A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease Donald P. Tashkin, M.D., Bartolome Celli, M.D., Step...
Background <ul><li>The rate of decline of FEV 1  is a marker of  COPD progression </li></ul><ul><li>Previous  prospective ...
What do we know about Tiotropium? <ul><li>Tiotropium is a  once-daily , inhaled  anticholinergic  drug that   provides at ...
Study Overview <ul><li>Prospective  4-years trial </li></ul><ul><li>Whether tiotropium   would  reduce the rate of decline...
Study Design <ul><li>4-year, randomized, double-blind, placebo-controlled,   parallel-group trial </li></ul><ul><li>Patien...
Study Design (cont.) <ul><li>18 µg  of  inhaled  tiotropium or a matching   placebo given  once daily </li></ul><ul><li>Al...
Patients <ul><li>490 investigational centers in 37   countries </li></ul><ul><li>Criteria for participation  :  </li></ul>...
Procedures <ul><li>Patients were  randomly  assigned   to receive either tiotropium or placebo </li></ul><ul><li>Clinic vi...
Results  Study Population <ul><li>Patients were recruited  from January 2003 through March 2004 </li></ul><ul><li>The stud...
<ul><li>Higher  proportion of patients in the  placebo group  discontinue the trial </li></ul><ul><li>These patients had  ...
Baseline characteristics  and concomitant use of respiratory   medications were  similar  in the two study groups  > 45 yr...
<ul><ul><li>Health-related quality of life ( lower scores indicating improvement)   </li></ul></ul><ul><ul><li>Exclusion c...
Rate of Decline in Lung Function <ul><li>Similar rates of decline in lung function  (in FEV 1  and FVC ) were seen in   th...
<ul><li>In the Tiotropium group, FEV 1  significantly improved before   and after bronchodilation </li></ul><ul><li>The  i...
In the tiotropium group, FVC significantly improved before   and after bronchodilation
<ul><li>SGRQ: scores   range from 0 to 100, with  lower scores indicating improvement   </li></ul><ul><li>Change of  4 uni...
Exacerbations <ul><li>Tiotropium  group had: </li></ul><ul><ul><li>Significant delay in the time   to the first exacerbati...
<ul><li>During a period of 4 years 941   patients died: 14.9% in the tiotropium group and 16.5% in the   placebo group </l...
Adverse Events <ul><li>The most common adverse events: COPD exacerbations, pneumonia, and dyspnea   , Respiratory failure,...
<ul><li>Tiotropium (at a dose of 18 µg   once daily)  improved: </li></ul><ul><ul><li>Lung function (FEV1, FVC) </li></ul>...
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A 4 Year Trial Of Tiotropium In Chronic Obstructive Pulmonary Disease

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A 4 Year Trial Of Tiotropium In Chronic Obstructive Pulmonary Disease

  1. 1. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease Donald P. Tashkin, M.D., Bartolome Celli, M.D., Stephen Senn, Ph.D., Deborah Burkhart, B.S.N., Steven Kesten, M.D., Shailendra Menjoge, Ph.D., Marc Decramer, M.D., Ph.D., for the UPLIFT Study Investigators Bassel Ericsoussi, PG-Y3 Internal Medicine Advocate Christ Medical Center N Engl J Med Volume 359(15):1543-1554 October 9, 2008
  2. 2. Background <ul><li>The rate of decline of FEV 1 is a marker of COPD progression </li></ul><ul><li>Previous prospective studies showed: </li></ul><ul><ul><li>Inhaled short-acting anticholinergic drugs, inhaled corticosteroids , or n -acetylcysteine don’t alter the rate of decline of FEV 1 in patients with COPD </li></ul></ul><ul><ul><li>Only smoking cessation alter the rate of decline of FEV 1 in patients with COPD </li></ul></ul>
  3. 3. What do we know about Tiotropium? <ul><li>Tiotropium is a once-daily , inhaled anticholinergic drug that provides at least 24-hour improvements in airflow and hyperinflation in patients with COPD. </li></ul><ul><li>Tiotropium showed improvements in exercise tolerance , health-related quality of life , and rates of dyspnea and exacerbations . </li></ul><ul><li>Retrospective study of 1-year, placebo-controlled trials: </li></ul><ul><ul><li>Tiotropium altered the rate of decline in FEV 1 . </li></ul></ul>
  4. 4. Study Overview <ul><li>Prospective 4-years trial </li></ul><ul><li>Whether tiotropium would reduce the rate of decline in FEV 1 in patients with COPD </li></ul><ul><li>Long-term effects of tiotropium therapy on the clinically important outcomes of health-related quality of life , exacerbations , related hospitalizations , and mortality . </li></ul>
  5. 5. Study Design <ul><li>4-year, randomized, double-blind, placebo-controlled, parallel-group trial </li></ul><ul><li>Patients with moderate-to-very-severe COPD (FEV1 < 65% of predicted) </li></ul><ul><li>Two primary end points : </li></ul><ul><ul><li>The yearly rate of decline in FEV 1 prebronchodilator (starting after day 30) </li></ul></ul><ul><ul><li>The yearly rate of decline in FEV 1 postbronchodilator (starting after day 30) </li></ul></ul><ul><li>Secondary outcome : </li></ul><ul><ul><li>The rate of decline in the forced vital capacity (FVC) and slow vital capacity (SVC) </li></ul></ul><ul><ul><li>Health-related quality of life (as measured by the total score on St. George's Respiratory Questionnaire (SGRQ), with lower scores indicating improvement) </li></ul></ul><ul><ul><li>Exacerbations of COPD (defined as an increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid) </li></ul></ul><ul><ul><li>Hospitalizations </li></ul></ul><ul><ul><li>The rate of death from any cause and from lower respiratory conditions </li></ul></ul>
  6. 6. Study Design (cont.) <ul><li>18 µg of inhaled tiotropium or a matching placebo given once daily </li></ul><ul><li>All respiratory medications , except other inhaled anticholinergic drugs, were permitted during the trial. </li></ul><ul><li>Smoking cessation programs were offered to all patients </li></ul>
  7. 7. Patients <ul><li>490 investigational centers in 37 countries </li></ul><ul><li>Criteria for participation : </li></ul><ul><ul><li>Moderate to very severe COPD (postbronchodilator FEV 1 of 70% or less of the predicted value) </li></ul></ul><ul><ul><li>Age of 40 years or more , </li></ul></ul><ul><ul><li>Smoking history of at least 10 pack-years </li></ul></ul><ul><li>Exclusion criteria : </li></ul><ul><ul><li>History of asthma </li></ul></ul><ul><ul><li>COPD exacerbation or respiratory infection within 4 weeks before screening </li></ul></ul><ul><ul><li>History of pulmonary resection </li></ul></ul><ul><ul><li>Use of supplemental oxygen for more than 12 hours per day </li></ul></ul><ul><ul><li>Coexisting illness that could preclude participation in the study or interfere with the study results. </li></ul></ul>
  8. 8. Procedures <ul><li>Patients were randomly assigned to receive either tiotropium or placebo </li></ul><ul><li>Clinic visits occurred at 1 month and 3 months and then every 3 months throughout the 4-year study period </li></ul><ul><li>Prebronchodilator spirometry was performed initially, followed immediately by the blinded administration of a study drug </li></ul><ul><li>Spirometry was again performed postbronchodilator </li></ul>
  9. 9. Results Study Population <ul><li>Patients were recruited from January 2003 through March 2004 </li></ul><ul><li>The study ended in February 2008 </li></ul><ul><li>5993 underwent randomization </li></ul><ul><li>4383 (73%) completed 2 years, 3891 (65%) completed 3 years, and 3569 (60%) completed at least 45 months </li></ul><ul><li>Treatment discontinuation in the placebo group is higher than the tiotropium group </li></ul><ul><li>The majority of discontinuations were due to adverse events. </li></ul>
  10. 10. <ul><li>Higher proportion of patients in the placebo group discontinue the trial </li></ul><ul><li>These patients had more severe airflow obstruction and more rapid decline in lung function than those who did not discontinue treatment </li></ul><ul><li>Patients in the placebo group who completed the trial probably represent &quot; healthy survivors ” </li></ul>
  11. 11. Baseline characteristics and concomitant use of respiratory medications were similar in the two study groups > 45 yr At least 10 packs-yr Moderate to very severe Moderate Severe Very severe According to criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD)
  12. 12. <ul><ul><li>Health-related quality of life ( lower scores indicating improvement) </li></ul></ul><ul><ul><li>Exclusion criteria: Use of supplemental oxygen for more than 12 hours per day </li></ul></ul>More than 90% of patients were receiving respiratory medications at baseline
  13. 13. Rate of Decline in Lung Function <ul><li>Similar rates of decline in lung function (in FEV 1 and FVC ) were seen in the two study groups: </li></ul><ul><ul><li>Tiotropium does not influence the decline in lung function over time </li></ul></ul><ul><ul><li>Ceiling effect: current management of COPD could affect the decline in lung function </li></ul></ul>
  14. 14. <ul><li>In the Tiotropium group, FEV 1 significantly improved before and after bronchodilation </li></ul><ul><li>The improvements in FEV 1 , ranged from 87 to 103 ml before bronchodilation </li></ul><ul><li>The improvements in FEV 1 , ranged from 47 to 65 ml after bronchodilation </li></ul>87 to 103 ml 47 to 65 ml (P<0.001).
  15. 15. In the tiotropium group, FVC significantly improved before and after bronchodilation
  16. 16. <ul><li>SGRQ: scores range from 0 to 100, with lower scores indicating improvement </li></ul><ul><li>Change of 4 units or more considered to be clinically significant </li></ul><ul><li>Tiotropium group had lower scores (indicating improvement) </li></ul><ul><li>The change in the score (2.3 to 3.3 units, P<0.001) is statistically significant but clinically is not significant (< 4 units) </li></ul>2.3 to 3.3 units, P<0.001 But clinically not significant (< 4 units) Health-Related Quality of Life
  17. 17. Exacerbations <ul><li>Tiotropium group had: </li></ul><ul><ul><li>Significant delay in the time to the first exacerbation </li></ul></ul><ul><ul><li>significant delay in the time to the first hospitalization for an exacerbation </li></ul></ul><ul><ul><li>Reduction in the mean number of exacerbations of 14% </li></ul></ul><ul><li>Increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid </li></ul>
  18. 18. <ul><li>During a period of 4 years 941 patients died: 14.9% in the tiotropium group and 16.5% in the placebo group </li></ul><ul><li>The mortality rate is lower in the tiotropium group, but statistically not significant </li></ul>Mortality
  19. 19. Adverse Events <ul><li>The most common adverse events: COPD exacerbations, pneumonia, and dyspnea , Respiratory failure, Myocardial infarction, stroke </li></ul><ul><li>> 1% of patients in either study group were either cardiac or respiratory in nature </li></ul><ul><li>Lower in the tiotropium group than in the placebo group </li></ul><ul><li>Reduced risk of congestive heart failure, COPD exacerbation, dyspnea, or respiratory failure </li></ul>RR < 1, favorable for Tiotropium P < 0.05
  20. 20. <ul><li>Tiotropium (at a dose of 18 µg once daily) improved: </li></ul><ul><ul><li>Lung function (FEV1, FVC) </li></ul></ul><ul><ul><li>health-related quality of life </li></ul></ul><ul><ul><li>rate of exacerbations </li></ul></ul><ul><ul><li>exacerbation-related hospitalizations </li></ul></ul><ul><ul><li>Reduced respiratory and cardiac morbidity (not significant) </li></ul></ul><ul><li>But did not alter the rate of decline in the FEV 1 in patients with COPD </li></ul><ul><li>The yearly rate of decline in FEV 1 was lower than the rates of decline reported previously: </li></ul><ul><ul><li>The presence of freely prescribed respiratory medications other than another inhaled anticholinergic agent </li></ul></ul><ul><ul><li>Higher proportion of patients stopped smoking (Only smoking cessation alter the rate of decline of FEV 1 in patients with COPD) </li></ul></ul>Discussion/Conclusion

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