Ted D. Williams PharmD Candidate OSU/OHSU COP

1. Combination Anti-Cholinergic COPD Therapy – Safety and Efficacy of Combining Ipratropium and Tiotropium Ted D. Williams PharmD Candidate OSU/OHSU COP

2. Outline • Case presentation • Clinical Question • Guideline Ambiguity • Primary Literature • Intervention

3. Case Presentation • CC • WB , a 68 yo male presents stating his physician sent him here for abnormal lab values. Pt c/o nausea and pain 8/10 which he states is normal for him. Pt also states mild SOB which he says is slightly worse than what he's used to. Pt is under examination for possible need for dialysis. Pt is in no acute distress, and is speaking with doctor. Pt placed on oxygen, EKG completed, IV established and fluid bolus initiated.

4. HPI Patient tried Advair in 4/06 and did not work Advair 250/50 one puff BID May 5/2008 FEV1 = 29% SH Active smoker ½ ppd, 50+ pack year history Has tried to quit several times Wife’s smoking makes it difficult for patient to quit Wife active smoker & afraid of O2 in the house Case – HPI/SH

5. Case - PMH • Current smoker • CKD + Anemia • MDD • Osteoporosis • Fever • Leukocytosis • Bladder CA • BPH/Prostate CA • COPD • CAD/Acute MI

6. Case - Objective • Pertinent Labs • PFT 8/19/2008 • FEV1% predicted=34 • FEV1/FVC=36 • FEV1% change post bronchodilator=3 • Non-Reversible • SP02 84-95% • SOB: stable, stating 97% on 3L. • GOLD Stage III – Severe COPD

7. Case - Medications • ALBUTEROL (HFA Aerosol) 90 mcg 2-4 puffs prn wheeze/ SOB • ASPIRIN (Tablet) 325 mg take one tablet by mouth one time a day • CALCIUM ACETATE (Tablet) 667 mg 1 tab with largest meal of day • DOXAZOSIN MESYLATE (Tablet) 8 mg 1 tab poqhs • HYDROCODONE BIT/ACETAMINOPHEN (Tablet) 10-325 mg 1 po q 6 hours • Influenza vaccination 2008, FM pharmacy, no date available • IPRATROPIUM/ALBUTEROL Combivent 18-103 mcg 2 puffs 4x/day • METOPROLOL SUCCINATE (Tablet SR 24 hr) 200 mg 1 tab by mouth daily • NIFEDIPINE (Tablet Sustained Release) SR 90 mg 1 tab po twice daily • NITROGLYCERIN (Tablet, Sublingual) Nitrostat 0.4 mg as needed • OMEPRAZOLE (Tablet, DR (E.C.)) Prilosec OTC 20 mg 1 PO twice daily • OXYCODONE HCL (Tablet IR ) 5 mg 1 po q 4-8 hours • Pneumococcal vaccination 11/11/08 • SERTRALINE HCL (Tablet) Zoloft 50 mg 1 tab daily • SIMVASTATIN (Tablet) 40 mg 1 tab by mouth daily at night

8. Clinical Question • Should Spiriva® (tiotropium) be added to Combivent® (ipratropium/albuterol)?

9. GOLD Guidelines - 2007

10. GOLD Guideline Treatments for Stage III COPD • Short Acting Bronchodilator (SABD) • Long Acting Bronchodilator (LABD) • “The choice between beta 2 agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual response in terms of symptom relief and side effects.” –GOLD Guidelines 2007 • Inhaled Glucocorticoids(in the presence of exacerbations)

11. Clinical Question • Ipratropium with tiotropium: • Is it effective? • Is it safe?

12. Spiriva Package Insert Drug Interactions • “…the co-administration of SPIRIVA HandiHaler with other anticholinergic containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended…”

13. Literature Search • OVID MEDLINE Search Criteria • Keyword Tiotropium (english, human trials) • Keyword ipratropium (english, human trials) • Results • 88 articles • Each abstract reviewed manually for relevance

14. Single Study of Relevance • Kerstjens, H., et al. Effects of Short-Acting Bronchodilators Added to Maintenance Tiotropium Therapy. CHEST 2007;132:1493-1499

15. Kerstjens, H., et al • General • Comparison of effects of short acting anticholinergic, beta agonist, and placebo as add on therapy to tiotropiummonotherapy • Design & Methods • Inclusion • %FEV1<=60% • Exclusion • COPD exacerbations within 6 weeks excluded • O2 • Asthma/allergic rhinitis • Design • Three arm (ipratropium 40mcg , fenoterol 200mcg, placebo) • n = 60, RCT, double blinded three way cross over • 3 week run in period • Baseline Parameters • FEV1 = 1.17 +/- 0.43 • FEV1 % predicted = 40.1 +/- 12.1 • FEV1/FVC = 43.0 +/- 9.9 • Statistics • Powered to detect a 60mL change in mean FEV1

16. Kerstjens, H., et al • Mean change in FEV1 • Addition of Fenoterol superior to placebo (137ml, p<0.0001) and Ipratropium (p<0.0001) • Addition of Ipratropium superior to placebo (52ml,p<0.002)

17. Kerstjmens, H., et al • Conclusions • Change in mean FEV1 of combination of anticholinergics (tiotropium + ipratropium) smaller than this study was powered to detect (60ml) • Combining ipratropium with tiotropium would not be expected to produce significant benefit • Limitations • Short term study • No longer term efficacy or safety data

18. Kerstjmens, H., et al • Questions generated • How does FEV1 change of 50mL compare with pushing the dose of tiotropium? • Missing reference • 22 Koenen-Bergman, M., Witek, T Jr, Tuerck D, et al. Pharmacologic effects of acute administration of ipratropium on top of maintenance treatmetn with tiotropium [abstract]. European Respiratory Journal 2003; 22(suppliment 45):67S. • This suppliment is no longer available at the European Respiratory Journal website

19. Comparisions of tiotropium dosing • A non-systematic literature search revealed two articles of interest • Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary diease (COPD) Maesen, FPV, Smeets, JJ, Sledsens, TJH, Wald, FDM, Cornelissen, PJG. European Respiratory Journal (ERJ) 1995; 8:1506-1513 • Long Acting Bronchodilation with Once-Daily Dosing of Tiotropium (Spiriva) in Stable Chronic Obstructive Pulmonary Disease. Littner, MR, Ilowite, JS, Tashkin, DP, Friedman, M, Serby, CW, Menjoge, SS, Witek, TJ. American Journal of Respiratory Critical Care Medicine (AJRCCM) 2000; 161:1136-1142

20. ERJ 1995 • Randomized, double blinded placebo controlled crossover. Single dose, 72 hour wash out period • n = 35 • Baseline • FEV1 = 1.69 +/- 0.48 • FEV1% predicted = 44% • FEV/FVC not available

21. ERJ 1995 • Double the dose produces a 20-33mL change in FEV1 in the 0-8 hour time block

22. Randomized double blinded parallel, placebo controlled. 29 days n=169 Baseline FEV1 = 1.08 +/- 0.34 FEV1 predicted = 42.3% FEV/FVC % = 43-49% AJRCCM 2000

23. Mean FEV1 increases approximately 40mL doubling from 18mcg to 36mcg AJRCCM 2000

24. Changes in FEV1 due to combination ipratropium + tiotropium are consistent with the response for doubling the dose of tiotropium Literature Conclusions

25. Two recent meta-analyses have shown an increased CV risk with the use of anticholinergic Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease.  JAMA 2008; 300 (12): 1439-1450 Lee TA, Pickard S, et al.  Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease.  Annals of Internal Medicine 2008; 149: 380-390. Safety

26. Safety • UPLIFT showed some increased CV Risk • Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554.

27. Safety • “In COPD patients with moderate to severe renal impairment (CrCl<50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC0–4), which was confirmed by plasma concentrations after dry powder inhalation” – Spiriva Package insert • Is this clinically relevant?

28. Gaps in Therapy

29. Possible Therapy Options • Retry long acting beta agonist and/or corticosteroid (Advair) • Retry Home O2 • Retry Smoking Cessation • Add Tiotropium once daily, D/C Combivent 4x/day

30. Actual Intervention • Based on patient’s comments, will not attempt smoking cessation at this time • Based on PMH, will not retry Advair • Patient expressed great perceived benefit from Combivent, so switching to tiotropium was not recommended • Convinced patient to retry home O2