1. To Inhale or Not to Inhale? Sukhjinder Sidhu Interior Health Pharmacy Resident September 13, 2013

2. Learning Objectives Describe the pathophysiology of COPD Become familiar with the clinical presentation and how to access severity of COPD Be able to explain the evidence for treatment of mild COPD Describe the role of ICS, LABA in management of COPD

3. Our Patient ID65 y.o. male (72.6 kg; 170 cm). Admitted Aug 21, 2013 to CTU. CC/HPISOB x 5-6 days accompanied by chest pain Some nausea and generalized weakness x 1/52 AllergiesNKDA Social HxQuit smoking 28 years ago (75 pack/yr hx) Ø Alcohol or illicit drug use Assisted living; wife died 3 months ago

4. Our Patient PMHx:MPTA: C. DifficileMetronidazole 500 mg PO TID x 14 days (finished Aug 18, 2013) Essential thrombocythemia Hydroxyurea 1000 mg PO daily Schizo-affectiveRisperidone 1 mg PO BID AnxietyDiazepam 10 mg PO QID PRN Citalopram 40 mg PO daily HTNNone HypothyroidismLevothyroxine 75 mcg PO daily Chronic prostatitisCiprofloxacin 1000 mg PO daily COPDNone Esophagitis/PUDRabeprazole 20 mg PO BID Tums 10 tab PO daily NauseaDimenhydrinate 100-200 mg PO BID-TID

5. Review of Systems VitalsT 36.6 HR 113 BP 105/69 RR 70 O2 sat 92% after neb CNS/NeuroA&O x 3 HEENTØ RESPLabored breathing; left side wheezing; Ø cough CVSRegular; S1/S2 normal; ECG flipped T’s GI6 loose BM today; distended; normal sounds GU> 300 mL urine PRV; SrCr 113; eGFR 56 ENDOTSH 7.31 MSK/DermPale skin LYTESNa 124 K 4.9 Cl 91 Bicarb 22 HEMEHgb 120 MCV 93.9 WBC 16.5 Neuts 13.53 Plts 1173

6. Investigations Diagnostics Day 0 (Admission) CXRHyperinflation consistent with COPD Day 1Chest CTBilateral pulmonary emboli CXRComparison - Ø HF Day 2V/Q ScanBilateral PE TEEModerate pulmonary hypertension Day 3CXRTiny bilateral pleural effusions Microbiology Day 1StoolC. Difficile Toxin B UrineNo growth

7. Course in Hospital Assessed by respirology – Diagnosed with pulmonary emboli – Diagnosed with COPD

8. Current Problems & Medications IndicationMedication Pulmonary emboliNadroparin 13,300 unit SC daily Warfarin to target INR 2-3 C. DifficileVancomycin 125 mg PO Q6H x 7 days COPDFluticasone 500 mcg INH Q12H Ipratropium 40 mcg INH QID Salbutamol 200 mcg INH QID & Q1H PRN Essential thrombocythemia Hydroxyurea 500 mg PO TID NauseaDimenhydrinate 50 mg IV Q6H PRN PUD/EsophagitisRanitidine 150 mg PO BID Schizo-affectiveRisperidone 1 mg PO BID AnxietyDiazepam 5-10 mg PO QID PRN Citalopram 40 mg PO daily HypothyroidismLevothyroxine 75 mcg PO daily

9. DRPs 1.GB is at risk of experiencing subsequent VTE’s or death secondary to non-adherence to his warfarin therapy and would benefit from reassessment of therapy. 2.GB is at risk of C. difficile treatment failure secondary to receiving a short duration of vancomycin therapy and would benefit from a 10 day duration. 3.GB is at risk of experiencing adverse events secondary to receiving COPD therapy without a clear diagnosis and unclear severity and would benefit from reassessment of his COPD therapy. 4.GB is at risk of developing pneumonia secondary to not receiving his pneumococcal vaccine and would benefit from a one-time administration of the vaccine.

10. DRP Focus GB is at risk of experiencing adverse events secondary to receiving COPD therapy without a clear diagnosis and unclear severity and would benefit from reassessment of his COPD therapy.

11. COPD Gradual & progressive loss of lung function due to chronic inflammatory changes Chronic airflow limitation – alveoli lose elasticity – alveolar destruction – ↑ mucus production Airway closure on expiration, leading to air trapping & hyperinflation nhlbi.nih.gov/health/health-topics/topics/copd/

12. COPD Can Respir J 2008;15(Suppl A):1A-8A Risk Factors – Cigarette smoking – Air pollution – Exposure to occupational dusts & chemicals Clinical Presentation – Chronic cough – Sputum production – Dyspnea – ↑RR – Breathing with pursued lips – Hyperinflation of the lungs

13. COPD Our patient – COPD stage = mild Hyperinflation present Ø PFTs Ø SOB Ø exacerbations Ø chronic cough Ø sputum production PTA Ø puffers

14. Goals of Therapy Reduce mortality Prevent or reduce hospitalizations Reduce frequency & severity of exacerbations Prevent disease progression Improve QOL by reducing impairment & disability Reduce adverse events

15. Therapeutic Approach Can Respir J 2008;15(Suppl A):1A-8A

16. Clinical Question In a patient with at most mild COPD will an inhaled corticosteroid with an anticholinergic compared to a prn short-acting beta agonist reduce mortality and exacerbations, and improve quality of life and symptoms without increasing the risk of adverse events?

17. Literature Search DatabasesMedline, PubMed Search TermsPulmonary Disease, Chronic Obstructive Anti-inflammatory Agents Bronchodilator Agents/ or albuterol/ or ipratropium/ Adrenergic beta-Agonists Results8 RCT’s TRISTAN TORCH 1 Meta-analysis 1 NICE Guideline

18. TRISTAN DesignRandomized, double-blind, parallel-group, placebo-controlled PopulationInclusion: Diagnosis of mod-severe COPD Poor reversibility of airflow obstruction Smoking hx of > 10 pack-years > 1 episode of acute COPD sx exacerbation/year in previous 3 yrs with > 1 being in year before trial requiring PO CCS, abx or both Baseline: N 1465; mean age 63; ~70-75% male; ~50% current smoker; FEV 1 ~45%; median use of relief meds/day ~3 InterventionSalmeterol 50 mcg INH BID vs. fluticasone 500 mcg INH BID vs. salmeterol 50 mcg INH/fluticasone 500 mcg INH BID vs. placebo x 12 months Primary Outcome Improvement in pretreatment FEV 1 Lancet 2003; 361:449-56.

19. TRISTAN PlaceboSalmeterolFluticasoneCombination FEV 1 1264 mL + 1323 mL* + 1302 mL* + 1396 mL* Exacerbations1.3/yr1.04/yr*1.05/yr*0.97/yr* SGRQ46.3 (47.1) 45.2 (48.7) 45.5 + (49.8) 44.1* (47.1) Any treatment-related adverse event 14%12%19%16% Cough, breathing disorder or lower respiratory infection 2% <1% Lancet 2003; 361:449-56. * SS vs. placebo + SS vs. combination

20. TRISTAN Limitations – Methodological How many pts taking anticholinergics? No adherence verification – Clinical Primary outcome (FEV 1 ) was a surrogate marker Improvement in SGRQ not clinically significant High drop-out rates – Pt has no subjective/objective data for having moderate-severe COPD Pt would not fit criteria to be enrolled in study Lancet 2003; 361:449-56.

21. TORCH DesignRandomized, double-blind, parallel-group, placebo-controlled PopulationInclusion: 40-80 y.o. Diagnosis of moderate COPD Poor reversibility of airflow obstruction Current/ex-smokers with > 10-pack year hx Baseline: N 6112; mean age ~65; 76% male; ~43% current smoker; FEV 1 ~44%; 20% on ICS, 9% on LABA, 27% on combo InterventionSalmeterol 50 mcg/fluticasone propionate 500 mcg BID vs. salmeterol 50 mcg BID vs. fluticasone 500 mcg BID vs. placebo x 3 years Primary Outcome All cause mortality at 3 years N Engl J Med 2007; 356:775-89.

22. TORCH N Engl J Med 2007; 356:775-89. PlaceboSalmeterolFluticasoneCombination Death at 3 yr15.2%13.5% 16.0% + 12.6% Mod-severe exacerbations 1.13/yr 0.97/yr* + 0.93/yr* + 0.85/yr* SGRQ+0.2 -0.8 + -1.8* + -3.0* Any adverse event90 89 Pneumonia0.04/yr 12.3% 0.04/yr 13.3% 0.07/yr* 18.3% 0.07/yr* 19.6% * SS vs. placebo + SS vs. combination

23. TORCH Limitations – Methodology Sponsor employee performed statistical analysis Underpowered for mortality outcome – Clinical High drop out rates Exacerbations: benefit from fluticasone or combo, must have 5 or 4 exacerbations/yr, respectively – not clinically significant Improvement in SGRQ not clinically significant – Pt has no subjective/objective data for having moderate- severe COPD Pt would not fit criteria to be enrolled in study N Engl J Med 2007; 356:775-89.

24. Summary of Evidence OutcomesTRISTANTORCH Reduce risk of mortalityØCombo: NSS Fluticasone: NSS Reduce exacerbationsCombo: SS Fluticasone: SS Combo: SS Fluticasone: SS Improve QOLCombo: SS Fluticasone: NSS Combo: SS Fluticasone: SS Adverse eventAny adverse event ↑ with combo & fluticasone ↑ pneumonia with combo & fluticasone

25. Alternatives for Symptom Management Short-acting beta agonist – Salbutamol Anticholinergics – Ipratropium – Tiotropium Long-acting beta-agonist – Salmeterol – Formeterol Inhaled corticosteroids

26. Application to GB Salbutamol PRNIpratropium SCH + Salbutamol PRN Fluticasone SCH NecessaryMild COPD?ØØ EffectiveYes Ø SafeYes Ø AdherencePRNAt risk Patient factorsØ↑ med burden CostCovered through PC

27. Therapeutic Plan 1.Discontinue fluticasone 500 mcg INH BID 2.Discontinue ipratropium 40 mcg INH QID 3.Discontinue salbutamol 200 mcg INH Q1H PRN 4.Initiate salbutamol 200 mcg INH Q4H PRN 5.Recommended one-time pneumococcal vaccine when stabilized

28. Monitoring Plan EfficacyDegree of ChangeWhen S:SOB Acute exacerbations Re-admissions Impairment of daily activities Absence Minimal – none Daily/ongoing Ongoing O:Vitals – RR, O2 satRemain stableDaily ToxicityDegree of ChangeWhen S:Anxiety Tremor Nervousness Palpitations Presence First week of tx O:TachycardiaPresenceFirst week of tx

29. Follow Up All COPD inhaler recommendations were accepted by MTU team Vancomycin increased to 10 days duration Applied for SA for rivaroxaban for treatment of PE Counseled patient on warfarin Counseled patient on proper inhaler use Recommended PFTs once stabilized