Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition that has traditionally required treatment with continuous intravenous epoprostenol via an indwelling central catheter.1–3 Such therapy improves outcome, but is fraught with side effects, expense, and risk of catheter-related complications. Therapy of PAH has evolved tremendously in recent years, reflecting the development of novel therapeutic agents and modes of delivery that target either vasodilator pathways that are deficient or vasoconstrictor pathways that are activated in PAH patients. These agents include oral endothelin antagonists (bosentan,4–6 sitaxsentan,7,8 ambrisentan9), phosphodiesterase (PDE)-5 inhibitors (sildenafil,10 tadalafil), and prostanoids that do not necessarily require intravenous delivery (inhaled iloprost,11,12 subcutaneous treprostinil13).
Treprostinil is a prostacyclin analog with a half-life of three hours, which, unlike epoprostenol, is stable at room temperature. It is US Food and Drug Administration (FDA)-approved for both intravenous and subcutaneous use. Owing to its stability, longer half-life, and equivalent hemodynamic effect when given subcutaneously, it has been clinically applied in this manner. Compared with placebo, subcutaneous treprostinil tends to improve exercise capacity on six-minute walk testing, quality of life, and hemodynamics, but the benefits in the randomized trial were quite small, probably reflecting low dosing in the short-term trial. At higher doses and among more symptomatic patients, the beneficial effects are much more pronounced.
Treprostinil exhibits a similar side-effect profile to epoprostenol, but also often produces pain at the infusion site. This may limit the ability to raise subcutaneous doses to a level likely to produce optimal benefit in some patients. However, it can be effective in patients who can tolerate appropriate subcutaneous doses. The expense of treprostinil is greater than that of epoprostenol, since it is less potent on a per milligram basis. The advantages of treprostinil are the potential absence of a central venous catheter if given subcutaneously, smaller infusion pump apparatus, and the use of a drug that does not need to be mixed with diluent by the patient immediately prior to administration. It is also effective for intravenous use, and its longer half-life compared with epoprostenol may be an advantage in the situation of an inadvertent disconnect during therapy of a highly dependent patient. Randomized placebo-controlled trials of inhaled and oral preparations of treprostinil are in progress.
Iloprost is a stable prostacyclin analog available in Europe for intravenous and aerosolized administration, and in the US for aerosolized administration. Inhaled iloprost improves functional class, exercise capacity, and pulmonary hemodynamics in open and randomized studies, with side effects of flushing, headache, and cough in some patients. The relatively short duration of action of inhaled iloprost means five- to 15-minute inhalations are required six to nine times daily in order to obtain a sustained clinical benefit. It is often used in combination with an oral agent such as bosentan or sildenafil. It does not appear to be as effective as continuous epoprostenol or treprostinil because its half-life is so short that pressures bounce back up between treatments. Patients with progressive symptoms despite inhaled iloprost combined with an oral agent should be converted from iloprost to a continuous prostanoid infusion.14
Bosentan is a non-selective endothelin receptor antagonist, blocking the action of endothelin-1 (ET-1), a potent vasoconstrictor and smooth-muscle mitogen, at endothelin A and B (ETA and ETB, respectively) receptors. Its therapeutic effect derives from reduction of vasoconstriction and pulmonary vascular hypertrophy caused by increased plasma levels of ET-1 in patients with PAH, and it is mediated predominantly via ETA receptors. Clinical studies of bosentan have demonstrated functional classification, improved pulmonary hemodynamics, and an augmented six-minute walk distance compared with placebo, leading to FDA approval of the medication. Side effects associated with bosentan include dose-dependent elevation of transaminases reflecting hepatic toxicity, syncope, and flushing.
Other Endothelin Receptor Antagonists
Sitaxsentan and ambrisentan are ETA receptor-selective agents that have completed randomized studies. Initial phase III study results suggest that both agents improve exercise capacity, functional class, and pulmonary hemodynamics at 12-week follow-up. Both are under consideration by the FDA and both appear to have similar efficacy to bosentan. Sitaxsentan has a serious interaction with warfarin that necessitates careful downward adjustment of warfarin dosing. Liver function test abnormalities may be less common with sitaxsentan and ambrisentan, but can still occur.
Nitric oxide (NO) is an endogenous vasodilator produced from L-arginine by endothelial cells. It vasodilates by producing cyclic guanosine monophosphate (cGMP), which in turn is degraded by PDE. Agents that inhibit the predominant PDE in the pulmonary vasculature (PDE5) augment the pulmonary vascular response to endogenous NO. Sildenafil is a potent and highly specific PDE5 inhibitor that is effective in improving six-minute walk distance, functional class, and hemodynamics in PAH. It is approved for treatment of PAH at a dose of 20mg three times a day. Randomized trials of the once-daily PDE5 inhibitor tadalafil are in progress.
This plethora of therapeutic alternatives is a welcome advance, but brings with it a host of critical issues that must be addressed in the next decade. These issues fall into three broad categories: defining the role of combination therapy, establishing the appropriate strategy and goals of therapy in order to optimize long-term outcome, and defining the role of antiproliferative therapy and understanding which agents are most effective in this regard.
Role of Combination Therapy
In order to understand this issue it is helpful to draw an analogy with the development of effective therapy for congestive heart failure (CHF). New therapeutic agents have usually been studied in addition to, not instead of, previously proven therapy. The randomized trials that demonstrated efficacy of beta-blockers in CHF, for example, studied patients who were already being treated with angiotensin-converting enzyme (ACE) inhibitors. With the results of these trials the therapeutic strategy became clear: add a beta-blocker to a regimen that includes an ACE inhibitor. Therapy for PAH has largely developed in silos (e.g. the randomized trials of sildenafil excluded patients on bosentan), thereby leaving the question of additive therapy unaddressed. This deficiency is now being addressed by randomized trials of combination therapy. However, conducting the necessary trials of combination therapy in PAH is more difficult than it was for CHF because of the much smaller cohort of PAH patients, complicating trial recruitment efforts.
Given the large number of possible therapeutic combinations and the need for larger trials to prove the efficacy of combination therapy, successful completion of these trials requires the careful attention of the PAH community. Fortunately, patients with PAH have traditionally been extremely supportive of research involvement and have been cared for at academic centers cognizant of the critical nature of PAH research. However, the deceptive simplicity of oral therapy poses some risk to this critical endeavor, if referral of PAH patients to centers engaged in research were to trail off as practitioners consider initiation of therapy in the non-academic practice setting. For this reason, and because monitoring therapy and prognosis in PAH remains highly complex, referral of patients to a tertiary PAH center is strongly encouraged. It is reasonable to hypothesize that ‘triple therapy’ with an endothelin antagonist, a PDE5 inhibitor, and a sustained-acting prostanoid will provide superior outcomes to less intensive therapy, but it will require the concerted efforts of the PAH community to test this important hypothesis.
Establishing the Appropriate Strategy and Goals of Therapy in Order to Optimize Long-term Outcome
Randomized placebo-controlled trials of PAH therapy have usually been short (12–16 weeks), and have had primary end-points of improvement in exercise tolerance (six-minute walk distance). Such an approach has been effective in bringing new therapeutic alternatives to market, but leaves important questions unanswered. Is tiered therapy (starting with an oral agent and adding a second agent, or switching to a different agent only when deterioration has occurred) an effective strategy, or is early aggressive therapy with a continuous prostanoid or combination therapy superior? What are the appropriate end-points in deciding when to alter therapy? For a patient who is currently being treated with oral monotherapy, which of the following end-points should be reached prior to a recommendation for additional therapy:
- failure to achieve or maintain a six-minute walk distance >380m;15
- failure to achieve or maintain World Health Organization (WHO) functional class II status;15
- failure to achieve or maintain a right atrial pressure of 12mmHg or less;15
- failure to achieve or maintain brain natriuretic peptide level <180pg/ml;16
- failure to achieve or maintain right-ventricular end-diastolic volume <84ml/m2;17 or
- none of the above—optimal outcome will be achieved by aggressive therapy earlier in the course of the disease, not by waiting until deterioration occurs.
Intermediate-term (two-year) observational studies of oral monotherapy with bosentan, reserving addition of other therapy for patients who deteriorate, suggest reasonable outcome, but the length of follow-up is too short for long-term outcomes of such a strategy to be certain, and addition of other therapies is often needed.18–20 An observational study of subcutaneous treprostinil found 70% four-year survival with monotherapy.21 Generating the necessary data to answer questions like these should be a top priority of the PAH community for the coming decade.
The six-minute walk distance is widely utilized in clinical practice and as an end-point in PAH trials, so there are ample data relating outcome to walk distance, demonstrating that PAH patients with a walk distance <380m despite at least three months of epoprostenol therapy had worse outcomes than patients with greater walk distances.11
Limitations of walk distance as a prognostic marker include failure to account for age, level of fitness, weight, and orthopaedic conditions. Young patients who are otherwise fit can sometimes maintain six-minute walk distances of 400–550m even in the presence of severe progressive PAH as exhibited by progressive right-ventricular dilation, worsening tricuspid regurgitation and need for escalating diuretic dosing, and elevated and/or rising B-type natriuretic peptide (BNP) levels. They appear to be at risk for rather abrupt clinical deterioration. For such patients, it is intuitively appealing to believe that increasingly aggressive therapy implemented prior to deterioration of six-minute walk distance should improve long-term outcomes, but such a strategy has never been extensively tested.
Goal-oriented therapy based on six-minute walk distance >380m, peak oxygen consumption >10.4ml/kg/min, and systolic blood pressure >120mmHg during exercise has been proposed as a strategy for guiding therapy.22 Future studies will increasingly examine the role of prognostic markers such as six-minute walk distance, neurohormones (BNP, N-terminal BNP), right-ventricular volume/function by magnetic resonance imaging (MRI) or computed tomography (CT), and hemodynamics (obtained via implantable hemodynamic monitors23 or serial catheterization) in guiding therapy and optimizing outcome.Distinguishing Disease-modifying Therapy from Symptomatic Relief
Treatment of inflammatory arthritides such as rheumatoid arthritis took a quantum step forward with the recognition of the role of therapies that not only relieve symptoms but also modify the course of the disease. This includes agents such as methotrexate and the tumor necrosis factor-alpha antagonists (e.g. infliximab). The understanding of which, if any, of the currently available vasodilator therapies for PAH are disease-modifying is in its infancy, due in large part to the short duration of randomized trials and the lack of readily available biomarkers of pulmonary vascular pathological progression. It is understood that the currently available agents appear to improve outcome compared with historical controls. This may reflect the antiproliferative effects of these agents, as demonstrated in animal models of PAH, but this remains to be proved in humans. Future studies will focus on the role of both novel vasodilator agents that may also possess antiproliferative effects such as Rho-kinase inhibitors (e.g. fasudil24–26), vasoactive intestinal peptide,27 and specific antiproliferative agents such as platelet-derived growth factor receptor inhibitors (e.g. imatinib28,29) and serine elastase inhibitors.30,31