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

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

Our Patient ID81 year old male admitted to EKRH on October 7 th, 2013 CC/HPISOB for 1 week that’s been getting progressively worse Headache, fatigue and confusion for 3 days prior to admission Morning prior to admission felt “unsteady on his feet” Mild, productive cough AllergiesAzithromycin (hives) Social HistoryLives at home with spouse No alcohol Quit smoking 30 + years ago

Our Patient Past Medical HistoryMedications Prior to Admission HypertensionHydrochlorothiazide 12.5mg po daily HyperlipidemiaRosuvastatin 20mg po daily COPDSalbutamol MDI 100mcg INH q4h prn Salmeterol 50mcg/Fluticasone 250mcg INH BID Budesonide 0.5mg/2mL nebules INH BID Ipratropium 40-80mcg INH QID and PRN Tiotropium 18ug INH daily Prednisone 10mg po x 3 days tapering by 2mg q3d during exacerbations Home oxygen prn

Our Patient Past Medical HistoryMedications Prior to Admission GERDPantoprazole 40mg po daily BPHDutasteride 0.5mg po daily Community Acquired Pneumonia Moxifloxacin 400mg po daily x 10 days (Sept/Oct 2013) Doxycycline 100mg po BID x 7 days (May 2013) Pseudomonal lung infection (June 2013) Ciprofloxacin 500mg po BID x 14 days

Review of Systems VitalsT: 36.8 BP: 118/64 HR: 64 RR: 24 SaO2: 91% RA CNSGCS x 15, A+O x 3, dizzy HEENTNormal RESPShortness of breath Productive cough (yellow/green phlegm) Wheezing FEV1 : 40% from CVSØ GINormal GUSrCr: 70 eGFR: 94 MSK/DERMWeakness ENDOØ HEMEWBC: 12.2 Neuts: 6.6 LYTESNa: 136 K: 4.1 Cl: 96

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

Current Problems and Medications COPD ExacerbationPrednisone 50mg po daily x 5 days Suspected Pseudomonal Lung Infection Ceftazidime 2 grams IV q8h Tobramycin 570mg IV daily Chronic COPDSalbutamol 0.5mg + Ipratropium 2.5mg/3mL nebules INH QID + PRN Tiotropium 18mcg INH daily Salmeterol 50mcg/Fluticasone 250mcg INH BID Budesonide 0.5mg/2mL nebules INH BID HyperlipidemiaAtorvastatin 40mg po daily BPHTamsulosin SR 0.4mg po daily VTE ProphylaxisHeparin 5000 units SC BID GERDPantoprazole 40mg po daily

List of DRPs 1)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 2)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 3)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 4)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

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

Background: Classification of COPD By Symptoms: COPD StageSymptoms MildSOB when hurrying on the level or walking up a slight hill ModerateSOB causing patient to stop after walking appox 100 m on level SevereSOB from COPD resulting in patient being too breathless to leave the house, breathless when dressing or undressing or presence of chronic respiratory failure or clinical signs of right heart failure Can Resp J 2008;15:1-8

Background: Classification of COPD By Lung Function: COPD StageSpirometry (postbronchodilator) MildFEV1 > 80% predicted FEV1/FVC<0.7 Moderate50% < FEV1 <80% predicted FEV1/FVC<0.7 Severe30% < FEV1 <50% predicted FEV1/FVC<0.7 Very SevereFEV1 <30% FEV1/FVC<0.7 Can Resp J 2008;15:1-8

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

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

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

Therapeutic Approach Can Resp J 2008;15:1-8

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?

Literature Search DatabasesMedline, google scholar Search TermsPulmonary Disease, Chronic Obstructive Ipratropium Tiotropium Combination Therapy Results1 Review article (Dec 2012) Hand searched references  2 trials

Cole 2012 Ann of Pharmacotherapy 2012, 46(12):

Kerstjens et al 2007 DesignRandomized, double-blind, placebo controlled three way cross over study PopulationInclusion: Clinical diagnosis of COPD (FEV 1 /FVC < 70% and FEV 1 < 60% predicted) > 40 years of age Smoking history > 10 pack years Excluded: Patients with asthma, atopy, allergic rhinitis or an elevated blood eosinophil count Baseline: N=60; mean age 63; ~75% male; 21 current smokers; FEV 1 ~40%; 100% on respiratory medication InterventionTiotropium 18mcg (placebo); and added on ipratropium 40mcg or fenoterol 200mcg Primary Outcome Peak FEV 1 (highest FEV 1 minus steady-state baseline FEV 1 )

Kerstjens et al 2007: Methodology

Results: Efficacy Fenoterol*Ipratropium*Placebo (Tiotropium only) Baseline FEV1 (% of predicted) 1170mL (40.1) 1170mL (40.1) 1170mL (40.1) Peak change in FEV1 315mL**230mL**178mL *statistically significant versus placebo (p<0.0001) **Fenoterol statistically significant versus ipratropium (p<0.0001)

Results: Safety Side EffectNumber of Participants Experienced HeadacheIpratropium (1), placebo (1) Tachycardia1 with fenoterol Paresthesia1 with fenoterol Constipation1 with placebo Hypertension1 with placebo

Study Limitations Methodology Single day (2 doses) Very short study small sample size Clinically FEV 1 is a surrogate marker Improvement in symptoms not reported Patients in trial were not on B2 agonist + 2 anticholinergics at any one time?

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

Cazzola et al 2008 DesignRandomized, double blind, crossover design PopulationInclusion: Clinical diagnosis of COPD (FVC < 70%; FEV 1 < 60% predicted) > 40 years of age Smoking history > 10 pack years No change in symptom severity/treatment in previous 4 wks No signs of respiratory tract infection in month prior to or during the trial Excluded: Patients with asthma, atopy, allergic rhinitis or an elevated blood eosinophil count, patients with BPH Baseline: N=30; age 69; ~80% male; 19/30 current smokers; FEV 1 ~50% InterventionTiotropium 18mcg INH + salbutamol 600mcg INH vs tiotropium 18mcg INH + ipratropium 120mcg INH vs tiotropium 18mcg INH + placebo Primary OutcomeFEV1 improvement induced by salbutamol 600mcg, ipratropium 120mcg or placebo over tiotropium 18mcg

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

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

Results: Efficacy Mean Maximum IncreaseP-value Salbutamol157mL- Ipratropium125mL- Placebo44mL- Salbutamol vs Placebo81mLp= Ipratropium vs Placebo68mLp= Salbutamol vs IpratropiumNot reportedP>0.05

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

Limitations Methodology Single day /very short study Sample size was small (30) Used higher than normal doses; unknown significance at lower doses Clinically FEV 1 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?

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”

Summary of Evidence for Combination Anticholinergic Therapy OutcomesBenefit Mortality? Exacerbations? Disease Progression? Signs/symptoms? Reduce adverse events? Improve QOL?

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?

Literature Search DatabasesMedline, google scholar Search TermsPulmonary Disease, Chronic Obstructive Ipratropium Tiotropium Limitsa.RCTs, english, humans b.meta-analyses Results14 RCTS 1 RCT: head to head comparison Excluded: non-relevant articles -cost-effectiveness ; pharmacoeconomics, drugs that are not of interest. 8 Meta-analyses All MAs had multiple studies but only 1 RCT comparing tiotropium vs ipratropium

Vincken 2002 DesignRandomized, double-blind, double-dummy parallel group, placebo- controlled trial X 1 year PopulationInclusion: Clinical diagnosis of COPD (FVC < 70% and FEV 1 < 65% predicted) > 40 years of age Smoking history > 10 pack years Baseline: N=535; mean age 63.4; ~85% male; unknown number of current smokers; FEV 1 ~40%; ~97% on pulmonary medication InterventionIpratropium 40mcg INH QID vs tiotropium 18mcg INH daily X 12 months OutcomesNo primary endpoint identified FEV 1 at 1 year COPD exacerbations and adverse events

Results Ipratropium (n=179) Tiotropium (n=356) P-value FEV 1 (at 1 year)Baseline: 1180mL At 1 year: 1150mL Baseline: 1250mL At 1 year: 1370mL p<0.001 Hospitalizations11.7%7.3%P=0.11 Exacerbations46%35%P=0.014 Meaningful increase in SGRQ* 35%52%P=0.001 Withdrew due to adverse effects 12.8% (n=23) 10.1% (n=36) P=0.089 Any treatment-related adverse related event Dry mouth: 6.1% Dry mouth: 12.1% -Mild, resolved during treatment in majority of patients P=0.03 *St. George’s Respiratory Questionaire

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 FEV 1 is 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)

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”

Summary of Evidence: Tiotropium vs Ipratropium OutcomesBenefit? MortalityX ExacerbationsY Disease Progression? Signs/symptomsY Reduce adverse eventsY Improve QOLY

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?)

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

Therapeutic Recommendation 1)Discontinue ipratropium 40-80mcg INH QID and PRN 2)Discontinue budesonide 0.5mg/2mL nebules INH BID 3)Continue salbutamol 100mcg INH q4h prn 4)Continue salmeterol 50mcg/fluticasone 250mcg INH BID 5)Continue tiotropium 18mcg INH daily

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

Monitoring Plan EfficacyDegree of ChangeWhen S:SOB Acute exacerbations Hospitalizations Absence Daily Ongoing O:Vitals: RR, Sa02StableDaily ToxicityDegree of ChangeWhen S:Headache Dry mouth Respiratory tract infection Dyspepsia Presence Ongoing O:RashPresenceOngoing

Follow-up Oct 10 th : Patient improved clinically Oct 13 th : Patient continued to improve Continued frequent inhaler use to control symptoms Oct 17 th : Course of antibiotics complete Oct 18 th : Medications were reconciled and plan was discussed with patient, physician and RT, with physician and RT to follow-up with patient in community Oct 19 th : 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

Questions… ?