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

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UPLIFTA 4-Year Trial of Tiotropium in Chronic
Obstructive Pulmonary Disease

• 10/28/2008
• Michael Rich

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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/
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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
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COPD - heterogeneity
Cachexia nl ABG Dyspnea at rest
Hypoxemia CO2 retention Pulm HTN R - HF
Cough Copious sputum Dilated airspaces
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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.
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• 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

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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
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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.
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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.
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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.
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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

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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

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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.

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Results

• Mean rate of decline in FEV1 - no significant
  difference

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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

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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)

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Results

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

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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

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Discussion

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

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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.
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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.

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