The Spectrum of Obstructive Lung Disease: Asthma & COPD Disclosures No Pharma Consulting, Research, Lectures Stephen C. Lazarus, M.D. Division of Pulmonary & Critical Care Medicine Cardiovascular Research Institute University of California San Francisco Advances in Internal Medicine San Francisco, CA June 26, 29 NHLBI - Asthma Clinical Research Network NHLBI - COPD Clinical Research Network NAEPP Coordinating Committee The Spectrum of Obstructive Lung Disease: Asthma & COPD Asthma: CFC-driven MDIs discontinued December 31, 28 Inhaled steroids reduce Asthma Exacerbations Asthma Exacerbations ----> loss of lung function Mild asthma may not require chronic controller Tx Linking ICS to ß-agonist rescue seems to work Pneumococcus, ASA, Vitamin D Anti-Reflux Therapy? Anti-Eosinophil Therapy? The Montreal Protocol International Environmental Treaty Banned CFCs in consumer aerosols US has eliminated almost all manufacture and importation of CFCs since January 1, 1996 Essential use Exemption for: - MDIs for Asthma and COPD - Space Shuttle and Titan Rockets Single ingredient albuterol CFC MDIs banned, effective December 31, 28. 1
Short-Acting ß-Adrenergic Agonists New Approach?? Short-Acting ß- Adrenergic Agonist + Inhaled Corticosteroid Fanta, CH N Eng J Med 36:12-14, 29 Beclomethasone vs Montelukast: Time Until First Asthma Attack Health Care Utilization Proportion of Patients Without Asthma Attacks 1..95.9.85.8.75.7 p =.1 beclomethasone compared with placebo p =.6 montelukast compared with placebo p =.129 montelukast compared with beclomethasone 1 2 3 4 5 6 7 8 9 Days Since Randomization Beclomethasone Montelukast Malmstrom et al. Ann Intern Med. 1999;13:487-495. Rate/1 PY 3 Budesonide 25 Nedocromil 2 15 1 5 2.5 P=.4 4.3 4.4 Hospitalizations P<.1 P=.2 22 16 12 Urgent visits CAMP, NEJM 343:154-163, 2 2
FACET Study: Formoterol and Budesonide in Moderate Asthma SOCS - Treatment Failure Rate P =.1 1..9.8.7.6.5.4.3.2.1 BUD 2 mcg/day BUD 2 mcg/day + Formoterol 24 mcg/day BUD 8 mcg/day BUD 8 mcg/day + Formoterol 24 mcg/dayl Pauwels RA, et al. N Engl J Med. 1997;337:145-1411 Treatment Failure, % Randomized Treatment Period, wk P=.18 P=.4 Lazarus et al. Asthma Clinical Research Network JAMA 285:2583-2593, 21 Probability 1..8.6.4.2 Kaplan-Meier Survival Curves: Withdrawal for Worsening Asthma Advair 25mcg FP 25mcg SALM 5mcg * differs from FP 25mcg, SALM and placebo, p.2 7 14 21 28 35 42 49 56 63 7 77 84 Study Day Shapiro et al. Am J Respir Crit Care Med 2;161:527-534 * Q1: Every patient with persistent asthma should receive: 1. Prn ß-agonist 2. Regular ICS + prn ß-agonist 3. Prn ICS + prn ß-agonist 2% 92% 6% 1 2 3 3
Should all patients with asthma be treated regularly with an inhaled corticosteroid? The IMPACT Study IMPACT Protocol Design N = 225 Budesonide Zafirlukast (therapy only as needed) Week 4 6 8 21 34 47 56 6 62 Visit 3 5 6 7 8 11 12 13 14 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 Change in AM PEF (%) Baseline to End Treatment 1 5 P=.94 Bud Zaf PRN 5 2-2 -5 Change in FEV 1 (% Change baseline to end treatment) Pre Albuterol FEV 1 Bud Zaf PRN * FEV 1 (%) 5 2-2 -5 Post Albuterol FEV 1 Bud Zaf PRN Boushey et al N Engl J Med 352:1525-1528, 25 *P =.5 P =.292 Boushey et al N Engl J Med 352:1525-1528, 25 4
Asthma Exacerbation Rates (symptoms warranting course of oral CS) 47.8 wks Controller.48 wks Controller IMPACT: Other Outcomes Changes in Asthma control, Asthma-specific quality of life, and symptom-free days ACQ AQLQ SFD/2wks Budesonide -.4 +.5 +4. Zafirlukast -.2 +.3 +3.1 PRN -.3 +.3 +2.9 P=.1 P=.18 P=.3 Boushey et al N Engl J Med 352:1525-1528, 25 Boushey et al N Engl J Med 352:1525-1528, 25 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. 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 352:1525-1528, 25 Boushey et al N Engl J Med 352:1525-1528, 25 5
Inhaled Steroids - not Disease Modifying Inhaled Steroids - not Disease Modifying Triamcinalone Triamcinalone Salmeterol Salmeterol Triamcinalone Triamcinalone Sovijarvi et al. Thorax 58: 5 54, 23. Lazarus et al. JAMA 285:2583-93, 21 Q2: Your patient has 3-4 exacerbations/yr. Between exacerbations she s asymptomatic. Treat her with: 1. Regular ICS 2. Regular ICS only when symptomatic 3. Prn ICS 55% N = 7,241, ages 5-66 The START Study Mild asthma; symptoms weekly; <2 years Baseline Pre-Bronchodilator FEV1 ~86% Baseline Post-Bronchodilator FEV1 ~97% Intervention: Budesonide DPI, 2-4 mcg 1x/day vs X 3 years 33% 12% Outcomes: *Budesonide reduced Exacerbations *Budesonide reduced decline in FEV1 1 2 3 Pauwels et al. Lancet 361:171-176, 23 6
The START Study N = 7,241, ages 5-66 Mild asthma; symptoms weekly; <2 years Baseline Pre-Bronchodilator FEV1 ~86% Baseline Post-Bronchodilator FEV1 ~97% Intervention: Budesonide DPI, 2-4 mcg 1x/day vs X 3 years Do Exacerbations Contribute to Decline of Lung Function Over Time in Asthma? Outcomes: *Budesonide reduced Exacerbations *Budesonide reduced decline in FEV1 Pauwels et al. Lancet 361:171-176, 23 Asthma Exacerbations Lead to Loss of Lung Function Asthma Exacerbations Lead to Loss of Lung Function Budesonide Budesonide Change in FEV1 (%) over 3 yrs -5 P=.57 No SARE SARE Change in FEV1 (%) over 3 yrs -5 P=.12 No Systemic Steroids P<.1 P<.1 Systemic Steroids P<.42 P=.6-1 -1 O Byrne et al. Am J Respir Crit Care Med 179:19-24, 29 O Byrne et al. Am J Respir Crit Care Med 179:19-24, 29 7
FACET: Changes Associated with Exacerbations FACET: Changes Associated with Exacerbations Tattersfield et al. Am J Respir Crit Care Med 16:594-599, 1999 Tattersfield et al. Am J Respir Crit Care Med 16:594-599, 1999 Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma Prn BDP/S Regular BDP Regular BDP/S Prn S 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) Papi et al. N Engl J Med 27;356:24-52. O Byrne P, et al. Am J Resp Crit Care Med 25; 171:129-136 8
Time to First Exacerbation Inhaled Corticosteroids O Byrne P, et al. Am J Resp Crit Care Med 25; 171:129-136 Fanta, CH N Eng J Med 36:12-14, 29 Inhaled Long-Acting ß-Agonists Q3: I routinely give Pneumovax to: 1. All patients with severe asthma 2. Elderly asthmatics 3. Asthmatics with co-morbid conditions 4. All asthmatics 19-64 years old 6% 3% Fanta, CH N Eng J Med 36:12-14, 29 7% 2% 1 2 3 4 9
Asthma and Pneumococcal Infections Asthma and Pneumococcal Infections Asthma is an independent risk factor for invasive pneumococcal disease. - nested case-control study - 2 to 49 years old - Tennessee Medicaid (1995-22) Talbot et al N Eng J Med 352:282-9, 25 Adults with asthma may be at increased risk for serious pneumococcal disease - (OR, 6.7; 95% CI, 1.6-27.3; P =.1) - retrospective case-control study - Rochester Minnesota (1964-1983) Juhn et al J Allergy Clin Immunol 122:719-23, 28 Possible Mechanisms: Disrupted airway epithelial barrier Increased and aberrant mucus production Alterations in innate and adaptive immunity Genetic factors Immunosuppressive medications Increased pneumococcal colonization Asthma and Pneumococcal Vaccination October 25, 28: The U.S. Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) voted unanimously yesterday to recommend that adults ages 19 to 64 with asthma receive pneumococcal polysaccharide vaccine (PPSV23) Aspirin and Asthma Worsens AERD (Triad Asthma) New asthma less likely among women who used 1 aspirin frequently (Nurses Health Study) 22% reduction in asthma incidence in men randomized to aspirin QOD (Physicians 2 Health Study) 1% reduction in asthma incidence in women randomized to aspirin QOD (Womens Health 3 Study) 1 Barr et al: Am J Respir Crit Care Med 169:836, 24 2 Barr et al: Am J Respir Crit Care Med 175:12, 27 3 Kurth et al: Thorax Jun;63:514, 28 1
Vitamin D and Asthma Vit D has potent immunomodulatory effects Vit D inhibits TH1,?TH2, induces IL-1, Tregs Maternal Vit D intake during pregnancy inversely associated with asthma symptoms in early childhood Camargo et al: Am J Clin Nutr 85:788, 27, 27 Vit D inversely associated with markers of asthma and allergy severity - IgE, eosinophils - Methacholine reactivity - Asthma hospitalization - Medication requirements Brehm et al: Am J Respir Crit Care Med 179:765, 29 Q4: Your patient has poor asthma control, despite high-dose ICS, LABA, LTRA. Which approach is now reasonable? 1. Empiric anti-reflux treatment (PPI) 2. 24-hr ph monitoring, to guide PPI tx 3. Careful history of GERD, to guide PPI 55% tx 11% 34% 1 2 3 Treatment with a PPI does not improve asthma control in patients with poorly controlled asthma and asymptomatic GERD 11
COPD 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 Deaths per 1, 6 5 4 3 2 1 Age-Adjusted Death Rates for COPD, U.S., 196-1995 White Male Black Male White Female Black Female 196 1965 197 1975 198 1985 199 1995 2 Percent Change in Age-Adjusted Death Rates (US, 1965 1998) Proportion of 1965 Rate 3. 2.5 2. 1.5 CHD Stroke Other CVD COPD All other causes Q 5: Which of the following has been shown to slow the loss of lung function in COPD? 1. Smoking Cessation 2. Salmeterol, Fluticasone, SM/FP 3. Tiotropium 4. All of the above 55% 41% 1..5. 59% 64% 35% +163% 7% 1965 1998 1965 1998 1965 1998 1965 1998 1965 1998 % 4% 1 2 3 4 12
. Effect of Smoking Cessation on FEV 1 Post Bronchdilator FEV 1 (liters) 2.9 2.8 2.7 2.6 2.5 Sustained Quitters Continuing Smokers Effects of a Smoking Cessation Intervention on 14.5-year Mortality 2.4 Screen 2 1 2 3 4 5 Follow-up in years JAMA 272:1497,1994. Anthonisen et al Ann Intern Med 25; 142:233-239 Effects of a Smoking Cessation Intervention on 14.5-year Mortality Effects of a Smoking Cessation Intervention on 14.5-year Mortality P=.1 P=.3 Anthonisen et al Ann Intern Med 25; 142:233-239 Anthonisen et al Ann Intern Med 25; 142:233-239 13
Effects of a Smoking Cessation Intervention on 14.5-year Mortality % Subjects Abstinent Weeks 9-12 6 5 Continuous Abstinence with Varenicline (Chantix ) OR - 3.85 (95% CI, 2.7-5.5; P<.1) OR - 1.93 (95% CI, 1.4-2.68; P<.1) N=3659; 1 cigs/day; mean = 21/day x 25 yrs Treated x 12 weeks 6 5 OR - 3.85 (95% CI, 2.69-5.5; P<.1) OR - 1.9 (95% CI, 1.38-2.62; P<.1) Chantix 1 BID Bupropion SR 4 44 P<.1 4 43.9 P=.1 3 29.5 3 29.8 2 1 17.7 2 1 17.6 Anthonisen et al Ann Intern Med 25; 142:233-239 Gonzales et al, JAMA 296: 47-55, 26 Jorenby et al, JAMA 296: 56-63, 26 % Subjects Abstinent Weeks 9-52 3 25 Continuous Abstinence with Varenicline (Chantix ) OR - 3.9 (95% CI, 1.95-4.91; P<.1) OR - 1.46 (95% CI,.99-2.17; P=.57) N=3659; 1 cigs/day; mean = 21/day x 25 yrs Treated x 12 weeks 3 25 OR - 2.66 (95% CI, 1.72-4.11; P<.1) OR - 1.77 (95% CI, 1.19-2.63; P=.4) Chantix 1 BID Bupropion Smoking Cessation 2 15 1 5 21.9 51 16.1 12 4 P=.1 8.4 2 15 1 5 23 14.6 P=.8 1.3 Gonzales et al, JAMA 296: 47-55, 26 Jorenby et al, JAMA 296: 56-63, 26 14
Inhaled Corticosteroids and COPD Lung Health Study II 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 Change from Baseline FEV 1 (ml) (after bronchodilator) 5-5 -1-15 -2-25 -3 Triamcinolone (6 µg bid) -35..5 1. 1.5 2. 2.5 3. 3.5 4. Follow-up (years) NEJM 2; 343:192-199 COPD Exacerbations (Lung Health II) COPD Exacerbations (ISOLDE - stratified by FEV 1 ) Respiratory Exacerbations (per 1 person-years) 32 28 24 2 16 12 8 4 28.2 p =.5 21.1 Triamcinolone 3. 2.5 2. 1.5 1..5. 2.64 Fluticasone * 1.72 1.86 1.41 1.24 1.24 <1.25 1.25-1.54 >1.54 FEV1 (liters) * NEJM 2; 343:192-199 Burge et al. Br Med J. 2; 32:1297-133. 15
Effects of Inhaled Corticosteroids in COPD: Meta-Analysis Relative Risk of Exacerbations in Patients With COPD Treated With Inhaled Corticosteroids vs Author Vestbo et al Bourbeau et al Burge et al Lung Health Study Weir et al Paggiaro et al Overall What is the Role of Inhaled Bronchodilators in COPD?..5 Relative 1. 1.5Risk 2. 2.5 3. Alsaeedi A et al. Am J Med. 22;113:59-65. % of COPD patients with 15% in FEV 1 (Days 1, 29, 57 &/or 85) FEV 1 : Tiotropium vs. Day 1 Day 8 Day 92 Day 344 1.3 Tiotropium (n=518) 1.2 FEV 1 (L) 1.1 1. (n=328).9-6 -5 3 6 12 18 Time (minutes) Dorinsky et al. Chest 1999; 115:966-71 Casaburi R et al. Eur Respir J 22; 19: 217-224 16
Tiotropium Reduces Exacerbations and Hospitalizations vs Ipratropium Tiotropium reduces Exacerbations in COPD Probability of no hospitalization 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 Niewoehner et al Annals Int Med 143:317-26, 25 Vincken W et al. Eur Respir J. 22;19:29-16. Tiotropium reduces Exacerbations in COPD Niewoehner et al Annals Int Med 143:317-26, 25 Salmeterol and Fluticasone Proprionate and Survival in COPD (TORCH) N = 6112 4-8 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 Calverley NEJM 27; 356:775-89 X 3 years Primary Outcome: Death from All Causes 17
TORCH TORCH Calverley NEJM 27; 356:775-89 Celli et al Am J Respir Crit Care Med 178:332-38, 28 Health Status (SGRQ) TORCH (UPLIFT) Calverley NEJM 27; 356:775-89 Tashkin et al NEJM 359:1543-54, 28 18
1 Survival in Hypoxic COPD Patients using Oxygen (UPLIFT) Cumulative Survival (%) 8 6 4 2 NOTT (24h) NOTT (12h) MRC (15h) MRC (controls) Tashkin et al NEJM 359:1543-54, 28 1 2 3 4 5 6 Time (years) AIM 93:391, 198 Lancet 1:681, 1981. Downward Spiral In Function Associated With COPD Disease Dyspnea Inactivity Deconditioning 19