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To Inhale or Not to Inhale? Sukhjinder Sidhu Interior Health Pharmacy Resident September 13, 2013 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 Our Patient ID 65 y.o. male (72.6 kg; 170 cm). Admitted Aug 21, 2013 to CTU. CC/HPI SOB x 5-6 days accompanied by chest pain Some nausea and generalized weakness x 1/52 Allergies NKDA Social Hx Quit smoking 28 years ago (75 pack/yr hx) Ø Alcohol or illicit drug use Assisted living; wife died 3 months ago Our Patient PMHx: MPTA: C. Difficile Metronidazole 500 mg PO TID x 14 days (finished Aug 18, 2013) Essential thrombocythemia Hydroxyurea 1000 mg PO daily Schizo-affective Risperidone 1 mg PO BID Anxiety Diazepam 10 mg PO QID PRN Citalopram 40 mg PO daily HTN None Hypothyroidism Levothyroxine 75 mcg PO daily Chronic prostatitis Ciprofloxacin 1000 mg PO daily COPD None Esophagitis/PUD Rabeprazole 20 mg PO BID Tums 10 tab PO daily Nausea Dimenhydrinate 100-200 mg PO BID-TID Review of Systems Vitals T 36.6 HR 113 CNS/Neuro A&O x 3 HEENT Ø RESP Labored breathing; left side wheezing; Ø cough CVS Regular; S1/S2 normal; ECG flipped T’s GI 6 loose BM today; distended; normal sounds GU > 300 mL urine PRV; SrCr 113; eGFR 56 ENDO TSH 7.31 MSK/Derm Pale skin LYTES Na 124 HEME Hgb 120 MCV 93.9 WBC 16.5 Neuts 13.53 Plts 1173 K 4.9 Cl 91 BP 105/69 RR 70 O2 sat 92% after neb Bicarb 22 Investigations Diagnostics Day 0 (Admission) CXR Hyperinflation consistent with COPD Day 1 Chest CT Bilateral pulmonary emboli CXR Comparison - Ø HF V/Q Scan Bilateral PE TEE Moderate pulmonary hypertension CXR Tiny bilateral pleural effusions Day 2 Day 3 Microbiology Day 1 Stool C. Difficile Toxin B Urine No growth Course in Hospital • Assessed by respirology – Diagnosed with pulmonary emboli – Diagnosed with COPD Current Problems & Medications Indication Medication Pulmonary emboli Nadroparin 13,300 unit SC daily Warfarin to target INR 2-3 C. Difficile Vancomycin 125 mg PO Q6H x 7 days COPD Fluticasone 500 mcg INH Q12H Ipratropium 40 mcg INH QID Salbutamol 200 mcg INH QID & Q1H PRN Essential thrombocythemia Hydroxyurea 500 mg PO TID Nausea Dimenhydrinate 50 mg IV Q6H PRN PUD/Esophagitis Ranitidine 150 mg PO BID Schizo-affective Risperidone 1 mg PO BID Anxiety Diazepam 5-10 mg PO QID PRN Citalopram 40 mg PO daily Hypothyroidism Levothyroxine 75 mcg PO daily 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. 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. 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/ COPD • 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 Can Respir J 2008;15(Suppl A):1A-8A COPD • Our patient – COPD stage = mild • • • • • • • Hyperinflation present Ø PFTs Ø SOB Ø exacerbations Ø chronic cough Ø sputum production PTA Ø puffers 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 Therapeutic Approach Can Respir J 2008;15(Suppl A):1A-8A 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? Literature Search Databases Medline, PubMed Search Terms Pulmonary Disease, Chronic Obstructive Anti-inflammatory Agents Bronchodilator Agents/ or albuterol/ or ipratropium/ Adrenergic beta-Agonists Results 8 RCT’s • TRISTAN • TORCH 1 Meta-analysis 1 NICE Guideline TRISTAN Design Randomized, double-blind, parallel-group, placebo-controlled Population Inclusion: 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; FEV1 ~45%; median use of relief meds/day ~3 Intervention Salmeterol 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 FEV1 Lancet 2003; 361:449-56. TRISTAN Placebo Salmeterol Fluticasone Combination FEV1 1264 mL+ 1323 mL*+ 1302 mL*+ 1396 mL* Exacerbations 1.3/yr 1.04/yr* 1.05/yr* 0.97/yr* SGRQ 46.3 (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% 2% 2% <1% * SS vs. placebo + SS vs. combination Lancet 2003; 361:449-56. TRISTAN • Limitations – Methodological • How many pts taking anticholinergics? • No adherence verification – Clinical • Primary outcome (FEV1) 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. TORCH Design Randomized, double-blind, parallel-group, placebo-controlled Population Inclusion: 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; FEV1 ~44%; 20% on ICS, 9% on LABA, 27% on combo Intervention Salmeterol 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. TORCH Placebo Salmeterol Fluticasone Combination Death at 3 yr 15.2% 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 event 90 90 90 89 Pneumonia 0.04/yr 12.3% 0.04/yr 13.3% 0.07/yr* 18.3% 0.07/yr* 19.6% * SS vs. placebo + SS vs. combination N Engl J Med 2007; 356:775-89. 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 moderatesevere COPD • Pt would not fit criteria to be enrolled in study N Engl J Med 2007; 356:775-89. Summary of Evidence Outcomes TRISTAN TORCH Reduce risk of mortality Ø Combo: NSS Fluticasone: NSS Reduce exacerbations Combo: SS Fluticasone: SS Combo: SS Fluticasone: SS Improve QOL Combo: SS Fluticasone: NSS Combo: SS Fluticasone: SS Adverse event Any adverse event ↑ with combo & fluticasone ↑ pneumonia with combo & fluticasone Alternatives for Symptom Management • Short-acting beta agonist – Salbutamol • Anticholinergics – Ipratropium – Tiotropium • Long-acting beta-agonist – Salmeterol – Formeterol • Inhaled corticosteroids Application to GB Salbutamol PRN Necessary Ipratropium SCH + Salbutamol PRN Fluticasone SCH Mild COPD? Ø Ø Effective Yes Yes Ø Safe Yes Yes Ø Adherence PRN At risk At risk Ø ↑ med burden ↑ med burden Patient factors Cost Covered through PC Covered through PC Covered through PC Therapeutic Plan 1. 2. 3. 4. 5. Discontinue fluticasone 500 mcg INH BID Discontinue ipratropium 40 mcg INH QID Discontinue salbutamol 200 mcg INH Q1H PRN Initiate salbutamol 200 mcg INH Q4H PRN Recommended one-time pneumococcal vaccine when stabilized Monitoring Plan Efficacy Degree of Change When S: SOB Acute exacerbations Re-admissions Impairment of daily activities Absence Absence Absence Minimal – none Daily/ongoing Ongoing Ongoing Ongoing O: Vitals – RR, O2 sat Remain stable Daily Toxicity Degree of Change When S: Anxiety Tremor Nervousness Palpitations Presence Presence Presence Presence First week of tx First week of tx First week of tx First week of tx O: Tachycardia Presence First week of tx 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