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(Chest. 2005;128:622S-628S.)
© 2005 American College of Chest Physicians

Clinical Challenges in Pulmonary Hypertension*

Roger S. Mitchell Lecture

Steeve Provencher, MD; Xavier Jais, MD; Azzedine Yaici, MD; Olivier Sitbon, MD; Marc Humbert, MD, PhD and Gérald Simonneau, MD

* From the Centre des Maladies Vasculaires Pulmonaires (UPRES EA 2705), Service de Pneumologie et Réanimation Respiratoire, AP-HP-Université Paris Sud XI, Hôpital Antoine Béclère, Clamart, France.

Correspondence to: Steeve Provencher, MD, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France; e-mail: steeveprovencher{at}hotmail.com


   Abstract
TOP
 Abstract
Introduction
 Diagnostic Challenges
 Therapeutic Challenges
 Current and Future Strategies...
 Conclusion
 References
 
Despite major advances in our understanding of the pathophysiologic processes leading to pulmonary arterial hypertension and recent developments in therapeutic approaches, the long-term prognosis for patients with pulmonary arterial hypertension remains unsatisfactory. Early detection and adequate clinical classification of the disease, better assessment of patients’ prognosis, and improved therapeutic strategies are important challenges for clinicians in coming years.

Key Words: chronic thromboembolic pulmonary hypertension • combination therapy • early detection • venoocclusive disease • walk test


   Introduction
TOP
 Abstract
 Introduction
Diagnostic Challenges
 Therapeutic Challenges
 Current and Future Strategies...
 Conclusion
 References
 
The most serious chronic disorder of the pulmonary circulation is certainly pulmonary arterial hypertension (PAH), a syndrome of diverse etiology and pathogenesis characterized by the persistent increase in pulmonary vascular resistance potentially leading to right heart failure and death.12 Recent improvements in our understanding of this syndrome have been quite remarkable, including the identification of a gene responsible for inherited forms of PAH, a better understanding of the pathobiological pathways involved in the development of pulmonary hypertension,3 and the development of medical therapies targeting these different pathways.4 However, pulmonary hypertension still challenges physicians with both its diagnosis and treatment.


   Diagnostic Challenges
TOP
 Abstract
 Introduction
 Diagnostic Challenges
Therapeutic Challenges
 Current and Future Strategies...
 Conclusion
 References
 
Early Detection of Pulmonary Arterial Hypertension
Early recognition of pulmonary hypertension is a real challenge for clinicians. It is thought that the detection and treatment of the disease in the early, and possibly more reversible, stages of the disease might be associated with improved survival. In idiopathic PAH, the initiation of IV epoprostenol at a less advanced stage of the disease, as assessed by the New York Heart Association (NYHA) functional class III compared to class IV, resulted in improved long-term survival in two large cohorts of idiopathic PAH patients.25 NYHA functional class II patients might also benefit from earlier treatment, although specific randomized trials are needed to test this hypothesis. However, pulmonary hypertension does not become clinically manifest until pulmonary vascular disease is advanced.1 Therefore, strategies allowing the identification of patients at a presymptomatic or very early symptomatic stage are necessary. Because of the low prevalence of PAH in the general population, systematic screening for the early detection of presymptomatic disease will probably remain restricted to individuals who are at moderate-to-high risk of developing the disease such as first-degree relatives of familial PAH patients, patients with congenital heart disease with systemic-to-pulmonary shunts, and patients with the scleroderma spectrum of disease.6 Moreover, there is still a significant delay between the first symptom of the disease and the diagnosis. In a recent national registry in France,7 PAH was diagnosed in 75% of patients who were in NYHA functional class III or IV, which is similar to the data obtained > 15 years ago in the National Institutes of Health registry.1 A high index of suspicion is mandatory in view of unexplained compatible symptoms, especially for patients with predisposing conditions (eg, HIV infection and portal hypertension) and for patients with symptoms that are unexplained by the physiologic impairment caused by the concomitant disease. Consequently, educational programs to sensitize clinicians to the nonspecificity of presenting symptoms are clearly needed.

Echocardiography is a noninvasive method providing an estimate of systolic pulmonary artery pressure in most patients.6 This feature justifies its application as the most commonly used screening tool for pulmonary hypertension despite the fact that the accuracy of echocardiography for the estimation of systolic pulmonary artery pressure is imperfect.6 In the very early stage of the disease, it is thought that pulmonary artery pressure may be normal at rest but increases to abnormally high levels during conditions of increased blood flow, such as during exercise.8 However, the significance of the abnormal elevation of estimated pulmonary artery pressure during exercise is not clear.

Finally, germline mutations for the gene coding for the bone morphogenetic protein receptor II have been identified in approximately 50%, 25%, and 10%, respectively, of patients with familial PAH, sporadic idiopathic PAH, and PAH associated with anorexigen exposure.9 As these mutations are inherited in an autosomal-dominant manner, family members are at risk of developing the disease. However, because the penetration of these mutations may be as low as 10 to 20%, most individuals with the mutation will remain free of the disease. Moreover, the relatives of patients with familial PAH who do not have an identifiable mutation may be at risk of developing the disease. Therefore, the role of genetic testing in the presymptomatic detection of the disease is currently limited.

Adequate Clinical Classification of Pulmonary Hypertension
Numerous conditions are known to lead to or to be associated with the development of pulmonary hypertension (Table 1 ). These conditions are classified into four distinct groups based on their similar clinical presentation, pathology, pathophysiology, prognosis, and, most of all, similar therapeutic approach.10 Some aspects of this classification deserve special consideration.


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  		Table 1. Diagnostic Classification of Pulmonary Hypertension*

 
Recognition of proximal chronic thromboembolic pulmonary hypertension is of major importance. It is the only curable form of precapillary pulmonary hypertension. Therefore, a ventilation/perfusion lung scan is mandatory in all patients with pulmonary hypertension as spiral CT scanning cannot rule out chronic thromboembolic pulmonary hypertension.11 In patients with abnormal ventilation/perfusion lung scan findings, pulmonary angiography is required for the adequate assessment of patient’s operability by thromboendarterectomy for thromboendarterectomy. In future years, MRI and multislice CT scanning may provide additional valuable information.12 Because radiologic findings are frequently subtle, considerable experience is needed for the interpretation of these examinations.11 Moreover, progressive distal vasculopathy, similar to the one observed in patients with idiopathic PAH, is thought to be responsible for the progressive clinical deterioration despite the lack of recurrence of emboli. Therefore, any delay in recognition and referral to experienced centers is likely to be associated with an increase in mortality.

Pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis are rare conditions, probably accounting for about 5% of patients who are referred for PAH.12 Although some patients present with a history of drug or chemical exposure, viral infection, and collagen vascular disease,13 the clinical presentation and pulmonary hemodynamics are similar to those of idiopathic PAH. Recognition of these entities is, however, essential as specific PAH treatment may be involved in the pathogenesis of fatal and nonfatal treatment-induced pulmonary edema.14 Only a histologic evaluation of a surgical lung biopsy specimen allows the diagnosis to be proven. This procedure is, however, at high risk in these patients with severe pulmonary hypertension.15 Major advances have been made in the noninvasive diagnostic approach of these conditions. Poorly defined nodular opacities, thickened septal lines, and adenopathies are frequently observed on thin-section CT scans.16 BAL can also demonstrate the presence of iron-laden macrophages suggestive of occult alveolar hemorrhage that is linked to chronic postcapillary obstruction.17 The pathophysiology of these two conditions remains poorly understood. Furthermore, the rarity of these conditions precludes any randomized therapeutic trial to be performed so that specific treatment, other than lung transplantation, remains purely empirical.

Finally, pulmonary hypertension is relatively common in the natural history of moderate-to-severe interstitial lung disease and COPD.18 However, a small subset of patients displays disproportionately severe pulmonary hypertension in comparison to the severity of hypoxemia and/or lung function alteration.19 There is increasing evidence that in such patients individual susceptibility,20 and perhaps a distinct physiopathology,21 may be involved in the development and progression of a specific vasculopathy. Whether these patients present a different clinical course and whether or not these patients could benefit from the specific treatment of that vasculopathy remains also unknown.


   Therapeutic Challenges
TOP
 Abstract
 Introduction
 Diagnostic Challenges
 Therapeutic Challenges
Current and Future Strategies...
 Conclusion
 References
 
Assessment of Disease Severity and Treatment Efficacy
Pulmonary hemodynamics, exercise capacity, several echocardiographic parameters, and biological markers have been shown to be related to the prognosis of PAH.22 Because survival cannot be used as an end point in short-term trials, most recent randomized trials evaluating PAH-specific treatments used the 6-min walk test and less commonly cardiopulmonary exercise testing as the primary end point. The NYHA functional class and hemodynamics were also frequently used as reinforcing secondary end points. The treatment effect on the distance walked in 6 min ranged from 16 to 76 m in these different trials.23 This treatment effect represents the mean increase for the whole group of treated patients, including those who clearly responded and those who clearly remained stable or worsened after treatment, and must not be viewed as the treatment goal for a given patient. Furthermore, the prognostic significance of this improvement in the distance walked in 6-min remains uncertain as the absolute distance walked in 6 min on treatment and not the change in the distance walked in 6 min has been shown to be related to prognosis in a cohort of idiopathic PAH patients who had been treated with epoprostenol.2 Therefore, for a given patient, a clinically significant improvement in the distance walked in 6-min might be substantially higher than the mean increase reported in these studies.

Patients whose conditions significantly worsen after treatment obviously require a modification of their therapy, probably to a more aggressive treatment. Conversely, patients with a dramatic clinical and/or hemodynamic improvement after treatment should probably continue receiving the same drug. A transition to a less limiting treatment, in case of previous therapy with IV epoprostenol or subcutaneous treprostinil, for example, might be considered in a small subset of patients.2425 Extreme caution is however necessary since recent experience suggests that even highly selected patients may significantly and irreversibly deteriorate during such a transition.25 Finally, determining the best therapeutic approach for patients with a clinical condition that only slightly worsened, remained stable, or nonsignificantly improved after treatment is also an important dilemma. The long-term prognosis for such patients is probably unsatisfactory, and new therapeutic options need to be evaluated in such situations. This is in contrast with patients who are less compromised at baseline (eg, NYHA functional class II) in whom a long-term stabilization of the disease might represent an adequate therapeutic response.

Interestingly, the improvement in exercise capacity is only partly related to changes in resting hemodynamics. The most likely explanation for this discrepancy is that resting pulmonary hemodynamics incompletely reflect exercise hemodynamics26. Exercise capacity is also largely influenced by patient characteristics including age, sex, height, and weight.27 Therefore, similar absolute values for the distance walked in 6-min or in peak oxygen uptake may represent tremendous differences in exercise limitations, depending on the patient’s characteristics. Since equations predicting the distance walked in 6-min and peak oxygen uptake are available,27 it might be more appropriate to express exercise capacity as the percentage of predicted values, although this remains to be evaluated.

Finally, the prognostic value of the 6-min walk test has been mostly validated in NYHA functional class III/IV idiopathic PAH patients.22 Extrapolating this prognostic significance and clinical utility to NYHA functional class I/II or PAH associated with other conditions might be suboptimal. As a matter of a fact, a plateau phenomenon has recently been described in NYHA functional class II patients who had been treated with sitaxsentan,28 meaning the closer you are from the normal distance walked in 6-min, the less likely that the increase in that distance will be significant even in case of clinical responsiveness. From a theoretical point of view, cardiopulmonary exercise testing would be more appropriate in such a setting. However, two recent trials23 failed to demonstrate the clinical utility of cardiopulmonary exercise testing in that setting. A decrease of its reproducibility in the context of a multicentric trial has been hypothesized to explain that phenomenon.


   Current and Future Strategies of Pulmonary Arterial Hypertension Treatment
TOP
 Abstract
 Introduction
 Diagnostic Challenges
 Therapeutic Challenges
 Current and Future Strategies...
Conclusion
 References
 
Conventional therapy (ie, anticoagulation, diuretics, and oxygen therapy), although recommended for most patients, is associated with poor long-term prognosis when used alone.1 Calcium channel blockers, traditionally used as treatment for PAH, are only effective in < 10% of patients referred to pulmonary vascular centers.29 Patients with a favorable acute response to therapy with a vasodilator, which was recently defined as a fall of mean pulmonary artery pressure of at least 10 to ≤ 40 mm Hg with an increase or unchanged cardiac output,23 are likely to display a sustained beneficial response to therapy with calcium channel blockers. For the remaining patients, however, therapy with calcium channel blockers will be ineffective or will have a deleterious effect, and other therapeutic approaches are required.

Recent advances3 in our understanding of the pathobiological factors leading to the pulmonary vascular disease have led to the development of new specific treatments. Novel therapies target the following three different pathobiological pathways: the prostacyclin pathway; the endothelin pathway; and the nitric oxide pathway.4 IV prostacyclin (epoprostenol), other prostanoid analogues (ie, beraprost, treprostinil, and iloprost), antagonists of endothelin receptors (ie, bosentan and sitaxsentan), and, more recently, phosphodiesterase type 5 inhibitors (ie, sildenafil) have been shown to improve exercise capacity as assessed by the 6-min walk test in short-term randomized placebo-controlled trials.2330 Hemodynamic improvement was also significant when assessed. These trials have allowed us to shift from a clinically based treatment strategy to an evidence-based strategy.23 However, because the baseline characteristics of the patients who entered these studies substantially differed from one study to the other, a comparison of the treatment effect described in these trials may be misleading. Moreover, a head-to-head comparison of these different compounds has never been in randomized controlled trials. Therefore, the choice of first-line therapy remains somewhat empirical based on clinicians’ experience, side effects, drug availability, and cost. For NYHA functional class III patients, most experts will generally recommend oral drugs as first-line therapy. Bosentan is the only oral drug that is currently approved in the United States and Europe. Conversely, IV epoprostenol remains the "gold standard" for NYHA functional class IV patients. Insufficient data preclude any clear recommendation for NYHA functional class II patients as no randomized trial specifically evaluated that subgroup of patients. Enrollment in clinical trials is therefore encouraged for these patients.23

Data on the long-term efficacy of these novel therapies are fairly limited. The beneficial effects of epoprostenol therapy appear to be sustained for years in many patients with idiopathic PAH.25 Bosentan also improved long-term survival compared to the predicted survival on the equation formulated from the National Institutes of Health registry in a cohort of idiopathic PAH patients.31 Although data from uncontrolled and observational studies are encouraging, the long-term beneficial effect of therapy with other prostanoid analogues,32 endothelin receptor antagonists,3334 and phosphodiesterase-5 inhibitors remains largely unknown. In the only long-term randomized trial ever performed on PAH-specific treatment,35 the initial improvement of exercise capacity at 3 and 6 months was no longer significant at 9 and 12 months. This fact emphasizes the need for long-term trials and large observational studies to evaluate the long-term efficacy of these specific treatments. Furthermore, factors at baseline or during the first months of treatment that are related to long-term prognosis and treatment efficacy need to be clarified in order to select the most appropriate therapeutic approach for a given patient.

Many series have described the efficacy of specific treatments in PAH associated with congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, and inoperable chronic thromboembolic pulmonary hypertension.4 However, only a few patients with these conditions have been included in recent randomized controlled trials, which were mostly restricted to patients with either idiopathic PAH or PAH associated with anorexigen exposure and the scleroderma spectrum of the disease. Although these different entities may share some common pathophysiologic processes, they may substantially differ in terms of therapeutic responses, as has been suggested in previous trials,3637 and must therefore be specifically evaluated.

Some short-term trials23 have demonstrated an improvement in the time to clinical worsening. However, only therapy with IV epoprostenol has been shown to improve the survival of PAH patients.38 Despite this improved survival, the long-term prognosis remains clearly unsatisfactory with a 3-year survival rate of about 63% in NYHA functional class III/IV patients who were treated with epoprostenol.25 Combination therapy using drugs with different mechanisms of action to maximize the clinical benefit is an emerging and attractive therapeutic option in PAH patients as this approach has proved to be more successful than single therapy in patients with many other severe conditions like HIV infection or cancer. Combination therapy might be used as an initial therapy or as an add-on therapy in case of condition deterioration or an unsatisfactory result of single therapy (Fig 1 ). Both strategies have been evaluated in nonrandomized trials combining sildenafil3940 or bosentan41 with prostanoids (ie, an add-on strategy) and in a recent placebo-controlled randomized trial42 comparing combination therapy with IV epoprostenol and oral bosentan to that with IV epoprostenol alone (the initial combination strategy). These studies suggested a greater improvement in the combination-therapy group with no significant increase of adverse events. However, because of concerns about efficacy, safety and cost, it is mandatory that combination therapies are carefully investigated in well-designed randomized controlled trials involving a large number of patients before such approach become standard practice.



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  		Figure 1. Strategies for the evaluation of combination therapy. The initial combination strategy implies that more than one drug is initiated as first-line therapy. This combination therapy should be compared to each single therapy separately. Conversely, as an add-on strategy, a second-line therapy is added in case of an unsatisfactory clinical response to the first-line therapy. This strategy needs to be compared to first-line therapy alone. Ideally, these strategies should be evaluated in a double-blind manner.

 
In selected patients with PAH who are unresponsive to maximal medical management, lung transplantation should be proposed.11 Atrioseptostomy at institutions with significant procedural and clinical experience has also been proposed in such situations.11 However, the types of procedures and the optimal timing of these procedures remain controversial.

Finally, new therapies are evolving. Numerous new compounds have been evaluated in either experimental studies or small case series, including vasoactive intestinal peptide,43 elastase inhibitors,44 selective serotonin reuptake inhibitors,45 and adrenomedullin.46 However, because the pathophysiology of PAH is complex and involves different and incompletely understood pathways, any single agent is unlikely to considerably improve the long-term prognosis of PAH patients.


   Conclusion
TOP
 Abstract
 Introduction
 Diagnostic Challenges
 Therapeutic Challenges
 Current and Future Strategies...
 Conclusion
References
 
Major advances in our understanding of the pathobiological pathways leading to pulmonary hypertension and in the development of therapeutic options targeting these abnormalities have been achieved in recent years. However, the current long-term prognosis remains unsatisfactory for most patients. Both basic and clinical research are essential to improve our knowledge about the pathophysiology of this disease and to improve patient management. Earlier detection and adequate clinical classification of the disease, better assessment of disease severity and treatment efficacy, and improved therapeutic strategies undoubtedly will be important challenges for clinicians in the coming years.


   Footnotes
 
Dr. Provencher was the recipient of a fellowship grant from Université Laval, Québec City, QC, Canada, and has received consulting fees from Actelion. Drs. Jais and Yaici have received no financial support and has not been involved with any organization with financial interest in the subject matter. Dr. Sitbon has received consulting and lecture fees from Actelion and Schering AG, and consulting fees from GlaxoSmithKline. Dr. Humbert has received consulting and lecture fees from Actelion and Schering AG, and consulting fees from Pfizer and Myogen. Dr. Simonneau has received consulting and lecture fees from Actelion and Schering AG, and consulting fees from Pfizer and Myogen.

The Centre des Maladies Vasculaires Pulmonaires has been supported by grants from Université Paris-Sud, Legs Poix, INSERM, and the Association Française contre le Myopathies.

Abbreviations: NYHA = New York Heart Association; PAH = pulmonary arterial hypertension


   References
TOP
 Abstract
 Introduction
 Diagnostic Challenges
 Therapeutic Challenges
 Current and Future Strategies...
 Conclusion
 References
 

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