Combination Therapy
Medical > Therapy > Specific treatments
Combination Therapy
Monotherapy of PAH has seen many significant improvements in various clinical endpoints. Since the increased understanding of the mechanisms involved in the pathogenesis of PAH has implicated the involvement of several pathways (1), further improvements in patient outcomes may be achieved by combining agents with complementary and synergistic mechanisms of action. So far, there are numerous small uncontrolled trial of various combination treatments in patients with PH (2-12). However, the first randomized trial combining bosentan versus placebo with epoprostenol in 33 patients (BREATHE-2) failed to show any significant differences between the two groups, despite the decrease in total pulmonary resistance was about 50 % greater in the patients receiving bosentan (13). The most likely reason for these statistically negative results was its lack of power.
Recently, a randomized study (STEP) of adding inhaled iloprost (mean daily dose 27 µg) to bosentan in 67 patients with PAH (55 % idiopathic, 45 % associated) mostly WHO/NYHA functional class III (94 %) showed an almost significant improvement in the 6-minute walking distance (6-MWD) of 26 meters (P=0.001) compared with placebo (14). Iloprost significantly improved the WHO/NYHA functional class (P=0.002), delayed the time to clinical worsening (P=0.022), and decreased pulmonary vascular resistance (P<0.001).
At the moment, there are numerous large randomized double-blind, placebo-controlled trials of drug combination treatments ongoing. Some of them are listed below. Until further data are available, however, routine combination therapy cannot generally be recommended.
Ongoing or unpublished trials
The PACES study (15) examined 267 patients in whom oral sildenafil 20 mg tid titrated to 40 mg and 80 mg tid, as tolerated, at four week intervals given for overall 4 months or placebo was added to established intravenous epoprostenol treatment. The 6-MWD increased by 26 meters (P<0.001). The combination therapy also decreased mPAP to a greater extent (-3.9 mm Hg, P<0.0001). Time to clinical worsening was significantly longer with combination therapy (P=0.012). No patients died during combination therapy versus 7 deaths in the control group.
In the TRIUMPH I study (16) approximately 150 NYHA Class III and IV patients with severe PAH at 14 study sites who are on a stable dose bosentan 125 mg bid. for at least 3 months will be randomized t o either Treprostinil inhalation solution or matching placebo.
Vision II study evaluates the safety and efficacy of the addition of inhaled iloprost in patients with PAH receiving oral sildenafil. The duration is 16 weeks of blinded study drug followed by 32 weeks of open-label iloprost.
FREEDOM - C analyzes the addition of oral treprostinil in patients with PAH who are currently receiving approved therapy (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). TreatmentStudy duration is 16 weeks, and the primary endpoint ist he 6-MWD.
COMPASS 1 evaluates the effect of a single dose of sildenafil on pulmonary hermodynamics in 45 patients with PAH already being treated with bosentan.
COMPASS 2 studies the effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in 600 symptomatic patients with PAH being treated with a stable dose of sildenafil equal to or greater than 20 mg tid for at least 12 weeks prior to randomization. The study duration is 16 weeks, and the primary endpoints are time to clinical worsening and the improvement in 6-MWD.
COMPASS 3 is an open-label, multi-center study in 100 patients designed to assess whether a core therapy of bosentan, either as monotherapy or with the addition of sildenafil, enables patients with PAH to achieve a 6 MWD of ≥380 meters after 28 weeks of therapy This design is also appropriate to pioneer the utility of cardiac MRI in assessing improved functional capacity in PAH and exploring its correlation with other parameters.
References:
1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-1436.
2. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858-863.
3. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-522.
4. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N, Ghofrani S, Enke B, Seeger W, Grimminger F. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-164.
5. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, Block LH. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-1295.
6. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007-1010.
7. Ikeda D, Tsujino I, Ohira H, Itoh N, Kamigaki M, Ishimaru S, Sakaue S, Nishimura M. Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension. J Cardiovasc Pharmacol 2005;45:286-289.
8. Gomberg-Maitland M, McLaughlin V, Gulati M, Rich S. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. Am J Cardiol 2005;96:1334-1336.
9. Hoeper MM, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, Wensel R, Ripken F, Bremer H, Kluge S, Hoeffken G, Behr J. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006;28:691-694.
10. Beyer S, Speich R, Fischler M, Maggiorini M, Ulrich S. Long-term experience with oral or inhaled vasodilator combination therapy in patients with pulmonary hypertension. Swiss Med Wkly 2006;136:114-118.
11. Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J 2003;22:330-334.
12. Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, Hassoun PM. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007;29:469-475.
13. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-359.
14. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257-1263.
15. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming T, Burgess G, Collings L, Cossons N, Badesch DB. Safety and efficacy of sildenafil-epoprostenol combination therapy in patients with pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2007;175:A300.
16. Triumph I. - Investigational clinical trial of TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension.
http://www.lungrx.com/triumph.html
Back to > Medical > Therapy > Specific treatments
Combination Therapy
Monotherapy of PAH has seen many significant improvements in various clinical endpoints. Since the increased understanding of the mechanisms involved in the pathogenesis of PAH has implicated the involvement of several pathways (1), further improvements in patient outcomes may be achieved by combining agents with complementary and synergistic mechanisms of action. So far, there are numerous small uncontrolled trial of various combination treatments in patients with PH (2-12). However, the first randomized trial combining bosentan versus placebo with epoprostenol in 33 patients (BREATHE-2) failed to show any significant differences between the two groups, despite the decrease in total pulmonary resistance was about 50 % greater in the patients receiving bosentan (13). The most likely reason for these statistically negative results was its lack of power.
Recently, a randomized study (STEP) of adding inhaled iloprost (mean daily dose 27 µg) to bosentan in 67 patients with PAH (55 % idiopathic, 45 % associated) mostly WHO/NYHA functional class III (94 %) showed an almost significant improvement in the 6-minute walking distance (6-MWD) of 26 meters (P=0.001) compared with placebo (14). Iloprost significantly improved the WHO/NYHA functional class (P=0.002), delayed the time to clinical worsening (P=0.022), and decreased pulmonary vascular resistance (P<0.001).
At the moment, there are numerous large randomized double-blind, placebo-controlled trials of drug combination treatments ongoing. Some of them are listed below. Until further data are available, however, routine combination therapy cannot generally be recommended.
Ongoing or unpublished trials
The PACES study (15) examined 267 patients in whom oral sildenafil 20 mg tid titrated to 40 mg and 80 mg tid, as tolerated, at four week intervals given for overall 4 months or placebo was added to established intravenous epoprostenol treatment. The 6-MWD increased by 26 meters (P<0.001). The combination therapy also decreased mPAP to a greater extent (-3.9 mm Hg, P<0.0001). Time to clinical worsening was significantly longer with combination therapy (P=0.012). No patients died during combination therapy versus 7 deaths in the control group.
In the TRIUMPH I study (16) approximately 150 NYHA Class III and IV patients with severe PAH at 14 study sites who are on a stable dose bosentan 125 mg bid. for at least 3 months will be randomized t o either Treprostinil inhalation solution or matching placebo.
Vision II study evaluates the safety and efficacy of the addition of inhaled iloprost in patients with PAH receiving oral sildenafil. The duration is 16 weeks of blinded study drug followed by 32 weeks of open-label iloprost.
FREEDOM - C analyzes the addition of oral treprostinil in patients with PAH who are currently receiving approved therapy (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). TreatmentStudy duration is 16 weeks, and the primary endpoint ist he 6-MWD.
COMPASS 1 evaluates the effect of a single dose of sildenafil on pulmonary hermodynamics in 45 patients with PAH already being treated with bosentan.
COMPASS 2 studies the effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in 600 symptomatic patients with PAH being treated with a stable dose of sildenafil equal to or greater than 20 mg tid for at least 12 weeks prior to randomization. The study duration is 16 weeks, and the primary endpoints are time to clinical worsening and the improvement in 6-MWD.
COMPASS 3 is an open-label, multi-center study in 100 patients designed to assess whether a core therapy of bosentan, either as monotherapy or with the addition of sildenafil, enables patients with PAH to achieve a 6 MWD of ≥380 meters after 28 weeks of therapy This design is also appropriate to pioneer the utility of cardiac MRI in assessing improved functional capacity in PAH and exploring its correlation with other parameters.
References:
1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-1436.
2. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858-863.
3. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-522.
4. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N, Ghofrani S, Enke B, Seeger W, Grimminger F. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-164.
5. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, Block LH. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-1295.
6. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007-1010.
7. Ikeda D, Tsujino I, Ohira H, Itoh N, Kamigaki M, Ishimaru S, Sakaue S, Nishimura M. Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension. J Cardiovasc Pharmacol 2005;45:286-289.
8. Gomberg-Maitland M, McLaughlin V, Gulati M, Rich S. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. Am J Cardiol 2005;96:1334-1336.
9. Hoeper MM, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, Wensel R, Ripken F, Bremer H, Kluge S, Hoeffken G, Behr J. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006;28:691-694.
10. Beyer S, Speich R, Fischler M, Maggiorini M, Ulrich S. Long-term experience with oral or inhaled vasodilator combination therapy in patients with pulmonary hypertension. Swiss Med Wkly 2006;136:114-118.
11. Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J 2003;22:330-334.
12. Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, Hassoun PM. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007;29:469-475.
13. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-359.
14. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257-1263.
15. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming T, Burgess G, Collings L, Cossons N, Badesch DB. Safety and efficacy of sildenafil-epoprostenol combination therapy in patients with pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2007;175:A300.
16. Triumph I. - Investigational clinical trial of TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension.
http://www.lungrx.com/triumph.html
Back to > Medical > Therapy > Specific treatments
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SSPH Research Prize 2012
Deadline for submission: April 30, 2012
Further information
Symposium "pulmonal-arterielle Hypertension im Kindesalter"
Donnerstag, 10. Mai 2012, 16.00-18.00, Bern
Further information:
5th International Congress of the Swiss Society of Pulmonary Hypertension (SSPH)
28.-29. September 2012, Thun, Congress Hotel Seepark Thun
Informationen: www.imk.ch/sgph2012
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