Review

Continuing Medical EducationNature Clinical Practice Cardiovascular Medicine (2007) 4, 319-329
doi:10.1038/ncpcardio0890  
Received 12 September 2006 | Accepted 1 March 2007

Pulmonary arterial hypertension: current therapeutic strategies

Aniket Puri, Michael D McGoon and Sudhir S Kushwaha*  About the authors

Correspondence *Mayo Clinic (GO 5-469), 200 First Street, SW, Rochester, MN 55905, USA

Email kushwaha.sudhir@mayo.edu

Summary

The treatment of pulmonary arterial hypertension—once a lethal condition—has evolved considerably over the past few years as the number of therapeutic options available to treat this disease has increased. In this Review we attempt to summarize the current knowledge of the pathogenesis of pulmonary hypertension, in relation to the therapies presently available and those that could become available in the near future. The use of prostacyclin and its analogs, calcium-channel blockers, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors is reviewed. Newer concepts, such as the use of combination therapy, and the potential for long-term disease amelioration and improvement of outcomes, are also discussed. The role of supportive care and medications not specific to pulmonary hypertension is also examined. In addition, we review the novel emerging therapies, such as imatinib, fasudil, simvastatin, ghrelin and vasoactive intestinal peptide, which hold therapeutic potential for disease modification as well as treatment of symptoms.

Review criteria

A search for original articles focusing on pulmonary hypertension and its treatment was performed in MEDLINE and PubMed with no date restrictions. All papers identified were English-language, full-text publications. The reference lists of identified articles were also searched for further papers and reviews.

Keywords:

endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclin, pulmonary arterial hypertension, pulmonary hypertension

Medscape Continuing Medical Education online

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Describe the pathogenesis of pulmonary arterial hypertension (PAH).
  2. Identify best practices for currently available treatments for PAH.
  3. Specify benefits of new treatments for PAH.

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Introduction

Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure (PAP) of greater than 25 mmHg at rest or at least 30 mmHg during exercise. These rises in PAP have to be associated with elevated pulmonary vascular resistance (PVR), and a mean pulmonary wedge pressure and left ventricular end diastolic pressure of less than 15 mmHg for diagnosis of PAH. Ultimately, continuous elevation of PAP and PVR causes failure of the right ventricle, leading to an inability to support the circulation and subsequent death.1

In 1998, the WHO (Evian) classification system was proposed, which sought to categorize different forms of pulmonary hypertension (PH) according to similarities in pathophysiological mechanisms, clinical presentation and therapeutic options.2 In 2003 in Venice, modifications were made to this system, with the aim of making it more comprehensive, easier to follow and more practical for clinicians (Box 1).3 In this system the risk factors and associated conditions were updated and modifications were proposed, including replacing the term 'primary pulmonary hypertension' with 'idiopathic pulmonary arterial hypertension (IPAH)'. Guidelines were also proposed to improve the classification of congenital systemic-to-pulmonary shunts.

Box 1 Revised clinical classification of pulmonary hypertension (Venice 2003).

  1. Pulmonary arterial hypertension
        1.1. Idiopathic
        1.2. Familial
        1.3. Associated with:
            1.3.1. Collagen vascular disease
            1.3.2. Congenital systemic-to-pulmonary shuntsa
            1.3.3. Portal hypertension
            1.3.4. HIV infection
            1.3.5. Drugs and toxins
            1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)
        1.4. Associated with significant venous or capillary involvement
            1.4.1. Pulmonary veno-occlusive disease
            1.4.2. Pulmonary capillary hemangiomatosis
        1.5. Persistent pulmonary hypertension of the newborn
  2. Pulmonary hypertension with left heart disease
        2.1. Left-sided atrial or ventricular heart disease
        2.2. Left-sided valvular heart disease
  3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
        3.1. Chronic obstructive pulmonary disease
        3.2. Interstitial lung disease
        3.3. Sleep-disordered breathing
        3.4. Alveolar hypoventilation disorders
        3.5. Chronic exposure to high altitude
        3.6. Developmental abnormalities
  4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
        4.1. Thromboembolic obstruction of proximal pulmonary arteries
        4.2. Thromboembolic obstruction of distal pulmonary arteries
        4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
  5. Miscellaneous: Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

aGuidelines for classification of congenital systemic-to-pulmonary shunts: 1) Type: simple (atrial septal defect [ASD], ventricular septal defect [VSD], patent ductus arterious, total or partial unobstructed anomalous pulmonary venous return); combined (describe combination and define prevalent defect if any); or complex (truncus arteriosus, single ventricle with unobstructed pulmonary blood flow, atrioventricular septal defects). 2) Dimensions: small (ASD <2 cm and VSD <1 cm); or large (ASD >2 cm and VSD >1 cm). 3) Associated extracardiac abnormalities. 4) Correction status: noncorrected; partially corrected (age); or corrected (spontaneously or surgically [age]). Reprinted from the Journal of the American College of Cardiology, volume 43 (12 Suppl S), Simonneau G et al., Clinical classification of pulmonary hypertension, 5S–12S, © 2004 with permission from the American College of Cardiology Foundation.

IPAH—that is, PAH of unknown cause—is a rare disease that has in the past been associated with poor survival if patients do not receive treatment.4 PAH prevalence is increased when associated with other conditions, such as collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, and chronic hypoxemic lung disease.5 Some patients with IPAH have a familial variety, which in the NIH registry accounted for 6% of patients,3 and presents identically to the sporadic form of the disease.6 The bone morphogenetic protein receptor type II gene (BMPR2), a member of the transforming growth factor beta (TGF-beta) cell signaling family, has been implicated in PAH.7, 8 Heterozygous mutations within BMPR2 have been identified in familial PAH and in sporadic cases of IPAH, and could be associated with TGF-beta signaling abnormalities9, 10—a potential area for therapeutic intervention. A recent study has shown that patients with familial PAH or IPAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity, indicating that genetic testing could have a future role in guiding therapy.11 Other causes of PH include left-sided heart disease, chronic thromboembolic disease and inflammatory conditions that affect the lungs. This Review attempts to examine what is currently known about the pathogenesis of PAH, in relation to presently available and novel emerging therapies that hold promise for treatment as well as disease modification.

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Pathogenesis

The pathogenesis of PAH involves three major processes that contribute to narrowing of the pulmonary artery. The first, vasoconstriction, occurs as a result of an imbalance between vasodilators and vasoconstrictors in the pulmonary circulation. Vascular smooth muscle and endothelial cell proliferation results in vascular remodeling. Finally, coagulation abnormalities result in thrombosis in situ, which contributes to elevated PVR. A decrease in the ratio of the metabolites of prostacyclin to those of thromboxane,12 in addition to reduced production of nitric oxide,13 contributes to endothelial dysfunction. The expression of endothelin-1 is also increased in patients with PAH, indicating that it has a pathogenic role.14 Thrombosis may be secondary to endothelial injury, enhanced procoagulant activity, platelet abnormalities and abnormal fibrinolysis. Abnormalities include elevated levels of von Willebrand's factor, plasma fibrinopeptide A, plasminogen activator inhibitor-1, platelet-derived growth factor (PDGF) and TGF-beta, and decreased levels of tissue plasminogen activator, thrombomodulin, prostacyclin and nitric oxide. In addition, histopathologic observations of thrombosis in situ support a role for aberrant thrombosis in pulmonary vasculopathy.15

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Established Therapies

Treatment algorithms in PAH have been well described elsewhere and will not be reproduced here.16 Although most of the trials of PAH therapy carried out to date have defined the therapy presently available for IPAH, the established therapies described in this Review—summarized in Tables 1 and 2—can also apply to the treatment of other forms of PAH. Two studies have included patients with PH related to thromboembolic disease.17, 18 Furthermore, patients with PH related to connective tissue19 or lung disease20 could also respond to presently available IPAH therapies.

Table 1 Established and currently investigated (or potential) therapeutic options for pulmonary hypertension
Table 1 - Established and currently investigated (or potential) therapeutic options for pulmonary hypertension
Full tableFigures & Tables indexDownload PowerPoint slide (350K)

Table 2 Existing combination and supportive therapeutic options for pulmonary hypertension
Table 2 - Existing combination and supportive therapeutic options for pulmonary hypertension
Full tableFigures & Tables indexDownload PowerPoint slide (317K)

Calcium-channel blockers

Patients who might respond to long-term therapy with calcium-channel blockers (CCBs) are identified by their initial response to a vasodilator challenge.21, 22 Vasodilator testing is typically performed with potent, short-acting, titratable vasodilators such as nitric oxide,22 prostacyclin23 and adenosine.24 A response is considered positive if there is a 10 mmHg decrease in the mean PAP, to a value of less than 40 mmHg; a response is considered equivocal if there is a decrease in the resistance alone without a change in the PAP. If the response is positive the patient could benefit from CCB therapy.25 The CCBs predominantly used are nifedipine and diltiazem.26 Amlodipine is also effective and is increasingly used.27, 28 Notably, only approximately 10–15% of patients with IPAH will meet the criteria for a positive response, and only half of those will receive sustained clinical and hemodynamic benefits.25 Patients who respond to CCB therapy with a fall in pulmonary pressures have an excellent 3-year survival compared with matched untreated nonresponders from the NIH registry. After 5 years 94% of patients who responded to CCB therapy were alive, compared with 55% who did not respond to CCB therapy.26

Anticoagulation

In the absence of any contraindication,16 anticoagulation with warfarin is generally recommended on the basis of findings from retrospective, single-center studies that indicated an improved survival in those with IPAH.26, 29 According to an analysis of clinical trials published in 2004, oral anticoagulants, typically warfarin in a loading dose of 2–10 mg with a target international normalized ratio between 2.0 and 2.5, were administered to between 51% and 86% of patients.16 Aspirin and clopidogrel in combination with epoprostenol could improve platelet function parameters in patients with PH;30 however, this combination is not presently a recommended therapy as a clear clinical benefit has not been demonstrated.

Prostacyclin therapy

In patients with a negative vasodilator challenge result, severe PAH and evidence of right ventricular dysfunction, therapy with chronic intra-venous epoprostenol should be considered. Presently, epoprostenol seems to be the most potent treatment available for this group of patients, although no findings from direct comparison trials with other agents are available. Although epoprostenol produces an acute hemodynamic effect in some patients,23 most patients experience long-term benefit despite the absence of any acute hemodynamic change. This benefit could be secondary to an effect on pulmonary vascular remodeling.31 An initial 3-month prospective, open, randomized trial demonstrated that epoprostenol improved hemodynamic characteristics, exercise tolerance, quality of life, and survival in patients in NYHA functional classes III and IV compared with a similar group of patients who received conventional therapy (i.e. diuretics, cardiac glycosides, oral vasodilators and anticoagulants).32 Of note, the dose of prostacyclin has to be increased on a regular basis, possibly because of tachyphylaxis, and administration can produce pulmonary edema in patients with veno-occlusive disease. Furthermore, acute withdrawal of the medication can result in rebound PAH, which can be fatal. Other adverse effects include jaw pain, cutaneous and gastrointestinal symptoms, and myalgias and foot or leg pain.

Studies of patients with PAH treated with epoprostenol have shown a survival of about 65% after 3 years.33, 34 Although long-term follow-up data exist on the use of intravenous epoprostenol, in the present era this drug is no longer the first-choice agent because of the availability of newer oral agents, which are usually tried first. Epoprostenol tends to be reserved as therapy for patients who present with severe hemodynamic compromise.

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New Therapies and Approaches

Prostacyclin analogs

The effects of continuous subcutaneous administration of the synthetic prostacyclin analog treprostinil in patients with PAH were studied in a large randomized controlled trial, and improvements in exercise capacity, hemodynamics and clinical event rate were demonstrated.35 In this study of 470 patients, the treprostinil-treated group demonstrated no deterioration in 6 min walk test distance, whereas the placebo-treated group did show a decrease from baseline to week 12 (P = 0.06). Although there was no significant difference in mean PAP between the two treatment groups, there was a significant decrease in the PVR index with treprostinil therapy (P = 0.0002). The adverse effects reported included the presence of pain at the injection site, and 8% of patients discontinued the medication. An additional controlled pilot study was performed with treprostinil in 26 patients with PAH and showed trends in the improvement of 6 min walk test and in the reduction of PVR.36 Since 2002, subcutaneous treprostinil has been approved by the FDA for use in the US in patients with PH in NYHA classes II, III and IV; however, because of injection site pain it can be difficult to achieve the desired dose. Subcutaneous treprostinil is not yet widely available in Europe. An initial pilot study and a subsequent small randomized controlled trial of intravenous treprostinil concluded that long-term intravenous infusion of this agent was safe and effective for the treatment of patients with PAH.37, 38 As with subcutaneous treprostinil, intravenous treprostinil has been approved for use in the US but is not widely available in Europe.

A study of aerosolized iloprost in 35 patients with PAH demonstrated that a 14–17 mg dose of this agent was more potent than 40 ppm of inhaled nitric oxide as a pulmonary vasodilator.39 Subsequently, inhaled iloprost was evaluated in a randomized controlled trial that enrolled patients with PAH and compared this agent with placebo.17 The study showed that iloprost increased exercise capacity and improved symptoms, PVR, and time to clinical events in patients with IPAH. Hoeper et al. showed that a single inhalation of iloprost resulted in a 10–20% reduction in mean PAP, lasting for 45–60 min.39 A long-term uncontrolled study of 25 patients with PAH treated with inhaled iloprost for at least 1 year showed an increase in 6 min walk test distance of 85 m, a reduction in mean PAP of 7 mmHg and an increase in cardiac index of 0.6 l/min/m2.40 One potential advantage of this medication compared with intravenous epoprostenol is that iloprost might cause less ventilation–perfusion mismatch; however, the long-term efficacy of inhaled iloprost has yet to be established.

Beraprost is an oral prostacyclin analog that showed some benefit in an initial pilot study,41 and two randomized controlled trials.42, 43 Improvement in exercise capacity and clinical events was observed after 6 months of treatment but was not evident thereafter.43 At the present time beraprost is only approved for the treatment of PH in Japan and South Korea.

Endothelin and endothelin-receptor antagonists

Endothelin-1 levels are significantly elevated in patients with PAH. A powerful rationale, therefore, exists for the use of endothelin-receptor antagonists.44 Endothelin-1 induces vasoconstriction and myocyte hypertrophy, and concentration correlates with PAH severity and prognosis. Furthermore, endothelin-1 receptors are highly expressed in the plexiform lesions in PAH.14 Endothelin receptors consist of two subtypes. The endothelin-A (ETA) receptor is responsible for smooth muscle vasoconstriction and proliferation. ETA receptor stimulation causes increased inotropic activity, vasoconstriction and smooth-muscle-cell proliferation. Stimulation of endothelin-B (ETB) receptors on endothelial cells, on the other hand, has antagonistic actions and results in nitric oxide and prostacyclin release as well as increased endothelin clearance, but stimulation of ETB receptors in smooth muscle cells also provokes proliferation and vasoconstriction.44, 45, 46, 47 For this reason, it is unclear whether selective ETA receptor blockade is advantageous compared with dual blockade of both the ETA and ETB receptors. The orally administered, dual endothelin-receptor antagonist bosentan has been evaluated in randomized controlled trials that have shown improvement in exercise capacity, NYHA class, hemodyamics, echocardiographic and Doppler variables, and time to clinical worsening in patients with PAH.46, 48, 49 On the basis of these results, in the US bosentan has been approved for the treatment of NYHA class III and IV patients with PAH (only class III patients are approved to receive treatment in Europe). The most significant adverse effect of bosentan is liver function abnormality, which occurs in approximately 12% of patients.46

Sitaxentan is an endothelin-receptor antagonist that is significantly more selective for the ETA than the ETB receptor. This agent has been assessed in a randomized controlled trial of 178 patients with PH (NYHA class II, III or IV), and improved patients' exercise capacity, hemodynamics and clinical event rates.50 Another controlled trial randomly allocated 247 patients with PAH to placebo (n = 62), 50 mg sitaxentan (n = 62) or 100 mg sitaxentan daily (n = 61). After 18 weeks, patients treated with 100 mg sitaxentan had improved 6 min walk test distance (P = 0.03) and NYHA class (P = 0.04) compared with placebo-treated patients.51 Sitaxentan has been approved for use in Europe and Australia and is under consideration for approval in the US. Ambrisentan (currently in phase III trials) is another selective ETA receptor antagonist, with favorable pharmacokinetics and good safety profile.52 Thus far ambrisentan has been reported only in a blinded, dose-comparison pilot study in 64 patients with PAH. In a dose ranging study after 12 weeks, ambrisentan significantly improved 6 min walk test distance, NYHA class and mean PAP. Mild adverse events, including elevated liver enzyme levels, were present in only 3% of patients.53 Importantly, unlike sitaxentan, ambrisentan has no drug interactions, especially with warfarin-type anticoagulants.50

Phosphodiesterase type 5 inhibitors

Sildenafil is an oral selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5, which exerts its effects by increasing intracellular cyclic GMP levels. This increase induces relaxation of and has antiproliferative effects on vascular smooth muscle cells.54 A number of small, largely uncontrolled studies have reported favorable effects of sildenafil in patients with PH.55, 56, 57, 58 The findings of a pivotal randomized controlled trial of 278 patients with PH in NYHA classes II and III showed improved 6 min walk test distances and reduced mean PAP after 12 weeks with sildenafil.59 A study of tadalafil (a newer phosphodiesterase type 5 inhibitor that acts longer than sildenafil) also showed a favorable patient outcome, indicating that tadalafil could also be useful in the treatment of PH.60

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Novel Speculative Therapies

A summary of all novel, emerging therapies examined here can be found in Table 3. Rho-kinase-mediated calcium sensitization is central in mediating the sustained vasoconstriction and increased vasoreactivity in the rat hypoxic model of PAH,61 which when treated with the Rho-kinase inhibitor fasudil exhibits reduced PAP.62 The first clinical study with intravenous fasudil enrolled nine patients with severe PAH and found that fasudil treatment caused a slight decrease in the mean PAP along with an increase in the cardiac index, though neither response was significant. Fasudil did, however, cause a significant decrease in PVR.63 In theory, the beneficial effect of phosphodiesterase type 5 inhibitors, such as sildenafil, could in part be mediated by Rho-kinase inhibition.64

Table 3 Speculative therapeutic options for pulmonary hypertensiona
Table 3 - Speculative therapeutic options for pulmonary hypertensiona
Full tableFigures & Tables indexDownload PowerPoint slide (246K)

PDGF has been implicated in endothelial cell dysfunction and proliferation and migration of vascular smooth muscle cells, which in turn might be involved in the vascular remodeling observed in PAH.65 Furthermore, PDGF is implicated in chronic myeloproliferative disorders (including myelofibrosis) that are associated with a high incidence of PAH,66 which indicates that bone marrow fibrosis could be associated in part with the development of PAH.67 Imatinib, a PDGF receptor antagonist approved for the treatment of chronic myeloid leukemia, has been used in patients with PAH. An animal study showed reversal of pulmonary vascular remodeling and improvement of PAH with imatinib.68 In an initial case report of its use in a patient already receiving combination therapy, the patient showed improved 6 min walk test distance, hemodynamics and NYHA class after 3 months of imatinib treatment. Follow-up after 6 months of treatment revealed sustained clinical efficacy.69 Further case reports have followed since, implying imatinib's efficacy in cases of severe PAH.70, 71 Toxic effects on the heart, however, could be an adverse effect of long-term use, which might limit its utility.72

A study of simvastatin demonstrated improvement in the bone morphogenetic protein receptor type-2 signaling pathway in pulmonary artery smooth muscle and lung microvascular endothelial cells.73 Although further studies are needed, this finding indicates that simvastatin could enhance endothelial function. Simvastatin might also be effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions.74 A small study of 16 patients reported improvements in 6 min walk tests in patients receiving 20–80 mg of simvastatin daily.75 Other emerging therapeutic possibilities include ghrelin, an endogenous vasodilatory peptide that also stimulates the release of growth hormone, and has been demonstrated to attenuate the development of PAH in a monocrotaline-treated animal model of PAH.76 Bradykinin is a potent modulator of endothelial-cell function and a study of a stable bradykinin receptor agonist has demonstrated bradykinin's capacity to reduce severe PAH and right ventricular hypertrophy.77 This study also showed bradykinin could induce apoptosis of hyperproliferative cells through endothelial nitric oxide activation and induction of prostacyclin production.

PAH is associated with increased lung expression of the 5-hydroxytryptamine transporter, which promotes smooth-muscle-cell proliferation78 and could potentially be involved in the development of PAH. Subtypes of the 5-hydroxytryptamine receptor could also be involved in the pathogenesis of PAH and are being targeted in PAH treatment.79 The selective 5-hydroxytryptamine transporter inhibitor fluoxetine has been shown to prevent or reverse PAH in a monocrotaline animal model of PAH,80 and could form the basis of a potential future therapeutic strategy in humans.

Vasoactive intestinal peptide (a neuropeptide with a potent bronchodilator, systemic and pulmonary vasodilator properties81) has been shown to be decreased in the serum and lung tissue of patients with PAH.82 When administered in aerosol form, it improved hemodynamic parameters without adverse effects in a small pilot study of eight patients.82 Longer-term studies will be necessary to assess the therapeutic potential of this agent.

The voltage-gated potassium channel might also have a role in the pathogenesis of pulmonary hypertension,83 interacting with endothelin-184 as well as 5-hydroxytryptamine.79 Studies of voltage-gated potassium-channel overexpression achieved by nebulized adenoviral Kv1.5 gene therapy85 or oral dichloroacetate86 can regress experimental PAH and could have therapeutic potential.

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Other Empirical Treatments

Whether physical activity adversely affects the evolution of PAH is unclear. Hypoxia promotes vasoconstriction and so should be avoided. Although improvement with low-flow supplemental oxygen has been reported, this improvement could be caused by increased peripheral oxygen delivery rather than attenuation of alveolar hypoxia. The benefits of supplemental oxygen have not been confirmed in controlled trials. Patients with PAH have increased susceptibility to pulmonary infections, which are poorly tolerated. Such infections, therefore, need to be recognized and treated promptly. Furthermore, pregnancy is contraindicated as it is associated with an increased rate of deterioration of health and death in these patients.87

Fluid overload secondary to right heart failure can be treated with diuretics for symptomatic relief. In recent randomized controlled PAH trials, the majority of patients were already receiving diuretics. Although there are no data on the effects of digoxin in the long-term treatment of PH, this drug could be useful if there is evidence of cardiac impairment and reduced cardiac output—short-term intravenous administration of digoxin in IPAH produces a modest increase in cardiac output and a significant reduction in circulating norepinephrine.88 Patients with end-stage right heart failure secondary to PAH can benefit from inotropic agents such as dobutamine, milrinone or dopamine,89 although the reasons for this benefit are unclear. Eventually, those patients with end-stage right heart failure in whom medical therapy is failing could be considered for a lung or heart–lung transplantation.90 The possible pathogenic role of angiotensin II in vascular smooth muscle hypertrophy and proliferation in PAH, and the possible linkage of this pathway with TGF-beta91 (which might also have a role in the pathogenesis of PAH), means that angiotensin-converting-enzyme inhibition or angiotensin-receptor blockade could be a possible adjunctive therapy.92

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Choice of Therapy

The decision of which agent to use is largely dependent on the severity of PAH at presentation and, to some extent, on patient preference. In patients who are WHO functional class I–II at presentation, an oral agent, such as an endothelin-receptor antagonist or phosphodiesterase inhibitor, is usually an appropriate first choice and often results in symptomatic improvement. For patients who present with evidence of right heart failure or right ventricular dysfunction, a parenteral agent (typically epoprostenol or a prostacyclin analog) can be appropriate, but the initiation of oral agents should also be considered. Increasingly, many patients are hesitant to consider a parenteral agent in the face of available oral agents; however, no long-term data exist regarding the use of the oral agents in patients with severe right ventricular dysfunction.

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Combination Therapy

As different factors contribute to the development and progression of PAH, the disease should be approached from different therapeutic angles. Data supporting this concept are accumulating and consideration should be given to a combination therapy approach started early. The efficacy and safety of the combination of bosentan and epoprostenol were investigated in a study of 33 patients with severe PAH enrolled in a placebo-controlled, prospective study.93 Although improved hemodynamics, exercise capacity and NYHA class were observed in both groups, the data showed a trend for a greater improvement in all hemodynamic parameters in the combination-treatment group than in the placebo-treatment group.93 The data concerning inhaled iloprost and bosentan is less clear; uncontrolled studies have demonstrated variable results.94, 95 Two randomized controlled trials have also provided mixed results, with one study failing to show an improvement94 and the other study indicating that the combination is safe and possibly effective.96 The difficulties of assessing the results of these studies have been highlighted in an editorial by Gomberg-Maitland,97 which accompanied the study from Hoeper et al.94 This editorial suggested that the difficulty could relate in part to the severity of illness of some of the patients entering these studies. Wilkens and colleagues found that the addition of sildenafil to inhaled iloprost was beneficial in reducing mean PAP and enhanced the latter agent's effect.98 There could also be benefit from combining subcutaneous treprostinil with sildenafil,99 implying that oral sildenafil could also enhance the effect of intravenous epoprostenol. Another logical combination would be bosentan and sildenafil; animal studies have shown that this combination has an incremental effect in decreasing PAP, reducing plasma catecholamine levels, maintaining body weight and reducing mortality risk.100, 101 Similarly, the combination of bosentan and tadalafil could prove effective.102 Further studies are planned or ongoing to evaluate the therapeutic potential of various combination therapies.

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Conclusions

The development of severe right heart dysfunction remains the main obstacle to long-term survival for patients with PAH; however, with the availability of multiple agents and the potential for combination therapy, as well as the use of emerging therapies to modify the disease early in its course, the treatment of PAH is now entering a new era. This change could result in improved patient survival and quality of life. It must be stated, however, that these therapies should be initiated at centers experienced in the management and follow-up of patients with PAH. The agents presently available have generally been assessed in randomized controlled trials of patients with IPAH; therefore, it is not yet known whether the use of these agents can be projected to patients with secondary PAH, who form the vast majority of patients with PAH.

Key points

  • Therapy for pulmonary hypertension has evolved significantly over the past few years with the availability of new prostanoids, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors
  • A response to vasodilator challenge should determine which patients might benefit from a period of calcium-channel blocker therapy
  • Continuous infusion therapy with intravenous epoprostenol should generally be reserved for those patients in whom oral therapies are failing, those with progression of disease, or those who present with evidence of significant right ventricular dysfunction
  • After appropriate work-up, the first-choice treatment for most patients at initial presentation is an oral agent, either an endothelin-receptor antagonist (such as bosentan) or a phosphodiesterase type 5 inhibitor (such as sildenafil)
  • Combination therapy is increasingly used and could be beneficial in some patients
  • Therapies that could become available in the foreseeable future will offer other therapeutic options for this patient group

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Acknowledgments

Charles P Vega, University of California-Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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