Inhaled Anticholinergics for COPD: Breathing Life into the Debate

Manish Khullar, BSc PharmInterior 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 PatientID 81 year old male admitted to EKRH on October 7th, 2013CC/HPI SOB for 1 week that’s been getting progressively worse

Headache, fatigue and confusion for 3 days prior to admissionMorning prior to admission felt “unsteady on his feet” Mild, productive cough

Allergies Azithromycin (hives)

Social History Lives at home with spouseNo alcoholQuit smoking 30 + years ago

Our PatientPast Medical History Medications Prior to Admission

Hypertension Hydrochlorothiazide 12.5mg po daily

Hyperlipidemia Rosuvastatin 20mg po daily

COPD Salbutamol MDI 100mcg INH q4h prnSalmeterol 50mcg/Fluticasone 250mcg INH BIDBudesonide 0.5mg/2mL nebules INH BIDIpratropium 40-80mcg INH QID and PRN Tiotropium 18ug INH dailyPrednisone 10mg po x 3 days tapering by 2mg q3d during exacerbations Home oxygen prn

Our PatientPast Medical History Medications Prior to Admission

GERD Pantoprazole 40mg po daily

BPH Dutasteride 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 SystemsVitals T: 36.8 BP: 118/64 HR: 64 RR: 24 SaO2: 91% RA

CNS GCS x 15, A+O x 3, dizzy

HEENT Normal

RESP Shortness of breathProductive cough (yellow/green phlegm) WheezingFEV1 : 40% from

CVS Ø

GI Normal

GU SrCr: 70 eGFR: 94

MSK/DERM Weakness

ENDO Ø

HEME WBC: 12.2 Neuts: 6.6

LYTES Na: 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 Exacerbation Prednisone 50mg po daily x 5 days

Suspected Pseudomonal Lung Infection

Ceftazidime 2 grams IV q8hTobramycin 570mg IV daily

Chronic COPD Salbutamol 0.5mg + Ipratropium 2.5mg/3mL nebules INH QID + PRNTiotropium 18mcg INH daily Salmeterol 50mcg/Fluticasone 250mcg INH BIDBudesonide 0.5mg/2mL nebules INH BID

Hyperlipidemia Atorvastatin 40mg po daily

BPH Tamsulosin SR 0.4mg po daily

VTE Prophylaxis Heparin 5000 units SC BID GERD Pantoprazole 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 Stage Symptoms

Mild SOB when hurrying on the level or walking up a slight hill

Moderate SOB causing patient to stop after walking appox 100 m on level

Severe SOB 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 Stage Spirometry (postbronchodilator)

Mild FEV1 > 80% predictedFEV1/FVC<0.7

Moderate 50% < FEV1 <80% predicted FEV1/FVC<0.7

Severe 30% < FEV1 <50% predictedFEV1/FVC<0.7

Very Severe FEV1 <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: FEV1 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 SearchDatabases Medline, google scholar

Search Terms Pulmonary Disease, Chronic ObstructiveIpratropiumTiotropiumCombination Therapy

Results 1 Review article (Dec 2012)• Hand searched references 2 trials

Cole 2012

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

Kerstjens et al 2007Design Randomized, double-blind, placebo controlled three way cross over

studyPopulation Inclusion:

Clinical diagnosis of COPD (FEV1/FVC < 70% and FEV1 < 60% predicted) > 40 years of ageSmoking history > 10 pack yearsExcluded:Patients with asthma, atopy, allergic rhinitis or an elevated blood eosinophil count Baseline:N=60; mean age 63; ~75% male; 21 current smokers; FEV1 ~40%; 100% on respiratory medication

Intervention Tiotropium 18mcg (placebo); and added on ipratropium 40mcg or fenoterol 200mcg

Primary Outcome

Peak FEV1 (highest FEV1 minus steady-state baseline FEV1)

Kerstjens et al 2007: Methodology

Results: EfficacyFenoterol* 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: SafetySide Effect Number of Participants Experienced

Headache Ipratropium (1), placebo (1)

Tachycardia 1 with fenoterol

Paresthesia 1 with fenoterol

Constipation 1 with placebo

Hypertension 1 with placebo

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?

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 2008Design Randomized, double blind, crossover design

Population Inclusion:Clinical diagnosis of COPD (FVC < 70%; FEV1 < 60% predicted)> 40 years of ageSmoking history > 10 pack yearsNo 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 BPHBaseline:N=30; age 69; ~80% male; 19/30 current smokers; FEV1 ~50%

Intervention Tiotropium 18mcg INH + salbutamol 600mcg INH vs tiotropium 18mcg INH + ipratropium 120mcg INH vs tiotropium 18mcg INH + placebo

Primary Outcome FEV1 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: 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 • 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?

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

Outcomes Benefit

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 SearchDatabases Medline, google scholar

Search Terms Pulmonary Disease, Chronic ObstructiveIpratropiumTiotropium

Limits a. RCTs, english, humansb. meta-analyses

Results 14 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 Design Randomized, double-blind, double-dummy parallel group, placebo-

controlled trial X 1 year Population Inclusion:

Clinical diagnosis of COPD (FVC < 70% and FEV1 < 65% predicted)> 40 years of ageSmoking history > 10 pack yearsBaseline:N=535; mean age 63.4; ~85% male; unknown number of current smokers; FEV1 ~40%; ~97% on pulmonary medication

Intervention Ipratropium 40mcg INH QID vs tiotropium 18mcg INH daily X 12 months

Outcomes No primary endpoint identifiedFEV1 at 1 year COPD exacerbations and adverse events

ResultsIpratropium

(n=179)Tiotropium

(n=356)P-value

FEV1 (at 1 year) Baseline: 1180mL

At 1 year: 1150mL

Baseline: 1250mL At 1 year: 1370mL

p<0.001

Hospitalizations 11.7% 7.3% P=0.11Exacerbations 46% 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 • FEV1 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

Outcomes Benefit?

Mortality X

Exacerbations Y

Disease Progression ?

Signs/symptoms Y

Reduce adverse events Y

Improve QOL Y

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 prn4) Continue salmeterol 50mcg/fluticasone

250mcg INH BID5) 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 PlanEfficacy Degree of Change When

S: SOBAcute exacerbationsHospitalizations

AbsenceAbsenceAbsence

DailyOngoingOngoing

O: Vitals: RR, Sa02 Stable Daily

Toxicity Degree of Change When S: Headache

Dry mouthRespiratory tract infection Dyspepsia

PresencePresencePresence

Presence

OngoingOngoingOngoing

Ongoing O: Rash Presence Ongoing

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

Questions…

?