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Pharmacological therapy in stable COPD

Dr John Haughney. Pharmacological therapy in stable COPD. Distribution of severity in Aberdeen and Denver after screening vs. a community sample . Price D, Tinkelman DG, Nordyke RJ, Isonaka S, Halbert RJ ERS 2004

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Pharmacological therapy in stable COPD

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  1. Dr John Haughney Pharmacological therapy in stable COPD

  2. Distribution of severity in Aberdeen and Denver after screening vs. a community sample Price D, Tinkelman DG, Nordyke RJ, Isonaka S, Halbert RJ ERS 2004 Lange P, et al. The quality of COPD care in general practice in Denmark: the KVASIMODO study. Prim Care Respir J. 2007 Jun;16(3):174-81

  3. Why bother to find COPD early Because: • COPD results in major morbidity, mortality and expense • COPD is frequently un-diagnosed or mis-diagnosed and when diagnosed often late in the disease • We have the tools to diagnose earlier • There is effective treatment for COPD to improve symptoms, prognosis and quality of life Price D, Duerden M. BMJ 2003

  4. 208 152 134 124 Improvement in bronchial obstruction after smoking cessation 80 76 72 More reversibility In mildCOPD 2682 2335 FEV1 (% predicted) 2059 1818 1652 B/L 1 2 3 4 5 Years in study Scanlon PD et al: Lung Health Study AJRCCM 2000

  5. COPD evidence based medicineMajor studies - methodology & objective outcomes • Chronic treament • Short-acting bronchodilators • Beta agonists • Anticholinergics • Long-acting bronchodilaters • Beta agonists • Anticholinergics • Inhaled corticosteroids (combinations) • Oxygen • ?others • Acute treatment • Oral steroids • Antibiotics

  6. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  7. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  8. Airflowlimitation in COPD: reducedelasticrecoilleadstohyperinflation COPD Normal Reduced IC Impaired chest wall and diaphragm mechanics – work of breathing  – dyspnea  IC = inspiratory capacity

  9. COPD Normal Price D, et al. Prim Care Respir J 2005; 14:285-93.

  10. Bronchodilator Rationale in COPD Bronchodilation Basal Tone Bronchoconstriction Blockade of cholinergic tone Exogenous stimulus Asthma (Multiple endogenous mediators) Effect of bronchodilator drug Predicted normal basal diameter Blockade of cholinergic tone COPD Resistance 1/r4 Effect of bronchodilator drug

  11. Short-acting bronchodilators in asthma & COPD I=ipratropium bromide β=fenoterolP=placebo I + β = ipratropium bromide + fenoterol Asthma 0.8 0.6 0.4 0.2 0 COPD I+β β 0.4 0.2 Increase in FEV1 (L) I+β I I β P 1 2 3 0 1 2 3 P Time (h) Lefcoe et al. Chest 1982;82:300–5

  12. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  13. Long-acting beta agonists compared to ipratropium Change from baseline FEV1 (L) * * * * * * + * * * * + * p<0,001 vs placebo + p£0,026 vs ipra Time (Hours) Ref. Donald A Mahler et al. Chest/115/4/april,1999

  14. Tiotropium in moderate and severe COPD Change in SGRQ Score Over 1 Year (Vs. Placebo1 & Ipratropium2) = = Ipratropium Ipratropium Tiotropium (n Tiotropium (n 327) 327) 46 46 = = (n (n 159) 159) baseline baseline 44 44 T T - - I I = = - - 3.3 3.3 42 42 * * 40 40 † † * * * * 38 38 8 8 182 182 364 364 Test day Test day Casaburi R et al. Eur Respir J 2002;19:217-224

  15. What about bronchodilators in general practice? Active treatment (12 weeks)Double-blind Run-in Usual treatment + Tiotroprium Usual treatment FEV1/FVC <70% 30%<FEV1<65% No anticholinergics Usual treatment + Tiotropium placebo 0 2 14 Weeks * 48 primary care UK centres Freeman D, Price D et al Respiratory Research 2007

  16. Beta agonist usage Week Placebo (n = 183) Occasions Tiotropium (n = 194) p < 0.05 tiotropium versus placebo from Week 1 to Week 12 Freeman D, Price D et al Respiratory Research 2007

  17. Exacerbations * p<0.05 Freeman D, Price D et al Respiratory Research 2007

  18. UPLIFT®Design and Method Run in 2- 4 weeks Treatment period 4 years (48 months) 30-days follow up (for completers and non-completers) 1440 days 1470 days Tiotropium 18 µg qd All previously prescribed respiratory medications Stop: Tiotropiumqd Start: Ipratropiumqid All previously prescribed respiratory medications (except inhaled anticholinergics) All previously prescribed respiratory medications permitted except inhaled anticholinergics Placebo qd Day 1 Randomization Day 30 Every 6 months 4 years end of trial End of follow up Screen Spirometry Spirometry + SGRQ Spirometry Spirometry + SGRQ Spirometry + SGRQ Spirometry Vital status SAAC = short-acting anticholinergic; SGRQ = St George’s Respiratory Questionnaire

  19. Tiotropium Control 1.50 * * * * 1.40 * * * Baseline n=2516 * 1.30 * Postbronchodilator * * * 47-65 mL FEV1 (L) * * 1.20 n=2374 * * * * Prebronchodilator 1.10 Baseline n=2494 87-103 mL 1.00 n=2363 0 1 0 6 42 48 12 18 24 30 36 Day 30 (steady state) Months Tiotropium Provides Significant and Sustained Improvements in Pre- and Postbronchodilator FEV1 *P<0.001 versus control Tashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54

  20. Quality of life using SGRQ total score in UPLIFT in GOLD stage II vs. whole study population – greater benefit in GOLD II 50 50 Tiotropium Control (74% ICS & 72% LABA) 45 45 * * * * * 40 40 * * * SGRQ Total Score Difference: 2.0-3.3 units  = 2.3 units * * * * * * 35 35 * * 0 0 0 6 42 48 12 18 24 30 36 0 6 12 18 24 30 36 42 48 whole study population GOLD Stage II Difference: 2.9 – 3.9 units (p<0.001 at all time points) Improvement SGRQ Total Score (Units) Month Month Tashkin DP et al. NEJM 2008;359:1543-54 Decramer M et al. Lancet 2009

  21. Tiotropium Significantly Reduces the Risk of Exacerbations in UPLIFT® Control Tiotropium 80 60 HR=0.86 (0.81, 0.91) P<0.001 (log-rank test) Probability of exacerbation (%) 40 14% reduction in all patients 20% in GOLD II 20 0 0 6 12 18 24 30 36 42 48 Months HR = Hazard ratio (95% confidence intervals) Tashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54

  22. Follow-up for Mortality in UPLIFT® Was High (Approaching 100%) Tiotropium n=2986 Control n=3006 100 90 80 70 60 Percent of patients (%) 50 40 30 20 10 0 12 18 24 30 36 42 45 Months 98 97 95 95 75 75 Day 1440 Day 1470 aTashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54UPLIFT® Study data on file, BoehringerIngelheim/Pfizer

  23. HR=0.87 (0.76, 0.99) P=0.034 (log-rank test) Tiotropium Significantly Reduces the Risk of All-Cause Mortality in the Vital Status Analysis Until Day 1440 HR = Hazard ratio, 95% confidence intervals Tashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54

  24. POET-COPD: Double-Blind, Double-Dummy Treatment period 12 months Follow-up SAEs 30 days Run in 2 weeks Tiotropium 18 µg Handihaler® once daily All previously prescribed COPD medications permitted (except anticholinergics and beta-agonists, but salbutamol) Salmeterol 50 µg MDI twice daily Screening 12 months End of trial Day 1Randomization 8 months 2 months 4 months Exacerbations at Clinic Visits/Vital Status Exacerbations collected during monthly telephone contacts MDI=metered-dose inhaler; SAE=serious adverse event.

  25. Primary Endpoint: Time to 1st Exacerbation Tiotropium Salmeterol 50 45 40 35 30 Estimated probability of COPD exacerbation (%) 25 20 15 Hazard ratio = 0.83 (95% CI, 0.77, 0.90) p=0.0001 (log-rank test) 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) No. of patients at risk:

  26. Secondary Endpoint:Time to 1st Hospitalized Exacerbation 20 15 Tiotropium Salmeterol 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Estimated probability of hospitalized COPD exacerbation (%) Hazard ratio = 0.72 (95% CI, 0.61, 0.85) p=0.0005 (log-rank test) Time to event (days) No. of patients at risk:

  27. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  28. Greater bronchodilatation with tiotropium and long acting beta agonists Tiotropium x 1 Formoterol x 2 3,4 Tiotropium and Formoterol x 1 3,2 3,0 FVC (L) 2,8 2,6 2,4 0 2 4 6 8 10 12 14 16 18 20 22 24 09.00 15.00 21.00 03.00 09.00 Van Noord et al., EurRespir J 2005; 26:214-222

  29. INTRUST 1 INTRUST 2 • INTRUST: Indacaterol plus tiotropium significantly improves bronchodilationvstiotropium alone FEV1 AUC5 min–8 h and trough FEV1 at Week 12 160 140 120 100 80 60 40 20 0 Data are LSM and 95% CI for the treatment difference between indacaterol plus tiotropium and tiotropium alone ***p<0.001 for indacaterol plus tiotropium versus tiotropium alone *** *** FEV1 treatment difference (mL) *** *** FEV1 AUC5 min–8 h (primary endpoint) Trough FEV1 (key secondary endpoint) NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Mahler et al. Thorax 2012

  30. *p<0.05 vs tiotropium; **Total COPD symptom scores were the sum of scores for dyspnea (0 = none to 4 = severe), wheezing, cough, and chest tightness (0 = none to 3 = very uncomfortable) Formoterol + tiotropium significantly improved symptoms of COPD vs. tiotropium alone Tiotropium Formoterol + Tiotropium Change from baseline in Total COPD symptom scores** AM PM AM/PM average 0 –0.2 –0.4 –0.6 –0.8 –1 –1.2 –1.4 –1.6 Mean change insymptom score * * * Tashkin et al. COPD 2009

  31. Tiotropium and olodaterol in combination N = 232 Randomised, double-blind, 4-period, incomplete crossover study Addition of tiotropium (T) to olodaterol (O) resulted in significant improvements in FEV1 versus O alone. These data support further investigation of T 2.5 and 5 μg combined with O 5 μg in the Phase III T+O clinical trial programme. Aalbers et al. Abstract ERS 2012

  32. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  33. Recommendations for ICS in COPD: what is the evidence? • Patients with FEV1 <60% and moderate to very severe; combination ICS + LABA • Benefits: • Symptoms • Lung function • Quality of Life • Exacerbation reduction • Patients with FEV1 <60%; ICS • Benefits: • Symptoms • Lung function • Quality of Life • Exacerbation reduction Relatively small effects Greater effect than either alone • Disadvantages: • Pneumonia more common • Local side effects (oropharyngeal, laryngeal, skin bruising, cataracts, and osteopenia) Adapted from: http://www.goldcopd.org/uploads/users/files/GOLD_Pocket_may2512.pdf

  34. 40 30 Reduction in exacerbations (%) 20 10 0 <1.25 1.25–1.54 >1.54 FEV1 (litres) Inhaled steroids in COPD vs. COPD severityExacerbation reduction stratified by baseline FEV1 Burge PS et al. BMJ 2000 13;320:1297-303

  35. # p=0.45; ¶ p=0.022. Placebo Fluticasone propionate Percentage of patients with ≥1 corticosteroid treated exacerbations / year

  36. Run-in Randomisation Treatment Follow-up Salmeterol/fluticasone DPI 50/500 µg b.i.d. Fluticasone DPI 500 µg b.i.d. Salmeterol DPI 50 µg b.i.d. Placebo Salbutamol available as reliever medication to all patients 36.5 –0.5 0 24 12 36 TORCH Month: • Primary endpoint: all-cause mortality over 3 years Vestbo J, et al. EurRespir J 2004;24:206–210;Calverley PM, et al. New Engl J Med 2007;356:775–789. .

  37. Results FEV1 (mL) 1350 1300 1250 1200 1150 1100 –39 mL/yr –42 mL/yr –42 mL/yr –55 mL/yr 0 24 48 72 96 120 156 Time (weeks) Control SAL FP SFC • SFC significantly reduced the rate of decline in lung function compared with placebo (39mL/year vs 55mL/year, difference 16mL/year p<0.001) Error bars represent 5% and 95% confidence intervals Celli et al. Am J Respir Crit Care Med 2008

  38. SGRQ total score<50% pre-bronchodilator FEV1 Adjusted mean change SGRQ total score (units) 3 2 1 0 –1 –2 –3 –4 –5 Control Salmeterol Fluticasone Fluticasone/ salmeterol * * † ‡ 0 24 48 72 96 120 156 Time (weeks) No. of subjects 1149 1148 1155 1133 854 906 942 941 781 844 848 873 726 807 807 814 675 723 751 773 635 701 686 731 569 634 629 681 *p<0.001 vs control; †p<0.001 vs SALM; ‡p=0.038 vs FP CalverleyPM, et al. New Engl J Med 2007;356:775–789.

  39. The TORCH study: the effects of ICS treatments for COPD ***p<0.001 vs. placebo, *p<0.05 vs. placebo. RR = rate ratio. Effect of treatment on the annual rate of exacerbations Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775-89. Price et al. Prim Care Respir J 2012; 21(2): 208-213

  40. The risks of ICS treatment for COPD Risk of fractures with increasing dose of inhaled corticosteroid: results from observational studies included in a meta-analysis. Adjusted rate ratios of hospitalisation for pneumonia associated with current use, past use and dose of ICS Loke YK, Cavallazzi R, Singh S. Thorax 2011;66(8):699-708. Ernst P, Gonzalez AV, Brassard P, Suissa S. Am J RespirCrit Care Med 2007;176(2):162-6. Price et al. Prim Care Respir J 2012; 21(2): 208-213

  41. ICS and the risk of diabetes • Case-control cohort analysis • Patients treated for respiratory disease 1990-2005 • Identified using the Quebec health insurance databases Cohort Entry New diabetes cohort: date of 3rd prescription for respiratory drug Diabetes progression cohort: date of first prescription for oral hypoclycemic agent followed until 1stantidiabetic medication, death, or 31/12/2007 New diabetes cohort Nested case-control analysis performed within the cohort Diabetes progression cohort followed until 1st insulin medication, death, or 31/12/2007 Suissa S et al. Am J Med. 2010 Nov;123(11):1001-6.

  42. Incidence of diabetes versus dose of prescribed inhaler steroid New Diabetes Cohort 95% confidence limits for the fitted dose-response curve. Diabetes Progression Cohort Suissa S et al. Am J Med. 2010 Nov;123(11):1001-6.

  43. Asthma phenotype in COPD *Heart failure, Angina or Myocardial Infarction; drugs for IHD drugs indistinguishable from drugs for hypertension Data on file, Optimum Patient Care: Price D. 2012

  44. But what about long-acting anticholinergic, long-acting beta agonist and ICS? Ann Intern Med. 2007 ;146(8):I12.

  45. Ann Intern Med. 2007 ;146(8):I12.

  46. Changes in health-related quality of life and FEV1 over 1 year. Ann Intern Med. 2007 ;146(8):I12.

  47. Pharmalogical therapy in stable COPD • COPD: why use bronchodilators? • Are long-acting bronchodilators better than short-acting? • What if one bronchodilator is not enough? • What about ICS treatment for COPD? • What do the new GOLD guidelines say about treating COPD?

  48. So what do we know about drug therapy? • COPD is more responsive to modification in early disease • Bronchodilators work in patients with COPD even if they don’t have a spirometric improvement on a reversibility test • Long-acting drugs are more effective than short-acting drugs • Long-acting anticholinergics do not reduce lung function decline in those already on drug therapy but does in those not on treatment and GOLD II patients • Long-acting anticholinergics improve health status, reduce exacerbations and appear to reduce mortality • If one long-acting bronchodilator for provide inadequate symptom relief use 2 • ICS reduce exacerbations especially in those with more severe disease • Combination therapy (ICS+LABA) improves health status, reduces exacerbations, reduces lung function decline and possibly mortality • Triple therapy (ICS+LABA+LAAC) more effective than single or combination therapy in those with more severe disease

  49. Combined assessment of COPD: a matrix approach 4 (C) (D) > 2 3 Risk (GOLD Classification of Airflow Limitation) Risk (Exacerbation history) (B) (A) 2 1 1 0 mMRC 0-1 CAT < 10 mMRC > 2 CAT >10 Symptoms (mMRC or CAT score) GOLD 2013

  50. GOLD 2013: managing COPD therapy* GOLD 4 ≥2 GOLD 3 Exacerbations per year GOLD 2 1 First choice Second choice 0 GOLD 1 mMRC0−1 CAT <10 mMRC ≥2 CAT ≥10 *Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference SABA: short-acting β2-agonist; SAMA: short-acting muscarinic antagonist; p.r.n.: as needed (pro re nata); LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PDE4-inh: phosphodiesterase-4 inhibitor Adapted from GOLD 2013. Available from: www.goldcopd.org

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