© 2005 American Thoracic Society doi: 10.1164/rccm.2503002
Pulmonary Arterial HypertensionThe Race for the Most Effective Treatment
a Department of Internal Medicine, Division of Cardiovascular Disease, University of Michigan, Ann Arbor, Michigan In 1995, intravenous epoprostenol became the first U.S. Food and Drug Administration–approved therapy for pulmonary arterial hypertension (PAH). It was the only therapy available until the approval of bosentan in late 2001. Since then, two additional agents, treprostinil (both subcutaneous and intravenous) and inhaled iloprost, have received approval, and the additional indication of sildenafil for PAH is imminent. Other endothelin receptor antagonists, sitaxsentan and ambrisentan, are in late stages of clinical development and may receive approval in the next 1 to 2 years. These therapies target one of three different pathways involved in the pathobiology of PAH: the prostacylin pathway (epoprostenol, treprostinil, iloprost), the endothelin pathway (bosentan, sitaxsentan, ambrisentan), and the nitric oxide pathway (sildenafil) (1, 2). Physicians and patients now have a choice of therapies for this devastating disease. How do we choose? Comparing clinical trials performed over more than a decade is difficult at best. With the commercial availability of PAH therapies, the characteristics of patients enrolled into randomized placebo-controlled trials have shifted toward a less ill population. A well designed superiority study, or even a noninferiority study, would require a prohibitively large number of patients to be enrolled (3). In addition, such trials are of short duration, generally 3 to 4 months, leaving many questions regarding long-term efficacy, safety, and survival unanswered. Wilkins and colleagues (4) make the first attempt at a direct comparison of two oral therapies, bosentan and sildenafil, with the Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study, published in this issue (pp. 1292–1297). This 26-patient study found no significant difference in the primary endpoint of right ventricular mass, or the more common endpoint of 6-minute walk distance, over a 16-week period. Trends, however, were in favor of sildenafil, with a reduction in right ventricular mass of 8.8 g in the sildenafil group and 3.0 g in the bosentan group, and increases in 6-minute walk distance of 75 m (imputing a 0 for the patient who died, or 114 m excluding this patient) and 59 m, respectively, in the two groups. The choice of right ventricular mass as measured by magnetic resonance imaging is an intriguing, but perhaps premature, endpoint. Right ventricular hypertrophy is a necessary and life-saving adaptive mechanism to pulmonary vascular obliteration, and the prognostic implications of changes in right ventricular muscle mass have never been determined. Substantial and sustained reductions in pulmonary artery pressure might lead to remodeling of the right ventricle. However, a clinically meaningful reduction in right ventricular mass will likely require longer than 4 months of therapy. At this time, we feel that right ventricular mass as measured by magnetic resonance imaging is an investigational tool and most appropriate as a secondary or supportive endpoint. The secondary endpoint of 6-minute walk distance, commonly used in clinical trials and familiar to most clinicians, is provocative. In both treatment groups, the improvement in 6-minute walk distance exceeded that reported in the large placebo-controlled trials. Rubin and coworkers (5) reported a placebo-corrected treatment effect of 44 m with bosentan (5), whereas Ghofrani found placebo-corrected improvements of 45, 46, and 50 m, respectively, in the 20, 40, and 80 mg three-times-daily sildenafil study groups. The improvements of 75 m with sildenafil and 59 m with bosentan in the SERAPH trial are most likely the result of the small sample size, and potentially a handful of quite exuberant responders in the sildenafil group, as pictured in Figure 3 of the article by Wilkins and colleagues. Nevertheless, the consistent improvement in exercise capacity demonstrated with both bosentan and sildenafil in numerous trials secures a role for each in the management of PAH. Although the SERAPH study is an admirable endeavor, it is not without limitations—principally, the small sample size. The imbalance in baseline characteristics, particularly regarding the use of calcium channel blockers, the lack of invasive hemodynamic data, and the short study duration are other limitations. Furthermore, although it may have been a chance occurrence, the sudden death of one patient in the sildenafil group is concerning and warrants further vigilance. So again, we ask, how do we choose? Do the results of the SERAPH study insinuate that sildenafil is preferable to bosentan? Absolutely not. Although the 6-minute walk improvements might appear more profound with sildenafil in this small trial, the differences were not statistically significant. Randomized placebo-controlled trials have established comparable improvements in 6-minute walk distance and hemodynamics with both treatments. In the pivotal placebo-controlled trial, bosentan also decreased time to clinical worsening, and long-term observational data have suggested an improvement in survival (5, 6). Comparable long-term data are not yet available for sildenafil. Does that make bosentan the drug of first choice? It's too soon to tell. Although the results of the 3-month placebo-controlled trial with sildenafil are encouraging, and similar to that of bosentan, we await longer term data. Improving exercise capacity and hemodynamics is a first step. Augmenting survival is the long-term goal. Although we are delighted to have both bosentan and sildenafil in our therapeutic armamentarium, neither is a panacea. Although both drugs ameliorate symptoms and improve exercise capacity, neither normalizes hemodynamics nor shifts all patients to functional class I status. To us, the question is not "bosentan or sildenafil?" The question is "bosentan and sildenafil?" Our colleagues on the left side of the heart are years ahead of us with regard to combination therapy. They have identified multiple aberrant pathways in the pathogenesis of left ventricular systolic dysfunction, and now, successfully, use medicines with multiple mechanisms of action to treat that disorder (7). We have now identified multiple pathways involved in the pathogenesis of PAH. Why not target them all? Small, uncontrolled trials have suggested beneficial effects of combinations of both prostanoids with sildenafil (8–10), and bosentan with sildenafil (11). Although the potential for a drug–drug interaction between bosentan and sildenafil cannot be discounted, a well designed trial with the combination of two oral therapies is urgently needed. Who knows? By the time the bosentan and sildenafil study is completed, we might have a long-acting oral or inhaled prostanoid to add to the mix. We might be a decade behind our colleagues on the left side of the heart, but we are poised to catch up to them. FOOTNOTES Conflict of Interest Statement: V.V.M. has served as a consultant, speaker, and/or member of the advisory board for Actelion, CoTherix, Encysive, Myogen, Pfizer, and United Therapeutics. Over the past 3 years, her center has received $95,571 from CoTherix, $68,831 from Encysive, $204,000 from Pfizer, and $184,394 from United Therapeutics for participation in multicenter clinical trials; M.M.H. received honorariums from Actelion Pharmaceuticals for speaking at conferences and consultancies. He has received a grant from Actelion Pharmaceuticals. He has also received speaker's fees from Pfizer Ltd. and Schering, Germany. REFERENCES
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