Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The Sildenafil Use in Pulmonary Hypertension (SUPER) trial (Nov. 17 issue)1 has led to the approval of sildenafil for the treatment of pulmonary arterial hypertension by the Food and Drug Administration and its European counterpart, the European Medicines Agency. Although the availability of a new treatment is embraced, the agencies have created a major problem by restricting the sildenafil dose to 20 mg three times a day. The SUPER trial involved three doses — 20 mg, 40 mg, and 80 mg three times a day. Although all doses had similar effects with regard to the distance walked in six minutes, there was a trend toward improved hemodynamics with increasing doses of sildenafil, apparently without causing an increase in side effects. Impressive results were reported from the open-label extension of the SUPER trial, in which the majority of patients received 80 mg three times a day. The long-term efficacy of the approved dose of 20 mg three times a day remains unknown, and this dose may prove insufficient when patients are treated over extended periods of time, especially when they are receiving concomitant bosentan therapy.2,3 Although probably intended to protect patients, the decision to limit the sildenafil dose to 20 mg three times a day may cause substantial harm by preventing the use of appropriate doses.
Marius M. Hoeper, M.D.
Tobias Welte, M.D.
Hannover Medical School
30627 Hannover, Germany
hoeper.marius@mh-hannover.de
Dr. Hoeper reports having received lecture fees and consulting fees from Pfizer and Actelion.
References
Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-2157.
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.
Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005;60:107-112.
To the Editor: In a double-blind, randomized, placebo-controlled study, Galiè et al.1 showed that sildenafil improves exercise capacity, World Health Organization (WHO) functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. As stated in the introduction of this report, four agents are currently approved and recommended according to international guidelines1 for the treatment of pulmonary arterial hypertension: intravenous epoprostenol, inhaled iloprost, subcutaneous and intravenous treprostinil and oral bosentan. Intravenous epoprostenol2 and oral bosentan3 have been shown to improve survival in prospective, randomized, placebo-controlled trials involving patients with idiopathic pulmonary arterial hypertension. Galiè, in a review,4 stated that a substantial part of the treatment effect observed in placebo-controlled studies is linked to a deterioration in the condition of placebo-treated patients. Owing to the fact that randomized, placebo-controlled studies showed a survival advantage in already-approved drugs, new placebo-controlled studies and publications on this topic should be restrained. A clear preference should be given by both clinicians and journal editors to studies comparing existing and approved treatments for pulmonary arterial hypertension.
Gabriel Izbicki, M.D.
Dror Rosengarten, M.D.
Elie Picard, M.D.
Shaare Zedek Medical Center
91301 Jerusalem, Israel
izbicki@szmc.org.il
References
Galie N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:Suppl 12:81S-88S.
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-788.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
Galie N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Eur Respir J 2002;20:1037-1049.
To the Editor: Galiè et al. are not sufficiently explicit in reporting exclusion criteria for the enrollment of subjects in their study of sildenafil citrate therapy for pulmonary arterial hypertension. Presumably, coexisting chronic lower respiratory tract disease, such as chronic obstructive pulmonary disease (COPD), was an exclusion criterion; however, the authors do not state this, nor do they report a case definition of COPD or other chronic lower respiratory tract diseases used to exclude potential subjects during screening. The authors present no information on smoking history or pulmonary function in enrolled subjects.
Pulmonary hypertension associated with chronic lower respiratory tract disease, such as COPD, is much more prevalent than the relatively uncommon class of pulmonary hypertension studied in this trial.1 Galiè et al. should state, explicitly, that findings from their investigation should not be presumed generalizable to patients with the most common presentations of pulmonary hypertension, including that associated with COPD, and that another prospective randomized, controlled trial would be necessary to determine the effects of sildenafil citrate in this large population with pulmonary hypertension.
Ware G. Kuschner, M.D.
Veterans Affairs Palo Alto Health Care System
Palo Alto, CA 94304
ware.kuschnermd@med.va.gov
References
Hyduk A, Croft JB, Ayala C, Zheng K, Zheng ZJ, Mensah GA. Pulmonary hypertension surveillance -- United States, 1980-2002. MMWR Surveill Summ 2005;54:1-28.
The authors reply: Although we agree with Dr. Izbicki and colleagues that studies comparing treatments would help physicians in selecting therapy, from both a practical and regulatory perspective it is necessary first to demonstrate the therapeutic efficacy of a drug. Furthermore, comparative studies are complicated by issues involving blinding and the need for large sample sizes. Among currently approved treatments for pulmonary arterial hypertension, only intravenous epoprostenol has been shown to improve survival in a controlled clinical trial involving severely compromised patients.1 Patients in WHO class IV who were eligible for this treatment were excluded from subsequent clinical trials for ethical reasons. The SUPER study protocol was discussed in 2001 and 2002 with regulatory authorities. Local institutional review boards or independent ethics committees of all participating centers approved the protocol, and written informed consent was obtained from all patients. Neither increased mortality nor deterioration in terms of exercise capacity from baseline was observed in the placebo group of the SUPER study.
The SUPER study included only patients with pulmonary arterial hypertension2 and consisted of persons with idiopathic pulmonary arterial hypertension and that associated with connective-tissue diseases or corrected congenital heart diseases. The criteria used to exclude patients with serious parenchymal lung diseases as the causes of pulmonary hypertension, which have been used in all studies of pulmonary arterial hypertension, were restrictive lung disease (involving a total lung capacity of less than 60 percent predicted) and obstructive airway disease (a forced expiratory volume in one second that was less than 80 percent of the predicted value). Accordingly, the results of the SUPER study cannot be extrapolated for patients with pulmonary hypertension related to lung diseases.
Drs. Hoeper and Welte are correct in their suggestion that there is a linear trend in the response among the doses in the hemodynamic measures and in the percentages of patients who improved by at least one WHO functional class. The absence of a dose–response effect on the primary end point (exercise capacity) or on tolerability with the three sildenafil doses (20 mg, 40 mg, and 80 mg three times daily) may be related to complete inhibition of phosphodiesterase type 5 with the lowest dose. However, in the extension study, all patients were treated with 80 mg three times daily (if tolerated), and we do not have prospective information on the long-term efficacy of the approved dose of 20 mg three times daily. Based on these data, 20 mg three times daily appears to be a reasonable initial dose; an increase to 40 mg three times daily, 80 mg three times daily, or both may be considered in order to achieve or maintain favorable effects. We recognize that limited data are currently available regarding the optimal dose of sildenafil for long-term treatment and that the use of higher doses may be hampered by the restricted approval.
Nazzareno Galiè, M.D.
University of Bologna
40138 Bologna, Italy
nazzareno.galie@unibo.it
Lewis J. Rubin, M.D.
University of California at San Diego
La Jolla, CA 92103-8372
Gérald Simonneau, M.D.
Hopital Antoine Béclère
92140 Clamart, France
References
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302.
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:Suppl 12:5S-12S.
Marius M. Hoeper, M.D.
Tobias Welte, M.D.
Hannover Medical School
30627 Hannover, Germany
hoeper.marius@mh-hannover.de
Dr. Hoeper reports having received lecture fees and consulting fees from Pfizer and Actelion.
References
Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-2157.
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.
Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005;60:107-112.
To the Editor: In a double-blind, randomized, placebo-controlled study, Galiè et al.1 showed that sildenafil improves exercise capacity, World Health Organization (WHO) functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. As stated in the introduction of this report, four agents are currently approved and recommended according to international guidelines1 for the treatment of pulmonary arterial hypertension: intravenous epoprostenol, inhaled iloprost, subcutaneous and intravenous treprostinil and oral bosentan. Intravenous epoprostenol2 and oral bosentan3 have been shown to improve survival in prospective, randomized, placebo-controlled trials involving patients with idiopathic pulmonary arterial hypertension. Galiè, in a review,4 stated that a substantial part of the treatment effect observed in placebo-controlled studies is linked to a deterioration in the condition of placebo-treated patients. Owing to the fact that randomized, placebo-controlled studies showed a survival advantage in already-approved drugs, new placebo-controlled studies and publications on this topic should be restrained. A clear preference should be given by both clinicians and journal editors to studies comparing existing and approved treatments for pulmonary arterial hypertension.
Gabriel Izbicki, M.D.
Dror Rosengarten, M.D.
Elie Picard, M.D.
Shaare Zedek Medical Center
91301 Jerusalem, Israel
izbicki@szmc.org.il
References
Galie N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:Suppl 12:81S-88S.
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-788.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
Galie N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Eur Respir J 2002;20:1037-1049.
To the Editor: Galiè et al. are not sufficiently explicit in reporting exclusion criteria for the enrollment of subjects in their study of sildenafil citrate therapy for pulmonary arterial hypertension. Presumably, coexisting chronic lower respiratory tract disease, such as chronic obstructive pulmonary disease (COPD), was an exclusion criterion; however, the authors do not state this, nor do they report a case definition of COPD or other chronic lower respiratory tract diseases used to exclude potential subjects during screening. The authors present no information on smoking history or pulmonary function in enrolled subjects.
Pulmonary hypertension associated with chronic lower respiratory tract disease, such as COPD, is much more prevalent than the relatively uncommon class of pulmonary hypertension studied in this trial.1 Galiè et al. should state, explicitly, that findings from their investigation should not be presumed generalizable to patients with the most common presentations of pulmonary hypertension, including that associated with COPD, and that another prospective randomized, controlled trial would be necessary to determine the effects of sildenafil citrate in this large population with pulmonary hypertension.
Ware G. Kuschner, M.D.
Veterans Affairs Palo Alto Health Care System
Palo Alto, CA 94304
ware.kuschnermd@med.va.gov
References
Hyduk A, Croft JB, Ayala C, Zheng K, Zheng ZJ, Mensah GA. Pulmonary hypertension surveillance -- United States, 1980-2002. MMWR Surveill Summ 2005;54:1-28.
The authors reply: Although we agree with Dr. Izbicki and colleagues that studies comparing treatments would help physicians in selecting therapy, from both a practical and regulatory perspective it is necessary first to demonstrate the therapeutic efficacy of a drug. Furthermore, comparative studies are complicated by issues involving blinding and the need for large sample sizes. Among currently approved treatments for pulmonary arterial hypertension, only intravenous epoprostenol has been shown to improve survival in a controlled clinical trial involving severely compromised patients.1 Patients in WHO class IV who were eligible for this treatment were excluded from subsequent clinical trials for ethical reasons. The SUPER study protocol was discussed in 2001 and 2002 with regulatory authorities. Local institutional review boards or independent ethics committees of all participating centers approved the protocol, and written informed consent was obtained from all patients. Neither increased mortality nor deterioration in terms of exercise capacity from baseline was observed in the placebo group of the SUPER study.
The SUPER study included only patients with pulmonary arterial hypertension2 and consisted of persons with idiopathic pulmonary arterial hypertension and that associated with connective-tissue diseases or corrected congenital heart diseases. The criteria used to exclude patients with serious parenchymal lung diseases as the causes of pulmonary hypertension, which have been used in all studies of pulmonary arterial hypertension, were restrictive lung disease (involving a total lung capacity of less than 60 percent predicted) and obstructive airway disease (a forced expiratory volume in one second that was less than 80 percent of the predicted value). Accordingly, the results of the SUPER study cannot be extrapolated for patients with pulmonary hypertension related to lung diseases.
Drs. Hoeper and Welte are correct in their suggestion that there is a linear trend in the response among the doses in the hemodynamic measures and in the percentages of patients who improved by at least one WHO functional class. The absence of a dose–response effect on the primary end point (exercise capacity) or on tolerability with the three sildenafil doses (20 mg, 40 mg, and 80 mg three times daily) may be related to complete inhibition of phosphodiesterase type 5 with the lowest dose. However, in the extension study, all patients were treated with 80 mg three times daily (if tolerated), and we do not have prospective information on the long-term efficacy of the approved dose of 20 mg three times daily. Based on these data, 20 mg three times daily appears to be a reasonable initial dose; an increase to 40 mg three times daily, 80 mg three times daily, or both may be considered in order to achieve or maintain favorable effects. We recognize that limited data are currently available regarding the optimal dose of sildenafil for long-term treatment and that the use of higher doses may be hampered by the restricted approval.
Nazzareno Galiè, M.D.
University of Bologna
40138 Bologna, Italy
nazzareno.galie@unibo.it
Lewis J. Rubin, M.D.
University of California at San Diego
La Jolla, CA 92103-8372
Gérald Simonneau, M.D.
Hopital Antoine Béclère
92140 Clamart, France
References
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302.
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:Suppl 12:5S-12S.