Walter Vincken, University Hospital Brussels (UZ Brussel)
8 December 2010
Letter to the Editor of BMC Pulmonary Medicine.
Tiotropium in the treatment of COPD.
I read with interest Neyt et al.’s article published on-line in BMC Pulmonary Medicine on September 15, 2010.(1) In this cost-utility analysis, they question the ‘value for money’ of tiotropium in the treatment of chronic obstructive pulmonary disease (COPD) utilizing Belgian reimbursement regulations ‘under real-world conditions’. However valuable their analysis might seam, in doing so, they only took into consideration the effects of tiotropium on exacerbation- and hospitalization rates, including effects on quality of life (QoL) related to avoiding exacerbations. As already pointed out by Kostikas and Bouros in their commentary in the same issue of your journal (2), such an approach neglects the beneficial effects that patients in the real ‘real-world’ experience day after day for the rest of their lives, i.e. clinically important improvements in dyspnea, exercise tolerance and QoL not linked to exacerbations. Numerous double-blind, randomized clinical trials (RCT) in large patient populations, with a duration from 3 to 12 months comparing tiotropium to placebo (3-15), ipratropium (16) or salmeterol (17,18), are available, showing that tiotropium improves statistically significantly and clinically importantly airway obstruction, hyperinflation, dyspnea, need for rescue-medication, exercise tolerance and/or QoL. Although the UPLIFT trial (3, following up nearly 6000 COPD patients during 4 years (and thereby the largest ever trial in COPD), failed to reveal an effect of tiotropium (inhaled on top of usual treatment) on the decline in FEV1, other important long-term benefits of tiotropium such as a significant reduction in mortality risk was clearly present, a finding denied by Neyt et al.(1) but recently included in the Summary of Product Characteristics of tiotropium. Finally, Neyt et al.’s (1) statement that tiotropium “does not perform much better than its comparator”, i.e. salmeterol, on COPD exacerbations and related hospitalizations is now also to be considered out-dated in view of a large 1-year RCT (19) including over 7000 COPD patients recently presented at the Annual Congress of the European Respiratory Society (admittedly one week after their publication). In this so-called POET trial tiotropium compared to salmeterol significantly delayed the time to first exacerbation (primary endpoint) by 17% (p<0.0001) as well as time to first hospitalization (by 28%; p<0.0001). Tiotropium also significantly reduced the annual rate of exacerbations and exacerbation-related hospitalizations (p<0.002). The POET trial (19) thereby unequivocally confirms the trends observed in previous, smaller and shorter, trials (17, 18). In conclusion, as valuable as it is, Neyt et al.’s (1) work does not take into consideration all scientifically proven and clinically important aspects of undecipherable value in the real-life daily management of COPD patients whose suffering can nowadays clearly be alleviated by long-acting bronchodilators in general and tiotropium in particular. The question is whether and how much society is willing to pay for the benefit of patients with COPD, a disease that only recently is receiving the attention it deserves.
Walter Vincken, M.D., Ph.D. Head Respiratory Division, University Hospital Brussels (UZ Brussel), and Professor in respiratory physiology, pathophysiology and pulmonary medicine, Vrije Universiteit Brussel.
References:
1. Neyt M, et al. Tiotropium’s cost-effectivenss for the treatment of COPD: a cost-utility analysis under real-world conditions. BMC Pulmonary Medicine 2010, 10:47 doi:10.1186/1471-2466-10-47 2. Kostikas K, Bouros D. “Show me the money”: a fair criticism of economic studies on inhaled bronchodilators for COPD. BMC Pulmonary Medicine 2010, 10:48 doi: 10.1186/1471-2466-10-48 3. Tashkin D, et al. A 4 year trial of tiotropium in COPD (UPLIFT trial) New England Journal of Medicine 2008, 359:1543-1554. 4. Tonnel AB, et al. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. International Journal of COPD 2008, 3:301-310. 5. Casaburi R, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive disease. Eur Respir J 2002, 19:217-224. 6. Dusser D, et al. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 2006, 27:547-555. 7. Verkindre, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration 2006, 73:420-427. 8. Casaburi R, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilition in patients with COPD. Chest 2005, 127:809-817. 9. Ambrosino N, et al. Tiotropium and exercise training in COPD patients: effect on dyspnea and exercise tolerance. International Journal of COPD 2008, 3(4):771-780. 10. Beeh KM, et al. Wirksamkeit von tiotropiumbromid bei verschiedenen Schweregraden der chronisch-obstructiven lungenerkrankung (COPD). Pneumologie 2006, 60:341-346. 11. Chan CKM, et al. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J 2007, 14:465-472. 12. Niewoehner DE, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. Ann Intern Med 2005, 143:319-326. 13. Freeman D, et al. Efficacy and safety of tiotropium in COPD patients in primary care- the SPRUCE study. Respir Res 2007, 8:45. 14. Johansson G, et al. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Prim Care Respir J 2008, 17:169-175. 15. Moita J, et al. Tiotropium improves FEV1 in patients with COPD irrepsective of smoking status. Pulm Pharmacol Ther 2008, 21:146-151. 16. Vincken W, et al. Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. Eur Respir J 2002, 19:209-216. 17. Brusasco V, et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003, 58:399-404. 18. Briggs DD, et al. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD. Pulm Pharmacology & Ther 2005, 18:397-404. 19. Vogelmeier C, et al. Reductions in COPD exacerbations with tiotropium compared to salmeterol- the POET-trial. Eur Respir J 2010(suppl):P5091, ERS 2010, Barcelona.
Competing interests
WV has been a member of advisory boards for Altana/Nycomed, AstraZeneca, Boehringer Ingelheim/Pfizer, GlaxoSmithKline, Meda, MSD, Novartis and UCB; has given lectures for these pharmaceutical companies as well as for Abbott and Zambon; and has received research or educational grants from AstraZeneca, Boehringer Ingelheim/Pfizer, GlaxoSmithKline and Novartis.
Tiotropium’s cost-effectiveness
Marc Decramer, University of Leuven, Respiratory Division, Belgium
13 January 2011
Dear Editor,
I read with great interest the contribution “Tiotropium’s cost-effectiveness for the treatment of COPD: a cost-utility analysis under real world conditions” by Mattias Neyt, Stephan Devries, Nancy Thiry and Ann Van de Bruel1. This is a very interesting study and a nice application of cost-effectiveness analysis. Nevertheless, I would like to make two remarks. First, the 4-year UPLIFT study already provided us with indirect evidence of superiority of Tiotropium over the presently used long-acting β2-agonists or at least additive effects as the majority of the patients in both groups in this study were taking long-acting β2-agonists and inhaled corticosteroids (72-74% during the study)2. Under those conditions Tiotropium significantly improved outcomes such as FEV1, quality of life, risk of exacerbations and exacerbation-related hospitalizations. It did, however, not affect the mean number of exacerbations leading to hospitalizations, because they were infrequent, which is consistent with the analysis of Neyt et al1. In addition, there was a 13% reduction in mortality rate and a reduction in the incidence of respiratory failure. The latter changes may be viewed as suggestive evidence for disease modification. However, a trend for a reduction in mortality was also present with Salmeterol in the 4-year TORCH study, albeit not statistically significant3. Second, the recently presented POET-COPD study, a randomized controlled trial in which 7,376 patients were enrolled compared treatment with Tiotropium to Salmeterol during 1 year. A significant reduction in the risk for exacerbations (17%, P<0.0001) and exacerbation-related-hospitalizations (28%, P<0.0001) was found with Tiotropium compared to Salmeterol. My first remark is not likely to change the analysis and conclusion of Neyt et al. 1 significantly since the UPLIFT study did not provide a direct randomized controlled comparison between Tiotropium and Salmeterol. The second remark on the POET-COPD study4, however, is of great significance to the analysis of Neyt et al.
References 1. Neyt M., S. Devriese, N. Thiry, A. Van de Bruel. Tiotropium’s cost-effectiveness for the treatment of COPD: a cost-utilty analyqsis under real-world conditions. Pulmonary Medicine 2010. 2. Tashkin D.P., B.Celli, S.Senn, D.Burkhardt, S.Kesten, S.Menjoge, and M.Decramer. A 4-year trial of tiotropium in Chronoc Obstyructive Pulmonary Disease. N Eng J Med 2008; 359: 1543-54. 3. Calverley P.M., J.A. Anderson, B. Celli, G.T. Ferguson, C. Jenkins, P.W. Jones, J.C. Yates, J. Vestbo and TORCH-investigators. Salmeterol and flutocasone propionate and survival in chronic obstructive pulmonary disease. N Eng J Med 2007; 356: 775-89. 4. Vogelmeier C, B Hederer, T Glaab, H Schmidt, MPMH Rutten-van Mölken, KM Beeh, KF Rabe, and LM Fabbri. Reductions in COPD Exacerbations with Tiotropium compred to Sameterol- The POET-COPD trail (abstract). Eur Respir J 2010; P5091.
Competing interests
Prof.M. Decramer has been part of Advisory Board for Boehringer-Pfizer, GSK, Nycomed, and Altana. He has performed consulting work for Boehringer-Pfizer and GSK. He also received lecture fees from these companies. All of the above amounted to less than 10.000 euro per annum. As consultant to a pharmaceutical or medical device company he received money from Dompé, GSK, Boehringer and Nycomed. He received a research grant of 45.000 euro/year from AstraZeneca.
Tiotropium in the treatment of COPD
8 December 2010
Letter to the Editor of BMC Pulmonary Medicine.
Tiotropium in the treatment of COPD.
I read with interest Neyt et al.’s article published on-line in BMC Pulmonary Medicine on September 15, 2010.(1) In this cost-utility analysis, they question the ‘value for money’ of tiotropium in the treatment of chronic obstructive pulmonary disease (COPD) utilizing Belgian reimbursement regulations ‘under real-world conditions’. However valuable their analysis might seam, in doing so, they only took into consideration the effects of tiotropium on exacerbation- and hospitalization rates, including effects on quality of life (QoL) related to avoiding exacerbations. As already pointed out by Kostikas and Bouros in their commentary in the same issue of your journal (2), such an approach neglects the beneficial effects that patients in the real ‘real-world’ experience day after day for the rest of their lives, i.e. clinically important improvements in dyspnea, exercise tolerance and QoL not linked to exacerbations.
Numerous double-blind, randomized clinical trials (RCT) in large patient populations, with a duration from 3 to 12 months comparing tiotropium to placebo (3-15), ipratropium (16) or salmeterol (17,18), are available, showing that tiotropium improves statistically significantly and clinically importantly airway obstruction, hyperinflation, dyspnea, need for rescue-medication, exercise tolerance and/or QoL. Although the UPLIFT trial (3, following up nearly 6000 COPD patients during 4 years (and thereby the largest ever trial in COPD), failed to reveal an effect of tiotropium (inhaled on top of usual treatment) on the decline in FEV1, other important long-term benefits of tiotropium such as a significant reduction in mortality risk was clearly present, a finding denied by Neyt et al.(1) but recently included in the Summary of Product Characteristics of tiotropium.
Finally, Neyt et al.’s (1) statement that tiotropium “does not perform much better than its comparator”, i.e. salmeterol, on COPD exacerbations and related hospitalizations is now also to be considered out-dated in view of a large 1-year RCT (19) including over 7000 COPD patients recently presented at the Annual Congress of the European Respiratory Society (admittedly one week after their publication). In this so-called POET trial tiotropium compared to salmeterol significantly delayed the time to first exacerbation (primary endpoint) by 17% (p<0.0001) as well as time to first hospitalization (by 28%; p<0.0001). Tiotropium also significantly reduced the annual rate of exacerbations and exacerbation-related hospitalizations (p<0.002). The POET trial (19) thereby unequivocally confirms the trends observed in previous, smaller and shorter, trials (17, 18).
In conclusion, as valuable as it is, Neyt et al.’s (1) work does not take into consideration all scientifically proven and clinically important aspects of undecipherable value in the real-life daily management of COPD patients whose suffering can nowadays clearly be alleviated by long-acting bronchodilators in general and tiotropium in particular. The question is whether and how much society is willing to pay for the benefit of patients with COPD, a disease that only recently is receiving the attention it deserves.
Walter Vincken, M.D., Ph.D.
Head Respiratory Division, University Hospital Brussels (UZ Brussel), and
Professor in respiratory physiology, pathophysiology and pulmonary medicine, Vrije Universiteit Brussel.
References:
1. Neyt M, et al. Tiotropium’s cost-effectivenss for the treatment of COPD: a cost-utility analysis under real-world conditions. BMC Pulmonary Medicine 2010, 10:47 doi:10.1186/1471-2466-10-47
2. Kostikas K, Bouros D. “Show me the money”: a fair criticism of economic studies on inhaled bronchodilators for COPD. BMC Pulmonary Medicine 2010, 10:48 doi: 10.1186/1471-2466-10-48
3. Tashkin D, et al. A 4 year trial of tiotropium in COPD (UPLIFT trial) New England Journal of Medicine 2008, 359:1543-1554.
4. Tonnel AB, et al. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. International Journal of COPD 2008, 3:301-310.
5. Casaburi R, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive disease. Eur Respir J 2002, 19:217-224.
6. Dusser D, et al. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 2006, 27:547-555.
7. Verkindre, et al. The effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary disease. Respiration 2006, 73:420-427.
8. Casaburi R, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilition in patients with COPD. Chest 2005, 127:809-817.
9. Ambrosino N, et al. Tiotropium and exercise training in COPD patients: effect on dyspnea and exercise tolerance. International Journal of COPD 2008, 3(4):771-780.
10. Beeh KM, et al. Wirksamkeit von tiotropiumbromid bei verschiedenen Schweregraden der chronisch-obstructiven lungenerkrankung (COPD). Pneumologie 2006, 60:341-346.
11. Chan CKM, et al. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J 2007, 14:465-472.
12. Niewoehner DE, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. Ann Intern Med 2005, 143:319-326.
13. Freeman D, et al. Efficacy and safety of tiotropium in COPD patients in primary care- the SPRUCE study. Respir Res 2007, 8:45.
14. Johansson G, et al. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Prim Care Respir J 2008, 17:169-175.
15. Moita J, et al. Tiotropium improves FEV1 in patients with COPD irrepsective of smoking status. Pulm Pharmacol Ther 2008, 21:146-151.
16. Vincken W, et al. Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. Eur Respir J 2002, 19:209-216.
17. Brusasco V, et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003, 58:399-404.
18. Briggs DD, et al. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD. Pulm Pharmacology & Ther 2005, 18:397-404.
19. Vogelmeier C, et al. Reductions in COPD exacerbations with tiotropium compared to salmeterol- the POET-trial. Eur Respir J 2010(suppl):P5091, ERS 2010, Barcelona.
Competing interests
WV has been a member of advisory boards for Altana/Nycomed, AstraZeneca, Boehringer Ingelheim/Pfizer, GlaxoSmithKline, Meda, MSD, Novartis and UCB; has given lectures for these pharmaceutical companies as well as for Abbott and Zambon; and has received research or educational grants from AstraZeneca, Boehringer Ingelheim/Pfizer, GlaxoSmithKline and Novartis.
Tiotropium’s cost-effectiveness
13 January 2011
Dear Editor,
I read with great interest the contribution “Tiotropium’s cost-effectiveness for the treatment of COPD: a cost-utility analysis under real world conditions” by Mattias Neyt, Stephan Devries, Nancy Thiry and Ann Van de Bruel1. This is a very interesting study and a nice application of cost-effectiveness analysis. Nevertheless, I would like to make two remarks. First, the 4-year UPLIFT study already provided us with indirect evidence of superiority of Tiotropium over the presently used long-acting β2-agonists or at least additive effects as the majority of the patients in both groups in this study were taking long-acting β2-agonists and inhaled corticosteroids (72-74% during the study)2. Under those conditions Tiotropium significantly improved outcomes such as FEV1, quality of life, risk of exacerbations and exacerbation-related hospitalizations. It did, however, not affect the mean number of exacerbations leading to hospitalizations, because they were infrequent, which is consistent with the analysis of Neyt et al1. In addition, there was a 13% reduction in mortality rate and a reduction in the incidence of respiratory failure. The latter changes may be viewed as suggestive evidence for disease modification. However, a trend for a reduction in mortality was also present with Salmeterol in the 4-year TORCH study, albeit not statistically significant3. Second, the recently presented POET-COPD study, a randomized controlled trial in which 7,376 patients were enrolled compared treatment with Tiotropium to Salmeterol during 1 year. A significant reduction in the risk for exacerbations (17%, P<0.0001) and exacerbation-related-hospitalizations (28%, P<0.0001) was found with Tiotropium compared to Salmeterol. My first remark is not likely to change the analysis and conclusion of Neyt et al. 1 significantly since the UPLIFT study did not provide a direct randomized controlled comparison between Tiotropium and Salmeterol. The second remark on the POET-COPD study4, however, is of great significance to the analysis of Neyt et al.
References
1. Neyt M., S. Devriese, N. Thiry, A. Van de Bruel. Tiotropium’s cost-effectiveness for the treatment of COPD: a cost-utilty analyqsis under real-world conditions. Pulmonary Medicine 2010.
2. Tashkin D.P., B.Celli, S.Senn, D.Burkhardt, S.Kesten, S.Menjoge, and M.Decramer. A 4-year trial of tiotropium in Chronoc Obstyructive Pulmonary Disease. N Eng J Med 2008; 359: 1543-54.
3. Calverley P.M., J.A. Anderson, B. Celli, G.T. Ferguson, C. Jenkins, P.W. Jones, J.C. Yates, J. Vestbo and TORCH-investigators. Salmeterol and flutocasone propionate and survival in chronic obstructive pulmonary disease. N Eng J Med 2007; 356: 775-89.
4. Vogelmeier C, B Hederer, T Glaab, H Schmidt, MPMH Rutten-van Mölken, KM Beeh, KF Rabe, and LM Fabbri. Reductions in COPD Exacerbations with Tiotropium compred to Sameterol- The POET-COPD trail (abstract). Eur Respir J 2010; P5091.
Competing interests
Prof.M. Decramer has been part of Advisory Board for Boehringer-Pfizer, GSK, Nycomed, and Altana. He has performed consulting work for Boehringer-Pfizer and GSK. He also received lecture fees from these companies. All of the above amounted to less than 10.000 euro per annum. As consultant to a pharmaceutical or medical device company he received money from Dompé, GSK, Boehringer and Nycomed. He received a research grant of 45.000 euro/year from AstraZeneca.