care Med 25; 171:

18 Smoking & Asthma 1-3% of asthmatics smoke Asthmatics who smoke have more symptoms, worse lung function, and poorer prognosis Relatively little is known about the effect of smoking on response to therapy in asthmatics The response to inhaled corticosteroids is blunted in asthmatics who smoke Risk Factors Associated with Persistent Airflow Limitation in Severe or Difficult-to-Treat Asthma Lee et al. CHEST 132: , 27

19 Smoking Increases Symptoms, Healthcare Utilization, Exacerbations of Asthma N=852 Stratified, Random Sample from France, Germany, UK MV Analysis, not COPD, Adjust for BL, Demographics Symptoms and Resource Use Nighttime Asthma Symptoms ED Visit for Any Reason ED Visit for Asthma Exacerbation Hospitalization Smokers (n=271) 177 (67%) 67 (25%) 44 (16%) 5 (18%) Non-Smokers (n=581) 329 (58%) 87 (15%) 57 (1%) 65 (11%) OR (95% CI) 1.46 (1.7,1.97) P= (1.3,2.67) P< (1.17,2.72) P= (1.2,2.68) P=.4 Shavit et al. Qual Life Res 16: , 27 Effect of Smoking on Asthma Therapy (The ACRN s SMOG Study).2 Non-Smokers (n=44) Smokers (n=39) 15 Change in FEV1 (L) P =.3 P =.21 P =.6 P= Change in AM PEF (L/M) Beclomethasone Beclomethasone Lazarus et al (ACRN) AJRCCM 175:783, 27

20 Effect of Smoking on Asthma Therapy (The ACRN s SMOG Study) 15 P=.6 Non-Smokers Smokers P=.19 1 Change in AM PEF (L/M) 5 P=.3 P=.19 Beclomethasone Montelukast Lazarus et al (ACRN) AJRCCM 175:783, 27 Key Points - 1 New NHLBI/NAEPP Guidelines 27 (EPR 3 - a systematic review) Emphasis is on Severity, Control, Responsiveness Too many patients have poor asthma control Good Control is possible (and is associated with fewer exacerbations and improved QofL) Assessment of Control includes Impairment and Risk

21 Key Points - 2 Mild persistent asthma may not require daily medication (but mild asthma is rare) Prn (rescue) use of ICS/LABA looks promising (as primary therapy) for some patients with mild asthma and (in addition to controller therapy) for some with mod/severe asthma (but this is not approved, and needs further study). The response to steroids is blunted in asthmatics who smoke. Leukotriene modifiers may be useful in these patients. COPD

22 Key Points COPD = Inflammatory Disease Mortality is increasing (6th --> 1st; esp. women) Spirometry detects COPD without symptoms Smoking Cessation modifies natural history (lung function, mortality) Pharmacologic Therapy: ( it s not just for symptoms anymore ) - exacerbations, natural history? Pulmonary Rehab: reduces symptoms, depression, health care utilization; improves Q of L, exercise Inflammation in COPD versus Asthma COPD Macrophages Neutrophils CD-8 T-Lymphocytes Predominant Cells Asthma Eosinophils Activated Mast Cells CD-4 T Lymphocytes Predominant Cytokines Interleukin 8 Interleukin 4 Leukotriene B4 Interleukin 5 Tumor Necrosis Factor alpha Interleukin 13 Calverley, Barnes. AJRCCM 2; 161:

23 COPD versus Asthma (USA) Annual Estimated Condition Mortality (N) Annual Cost COPD 1, $25 billion Asthma 6, $12 billion Martin. Amer Acad Allergy, Asthma, and Immunol. 2 Deaths per 1, 6 Age-Adjusted Death Rates for COPD, U.S., White Male Black Male White Female Black Female

24 COPD Mortality by Gender U.S Number of Deaths x Men Women Year Since 1979 the death rate has increased 3 times more in women than in men 6 Changing Death Rates for Top U.S. Diseases Percent Change 4 2 COPD-Asthma Cancer -2-4 All Causes Cardiac Stroke Year Vital Statistics of the U.S

25 Percent Change in Age-Adjusted Death Rates (US, ) Proportion of 1965 Rate CHD Stroke Other CVD COPD All other causes % 64% 35% +163% 7% Smoking Cessation: the Lung Health Study Anthonisen et al. JAMA 272:1497 (1994) n = 5887 smokers; ages 35-6 (mean 48); FEV 1 = 63% Research Question: Does smoking intervention, ± ipratropium change the course of mild COPD Results: 22% of smoking intervention & 5% of usual care pts were sustained quitters Ipratropium made no difference Smoking cessation slowed the fall in FEV1

26 . Effect of Smoking Cessation on FEV 1 Post Bronchdilator FEV 1 (liters) Sustained Quitters Continuing Smokers 2.4 Screen Follow-up in years JAMA 272:1497,1994. Effects of a Smoking Cessation Intervention on 14.5-year Mortality Anthonisen et al Ann Intern Med 25; 142:

27 Effects of a Smoking Cessation Intervention on 14.5-year Mortality P=.3 Anthonisen et al Ann Intern Med 25; 142: Effects of a Smoking Cessation Intervention on 14.5-year Mortality P=.1 Anthonisen et al Ann Intern Med 25; 142:

28 Effects of a Smoking Cessation Intervention on 14.5-year Mortality Anthonisen et al Ann Intern Med 25; 142: What Can I Do To Get My Patient To Stop Smoking?

29 6 5 Bupropion and Smoking Cessation Smokers >18 years old >15 cigarettes/day Motivated to quit Medically stable % abstinence Placebo TNS Bup Bup +TNS Treatment Four treatment groups Placebo Bupropion (15 mg bid) Transdermal nicotine Bupropion + TNS Treatment duration 2 week baseline 7 week treatment 2 week taper Jorenby et al., NEJM 34:685, 1999 Continuous Abstinence with Varenicline (Chantix ) % Subjects Abstinent Weeks 9-12 OR (95% CI, ; P<.1) 5 OR (95% CI, ; P<.1) N=3659; 1 cigs/day; mean = 21/day x 25 yrs Treated x 12 weeks 6 5 Chantix 1 BID Bupropion SR Placebo OR (95% CI, ; P<.1) OR (95% CI, ; P<.1) 4 44 P< P= Gonzales et al, JAMA 296: 47-55, 26 Jorenby et al, JAMA 296: 56-63, 26

30 % Subjects Abstinent Weeks Continuous Abstinence with Varenicline (Chantix ) OR (95% CI, ; P<.1) OR (95% CI, ; P=.57) N=3659; 1 cigs/day; mean = 21/day x 25 yrs Treated x 12 weeks Chantix 1 BID Bupropion Placebo 3 25 OR (95% CI, ; P<.1) OR (95% CI, ; P=.4) P= P= Gonzales et al, JAMA 296: 47-55, 26 Jorenby et al, JAMA 296: 56-63, 26 Smoking Cessation

31 What is the Role of Inhaled Corticosteroids in COPD? Inhaled Corticosteroids and COPD Decrease in FEV1/year STUDY SITES COMPARISON SMOKERS QUITTERS Lung Health Study US + Canada Smokers vs Quitters 62 ml 32 ml STUDY SITES COMPARISON PLACEBO STEROID Copenhagen City Denmark BUD vs PBO 42 ml 42 ml EUROSCOP Europe BUD VS PBO 69 ml 57 ml ISOLDE Europe FP vs PBO 59 ml 5 ml Lung Health Study II US + Canada TAC vs PBO 47 ml 44 ml

32 Lung Health Study II Change from Baseline FEV 1 (ml) (after bronchodilator) Placebo Triamcinolone (6 µg bid) Follow-up (years) NEJM 2; 343: COPD Exacerbations (Lung Health II) Respiratory Exacerbations (per 1 person-years) p = Placebo Triamcinolone NEJM 2; 343:

33 COPD Exacerbations (ISOLDE - stratified by FEV 1 ) Exacerbations (per year) * Placebo Fluticasone < >1.54 * FEV1 (liters) Burge et al. Br Med J. 2; 32: Effects of Inhaled Corticosteroids in COPD: Meta-Analysis Relative Risk of Exacerbations in Patients With COPD Treated With Inhaled Corticosteroids vs Placebo Author Vestbo et al Bourbeau et al Burge et al Lung Health Study Weir et al Paggiaro et al Overall Relative Risk Alsaeedi A et al. Am J Med. 22;113:59-65.

34 What is the Role of Inhaled Bronchodilators in COPD? % of COPD patients with 15% in FEV 1 (Days 1, 29, 57 &/or 85) Dorinsky et al. Chest 1999; 115:966-71

35 Ipratropium and Albuterol Combination vs Single Agent Percentage Changes in Mean FEV 1 from Test Day Baselines Percentage Change Test Day 1 Test Day 85 4 Ipratropium + Albuterol 35 3 Albuterol 25 Ipratropium Percentage Change Ipratropium + Albuterol (n = 173) Albuterol (n = 165) Ipratropium (n = 176) Combivent Inhalation Aerosol Study Group. Chest. 1994;15: Ipratropium and Albuterol vs Either Agent Alone Percentage of Patients with Exacerbations COPD Exacerbation Frequency 18% Albuterol N = 1,67, FEV1 65% Alb vs IPB vs Alb+IPB x 12 weeks 12% 12% Ipratropium Ipratropium Plus Albuterol Friedman M et al. Chest. 1999;115:

36 Long-Term Treatment of COPD with Salmeterol and Ipratropium 4 36% % of Patients with an Exacerbation in 12 weeks 2 23% 13%* Placebo Salmeterol Salmeterol Plus Ipratropium *P <.1 vs placebo. van Noord JA et al. Eur Respir J. 2;15: FEV 1 : Tiotropium vs. Placebo Day 1 Day 8 Day 92 Day Tiotropium (n=518) 1.2 FEV 1 (L) Placebo (n=328) Time (minutes) Casaburi R et al. Eur Respir J 22; 19:

37 Mean change in trough FEV 1 after Tiotropium or Ipratropium x 1yr Vincken et al. Eur Respir J 22; 19:29-16 Probability of no hospitalization Tiotropium Reduces Exacerbations and Hospitalizations vs Ipratropium Tiotropium Ipratropium Time to first hospitalization: P=.48 Days on treatment Probability of no exacerbations Tiotropium Ipratropium Time to first exacerbation: P=.8 Days on treatment Vincken W et al. Eur Respir J. 22;19:29-16.

38 Tiotropium reduces Exacerbations in COPD Niewoehner et al Annals Int Med 143:317-26, 25 Tiotropium reduces Hospitalizations in COPD Niewoehner et al Annals Int Med 143:317-26, 25

39 Tiotropium reduces Exacerbations in COPD Niewoehner et al Annals Int Med 143:317-26, 25 What is the Role of ICS + LABA (Combination) in COPD?

40 Salmeterol and Fluticasone Proprionate and Survival in COPD (TORCH) N = years old; 1 pack-years FEV1 < 6% predicted; FEV1/FVC.7 Salmeterol 5mcg BID vs Fluticasone 5mcg BID vs Salmeterol 5/Fluticasone 5 BID vs Placebo Calverley NEJM 27; 356: X 3 years Primary Outcome: Death from All Causes TORCH Calverley NEJM 27; 356:775-89

41 TORCH Celli et al Am J Respir Crit Care Med 178:332-38, 28 Health Status (SGRQ) TORCH Calverley NEJM 27; 356:775-89

42 (UPLIFT) Tashkin et al NEJM 359: , 28 (UPLIFT) Tashkin et al NEJM 359: , 28

43 PDE4 Inhibitors (Roflumilast) Calverley et al. Lancet 374:685-94, 29 PDE4 Inhibitors (Roflumilast) Fabbri et al. Lancet 374:695-73, 29

44 1 Survival in Hypoxic COPD Patients using Oxygen Cumulative Survival (%) NOTT (24h) NOTT (12h) MRC (15h) MRC (controls) AIM 93:391, 198 Lancet 1:681, Time (years) Downward Spiral In Function Associated With COPD Disease Dyspnea Deconditioning Inactivity

45 Pulmonary Rehabilitation Benefits all levels of disease severity Reduces respiratory symptoms Reduces anxiety and depression Reduces medical and hospital usage Improves exercise performance Improves quality of life Is typically provided as outpatient Can be initiated as an inpatient until functional ability has improved Key Points COPD = Inflammatory Disease Mortality is increasing (6th --> 1st; esp. women) Spirometry detects COPD without symptoms Smoking Cessation modifies natural history (lung function, mortality) Pharmacologic Therapy: ( it s not just for symptoms anymore ) - exacerbations, natural history? Pulmonary Rehab: reduces symptoms, depression, health care utilization; improves Q of L, exercise