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UPLIFT A 4Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

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is more than a pulmonary disorder. Impaired CV function ... Pink Puffer. COPD - heterogeneity. Cough. Copious sputum. Dilated airspaces. Hypoxemia ... – PowerPoint PPT presentation

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Title: UPLIFT A 4Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease


1
UPLIFTA 4-Year Trial of Tiotropium in Chronic
Obstructive Pulmonary Disease
  • 10/28/2008
  • Michael Rich

2
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3
Background
  • American Lung Association estimates that COPD
  • is 4th leading cause of death in USA
  • will be the 3rd leading cause of death in 2020
  • is a dis. of chronic smokers - 80-90
  • is more than a pulmonary disorder
  • Impaired CV function
  • Increased risk of lung CA, osteoporosis,
    cachexia, depression

Smoking 101 fact sheet - American lung
association. http//www.lungusa.org/site/c.dvLUK9
O0E/b.39853/
4
Emphysema
Chronic Bronchitis
- Prod cough gt 3 mo/yr for gt 2 yrs - V/Q
Mismatch - Blue Bloater
- Dilation/destruction of airspaces - Matched V/Q
deficits - Pink Puffer
5
COPD - heterogeneity
Cachexia nl ABG Dyspnea at rest
Hypoxemia CO2 retention Pulm HTN R - HF
Cough Copious sputum Dilated airspaces
6
Landmark trials - Background
  • MRC (81) and NOTT (80) trials
  • Oxygen
  • Survival benefit for use gt 15 hrs/day
  • Benefit after 500 days

Nocturnal Oxygen Therapy Trial Group. Continuous
or nocturnal oxygen therapy in hypoxaemic chronic
obstructive pulmonary disease. Annals of
Internal Medicine, 198093 3. 391-398.
Medical Research Council Working Party.
Long-term domiciliary oxygen therapy in chronic
hypoxic cor pulmonale, complicating chronic
bronchitis and emphysema. The Lancet, March 28,
1981 681-685.
7
  • Medicare guidelines
  • O2 therapy if PaO2 lt 55 mm Hg or O2Sat lt 88
  • These recs largely based on MRC and NOTT trials
    inclusion criteria
  • May not identify all the patients who would
    benefit from supplemental O2

8
Landmark trials - Background
  • Lung Health Study (02)
  • Abstinence from smoking
  • Sustained 50 percent reduction in the rate of
    FEV1 decline - unique
  • Survival benefit

Anthonisen NR, Connett JE, Murray RP. Smoking and
lung function of Lung Health Study participants
after 11 years. Am J Respir Crit Care Med
2002166675-679
9
Landmark trials - Background
  • TORCH trial (07) LABA Inhaled steroid
  • Lung health study research group (01) Inhaled
    steroid
  • Decreased exacerbations
  • Increased QOL
  • Non-significant decrease in mortality
  • Non-significant effect on FEV1
  • LABA alone - mixed results
  • Alsaeedi A, Sin DD, McAlister FA. The effects of
    inhaled corticosteroids in chronic obstructive
    pulmonary disease a systematic
  • review of randomized placebo-controlled trials.
    Am J Med 200211359-65.

Calverley PM, Anderson JA, Celli B, Ferguson GT,
Jenkins C, Jones PW, Yates JC, Vestbo J TORCH
investigators. Salmeterol and fluticasone
propionate and survival in chronic obstructive
pulmonary disease. N Engl J Med. 2007 Feb
22356(8)775-89.
10
Landmark trials - Background
  • Anticholinergics
  • Tiotropium - introduced in 2003
  • Tiotropium (24 hrs) gt Ipratropium (6hrs)
  • Decreased exacerbations, increased QOL (1)
  • LA-AC superior to LABA as monoTx (2)
  • LA-AC has potential to slow rate of decline in
    FEV1 - retrospective analysis (3)

(1)Barr RG, Bourbeau J, Camargo CA. Tiotropium
for stable chronic obstructive pulmonary disease.
Cochrane Database of Systematic Reviews 2005,
Issue 2. Art. No. CD002876. DOI
10.1002/14651858.CD002876.pub2
(2)Tashkin DP, Cooper CB. The role of long-acting
bronchodilators in the management of stable COPD.
Chest 2004 Jan125(1)249-59
(3)Anzueto A, Tashkin D, Kesten S. One-year
analysis of longitudinal changes in spirometry in
patients with COPD receiving Tiotropium. Pulm
Pharmacol Ther. 200518(2)75-81.
11
Background
  • UPLIFTs Question
  • Can daily treatment with tiotropium reduce the
    rate of decline in FEV1 over time in patients
    with COPD?

Medical Research Council Working Party. (1981)
Long-term domiciliary oxygen therapy in chronic
hypoxic cor pulmonale, complicating chronic
bronchitis and emphysema. The Lancet, March 28
681-685.
12
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13
Methods
  • Study Design
  • Tiotropium is co-marketed by Boehringer-Ingelheim
    and Pfizer
  • UPLIFT study sponsored by Boehringer-Ingelheim
  • Randomized, double-blind, parallel group, 4-year
    trial
  • Primary outcomes
  • Yearly rate of decline in FEV1 - pre and post
    bronchodilator - over 4 years
  • Secondary outcomes
  • Other spirometry measures, Exacerbations, QOL,
    Adverse events

14
Methods
  • Study Design
  • 490 centers in 37 countries
  • 5993 patients randomized, 3569 completed 45 mos
    65
  • Dropouts - reminiscent of TORCH trial
  • Power - variability among patients and in FEV1
    measures
  • Procedures
  • Spirometry (pre and post)
  • 48 hr washout of bronchodilators
  • 80 mcg Ipratropium 400 mcg of Albuterol one
    hour later

15
Methods
  • Study Design
  • Inclusion
  • gt40 yo, smoking hx gt 10 pack yrs,
    post-bronchodilator FEV1 lt 70 of predicted
  • Exclusion
  • Other significant disease, hx of Asthma, hx of
    Pulm resection, use of supplemental O2 gt 12
    hrs/day.

16
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17
Results
  • Mean rate of decline in FEV1 - no significant
    difference

18
Results
  • Quality of Life
  • St. George's Respiratory Questionnaire
  • Social and psychological impact
  • Symptom
  • Activity
  • 10-minutes
  • Adverse events
  • No difference between groups
  • Decreased CV events in Tiotropium group

19
Results
  • Exacerbations
  • Decreased number of exacerbations
  • 14 decrease (P 0.001)
  • Delay in time of first exacerbation
  • From 12.5 mos (95 CI) to 16.7 mos (95 CI)

20
Results
  • Mortality
  • 11 non-significant reduced risk of death (P
    0.09)

21
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22
Discussion
  • Inability to alter rate of decline in FEV1
  • Low percentage of current smokers
  • Allowed for other Rx
  • Power - increased dropouts in placebo group
  • Similar to TORCH Mortality (P 0.052) - power
    issues
  • Different than TORCH
  • Not combo Tx or placebo 40 dropout
  • LA-AC or placebo other Rx 40 dropout
  • Lung Health Study - smoking cessation
  • Remarkable 94 five-year follow-up
  • Measurement of FEV1 has limited accuracy and
    limited precision d/t testing mechanisms and
    patient variability
  • Therefore, a follow-up of 3 yrs is required to
    estimate the decline in forced expiratory volume
    in one second

23
Discussion
  • Improved
  • Airflow obstruction
  • Vital capacity
  • Quality of life
  • Decreased
  • Exacerbations
  • Hospitalizations

24
Discussion
  • CV risk from inhaled anticholinergics?
  • Increased risk for mortality and/or CV events
  • Meta-analysis of 15,000 patients (1)
  • Case control series of 32,000 (2)
  • Editorial Time to divide and conquer
  • Chronic bronchitis and Emphysema

1. Singh S, et al. Inhaled anticholinergics and
risk of major adverse cardiovascular events in
patients with COPD. JAMA, 2008 300(12)
1439-1450.
2. Lee TA, Pickard S, et al. Risk of death
associated with medications for recently
diagnosed COPD. Annals of Internal Medicine
2008 149380-390.
25
References
  • Tashkin DP, Celli B, Senn S, Burkhart D, Kesten
    S, Menjoge S, Decramer M. A 4-year trial of
    tiotropium in chronic obstructive pulmonary
    disease. N Engl J Med 2008 359 1543-1554
  • Alsaeedi A, Sin DD, McAlister FA. The effects of
    inhaled corticosteroids in chronic obstructive
    pulmonary disease a systematic review of
    randomized placebo-controlled trials. Am J Med
    200211359-65.
  • Calverley PM, Anderson JA, Celli B, Ferguson GT,
    Jenkins C, Jones PW, Yates JC, Vestbo J TORCH
    investigators. Salmeterol and fluticasone
    propionate and survival in chronic obstructive
    pulmonary disease. N Engl J Med. 2007 Feb
    22356(8)775-89.
  • Smoking 101 fact sheet - American lung
    association. http//www.lungusa.org/site/c.dvLUK9
    O0E/b.39853/
  • Nocturnal Oxygen Therapy Trial Group. Continuous
    or nocturnal oxygen therapy in hypoxaemic chronic
    obstructive pulmonary disease. Annals of Internal
    Medicine, 198093 3. 391-398.
  • Medical Research Council Working Party.
    Long-term domiciliary oxygen therapy in chronic
    hypoxic cor pulmonale, complicating chronic
    bronchitis and emphysema. The Lancet, March 28,
    1981 681-685.
  • Anthonisen NR, Connett JE, Murray RP. Smoking and
    lung function of Lung Health Study participants
    after 11 years. Am J Respir Crit Care Med
    2002166675-679
  • Barr RG, Bourbeau J, Camargo CA. Tiotropium for
    stable chronic obstructive pulmonary disease.
    Cochrane Database of Systematic Reviews 2005,
    Issue 2. Art. No. CD002876. DOI
    10.1002/14651858.CD002876
  • Tashkin DP, Cooper CB. The role of long-acting
    bronchodilators in the management of stable COPD.
    Chest 2004 Jan125(1)249-59.
  • Anzueto A, Tashkin D, Kesten S. One-year
    analysis of longitudinal changes in spirometry in
    patients with COPD receiving Tiotropium. Pulm
    Pharmacol Ther. 200518(2)75-81.

26
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