UPLIFT

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Tashkin DP, et al. "A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease". The New England Journal of Medicine. 2008. 395(15):1543-1554.
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Clinical Question

In patients with COPD, what are the effects of tioptropium on the rate of decline in lung function, exacerbations, related hospitalizations, and mortality?

Bottom Line

Tiotropium did not significantly slow the decline of FEV1, but did reduce the incidence of COPD exacerbations among individuals with moderate to severe COPD, and showed a trend towards improved survival.

Major Points

The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial investigated whether the long-acting anticholinergic drug tiotropium would decrease the rate of decline in FEV1 among patients with COPD. UPLIFT did not show an improvement in this primary endpoint, but it did show that tiotropium was associated with a reduced risk of exacerbations and a trend towards decreased 4-year mortality.

UPLIFT is widely regarded as one of the largest and most well designed trials in the COPD literature. Its results have led many clinicians to begin prescribing tiotropium to patients with COPD who have unacceptably frequent exacerbations. This approach has been met with some skepticism however, some of which is based upon cost analysis; for example, a subsequent analysis demonstrated an unfavorable incremental cost-effectiveness ratio associated with blanket administration of tiotropium to this population.[1]

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=5,993
    • Tiotropium (n=2,987)
    • Placebo (n=3,006)
  • Setting: 487 centers in 37 countries
  • Enrollment: January 2003 to March 2004
  • Median duration of treatment: 3.9 years
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Rate of decline in mean prebronchodilator FEV1
    • Rate of decline in mean postbronchodilator FEV1

Population

Inclusion Criteria

  • COPD
  • Age ≥40 years
  • Postbronchodilator FEV1/FVC ≤70% and FEV1 ≤70%
  • Smoking history of ≥10 pack-years

Exclusion Criteria

  • History of asthma
  • COPD exacerbation or respiratory infection within 4 weeks of screening
  • History of pulmonary resection
  • Use of supplemental oxygen ≥12 hours/day
  • Presence of a coexisting illness that could preclude participation in the study or interfere with the study results

Baseline Characteristics

  • Mean age: 65 years
  • Male: 75%
  • BMI: 26
  • Current smokers: 30%
  • Smoking history: 48.6 pack-years
  • Baseline spirometry: pre-bronchodilation vs. post-bronchodilation
    • FEV1: 1.10L (39% predicted) vs. 1.32L (48% predicted)
    • FVC: 2.63L vs. 3.09L
    • FEV1/FVC: 42.3% vs. 43.4%
  • GOLD grading[2]
    • II: 46%
    • III: 44%
    • IV: 9%

Baseline Medications

  • Any: 93%
  • Inhaled anticholinergic
    • Short-acting: 45%
    • Long-acting: 2%
  • Inhaled β2-agonists
    • Short-acting: 68%
    • Long-acting: 60%
  • Corticosteroid
    • Inhaled: 62%
    • Oral: 8%
  • Theophylline: 29%

Interventions

  • Spirometry performed at randomization, at 1-month visit, at 6-month follow-up visits, and at 30-day follow-up visit after study end.
  • Mean FEV1 measured before the use of study drug (prebronchodilator) and short-acting bronchodilators in the morning, from day 30 (steady state) until study end.
  • Mean FEV1 measured after the use of study drug (postbronchodilator), from day 30 (steady state) until study end.
  • At end of study, both arms were provided with and asked to take 40μg of ipratropium four times daily and to return for final assessment 30 days later.
  • All respiratory medications, except other inhaled anticholinergics, permitted.

Outcomes

Comparisons are tiotropium vs. placebo.

Primary Outcomes

Rate of decline in mean prebronchodilator FEV1
30 mL/yr in each (P=0.95)
Rate of decline in mean postbronchodilator FEV1
40 vs. 42 mL/yr (P=0.21)

Secondary Outcomes

Rate of decline in mean prebronchodilator FVC
43 vs. 39 mL/yr (P=0.30)
Rate of decline in mean post-bronchodilator FVC
61 mL/yr in each (P=0.84)
Mean absolute change in SGRQ total score at each time point throughout 4-year period
2.3 vs. 3.3 (P<0.001)
Improvement of ≥4 units in SGRQ total scores from baseline at 4 years
45% vs. 36% (P<0.001)
Health-related quality of life, as measured on SGRQ
1.25 vs 1.21 (P=0.78)
Median time to first exacerbation
16.7 vs. 12.5 months (P<0.001)
Exacerbations of COPD
0.73 vs. 0.85 events/patient-year (RR 0.86; 95% CI 0.81-0.91; P<0.001)
Exacerbations of COPD
12.11 vs. 13.64 days/patient-year (RR 0.89; 95% CI 0.83-0.95; P=0.001)
Exacerbations leading to hospitalization
0.15 vs. 0.16 events/patient-year (RR 0.94; 95% CI 0.82-1.07; P=0.34)
Mortality for 4 years plus 30 days (1,470 days), intention-to-treat per-protocol analysis
14.9% vs. 16.5% (HR 0.89; 95% CI 0.79-1.02; P=0.09)
Mortality for 4-year (1,440 days), protocol-defined study period
14.4% vs 16.3% (HR 0.87; 95% CI 0.76 to 0.99; P not specified)

Subgroup Analysis

No significant heterogeneity in the effect of tiotropium according to the baseline variables examined.

Adverse Events

Adverse events: 93% vs. 92%

Serious
52% vs. 50%
Fatal
13% vs. 14% (HR 0.84; 95% CI 0.73-0.97)

Incidence rate of serious adverse events per 100 patient-years:

Cardiac
3.6 vs. 4.2 (RR 0.84; 95% CI 0.73-0.98; P<0.05)
CHF
0.3 vs. 0.5 (RR 0.59; 95% CI 0.37-0.96; P<0.05)
MI
0.69 vs. 0.97 (RR 0.71; 95% CI 0.52-0.99; P<0.05)
Lower respiratory
11.3 vs. 13.5 (RR 0.84; 95% CI 0.77-0.92; P<0.05)
COPD exacerbation
8.2 vs. 9.7 (RR 0.84; 95% CI 0.76-0.94; P<0.05)
Dyspnea
0.4 vs. 0.6 (RR 0.61; 95% CI 0.40-0.94; P<0.05)
PNA
3.3 vs. 3.5 (RR 0.95; 95% CI 0.81-1.11; P=NS)
Respiratory failure
0.90 vs. 1.31 (RR 0.69; 95% CI 0.52-0.92; P<0.05)

Criticisms

  • High dropout rate by 45 months: 36% vs. 45% (HR 0.89; 95% CI 0.85-0.94; P<0.001)
  • High proportion of males (75%) limits generalizability
  • Unfavorable cost-effectiveness ratio associated with tiotropium, mostly due to high cost of the drug

Funding

Supported by Boehringer Ingelheim and Pfizer, with multiple disclosures listed in article.

Additional Resources

  1. Neyt M, et al. "Tiotropium's cost-effectiveness for the treatment of COPD: a cost-utility analysis under real-world conditions." BMC Pulm Med. 2010 Sep 15;10:47.
  2. Global Strategy for the Diagnosis, Management, and PRevention of Chronic Obstructive Pulmonary Disease (Revised 2011)