European Heart Journal Advance Access originally published online on February 3, 2006
European Heart Journal 2006 27(5):510-511; doi:10.1093/eurheartj/ehi703
‘Raising the bar’ for the treatment of pulmonary arterial hypertension
Pulmonary Hypertension Program, University of Michigan, 1500 E. Medical Center Drive, Women's Hospital, Room L3119, Ann Arbor, MI 48109-0273, USA
* Corresponding author. Tel: +1 734 936 5383; fax: +1 734 763 7390. E-mail address: vmclaugh{at}umich.edu
This editorial refers to ‘Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension’
by S. Provencher et al., on page 589
Historically, idiopathic pulmonary arterial hypertension (IPAH, formerly referred to as primary pulmonary hypertension) has been considered a fatal disease. The natural history of IPAH was well described by the American National Institutes of Health (NIH) Registry of the 1980s. A median survival of 2.8 years with estimated single-year survival rates at 1, 3, and 5 years of 68, 48, and 35%, respectively were documented.1 Predictors of a poor prognosis included advanced functional class and haemodynamics (right atrial pressure, cardiac index, and pulmonary artery pressure). Fortunately, much has changed since the 1980s. We now several novel therapeutic options including prostacyclins, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors, all of which have improved exercise endurance in clinical trials. Surely, we have improved survival in IPAH, haven't we?
Classically, controlled clinical trials in pulmonary arterial hypertension (PAH) have studied the primary endpoint of 6-min walk distance over a short duration (12–16 weeks). Regulatory authorities have accepted the 6-min walk distance as a reliable and reproducible indicator of drug efficacy. Withholding therapy for more than 12–16 weeks was felt to be unethical, particularly early on, when the most ill patients were being entered into clinical trials. The only randomized controlled trial to ever demonstrate a survival benefit in IPAH was the open label trial with intravenous (IV) epoprostenol reported by Barst et al.2 In that 81-patient trial, 8 patients, all of whom were randomized to conventional therapy alone, died over the 12-week study, resulting in a mortality of 20%. Notably, a quarter of the patients in that trial were functional class IV at baseline. Subsequent open label observational experiences have also demonstrated a survival benefit with IV epoprostenol, either compared with historical controls, or the expected survival based on the NIH equation.3,4 Despite this apparent survival benefit, the 3-year survival with IV epoprostenol monotherapy in both these series of functional class III and IV IPAH patients was 63%. In both series, functional class was predictive of survival, both at the initiation of therapy, and when assessed after 3 or more months of therapy. Consequently, and appropriately, the most ill patients are no longer entered into clinical trials, but are treated with active medications. With less ill patients in clinical trials, over short periods of time, other therapies such as bosentan, sildenafil, treprostinil, and iloprost have established improvements in 6-min walk, leading to regulatory approval.5–9 The important question of longer term outcomes has not been answered by these brief trials.
Provencher et al.10 describe the long-term outcomes of 103 consecutive functional class III and IV IPAH patients treated with the oral endothelin receptor antagonist, bosentan, as first-line therapy. Using a stringent treatment algorithm, additional therapy with prostanoids (primarily IV epoprostenol) was recommended for patients with functional class IV symptoms on treatment, or persistent functional class III symptoms after at least 4 months of treatment, together with (1) a 6-min walk distance of <250 m; (2) a >10% decrease in 6-min walk distance from the previous value in two tests performed at least 2 weeks apart; or (3) a cardiac index of <2.2 L min–1 m–2. At 4 months, improvements in 6-min walk distance (42 m) and haemodynamics were similar to the findings of the randomized controlled trials.5,6 Functional class improved in 48% of patients, remained stable in 42%, and deteriorated in 9%. Overall survival estimates at 1 and 2 years were 90 and 87%, respectively. However, event-free survival estimates were 61 and 44% at 1 and 2 years, respectively. During the mean follow-up period of 24±15 months, 13 patients died (8 after the initiation of a prostanoid) and 36 were treated with a prostanoid. Prostanoid therapy was proposed to an additional nine patients who either declined (n=5) or were unable to manipulate the complex delivery system (n=4). Important predictors of outcome included the 6-min walk distance and right atrial pressure at baseline, and the 6-min walk distance, increase in 6-min walk distance, and decrease in total pulmonary resistance at 4 months of therapy. These overall survival data are similar to those previously reported among the 169 IPAH patients who were followed in an open label fashion after participation in the placebo-controlled trials in whom the 1 and 2 year survival estimates were 96 and 89%, respectively.11 Conversely, a greater proportion of patients in the current study received additional prostanoid therapy, no doubt a result of the demanding treatment algorithm.
Provencher et al. are to be applauded for this exceptional work. Notwithstanding the many limitations of a retrospective analysis, Provencher et al. have described the outcomes with bosentan as first-line therapy in clinical practice. More importantly, they advocate that we ‘raise the bar’ for the treatment of PAH. Boosting 6-min walk distance by 40 m in a 16-week clinical trial may lead to regulatory approval, but in clinical practice over the longer term, we must elevate our treatment goals. Hoeper et al.12 have recently proposed a similar ‘goal-oriented’ treatment approach, with escalation of therapy if a patient did not achieve a 6-min walk >380 m, a peak oxygen uptake >10.4 mL min–1 kg–1, or a peak systolic blood pressure during exercise of >120 mmHg. Now that we have available therapies that target three different mechanisms of action, we have additional options should a patient not reach that desired goal.
Like many commendable studies, this research by Provencher et al. raises as many questions as it answers. How high should the bar be raised? What should be the treatment goals? What drugs should be used and in what order? Functional class, albeit subjective, is a powerful predictor of survival. Should we intensify medical therapy in patients who remain functional class III with suboptimal 6-min walks or haemodynamics as Provencher et al. did? Or given the prognostic implications of functional class in patients treated with IV epoprostenol in the longer term observational studies, should we strive to achieve functional class II status in all patients? What is the 6-min walk distance with which we should be content? How important are haemodynamic changes? As most patients prefer oral therapy, would adding sildenafil to bosentan achieve similar results? Given the wealth of data available attesting the benefits of IV epoprostenol in PAH, should a prostanoid (IV, inhaled, or oral) be part of the treatment regimen for most PAH patients? The questions could go on endlessly.
We now have therapeutic agents from three different classes with which to treat PAH patients. Although they have all demonstrated symptomatic benefit, none of them represent a cure for this devastating disease. In most cases, none of them normalize exercise endurance or haemodynamics. Although we continue to search for the cure for PAH, we are obligated to establish evidence-based practices that use our current tools as safely and effectively as possible. We need to further understand the treatment goals for which we should strive in our patients. Several randomized controlled clinical trials of combination therapy for PAH are currently underway, and others will be starting shortly. As a community, we are compelled to answer the questions of combination therapy and treatment goals in an evidence-based fashion. We need to learn not only whether combination therapy will allow a patient to walk another 40 m, but whether we really do improve longer term outcomes including survival. Yes, it is time to ‘raise the bar’ on the treatment of PAH.
Conflict of interest: Grant support for clinical trials: Actelion, CoTherix, Encysive, Lung Rx, Myogen, Pfizer, United Therapeutics Consultant and/or honoraria: Actelion, Caremark, Cotherix, Encysive, Myogen, Pfizer, Priority Healthcare, United Therapeutics.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi728 
References
- D'Alonzo G, Barst R, Ayres S, Bergofsky E, Brundage B, Detre K, Fishman A, Goldring R, Groves B, Kernis J. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Int Med 1991;115:343–349.
[Abstract/Free Full Text] - Barst R, Rubin L, Long W, McGoon M, Rich S, Badesch D, Groves B, Tapson V, Bourge R, Brundage B, Koerner S, Langleben D, Keller C, Murali S, Uretsky B, Clayton L, Jobsis M, Blackburn S, Shortino D, Crow J. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296–301.
[Abstract/Free Full Text] - Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–788.
[Abstract/Free Full Text] - McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477–1482.
[Abstract/Free Full Text] - Rubin L, Badesch D, Barst R, Galie N, Black C, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
[Abstract/Free Full Text] - Channick R, Simonneau G, Sitbon O, Robbins I, Frost A, Tapson V, Badesch D, Roux S, Rainisio M, Bodin F, Rubin L. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–1123.[CrossRef][Web of Science][Medline]
- Galie N, Ghofrani H, Torbicki A. Sildenafil citrate for pulmonary arterial hypertension. N Engl J Med 2005;353:38–47.
- Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800–804.
[Abstract/Free Full Text] - Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin L, Nikkho S, Speich R, Hoeper M, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani H, Manes A, Kiely D, Ewwert R, Meyer A, Corris P, Delcrox M, Gomez-Sanchez M, Siedentop H, Seeger W. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322–329.
[Abstract/Free Full Text] - Provencher S, Sitbon O, Humbert M, Ségolène C, Jais X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27:589–595. First published on January 23, 2006, doi:10.1093/eurheartj/ehi728.
[Abstract/Free Full Text] - McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244–249.
[Abstract/Free Full Text] - 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.
[Abstract/Free Full Text]
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Related articles in EHJ:
- Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension
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EHJ 2006 27: 589-595.[Abstract] [FREE Full Text]
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