Inhaled Anticholinergics for COPD: Breathing Life into the Debate

1. Inhaled Anticholinergics for COPD: Breathing Life into the Debate Manish Khullar, BSc Pharm Interior Health Pharmacy Resident October 31, 2013

2. Learning Objectives • Become familiar with the clinical presentation and risk factors associated with COPD • Describe the classification of COPD and various methods of classification • Be able to explain the evidence for inhaled anticholinergics in the management of severe COPD

3. Our Patient

4. Our Patient

5. Our Patient

6. Review of Systems

7. Investigations • Diagnostics: • Chest x-ray (upon admission): • Bibasilar atelectasis and scarring of the lungs

8. Current Problems and Medications

9. List of DRPs • JM is at risk of adverse effects of corticosteroids (headaches, nausea, infections, throat irritation, oral thrush) secondary to receiving duplicate therapy and would benefit from reassessment of his COPD therapy • JM is at risk of adverse effects of inhaled anticholinergics (headaches, chest pain, respiratory tract infections, urinary retention, dry mouth) secondary to receiving duplicate therapy and would benefit from reassessment of his COPD therapy • JM is at risk of adverse effects without added benefit secondary to concomitant use of tiotropium and ipratropium and would benefit from reassessment of his COPD therapy • JM is at risk of adverse effects without added benefit secondary to concomitant use of budesonide and fluticasone and would benefit from reassessment of his COPD therapy

10. DRP Focus • JM is at risk of adverse effects (headaches, chest pain, respiratory tract infections, urinary retention, dry mouth)without added benefit secondary to concomitant use of tiotropium and ipratropium and would benefit from reassessment of his COPD therapy

11. Background: Classification of COPD • By Symptoms: Can Resp J 2008;15:1-8

12. Background: Classification of COPD • By Lung Function: Can Resp J 2008;15:1-8

13. Clinical Presentation • Chronic cough • Sputum production • Dyspnea • Wheezing and chest tightness Can Resp J 2008;15:1-8

14. Back to Our Patient • COPD stage=moderate-severe • PFT: FEV1 40% of predicted • SOB after walking 1 block • Frequent exacerbations (#/year unknown) • Chronic cough • Sputum production

15. Goals of Therapy • Reduce mortality • Prevent/decrease morbidity (hospitalizations, exacerbations) • Prevent disease progression • Reduce signs and symptoms • Prevent adverse events • Improve quality of life

16. Therapeutic Approach Can RespJ 2008;15:1-8

17. Clinical Question #1 • In a patient with moderate-severe COPD, will combination ipratropium and tiotropium as compared to either alone reduce mortality, number of exacerbations, and improve quality of life and symptoms without increasing the risk of adverse events?

18. Literature Search

19. Cole 2012 Ann of Pharmacotherapy 2012, 46(12):1717-21

20. Kerstjens et al 2007

21. Kerstjenset al 2007: Methodology

22. Results: Efficacy *statistically significant versus placebo (p<0.0001) **Fenoterolstatistically significant versus ipratropium (p<0.0001)

23. Results: Safety

24. Study Limitations • Methodology • Single day (2 doses) • Very short study • small sample size • Clinically • FEV1 is a surrogate marker • Improvement in symptoms not reported • Patients in trial were not on B2 agonist + 2 anticholinergics at any one time?

25. Bottom Line of Study “Add on therapy with fenoteroland ipratropium results in additional significant bronchodilation, although fenoterol was more effective as add-on therapy to maintenance tiotropium therapy in patients with COPD…”

26. Cazzola et al 2008

27. Cazzola et al 2008: Methodology • 3-way crossover, double-blind treatment • Tiotropium for a 6 month period • 3 hours post-tiotropium dose, add on treatment with one of the following: • Ipratropium 120mcg • Salbutamol 600mcg • Placebo • Cumulative dose; 3 non-consecutive days • 1 puff, 1 puff, 2 puff, 2 puff regimen

28. Results Figure 1. Mean dose-response curves to inhaled salbutamol, ipratropium or placebo 3 hours after inhaling tiotropium 18mcg

29. Results: Safety • No adverse effects were reported throughout the trial…

30. Limitations • Methodology • Single day /very short study • Sample size was small (30) • Used higher than normal doses; unknown significance at lower doses • Clinically • FEV1 is a surrogate marker • Improvement in symptoms not identified • Relevance to our patient? • The patient was currently on both inhaled and oral corticosteroids; excluded patients who had either for at least 3 months • Excluded patients with BPH • Patients in trial were not on B2 agonist + 2 anticholinergics at any one time?

31. Bottom Line of Study “…there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium to tiotropium in patients with stable COPD”

32. Summary of Evidence for Combination Anticholinergic Therapy

33. Clinical Question #2 • In a patient with moderate-severe COPD, is tiotropium as compared to ipratropium more effective at reducing mortality, number of exacerbations, hospitalizations and improving quality of life and symptoms without increasing the risk of adverse events?

34. Literature Search

35. Vincken 2002

36. Results *St. George’s Respiratory Questionaire

37. Study Limitations • Methodology • Tiotropium n=356; Ipratropium n=179 • 1 year study • Allocation concealment not defined (selection bias?) • Blinding of outcome assessment (detection bias?) • % of current smokers? • Clinically • FEV1is a surrogate marker • Patients in this trial were stable for 6 weeks prior to start of trial • Very small number of patients were on oral corticosteroids (tiotroprium n=31; ipratropium n=19) • Participants were not on maximum dose of ipratropium (ie 320mcg/day)

38. Bottom Line of Study “Tiotropium showed consistently greater efficacy across all of the aforementioned outcome measures compared to ipratropium….once daily administration of tiotropium should be considered as first-line maintenance treatment in patients with COPD”

39. Summary of Evidence: Tiotropiumvs Ipratropium

40. Patient Specific Factors • Tiotropium is once daily; Ipratropium is QID • Patient is already on multiple inhalers • Patient and wife appear to be confused with the approach to treatment and inhaler use • Tiotropium is expensive • Diagnosis of COPD (FEV1 < 0.65 and FEV/FVC <0.7) • Inadequate response to ipratropium after 3 months at 12 puffs daily • Must be prescribed by a respirologist to be covered by pharmacare • However, cost is not an issue for this patient • Tolerability • Ipratropium is better tolerated • Tiotropium is associated with more dry mouth • Patient’s wife claims the patient seems to be doing better on tiotropium(due to concomitant use?)

41. Alternatives for Symptom Management • Short acting beta agonist • Salbutamol • Anticholinergics • Ipratropium • Tiotropium • Combination ipratropium + tiotropium • Long-acting beta-agonist • Salmeterol • Formoterol • Inhaled corticosteroids

42. Therapeutic Recommendation • Discontinue ipratropium 40-80mcg INH QID and PRN • Discontinue budesonide 0.5mg/2mL nebules INH BID • Continue salbutamol 100mcg INH q4h prn • Continue salmeterol 50mcg/fluticasone 250mcg INH BID • Continue tiotropium 18mcg INH daily

43. What Actually Happened… • Budesonide 0.5mg/2mL nebules INH BID was discontinued • Physician, RT, patient and were unaware of how often the patient was using the combivent • Physician wanted patient to remain on both anticholinergics • Patient to have a diary and document use of each inhaler

44. Monitoring Plan

45. Follow-up • Oct 10th: • Patient improved clinically • Oct 13th: • Patient continued to improve • Continued frequent inhaler use to control symptoms • Oct 17th: • Course of antibiotics complete • Oct 18th: • Medications were reconciled and plan was discussed with patient, physician and RT, with physician and RT to follow-up with patient in community • Oct 19th: • Patient discharged • New written care plan was provided • Oct 29th: • Spoke with RT and patient is doing well and is improving and is no longer on ipratropium

46. Questions… ?