To Inhale or Not to Inhale?

Sukhjinder SidhuInterior 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 PatientID 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 painSome 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 useAssisted living; wife died 3 months ago

Our PatientPMHx: 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 PRNCitalopram 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 BIDTums 10 tab PO daily

Nausea Dimenhydrinate 100-200 mg PO BID-TID

Review of SystemsVitals T 36.6 HR 113 BP 105/69 RR 70 O2 sat 92% after neb

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 K 4.9 Cl 91 Bicarb 22

HEME Hgb 120 MCV 93.9 WBC 16.5 Neuts 13.53 Plts 1173

InvestigationsDiagnostics

Day 0 (Admission)

CXR Hyperinflation consistent with COPD

Day 1 Chest CT Bilateral pulmonary emboli

CXR Comparison - Ø HF

Day 2 V/Q Scan Bilateral PE

TEE Moderate pulmonary hypertension

Day 3 CXR Tiny bilateral pleural effusions

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 & MedicationsIndication Medication

Pulmonary emboli Nadroparin 13,300 unit SC dailyWarfarin to target INR 2-3

C. Difficile Vancomycin 125 mg PO Q6H x 7 days

COPD Fluticasone 500 mcg INH Q12HIpratropium 40 mcg INH QIDSalbutamol 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 PRNCitalopram 40 mg PO daily

Hypothyroidism Levothyroxine 75 mcg PO daily

DRPs1. 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

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

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 SearchDatabases Medline, PubMed

Search Terms Pulmonary Disease, Chronic ObstructiveAnti-inflammatory AgentsBronchodilator Agents/ or albuterol/ or ipratropium/Adrenergic beta-Agonists

Results 8 RCT’s•TRISTAN•TORCH1 Meta-analysis1 NICE Guideline

TRISTANDesign Randomized, double-blind, parallel-group, placebo-controlled

Population Inclusion:Diagnosis of mod-severe COPDPoor reversibility of airflow obstructionSmoking 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.

TRISTANPlacebo 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%

Lancet 2003; 361:449-56.

* SS vs. placebo+ SS vs. combination

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.

TORCHDesign Randomized, double-blind, parallel-group, placebo-controlled

Population Inclusion:40-80 y.o.Diagnosis of moderate COPDPoor reversibility of airflow obstructionCurrent/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

N Engl J Med 2007; 356:775-89.

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/yr12.3%

0.04/yr13.3%

0.07/yr*18.3%

0.07/yr*19.6%

* SS vs. placebo+ SS vs. combination

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.

Summary of EvidenceOutcomes TRISTAN TORCH

Reduce risk of mortality Ø Combo: NSSFluticasone: NSS

Reduce exacerbations Combo: SSFluticasone: SS

Combo: SSFluticasone: SS

Improve QOL Combo: SSFluticasone: NSS

Combo: SSFluticasone: 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 GBSalbutamol PRN Ipratropium SCH +

Salbutamol PRNFluticasone SCH

Necessary Mild COPD? Ø Ø

Effective Yes Yes Ø

Safe Yes Yes Ø

Adherence PRN At risk At risk

Patient factors Ø ↑ med burden ↑ med burden

Cost Covered through PC Covered through PC Covered through PC

Therapeutic Plan

1. Discontinue fluticasone 500 mcg INH BID2. Discontinue ipratropium 40 mcg INH QID3. Discontinue salbutamol 200 mcg INH Q1H PRN4. Initiate salbutamol 200 mcg INH Q4H PRN5. Recommended one-time pneumococcal

vaccine when stabilized

Monitoring PlanEfficacy Degree of Change When

S: SOBAcute exacerbationsRe-admissionsImpairment of daily activities

AbsenceAbsenceAbsenceMinimal – none

Daily/ongoing OngoingOngoingOngoing

O: Vitals – RR, O2 sat Remain stable Daily

Toxicity Degree of Change When

S: AnxietyTremorNervousnessPalpitations

PresencePresencePresencePresence

First week of txFirst week of txFirst week of txFirst 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