Transcript Combination Anti-Cholinergic COPD Therapy – Safety and

Combination Anti-Cholinergic COPD
Therapy – Safety and Efficacy of
Combining Ipratropium and
Tiotropium
Ted D. Williams
PharmD Candidate
OSU/OHSU COP
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Outline
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Case presentation
Clinical Question
Guideline Ambiguity
Primary Literature
Intervention
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Case Presentation
• CC
– WB , a 68 yo male presents stating his physician
sent him here for abnormal lab values. Pt c/o
nausea and pain 8/10 which he states is normal
for him. Pt also states mild SOB which he says is
slightly worse than what he's used to. Pt is under
examination for possible need for dialysis. Pt is in
no acute distress, and is speaking with doctor. Pt
placed on oxygen, EKG completed, IV established
and fluid bolus initiated.
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Case – HPI/SH
• HPI
– Patient tried Advair in 4/06 and did not work
• Advair 250/50 one puff BID
• May 5/2008 FEV1 = 29%
• SH
– Active smoker
• ½ ppd, 50+ pack year history
• Has tried to quit several times
• Wife’s smoking makes it difficult for patient to quit
– Wife active smoker & afraid of O2 in the house
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Case - PMH
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Current smoker
CKD + Anemia
MDD
Osteoporosis
Fever
Leukocytosis
Bladder CA
BPH/Prostate CA
COPD
CAD/Acute MI
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Case - Objective
• Pertinent Labs
– PFT 8/19/2008
• FEV1% predicted=34
• FEV1/FVC=36
• FEV1% change post bronchodilator=3
– Non-Reversible
– SP02 84-95%
– SOB: stable, stating 97% on 3L.
– GOLD Stage III – Severe COPD
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Case - Medications
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ALBUTEROL (HFA Aerosol) 90 mcg 2-4 puffs prn wheeze/ SOB
ASPIRIN (Tablet) 325 mg take one tablet by mouth one time a day
CALCIUM ACETATE (Tablet) 667 mg 1 tab with largest meal of day
DOXAZOSIN MESYLATE (Tablet) 8 mg 1 tab po qhs
HYDROCODONE BIT/ACETAMINOPHEN (Tablet) 10-325 mg 1 po q 6 hours
Influenza vaccination 2008, FM pharmacy, no date available
IPRATROPIUM/ALBUTEROL Combivent 18-103 mcg 2 puffs 4x/day
METOPROLOL SUCCINATE (Tablet SR 24 hr) 200 mg 1 tab by mouth daily
NIFEDIPINE (Tablet Sustained Release) SR 90 mg 1 tab po twice daily
NITROGLYCERIN (Tablet, Sublingual) Nitrostat 0.4 mg as needed
OMEPRAZOLE (Tablet, DR (E.C.)) Prilosec OTC 20 mg 1 PO twice daily
OXYCODONE HCL (Tablet IR ) 5 mg 1 po q 4-8 hours
Pneumococcal vaccination 11/11/08
SERTRALINE HCL (Tablet) Zoloft 50 mg 1 tab daily
SIMVASTATIN (Tablet) 40 mg 1 tab by mouth daily at night
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Clinical Question
• Should Spiriva® (tiotropium) be added to
Combivent® (ipratropium/albuterol)?
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GOLD Guidelines - 2007
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GOLD Guideline Treatments for
Stage III COPD
• Short Acting Bronchodilator (SABD)
• Long Acting Bronchodilator (LABD)
– “The choice between beta 2 agonist, anticholinergic,
theophylline, or combination therapy depends on
availability and individual response in terms of symptom
relief and side effects.” –GOLD Guidelines 2007
• Inhaled Glucocorticoids (in the presence of
exacerbations)
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Clinical Question
• Ipratropium with tiotropium:
– Is it effective?
– Is it safe?
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Spiriva Package Insert
Drug Interactions
– “…the co-administration of SPIRIVA HandiHaler
with other anticholinergic containing drugs (e.g.,
ipratropium) has not been studied and is
therefore not recommended…”
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Literature Search
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OVID MEDLINE Search Criteria
1. Keyword Tiotropium (english, human trials)
2. Keyword ipratropium (english, human trials)
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Results
– 88 articles
– Each abstract reviewed manually for relevance
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Single Study of Relevance
• Kerstjens, H., et al. Effects of Short-Acting
Bronchodilators Added to Maintenance
Tiotropium Therapy. CHEST 2007;132:14931499
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Kerstjens, H., et al
• General
– Comparison of effects of short acting anticholinergic, beta agonist, and placebo as
add on therapy to tiotropium monotherapy
• Design & Methods
– Inclusion
• %FEV1<=60%
– Exclusion
• COPD exacerbations within 6 weeks excluded
• O2
• Asthma/allergic rhinitis
– Design
• Three arm (ipratropium 40mcg , fenoterol 200mcg, placebo)
• n = 60, RCT, double blinded three way cross over
• 3 week run in period
• Baseline Parameters
– FEV1 = 1.17 +/- 0.43
– FEV1 % predicted = 40.1 +/- 12.1
– FEV1/FVC = 43.0 +/- 9.9
• Statistics
– Powered to detect a 60mL change in mean FEV1
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Kerstjens, H., et al
• Mean change in FEV1
– Addition of Fenoterol superior to placebo (137ml, p<0.0001) and Ipratropium
(p<0.0001)
– Addition of Ipratropium superior to placebo (52ml,p<0.002)
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Kerstjmens, H., et al
• Conclusions
– Change in mean FEV1 of combination of
anticholinergics (tiotropium + ipratropium) smaller
than this study was powered to detect (60ml)
– Combining ipratropium with tiotropium would not
be expected to produce significant benefit
• Limitations
– Short term study
– No longer term efficacy or safety data
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Kerstjmens, H., et al
• Questions generated
– How does FEV1 change of 50mL compare with pushing the
dose of tiotropium?
• Missing reference
– 22 Koenen-Bergman, M., Witek, T Jr, Tuerck D, et al.
Pharmacologic effects of acute administration of
ipratropium on top of maintenance treatmetn with
tiotropium [abstract]. European Respiratory Journal 2003;
22(suppliment 45):67S.
– This suppliment is no longer available at the European
Respiratory Journal website
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Comparisions of tiotropium dosing
• A non-systematic literature search revealed two
articles of interest
– Tiotropium bromide, a new long-acting antimuscarinic
bronchodilator: a pharmacodynamic study in patients with
chronic obstructive pulmonary diease (COPD) Maesen,
FPV, Smeets, JJ, Sledsens, TJH, Wald, FDM, Cornelissen,
PJG. European Respiratory Journal (ERJ) 1995; 8:15061513
– Long Acting Bronchodilation with Once-Daily Dosing of
Tiotropium (Spiriva) in Stable Chronic Obstructive
Pulmonary Disease. Littner, MR, Ilowite, JS, Tashkin, DP,
Friedman, M, Serby, CW, Menjoge, SS, Witek, TJ. American
Journal of Respiratory Critical Care Medicine (AJRCCM)
2000; 161:1136-1142
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ERJ 1995
• Randomized, double blinded placebo controlled
crossover. Single dose, 72 hour wash out period
• n = 35
• Baseline
– FEV1 = 1.69 +/- 0.48
– FEV1% predicted = 44%
– FEV/FVC not available
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ERJ 1995
• Double the dose produces a 20-33mL change in FEV1
in the 0-8 hour time block
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AJRCCM 2000
• Randomized double blinded parallel, placebo
controlled.
• 29 days
• n=169
• Baseline
– FEV1 = 1.08 +/- 0.34
– FEV1 predicted = 42.3%
– FEV/FVC % = 43-49%
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AJRCCM 2000
• Mean FEV1 increases approximately 40mL
doubling from 18mcg to 36mcg
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Literature Conclusions
• Changes in FEV1 due to combination
ipratropium + tiotropium are consistent with
the response for doubling the dose of
tiotropium
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Safety
Two recent meta-analyses have shown an increased CV
risk with the use of anticholinergic
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Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of
major adverse cardiovascular events in patients with chronic
obstructive pulmonary disease. JAMA 2008; 300 (12): 1439-1450
Lee TA, Pickard S, et al. Risk for Death Associated with
Medications for Recently Diagnosed Chronic Obstructive
Pulmonary Disease. Annals of Internal Medicine 2008; 149: 380390.
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Safety
• UPLIFT showed some increased CV Risk
– Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic
obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554.
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Safety
• “In COPD patients with moderate to severe
renal impairment (CrCl<50 mL/min), the
intravenous administration of tiotropium
resulted in doubling of the plasma
concentrations (82% increase in AUC0–4),
which was confirmed by plasma
concentrations after dry powder inhalation” –
Spiriva Package insert
• Is this clinically relevant?
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Gaps in Therapy
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Possible Therapy Options
• Retry long acting beta agonist and/or
corticosteroid (Advair)
• Retry Home O2
• Retry Smoking Cessation
• Add Tiotropium once daily, D/C Combivent
4x/day
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Actual Intervention
• Based on patient’s comments, will not
attempt smoking cessation at this time
• Based on PMH, will not retry Advair
• Patient expressed great perceived benefit
from Combivent, so switching to tiotropium
was not recommended
• Convinced patient to retry home O2
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