Morbidity of copd symptoms
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Morbidity of copd symptoms Presentation Transcript

  • 1. The Morbidity of COPD Symptoms
  • 2. Learning Objectives • Appreciate the current epidemiology and gaps in the management of COPD in Canada • Recognize why diagnosing and treating COPD is important for physicians and their patients • Differentiate the clinical characteristics and diagnostic criteria for COPD and asthma • Discuss current management strategies for patients with COPD, contrasting the roles of bronchodilators and anti-inflammatory agents in current guidelines
  • 3. Case Study Mr. A.C. is a 61-year-old realestate agent who has recently undergone angioplasty. Until 6 months ago, you saw him infrequently in your practice, perhaps because you usually tried to discuss smoking cessation with him. Following an ER visit for chest pain he was managed by the cardiologists and underwent successful and uneventful angioplasty.
  • 4. Case Study (cont’d) • Mr. A.C. is trying to make lifestyle changes recommended to him, including participation in a cardiac rehab program • During his rehab, he frequently feels breathless, earlier than others in the group • He finds the incline on the treadmill difficult • He has no history of lung disease but has cut down his smoking to one cigarette at bedtime 4 months ago and has a 35 pack-year smoking history
  • 5. The Evolving Epidemiology of COPD in Canada
  • 6. Growing Burden of COPD Trends in age-standardized death rates for the 6 leading causes of death in the United States, 1970-2002 Jemal A, et al. JAMA. 2005 Sept. 14; 294(10):1255-9.
  • 7. COPD: The Leading Cause of Hospital Admissions Today 18,000 Single Hospitalization 1 Repeat Hospitalization 2 or More Repeat Hospitalizations Number of Patients 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 COPD Angina Asthma Heart Failure Diabetes Epilepsy Ambulatory Care Sensitive Condition* *An ambulatory care sensitive condition is a condition that is normally manageable on an outpatient basis. Data are for the Canadian population, excluding Quebec . Canadian Institute for Health Information. Health Indicators 2008. Ottawa: CIHI; 2008.
  • 8. COPD is Underdiagnosed: Screening Spirometry in Primary Practice Patients >40 years + 20 pack-year history of smoking visiting a primary care physician for any reason (n=1,003) Screening for COPD Patients meeting criteria for COPD* (n=208; 20.7%) Previous diagnosis of COPD (n=67; 32.7%) *Criteria for COPD: FEV1/FVC < 0.70 Hill K, et al. CMAJ. 2010 Apr. 20;182(7):673-8. Patients not meeting criteria for COPD* (n=795; 79.3%) No previous diagnosis of COPD (n=141; 67.3%)
  • 9. Deterioration in Lung Function versus Symptoms in COPD 100 Symptoms FEV1 (% of predicted) Severe 50 Asymptomatic 20 Lung function Lung function normal reduced Mild Axis of Progression Sutherland EM, et al. N Engl J Med 2004 Jun 24;350(26):2689-87.
  • 10. Why is pursuing the diagnosis of COPD important for Mr. A.C.?
  • 11. Relationship Between FEV1, Smoking Status and CV Mortality 8 Odds Ratio for CV mortality Current smoker Ex-smoker 6 Never-smoker 4 2 0 <65 65-79 80-100 FEV1 % pred Young RP, et al. Eur Respir J. 2007 Oct;30(4):616-22. >100
  • 12. Prediction of Death Within 5 years by GOLD Categories and Presence of Comorbid Disease # of comorbidities* Hazard ratio 100 Three Two One None 10 1 GOLD 3/4 GOLD 2 GOLD 1 *Diabetes, hypertension or CV disease Mannino DM, et al. Eur Respir J. 2008 Oct;32(4):962-9. R GOLD 0 Normal
  • 13. Comorbidities of COPD Cardiovascular disease is a major comorbidity in COPD and probably both the most frequent and most important disease co-existing with COPD. Other major comorbidities: – Osteoporosis often underdiagnosed and associated with poor health status and prognosis – Depression – Lung cancer (most frequent cause of death in mild COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.
  • 14. Case Study (cont’d) The rehab clinic placed him on salbutamol as needed and asked for him to follow up with his GP.
  • 15. How would you proceed with Mr. A.C’s assessment?
  • 16. Spirometry
  • 17. Mr. A.C.: Spirometry Results Pred. value Observed pre % Pred. Observed post % pred. % change FVC (L) 5.64 5.23 93 5.77 102 10.3 FEV1 (L) 4.57 2.92 64 3.01 66 3.2 81 56 69 52 64 -6.4 FEF25-75 (L/S) 11.27 5.52 49 5.70 51 3.3 FEF50 (L/S) 5.64 2.02 36 1.73 31 -14.3 FEF75 (L/S) 2.82 0.75 27 0.59 21 -21.2 VE (L/min) 173 -- -- -- -- -- Raw insp. (cmH2O/l/s) 0.68 1.71 256 Parameter FEV1/FVC (%)
  • 18. Are these results more compatible with asthma or COPD?
  • 19. Spirometry Results = Asthma PULMONARY FUNCTION ANALYSIS Spirometry Ref Pre Meas Pre % Ref Post Meas Post % Ref Post % Chg FVC Liters 3.81 3.45 90 3.78 99 10 FEV1 Liters 3.27 2.34 72 2.90 89 24 FEV1/FVC % 86 68 79 77 89 13 FEF25-75% L/sec 3.83 1.44 38 2.40 63 67 FEF50% L/sec 4.11 1.93 47 3.33 81 73 FEF75% L/sec 1.91 0.57 30 0.98 51 73 PEF L/sec 6.55 6.08 93 7.57 116 25 PIF L/sec 3.63 4.53 25 An acceptable effort was provided. There is evidence of slight airflow limitation that improved with acute bronchodilator. This study is similar to those seen in patients with asthma.
  • 20. Distinguishing Asthma from COPD Asthma COPD Age of onset Usually <50 years Usually >35 years Smoking history Not causal (but people with asthma sometimes smoke) Usually >10 pack-years Infrequent unless poorly Sputum production controlled Often in exacerbation-prone chronic bronchitis, infrequent in emphysema Allergies Often in early onset but less often in late onset 1/3 of the general population Disease course Stable (with exacerbations) Progressive worsening (with exacerbations) Spirometry More likely to normalize with treatment May improve but never becomes normal Clinical symptoms Intermittent and variable Persistent and variable Response to therapy Responds well to therapy, especially corticosteroids Does not respond as well to therapy Adapted from O’Donnell DE, et al.:Can Respir J. 2007 Sep;14 Suppl B:5B-32B.
  • 21. Case Study (cont’d) His post bronchodilator spirometry FEV1 FVC FEV1/FVC 66% 102% 0.52 He is using his salbutamol 3-5 times a day. How would you proceed?
  • 22. Evaluating COPD Severity
  • 23. Classification of COPD By Impairment of Lung Function* Spirometry (post bronchodilator) Stage FEV1 FEV1/FVC ≥80% predicted <0.7 Moderate 50-79% predicted <0.7 Severe 30-49% predicted <0.7 <30% predicted <0.7 Mild Very severe *In keeping with current GOLD criteria O'Donnell DE, et al. Can Respir J. 2008 Jan-Feb;15 Suppl A:1A-8A.
  • 24. MRC Dyspnea Scale and CTS COPD Classification none Grade 1 Grade 2 severe Stops for breath after walking 100 yards Grade 5 Severe Walks slower than people of the same age on the level or stops for breath while walking at own pace on the level Grade 4 Moderate Short of breath when hurrying on the level or walking up a slight hill Grade 3 Mild Breathless with strenuous exercise Too breathless to leave the house or breathless when dressing or undressing Fletcher CM, et al. Br Med J. 1959 Aug 29;1:257-66. O’Donnell DE, et al. Can Respir J. 2003 May-Jun;10 Suppl A:11A-33A.
  • 25. Lung Function and Symptoms: Both Are Tied to Outcomes Cumulative Percent Survival (%) Survival by ATS Stage (based on FEV1) Survival by Level of Dyspnea 100 100 Grade II (n=67) Stage I (n=42) Stage II (n=59) 80 Stage III (n=82) 60 80 60 40 40 20 Grade III (n=87) 20 p = 0.08 Grade IV (n=26) p < 0.001 Grade V (n=3) 0 0 0 10 20 30 40 50 Months of Follow-Up Nishimura K, et al. Chest. 2002 May; 121(5):1434-40. 60 70 0 10 20 30 40 50 Months of Follow-Up 60 70
  • 26. Mr. A.C.: CAT Score I never cough I cough all the time 1 I have no phlegm (mucus) in my chest at all 0 1 2 3 4 5 My chest is completely full of phlegm (mucus) 0 My chest does not feel tight at all 0 1 2 3 4 5 My chest feels very tight 3 When I walk up a hill or one flight of stairs I am not breathless 0 1 2 3 4 5 When I walk up a hill or on flight of stairs I am very breathless 3 I am not limited doing any activities at home 0 1 2 3 4 5 I am very limited doing activities at home 4 0 1 2 3 4 5 I am not at all confident leaving my home because of my lung condition 3 I sleep soundly Scoring range 0-40 0 1 2 3 4 5 0 1 2 3 4 5 I don’t sleep soundly because of my lung condition 1 I have lots of energy 0 1 2 3 4 5 I have no energy at all 3 I am confident leaving my home despite my lung condition Mr. A.C.'s CAT score = 18
  • 27. How would you treat Mr. A.C.?
  • 28. Benefits of Smoking Cessation
  • 29. Smoking Cessation and FEV1 100 80 FEV1 (%) 60 40 Quit age 45 Symptoms age 55 Disability 20 Death 0 20 30 40 50 60 Age (Years) Adapted from Fletcher C, et al. Br Med J. 1977 Jun;1(6077):1645-8. 70 80 90
  • 30. Why do we use bronchodilators as first-line therapy?
  • 31. Dynamic Lung Hyperinflation Normal COPD (n=25) (n=105) Volume (%pred TLC) 140 140 120 120 100 VT IC 100 IRV IC 80 80 60 60 40 40 RV 20 20 0 0 0 20 40 60 80 0 Ventilation (L/min) O'Donnell DE, et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):770-7. 20 40 60 80
  • 32. LAACs and LABAs Available in Canada Mode of action Long-acting anticholinergic (LAAC) Also known as long-acting muscarinic antagonist (LAMA) Individual agents Tiotropium Glycopyrronium Bromide Formoterol Long-acting beta2-agonist (LABA) Salmeterol Indacaterol
  • 33. Long-Acting Anticholinergics (LAACs) Also known as long-acting antimuscarinics (LAMAs)
  • 34. Tiotropium vs. Ipratropium: 3-month FEV1 Response Day 1 Day 8 Day 92 1.5 FEV1 (L) 1.4 1.3 1.2 Tiotropium 18 mcg o.d. (n=182) Ipratropium 40 mcg q.i.d. (n=93) 1.1 -60 -5 30 60 120 180 240 Time after Administration (minutes) Van Noord JA, et al. Thorax. 2000 Apr;55(4):289-94. 300 360
  • 35. FEV1 from 5 Minutes to 4 Hours Post-dose on Day 1 Glycopyrronium bromide provided significant early bronchodilation following the first dose, and was significantly more effective than OL tiotropium 18 µg o.d. Placebo 1.8 Tiotropium Glycopyrronium bromide 1.7 FEV1 (L) 1.6 1.5 1.4 1.3 1.2 0 1 2 3 Time post-dose (h) p<0.01 for glycopyrronium bromide versus tiotropium at all timepoints 5 min to 4 h Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14; Novartis, data on file. 4
  • 36. Time to First Moderate or Severe COPD Exacerbation Glycopyrronium bromide 50 µg o.d. significantly prolonged the time to first exacerbation versus placebo (HR 0.66, p=0.001), comparable with OL tiotropium 18 µg o.d. (HR 0.61, p=0.001 vs. placebo) Patients exacerbation free (%) 100 Treatment: Glycopyrronium bromide 50 μg o.d. Placebo OL Tiotropium 18 μg o.d. 90 80 70 60 50 40 0 4 8 12 Number at Risk Glycopyrronium bromide 495 Placebo 229 Tiotropium 245 451 202 222 426 188 209 16 20 24 28 32 36 40 Time to first exacerbation (weeks) 394 168 200 HR = hazard ratio Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14. 370 159 190 360 153 184 341 142 176 335 137 169 318 129 166 310 129 163 44 48 52 296 122 157 282 116 155 239 98 129
  • 37. Safety of anticholinergics
  • 38. The key findings were that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.
  • 39. Cardiovascular Events Composite Endpoint* Used by Singh et al1, applied to UPLIFT2 Placebo Tiotropium Rate Ratio† (95 % CI) n Rate‡ n Rate‡ Composite endpoint 246 2.89 208 2.25 0.78 (0.65, 0.94) Fatal composite 124 1.42 98 1.04 0.73 (0.56, 0.95) UPLIFT †rate ratio tio vs. placebo; ‡per 100 person-years of time at risk to tiotropium or placebo *SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death 1. Singh S, et al. JAMA. 2008 Sep 24;300(12):1439-50. 2. Tashkin DP, et al. N Engl J Med. 2008 Oct 9;359(15):1543-54.
  • 40. Adverse Events (n, %) in ≥3% of Any Treatment Group Glycopyrronium bromide 50 µg o.d. N=525 Placebo N=268 OL Tiotropium 18 µg o.d. N=267 Any adverse event 402 (76.6) 205 (76.5) 198 (74.2) COPD worsening 191 (36.4) 116 (43.3) 90 (33.7) Upper respiratory tract infection 57 (10.9) 33 (12.3) 30 (11.2) Nasopharyngitis 47 (9.0) 15 (5.6) 21 (7.9) Sinusitis 28 (5.3) 14 (5.2) 10 (3.7) Upper respiratory tract infection bacterial 28 (5.3) 28 (10.4) 21 (7.9) Headache 25 (4.8) 14 (5.2) 12 (4.5) Hypertension 21 (4.0) 12 (4.5) 14 (5.2) Urinary tract infection 14 (2.7) 8 (3.0) 16 (6.0) COPD worsening: includes chronic obstructive pulmonary disease (COPD) exacerbation. Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.
  • 41. Twice-daily Long-acting Beta2 agonists (LABAs)
  • 42. Salmeterol vs. Ipratropium vs. Placebo in COPD: Spirometric Impact Change from baseline in FEV1(L) 0.5 Salmeterol Ipratropium Placebo 0.4 Day 84 0.3 0.2 0.1 0.0 1 2 3 4 -0.1 Mahler DA, et al. Chest. 1999 Apr; 115(4):957-65. 5 6 7 8 Time (hours) 9 10 11 12 13
  • 43. Once-Daily LABAs
  • 44. Mean Change in FEV1 on Day 1 of Indacaterol Treatment FEV1 mean change from baseline (mL) Indacaterol 75 µg (N=150) Placebo (N=155) 250 200 150 5 mins post-dose 100 50 0 0 1 2 3 Time post dose (hours) Data are unadjusted means. Adapted from: Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012. Novartis Pharmaceuticals Inc. Data on file (Study B2355). 4
  • 45. Sustained Bronchodilation Over 24 Hours: Indacaterol vs. Placebo 1.60 Indacaterol 75 µg o.d. Placebo Improvement in FEV1 vs. placebo at every time point, measured by 24-hour spirometry 1.55 1.50 FEV1 (L) 1.45 1.40 1.35 1.30 1.25 Rapid onset within 5 minutes 1.20 0 4 8 12 Time (hours) 16 20 Adapted from: Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012. Novartis Pharmaceuticals Inc. Data on file (Study B2355). 24
  • 46. Recommended Next Step for Mr. A.C. • It has been 6 months since you have seen him • He has been taking a once daily LAMA + Salbutamol prn • Mr. A.C. has not had an exacerbation of his COPD • He states that he is still an MRC 3 dyspnea and has been needing a breakthrough salbutamol a few times a week How would you proceed?
  • 47. Rehabilitation Is A Powerful Tool For Improving QOL In COPD 0 Salmeterol1 Salmeterol/ fluticasone2 Tiotropium3 Rehabilitation4 -3.5 -4.5 -3.8 -7.1 -3.4 -2 -3 1 year -4 6 months -5 1 year Clinical significance threshold 1 year Improvement Changes in total SGRQ score -1 -6 -7 -8 SGRQ = St George’s Respiratory Questionnaire 1. Donohue JF, et al. Chest. 2002 Jul;122(1):47-55. 2. Calverley P, et al. Lancet. 2003 Feb 8;361(9356):449-56. 6 weeks 3. Vincken W, et al. Eur Respir J. 2002 Feb;19(2):209-16. 4. Griffiths TL, et al. Lancet. 2000 Jan 29;355(9201):362-8.
  • 48. Combining Bronchodilators in Mild to Moderate COPD
  • 49. Dual Bronchodilation with Formoterol + Tiotropium Total COPD Symptom Score‡ Trough FEV1: Change from baseline 200 150 † n=108 * n=118 n=127 0 * n=106 * n=121 n=121 n=121 100 n=129 50 0 Week 4 Week 8 Week 12 Last visit Mean change in symptom score Change from baseline in trough FEV1 (mL) 250 AM -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 * -1.4 -1.6 Formoterol (12 µg b.i.d.) + tiotropium (18 µg o.d.) PM AM/PM average * * Tiotropium (18 µg o.d.) *p<0.05; †p<0.001 vs. tiotropium; ‡ sum of scores for dyspnea (0 = none to 4 = severe), wheezing, cough, and chest tightness (0 = none to 3 = very uncomfortable). Tashkin DP, et al.:COPD .2009 Feb;6(1):17-25.
  • 50. LABA/LAMA Provides Better Improvements in Lung Function at 6 Weeks Than LABA/ICS Tiotropium 18 μg o.d. + formoterol 12 μg b.i.d. 1.8 Salmeterol 50 μg b.i.d. + fluticasone propionate 500 μg b.i.d. FEV1 (L) 1.7 1.6 1.5 1.4 1.3 0 1 2 3 4 5 6 7 8 9 Time after drug administration (hours) *p<0.05 between groups at each time point Rabe KF, et al. Chest. 2008 Aug;134(2):255-62. 10 11 12
  • 51. Is there any reason not to use ICS therapy at this point in his management?
  • 52. Lack of Benefit with LABA/ICS vs. LABA Alone in Stable COPD: Meta-analysis Study or Subgroup LABAs/ICS LABAs Risk Ratio Risk Ratio Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI 1.1.1 All-cause mortality Calverley (16) 2 358 3 372 1.1% Calverley (17) 5 254 14 255 5.3% Calverley (23) 193 1533 205 1521 78.4% Ferguson (25) 6 394 3 388 1.2% Kardos (24) 7 507 9 487 3.5% Safranski (20) 6 208 6 201 2.3% SCO100250 (29) 4 394 6 403 2.3% SCO100470 (30) 3 518 3 532 1.1% SCO40041 (28) 5 92 7 94 2.6% Tashkin (26) 7 845 1 284 0.6% Wouters (21) 2 189 4 184 1.5% Subtotal (95% CI) 5292 4721 100.0% Total events 240 261 Heterogeneity: Chi2 = 6.52, df = 10 (P = 0.77), I2 = 0% Test for overall effect Z = 1.27 (P = 0.20) Rodrigo GJ, et al. Chest. 2009 Oct;136(4):1029-38. 0.69 (0.12, 4.12) 0.36 (0.13, 0.98) 0.93 (0.78, 1.12) 1.97 (0.50, 7.82) 0.75 (0.28, 1.99) 0.97 (0.32, 2.95) 0.68 (0.19, 2.40) 1.03 (0.21, 5.07) 0.73 (0.24, 2.22) 2.35 (0.29, 19.04) 0.49 (0.09, 2.63) 0.90 (0.76, 1.06)
  • 53. Bone Density vs. Dose and Duration of ICS Therapy Lumbar Spine 2.0 Ward’s Triangle 2.0 r=-0.53 p=0.01 r=-0.58 p=0.005 Z score Z score 2.0 Femoral Neck -2.5 -2.5 0 Dose x Duration/BMI 4 r=-0.33 p=0.08 Z score -2.5 0 Dose x Duration/BMI Hanania NA, et al.: J Allergy Clin Immunol 1995; 96(5 Pt 1):571-9. 4 0 Dose x Duration/BMI 4
  • 54. "More" Combination Therapies Endurance Time (mins) 24 * Rehabilitation * 20 32% 42% 16 Control 12 8 Tiotropium 0 2 4 6 8 10 12 14 16 Weeks on Treatment * p<0.05 Casaburi R, et al. Chest. 2005 Mar;127(3):809-17. 18 20 22 24
  • 55. What If. . . Mr. A.C. has had a URTI and a worsening of his COPD He has ended up in the walk-in clinic and was sent home on antibiotics and prednisone for one week He comes back to you for follow up… Should you change therapy?
  • 56. Patients Who Exacerbate Frequently Account for a Small but Important Portion of the Overall COPD Population 27% 16% Hurst JR, et al. N Engl J Med. 2010 Sept 16;363(12):1128-38. 11%
  • 57. Risk Symptoms (C) (D) >2 3 2 (A) (B) 1 1 0 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Symptoms (mMRC or CAT score) Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011. (Exacerbation history) Lung function impairment 4 Risk GOLD assessment variables are similar to 2007 Cdn. Recommendations: (GOLD Classification of Airflow Limitation) GOLD: Combined Assessment of COPD
  • 58. Summary COPD is a lethal disease that has a profound impact on patient outcome as well as on the health care system. Patients at risk for COPD need to be diagnosed with spirometry. In the medical management of COPD, long-acting bronchodilators, even in mild or moderate disease are clinically beneficial. Introduction of an ICS (and only in combination with a LABA) should be done appropriately and in the right patient population.
  • 59. Patient Factors in COPD Management
  • 60. 12-month Persistence with Inhaled Medications: Canadian Data Ipratropium (Atrovent®) 8% Four times daily Ipratropium/salbutamol (Combivent®) 12% Formoterol (Oxeze®) Salmeterol (Serevent)® 16% 18% Twice daily Formoterol-budesonide (Symbicort®) 25% Salmeterol/fluticasone (Advair)® 32% Once daily Tiotropium (Spiriva®) 53% 0 10 20 30 40 % continuing for 12 months Adapted from Cramer JA, et al. Can Respir J. 2007 Jan-Feb;14(1):25-9. 50 60
  • 61. Does the device make a difference?
  • 62. COPD Treatment Options Tiotropium Salmeterol / Fluticasone Formoterol Salmeterol Indacaterol Formoterol/ Budesonide LAAC/ LAMA LAAC LABA + ICS (FDC) LABA LABA LABA LABA + ICS (FDC) Handihaler (18 µg/ inhalation) Mode of Action Glycopyrronium bromide Breezhaler (50 µg / inhalation) Aerolizer (12 µg / capsule) Diskus DPI (50 µg / inhalation) Breezhaler (75 µg / inhalation) Turbuhaler DPI (6 & 12 µg / inhalation) Diskhaler Disk DPI (50 µg / inhalation) Diskus DPI (50/250 µg and 50/500 µg / inhalation) Devices Aerosol MDI (25/50, 25/125 or 25/250 µg / inhalation) Turbuhaler DPI (110/6 or 200/6 μg / inhalation)
  • 63. Flow Rates with Various Inhalers Used for COPD Medications 120 Increasing Resistance Breezhaler® Flow rate (L/min) 100 Diskus® / Accuhaler® 80 Turbuhaler® HandiHaler® 60 kPa1/2 L-1 min 40 Breezhaler® Diskus®/Accuhaler® Turbuhaler® HandiHaler® 20 0 0 2 4 6 Inspiratory effort (kPa) 8 2.2 x 10-2 2.7 × 10-2 3.4 × 10-2 5.1 × 10-2 10 Diskus® and Accuhaler® are registered trademarks of GlaxoSmithKline; Turbuhaler® is a registered trademark of AstraZeneca; HandiHaler® is a registered trademark of Boehringer Ingelheim; Breezhaler® is a registered trademark of Novartis. Singh D, et al. Am J Respir Crit Care Med. 2010;181:A4419 (+ additional material from poster).
  • 64. Patient Education: There is Help! Certified Respiratory Educators (CREs) perform a critical role in improving the lives of Canadians living with respiratory illness. They assists with adherence, they deal with patient fears and review inhaler techniques. These highly professional, knowledgeable and skilled CREs support the disease management approach: education evaluation reinforcement Education takes time! “To be effective, education must be supported by a physician and provided by trained educators.” Dr. Ken Chapman President Canadian Network for Respiratory Care Learn more at the Canadian Network for Respiratory Care website at http://cnrchome.net
  • 65. Summary • COPD prevalence is increasing in Canada but underdiagnosis is common • Modern COPD algorithms are driven by symptoms plus future risk as determined by lung function and exacerbation history • For the non-exacerbation-prone COPD with mildto-moderate obstruction, use long acting bronchodilators; given once daily improves adherence. • For exacerbation-prone patients, triple therapy is recommended
  • 66. Back-up Information Additional supporting information for use at the facilitators' discretion
  • 67. What If? Mr. A.C. has had two more worsenings of his COPD over the next 9 months? He has ended up in walk in clinic and was sent home on antibiotics and prednisone for one week. He comes back to you for follow up… Should you change therapy?
  • 68. Mortality Increases with Frequency of AECOPD 1.0 Probability of surviving 0.8 0 AEs p<0.0002 0.6 1-2 AEs 0.4 p=0.069 >3 AEs 0.2 0.0 0 10 30 20 Time (months) Soler-Cataluña JJ, et al. Thorax. 2005 Nov;60(11):925-31. 40 50 60 p<0.0001
  • 69. Is triple therapy effective?
  • 70. OPTIMAL Study Design Tiotropium qd + Placebo MDI 2 puffs bid n=156 Run-in Tiotropium + Placebo R Tiotropium qd + Salmeterol MDI 2 puffs bid n=148 Tiotropium qd + Salmeterol/Fluticasone 50/250 MDI 2 puffs bid n=145 Visit: Month: 1 -0.5 2 0 3 1 Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55. 4 4 5 8 6 12
  • 71. OPTIMAL Study: Primary Outcome – Proportion of Patients with Exacerbations Tiotropium + placebo (n=156) 62.8 Tiotropium + salmeterol (n=148) 64.8 Tiotropium + fluticasone/salmeterol (n=145) 60 0 Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55. 20 40 % of patients 60 80
  • 72. OPTIMAL Study: Secondary Outcome Variable – COPD Hospitalizations Tiotropium + placebo (n=156) 49 Tiotropium + salmeterol (n=148) 38 Tiotropium + fluticasone/salmeterol (n=145) p = 0.01 26 0 Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55. 10 20 30 40 Number of patients 50 60
  • 73. What is the impact of oral PDE4 inhibitors (roflumilast)?
  • 74. Proportion of Patients with a Moderate or Severe Exacerbation Patients with an exacerbation (%) sal or tio + placebo 20 18 16 16 12 sal or tio + roflumilast 500 µg 11 11 8 4 0 n=83/467 n=51/466 n = 83/467 n = 51/466 Salmeterol study RiR = 0.60 (95% CI 0.43, 0.82) p = 0.0015 Exacerbation rates were based on a Poisson regression model. Risk ratios (RiR) were based on a log binomial regression model. Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703. n=58/372 n = 58/372 n=42/371 n = 42/371 Tiotropium study RiR = 0.73 (95% CI 0.51, 1.05) p = 0.0867
  • 75. Roflumilast: Incidence of AEs ( 2.5%)* AURA/HERMES 1 year Adverse Event HELIOS 6 months Roflumilast (n=1547) Placebo (n=1545) Tiotropium + Roflumilast (n=374) Tiotropium + Placebo (n=369) COPD 10% 13% 16% 19% Weight loss 10% 3% 6% <1% Diarrhea 8% 3% 9% <1% Nasopharyngitis 6% 6% 6% 5% Nausea 4% 2% 3% 1% Bronchitis 4% 4% 2% 3% Headache 3% 2% 2% 0% Back pain 3% 2% 2% 1% *Independent of investigator causality assessments Calverley PM, et al. Lancet. 2009 Aug 29; 374(9691):685-94. Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703.
  • 76. Risk of ICS
  • 77. Lack of Benefit with ICS on FEV1 Decline in COPD: Meta-analyses Authors Difference between ICS and placebo groups (95% CI) Highland et al. (2003)1 5.0 mL / year (-1.2 to 11.2) Sutherland et al. (2003)2 7.7 mL / year (1.3 to 14.2) 1. Highland KB, et al. Ann Intern Med. 2003 Jun 17;138(12):969-73. 2. Sutherland ER, et al. Thorax. 2003 Nov;58(11):937-41.
  • 78. Inhaled Corticosteroids and the Risk of Cataracts - Dose Response 3.1 Puffs/Wk > 28 15-28 14 or less 2.1 1.3 0 0.5 1 p < 0.001 Data are for posterior, subcapsular cataracts Cumming RG, et al.: N Engl J Med 1997; 337(1):8-14. 1.5 2 Prevalence ratio 2.5 3 3.5
  • 79. Increased Risk of Pneumonia with ICS vs. Placebo in COPD: Meta-analysis Subgroup # of events / # of patients Odds Ratio 95% CI 180 / 3633 1.51 1.08 – 2.10 356 / 4754 217 / 4728 1.72 1.28 – 2.30 641 / 8635 397 / 8361 1.60 1.33 – 1.92 ICS No ICS ICS vs. placebo 285 / 3881 ICS + LABA vs. LABA Total Singh S, et al.: Arch Intern Med 2009; 169(3):219-29.
  • 80. Increased Risk of New-onset Diabetes with Increasing ICS Dose 3.5 Rate Ratio 3.0 2.5 2.0 1.5 1.0 0.5 0 250 500 750 1000 1250 1500 Daily dose in fluticasone equivalents (mcg) Suissa S, et al. Am J Med. 2010 Nov;123(11):1001-6. 1750 2000
  • 81. Patient Preference
  • 82. Inhaler Regimens: Patient Preferences 27% Once Daily Twice Daily No Preference 12% Venables TL, et al. Br J Clin Res. 1996;7:15-32. 61%
  • 83. Breezhaler® vs. Handihaler®: Comfort, Simplicity & Confidence Mean score ± SE Breezhaler® 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 Handihaler® *** * * How comfortable is it to inhale through the inhaler? Overall, how simple is it to use the inhaler? How confident are you that you have taken the medication successfully? Breezhaler® is a registered trademark of Novartis. HandiHaler® is a registered trademark of Boehringer Ingelheim. *p<0.05, ***p=0.001 between the two inhalers Patient preference scores with respect to comfort, simplicity and confidence in use measured on a 10-point scale from 1 = not at all to 10 = extremely Chapman K, et al. Int J Chron Obstruct Pulmon Dis. 2011;6:353-63.
  • 84. Receptor Selectivity: Glycopyrronium Bromide versus Tiotropium M3:M2 selectivity ratio* Equilibrium affinity: Glycopyrronium bromide has greater M3 versus M2 receptor binding selectivity than tiotropium (5-fold vs. 2-fold) 14 12 10 8 6 4 2 0 12.9 Selectivity (ratio) pKi M2 Tiotropium Glycopyrronium bromide Tiotropium 10.050.05 10.370. 04 2 Glycopyrronium bromide 4.4 pKi M3 8.700.04 9.470.0 2 5 *Ratio of occupancy versus time over 24 hours t½ at M2 (min) t½ at M3 (min) Kinetic selectivity (ratio) Tiotropium 10.8 46.2 4.3 Glycopyrronium bromide 1.1 9.9 9.0 Novartis, data on file. Kinetic selectivity: Glycopyrronium bromide shows faster dissociation from M2 versus M3 receptor than tiotropium (9-fold vs. 4-fold) Clinical Implications a) faster time of onset b) ? Increased cardiac safety
  • 85. Sample: Plan of Action
  • 86. Tools and Resources Where can I learn more on the subject of spirometry in primary care? http://www.respiratoryguidelines.ca/2013cts-slide-kit-spirometry-in-primaary-care