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Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses

Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial... CURRENT OPINION European Heart Journal (2010) 31, 2080–2086 doi:10.1093/eurheartj/ehq152 Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses Nazzareno Galie ` , Massimiliano Palazzini , and Alessandra Manes Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy Received 5 March 2010; revised 6 April 2010; accepted 23 April 2010; online publish-ahead-of-print 26 May 2010 4,5 Pulmonary arterial hypertension (PAH) is a rare and severe clinical Pathology condition characterized by a progressive increase of pulmonary Pathological lesions in PAH patients affect the distal pulmonary vascular resistance leading to right ventricular failure and prema- arteries (,500 mm), in particular. The lesions are characterized ture death (Figure 1). Its prevalence ranges from 15 to 50 patients 2,3 by medial hypertrophy, intimal proliferative and fibrotic changes per million population and it affects a relatively young patient (concentric and/or eccentric), adventitial thickening with moderate population (average age of 50 years) when compared with the peri-vascular inflammatory infiltrates (Figures 1B and C and 2), more common thoracic organ diseases such as coronary artery complex lesions (plexiform, dilated), and thrombotic lesion. disease and chronic obstructive lung disease. PAH in adults includes at least nine clinical subgroups with virtually identical obstructive pathologic changes (Figures 1 and 2) in the distal pul- 6 – 8 monary arteries: idiopathic, heritable, drug- and toxin-induced, Pathobiology associated with, connective tissue diseases, HIV infection, portal The pathobiology of the distal pulmonary arteries in PAH patients hypertension, congenital heart disease, schistosomiasis, and 1 is multifactorial and involves various biochemical pathways and cell chronic haemolytic anaemia. types (Figure 2). Excessive vasoconstriction has been related to abnormal function or expression of potassium channels in the smooth muscle cells and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilator Pathogenesis and antiproliferative agents such as nitric oxide and prostacyclin, The exact processes that initiate the pathological changes seen in along with over-expression of vasoconstrictor and proliferative PAH are largely unknown. It is hypothesized that the interaction substances such as thromboxane A and endothelin. Many of between genetic predisposition and environmental risk factors these abnormalities both elevate vascular tone and promote vascu- (Figure 1) may be involved in the initial stages of the disease. lar remodelling by proliferative changes that involve several cell However, even the exact role of the auto-antibodies in connective types, including endothelial and smooth muscle cells as well as tissue diseases or the viral involvement in HIV infection is unclear. fibroblasts. In addition, in the adventitia, there is increased pro- It appears that a specific injury on the vessel wall of distal pulmon- duction of extracellular matrix including collagen, elastin, and fibro- ary arteries may initiate, in predisposed individuals, a pathobiologi- nectin and of matrix-bound smooth muscle cell mitogens, such as cal cascade of events which leads to a common final pathological basic fibroblast growth factor. Other matrix metalloproteases can obstructive condition (Figures 1B and C and 2). In the initial stimulate the production of tenascin, a smooth muscle cell mito- phases of these processes, the disease is asymptomatic, and detect- genic cofactor. Several additional growth factors including vascular able pathophysiological changes and symptoms limiting exercise endothelial growth factor, platelet-derived growth factor, insulin- capacity appear usually when the pathological lesions are fully like growth factor-1, and epidermal growth factor have been impli- developed (Figure 1). cated in the development of remodelling and all have been * Corresponding author. Tel: +39 051 349 858, Fax: +39 051 344 859, Email: [email protected] 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. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected] The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact [email protected]. Pulmonary arterial hypertension 2081 Figure 1 Schematic representation of pathogenesis, pathology, pathophysiology, and symptoms in pulmonary arterial hypertension. (A)Normal small distal pulmonary artery: the thin wall is constituted by a single elastic lamina and a thin layer of smooth muscle cells; a large lumen with red blood cells is also shown. (B) Distal pulmonary artery in pulmonary arterial hypertension: increased thickness of the media due to hypertrophy and hyperplasia of smooth muscle cells and moderate lumen reduction are present. This picture may represent an initial phase of the disease and/or the prevalent changes in patients responding to vasoreactivity tests. (C) Distal pulmonary artery in pulmonary arterial hypertension: increased thickness of the media and also of the intima due to proliferation/migration of myofibroblasts and fibrosis are present. Severe lumen reduction is also shown. This picture may represent an advanced phase of the disease and/or the prevalent changes in patients not responding to vasoreactivity tests. (D) Echocardiographic four-chamber view in pulmonary arterial hypertension: Severe dilatation of the right atrium and ventricle and reduction in size of the left ventricle are shown. ALK1, activin-like kinase-type 1 gene; BNP, brain natriuretic peptide; BMPR2, bone morphogenetic protein receptor type 2 gene; CHA, chronic haemolytic anaemia; CHD, congenital heart disease; CTD, connective tissue diseases; ENG, endoglin gene; HIV, human immunodeficiency virus; CMR, cardiac magnetic resonance; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; WHO, world health organization. The pathological pictures are a courtesy of Dr Carol Farver, Cleveland Clinic. reported to be increased (the molecule and/or the specific recep- thrombi are present in both the small distal pulmonary arteries tors) in the lung and/or in the blood of PAH patients. Reduced and in proximal elastic pulmonary arteries. plasma levels of other vasodilator and antiproliferative substances 9,10 such as vasoactive intestinal peptide have also been demonstrated. Pathophysiology Angiopoietin-1, an angiogenic factor essential for vascular lung development, seems to be up-regulated in cases of PAH correlat- The increase of pulmonary vascular resistance in PAH patients ing directly with the severity of the disease. Receptors of the bone is therefore related to different mechanisms, including vasocon- morphogenetic protein pathway, involved in cellular proliferation striction, proliferative and obstructive remodelling of the pulmon- and apoptosis, are down-regulated and/or malfunctioning in the ary vessel wall, inflammation, and thrombosis (Figure 2). lung vasculature of both heritable and acquired PAH. Inflammatory Vasoconstriction is likely prevalent in the small group of patients cells, cyto- and chemokines, and platelets (through the serotonin responding to the acute vasoreactivity test. pathway) may also play a significant role in PAH. Prothrombotic The increase in pulmonary vascular resistance leads to right abnormalities have been demonstrated in PAH patients and ventricular overload, hypertrophy, and dilatation and eventually ` 2082 N. Galie et al. Figure 2 Obstructive remodelling of a small pulmonary artery in pulmonary arterial hypertension (increased thickness of the three vessel layers and severe lumen reduction are shown) and ongoing pathobiological processes in the different layers of the vessel wall (yellow boxes) and in the blood. Asterisks indicate the potential processes involved. Corrective interactions of the related approved therapeutic inter- † ‡ § ventions are also reported (green boxes). *Vasoconstriction; Proliferation/migration; Inflammation; Thrombosis. B-FGF, basic fibroblast 2+ + growth factor; BMPR, bone morphogenetic protein receptor; [Ca ], intracellular calcium concentration; K ch, membrane potassium channels; SMC, smooth muscle cells; MFB, myofibroblasts; MMP, matrix metalloproteases; PDE-5, phosphodiesterase type 5; PDGF, platelet-derived growth factor; TxA , tromboxane A ; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide. The pathological picture 2 2 is a courtesy of Dr Carol Farver, Cleveland Clinic. to right ventricle failure and death (Figure 1). The importance of obstructive lesions and a reduction of the right ventricular after- the progression of right ventricle failure on the symptoms, exer- load (Figure 2). cise limitation, and outcome of PAH patients is confirmed by the prognostic impact of right atrial pressure, cardiac index and pul- Progress of medical treatment in monary arterial pressure, the three main haemodynamic factors pulmonary arterial hypertension linked to right ventricle pump function. Echocardiography and cardiac magnetic resonance parameters and brain natriuretic Two decades ago, patients with idiopathic PAH were defined as peptide plasma levels can also identify non-invasively the presence the ‘kingdom of the near-dead’ to outline their dismal median and extent of right ventricular dysfunction (Figure 1). Afterload survival rate that, at that time, was 2.8 years from the diagnosis, mismatch remains the leading determinant of right heart failure despite any available supportive treatment. Usually, rare and in patients with PAH because its removal, as follows lung trans- severe conditions are neglected by both the medical community plantation, leads almost invariably to sustained recovery of right and the pharmaceutical industry due to the intrinsic difficulties of ventricle function. It is, therefore, conceivable that the drug thera- performing experimental and clinical research in these fields. In pies tested in PAH patients have included compounds which fact, meaningful randomized controlled trials (RCTs) in these set- could potentially interfere with the pathobiological mechanisms tings require a worldwide collaboration of expert centres operat- of the disease trying to achieve a reverse remodelling of the ing with a similar standard of medical care and relatively large Pulmonary arterial hypertension 2083 financial resources with a rather high risk of study failure. The agree that in rare and severe conditions dramatically impairing recent history of drug development in PAH contradicts this tra- the functional capacity of relatively young patients, exercise ditional perspective and it is worthwhile to analyse the details of capacity improvement can be considered a worthwhile initial this phenomenon. objective. In addition, the usual concordant favourable changes in 12 13,14 Without a doubt, the progress made in the medical treatment of haemodynamics and TtCW observed in some studies PAH in the past 15 years is unique, particularly for a rare and reinforced the results of the 6MWT. The use of this test as a severe condition: almost 30 RCTs have been completed and primary endpoint has allowed reasonable study sample sizes more than 10 are either ongoing or planned. Twenty-five RCTs (from 100 to 500 patients) and randomized study duration have been published as of May 2010 (Figure 3). Eight drugs (ambri- (from 2 to 6 months), which are favourable feasibility character- sentan, bosentan, epoprostenol, iloprost, sildenafil, sitaxentan, istics in a rare and severe disease. On the other hand, these same tadalafil, treprostinil) belonging to three pharmacological classes characteristics have prevented the observation of effects on the (endothelin receptor antagonists, phosphodiesterase type-5 inhibi- mortality rate except for studies enrolling the most severe 15,16 tors, and prostanoids) administered by four different routes (oral, patient population. inhaled, subcutaneous, and intravenous) have been currently approved by the Food and Drug Administration (FDA) and/or by the European Medicines Agency (EMA). All three classes of Meta-analyses to assess the effect drugs exert both vasodilator and antiproliferative effects and inter- on mortality fere with the endothelial dysfunction abnormalities observed in PAH patients (Figure 2). Meta-analysis of multiple studies is a technique that may allow the analysis of parameters or events with a larger sample size and with additional statistical insights. This approach requires the Traditional endpoints for clinical inclusion of homogeneous studies as far as disease aetiology and study designs are concerned. A first meta-analysis on 16 trials in pulmonary arterial RCTs performed in PAH concluded that the treatments ‘pro- hypertension duced limited benefits in clinical end-points and failed to The traditional primary endpoint of the RCTs performed in PAH support a significant survival advantage’. However, the has been the 6 min walk test (6MWT) that assesses the exercise meta-analysis included both acute and long-term studies and capacity, and secondary endpoints have included haemodynamics one study on patients with lung fibrosis and did not consider and time to clinical worsening (TtCW), a composite endpoint six RCTs published before its submission. We performed a 13,14 12 including death, hospitalization, and disease progression. second meta-analysis on 23 RCTs in 3199 PAH patients pub- Based on the primary endpoint, the specific labelling indication lished as of October 2008. This analysis showed a reduction in of all approved medications for PAH usually includes the mortality ranging between 38 and 43% (according to different wording ‘to improve exercise capacity’ followed by the functional inclusion criteria) after an average treatment period of 14.3 classes of the patient population enrolled in the studies. This weeks. A subgroup analysis showed that all three classes of reflects the fact that both regulatory agencies and investigators PAH-approved drugs achieved a similar favourable reduction in Figure 3 Time-course of 25 published randomized controlled studies (identified by acronyms, if any, or drug and year of publication) in pul- monary arterial hypertension as of May 2010. Colour code identifies the design of the study: monotherapy (black): investigational drug vs. placebo in patients naive for pulmonary arterial hypertension approved drugs. Monotherapy and/or sequential combination (red): investigational drug vs. placebo in patients either naive for, or treated with pulmonary arterial hypertension approved drugs. Upfront combination (light blue): single drug vs. combination of two drugs in patients naive for pulmonary arterial hypertension approved drugs. ` 2084 N. Galie et al. Figure 4 Meta-analysis of published randomized controlled studies (identified by first author and year of publication) in pulmonary arterial hypertension as of May 2010. The primary analysis has included 3780 patients of 23 trials. The figure shows the cumulative RR estimate of death in active treatment groups when compared with control groups stratified according to treatment class (inverse variance method). Studies with no events in both groups were excluded. An overall reduction of mortality of 44% (P ¼ 0.016) is shown. The sensitivity analysis, including two additional studies (59 patients) in which two treatment strategies were compared, confirmed a reduction in mortality of 39% (P ¼ 0.041). The subgroup analysis of the three classes of approved drugs achieved a similar favourable reduction in mortality, although no statistical significance was achieved individually. RR, relative risk. Modified from Galie` et al. mortality, although no statistical significance was achieved indivi- patients treated with the targeted therapies currently approved dually. Updating our meta-analysis with two recently published for PAH. The limitations of this conclusion include the short dur- 18,19 studies, the overall reduction in mortality has been confirmed ation of the RCTs whose primary endpoint was not mortality and (Figure 4). These data have recently been validated by the authors the lack of evidence of a favourable long-term effect. of the first meta-analysis, who reported a reduction in mortality Nevertheless, we disagree with the opinion that the above limit- of 39%, analysing the data of 3363 patients. The concordance of ations are the key factors which should induce us to adopt new these results suggests, therefore, an improvement of survival in trial designs, new endpoints, and longer durations of the RCTs. Pulmonary arterial hypertension 2085 Given the higher mortality observed in the placebo groups of the dual endothelin receptor antagonists, prostanoids and non- 12,20 more recent meta-analyses on PAH trials and the higher rate prostanoid prostacyclin receptor agonists, and inhaled vasoactive of clinical deterioration observed in placebo-treated groups of indi- intestinal peptide. The efficacy of these new compounds needs 15,16,18,21 – 25 vidual PAH studies, it is not ethical, in our view, to to be demonstrated ‘on top of’ the available approved PAH drug repeat RCTs in naı¨ve PAH patients in order to satisfy the scientific therapies in order to avoid any delay in the initiation of effective curiosity of ‘desk trialists’. medications. Therefore, a combination approach is required also in this case. The way forward The true issues PAH patients and physicians face in the clinical Future study designs practice is the insufficient efficacy of the present therapeutic resources, despite clear progress and the escape from ‘the The future decisive challenge is the identification of the most kingdom of the near-dead’. The current treatment strategy, opti- appropriate study designs to demonstrate the efficacy-to-safety mized in recent guidelines, remains inadequate because the mor- ratio of combination strategies either with already approved tality rate continues to be high and the functional and drugs or with novel therapies. The replication of the traditional haemodynamic impairments are still extensive in many patients. phase III strategy (placebo-controlled design in treatment-naı¨ve The specific drugs approved for PAH are able to slow the pro- patients, 6MWT as primary endpoint assessed after 3–4 months gression of the disease but cannot be considered a cure for the of treatment) appears not to be suitable for practical and ethical majority of patients. reasons. In fact, the inclusion of patients on background effective Current and future plans devoted to increasing our ability to therapies will reduce our ability to demonstrate a difference treat PAH are facing new challenges which require scientific crea- between the ‘placebo-treated group’ and the ‘actively treated tivity and new research strategies. Possible working hypotheses group’, in particular, if exercise capacity is the primary endpoint. include the drug combination approach and new candidate This phenomenon was observed in the more recently completed classes of drugs. RCTs in which the treatment effect on the 6MWT ranged from 16,18,19,26 15 to 25 m when compared with the traditional 35 to 55 m observed in historical monotherapy studies. A possible sol- Combination therapy ution is the adoption of different primary endpoints, such as The rationale for combining approved PAH compounds is related TtCW, accepted by the regulatory agencies. This approach also to the different pathobiological pathways targeted by the three presents challenges, including the objective and uniform definition classes of approved PAH drugs (Figure 2). This combined approach of this composite endpoint and the sample size and/or duration of has successfully been employed in the treatment of other serious the study, which can be either pre-specified or based on the and chronic diseases such as congestive heart failure, HIV infection, number of observed events. Additional problems of multicentre and cancer. Combination therapy is currently recommended in and international studies are linked to the country-related hetero- PAH patients with suboptimal response to the initial monotherapy geneity of the PAH-approved medications, the different attitudes as an add-on with a compound of an alternative drug class (sequen- for hospitalization in different geographic areas, and the availability tial combination therapy). Different RCTs have currently shown of centres with experience in combination therapy. the efficacy of this strategy on the improvement of exercise Initial appropriate answers to solve these difficulties have been 16,18,19,21,26 16,18,26 capacity and the reduction of TtCW. given by the regulatory agencies and by the investigators. In fact, An emerging concept relates to the use of first-line combination in the recently published ‘Guideline on the Clinical Investigations therapy with two drugs in PAH patients when compared with the of Medicinal Products for the Treatment of PAH’, the Commit- initial monotherapy. This hypothesis was tested in the BREATHE-2 tee for Medicinal Products for Human Use (CHMP) of the EMA trial, but the small sample size of the study did not allow for a clarified the requirements for the approval of PAH medications, definitive conclusion. The appropriate design to assess the effi- indicating the characteristics of acceptable primary endpoints, cacy of this strategy appears to be a three-arm study, comparing including 6MWT and TtCW. Randomized controlled trials adopt- combination therapy with two arms of monotherapy, using the ing novel designs and TtCW as primary endpoint have already single compounds. been initiated. For example, a morbidity and mortality primary end- point has been adopted in the SERAPHIN study (Study with Endothelin Receptor Antagonist in Pulmonary arterial Hyperten- New candidate classes of drugs sion to Improve cliNical outcome), testing the efficacy of a new tis- Paradoxically, there is no shortage of novel candidate therapies for sular dual endothelin receptor antagonist, and in the AMBITION PAH, including drugs, gene, and/or stem-cell treatments. These study (A randomized, double-blind, placebo-controlled, multicen- approaches are intended to address alternative pathobiological tre study of first-line combination therapy with AMBrIsentan and pathways (Figure 2) or explore new strategies such as regenerative Tadalafil vs. monotherapy in subjects with pulmonary arterial medicine. New drugs with ongoing or planned phase III studies in hypertensION), testing the efficacy of the initial combination this field include oral compounds such as NO-independent stimu- therapy of a selective endothelin receptor antagonist and a phos- lators and activators of cyclic guanosine monophosphate, tyrosine phodiesterase type-5 inhibitor when compared with monotherapy kinase inhibitors (platelet-derived growth factor inhibitors), tissular using single compounds. ` 2086 N. Galie et al. 12. Galie N, Manes A, Negro L, Palazzini M, Bacchi Reggiani ML, Branzi A. A Conclusions meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394–403. In conclusion, the clear recent progress in the treatment of PAH 13. Peacock AJ, Naeije R, Galie N, Rubin L. End-points and clinical trial design in pul- supported by the concordant results of recent meta-analyses monary arterial hypertension: have we made progress? Eur Respir J 2009;34: 231–242. need to be further extended because the current treatment strat- 14. McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, egy is still not satisfactory. This requires a joint effort between Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. regulatory agencies, patient associations, investigators, and industry End points and clinical trial design in pulmonary arterial hypertension. J Am Coll for the development and completion of additional new RCTs. Cardiol 2009;54(Suppl. 1):S97–S107. 15. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, There is no time for sterile discussions about the extent of Tapson VF, Bourge RC, Brundage BH. A comparison of continuous intravenous current achievements based on others’ published papers. Let us epoprostenol (prostacyclin) with conventional therapy for primary pulmonary fight the battle against PAH ‘on the field’ together. Our patients hypertension. The Primary Pulmonary Hypertension Study Group [see com- ments]. N Engl J Med 1996;334:296–302. deserve this commitment. 16. Simonneau G, Rubin L, Galie` N, Barst RJ, Fleming T, Frost A, Engel PJ, Kramer MR, Funding Burgess G, Collings L, Cossons N, Sitbon O, Badesch BD, For the Pulmonary Arterial Hypertension combination Study of Epoprostenol and Sildenafil Funding to pay the Open Access publication charges for this article was (PACES) Study Group. Addition of sildenafil to long-term intravenous epoproste- provided by Dipartimento Cardiovascolare, Universita` di Bologna. nol therapy in patients with pulmonary arterial hypertension. Ann Intern Med 2008;149:521–530. Conflict of interest: N.G. has participated in advisory board activi- 17. Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, Tognoni G. ties for Actelion, Pfizer, United Therapeutics, Eli-Lilly, Bayer-Schering, A meta-analysis of trials of pulmonary hypertension: a clinical condition looking Encysive, and GlaxoSmithKline, Mondobiotec, given paid lectures for for drugs and research methodology. Am Heart J 2007;153:1037–1047. 18. Galie` N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, Actelion, Pfizer, Bayer-Schering, and Encysive. 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Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses

Galiè, Nazzareno; Palazzini, Massimiliano; Manes, Alessandra
European Heart Journal , Volume 31 (17) – May 26, 2010
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Abstract

CURRENT OPINION European Heart Journal (2010) 31, 2080–2086 doi:10.1093/eurheartj/ehq152 Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses Nazzareno Galie ` , Massimiliano Palazzini , and Alessandra Manes Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy Received 5 March 2010; revised 6 April 2010; accepted 23 April 2010; online publish-ahead-of-print 26 May 2010 4,5 Pulmonary arterial hypertension (PAH) is a rare and severe clinical Pathology condition characterized by a progressive increase of pulmonary Pathological lesions in PAH patients affect the distal pulmonary vascular resistance leading to right ventricular failure and prema- arteries (,500 mm), in particular. The lesions are characterized ture death (Figure 1). Its prevalence ranges from 15 to 50 patients 2,3 by medial hypertrophy, intimal proliferative and fibrotic changes per million population and it affects a relatively young patient (concentric and/or eccentric), adventitial thickening with moderate population (average age of 50 years) when compared with the peri-vascular inflammatory infiltrates (Figures 1B and C and 2), more common thoracic organ diseases such as coronary artery complex lesions (plexiform, dilated), and thrombotic lesion. disease and chronic obstructive lung disease. PAH in adults includes at least nine clinical subgroups with virtually identical obstructive pathologic changes (Figures 1 and 2) in the distal pul- 6 – 8 monary arteries: idiopathic, heritable, drug- and toxin-induced, Pathobiology associated with, connective tissue diseases, HIV infection, portal The pathobiology of the distal pulmonary arteries in PAH patients hypertension, congenital heart disease, schistosomiasis, and 1 is multifactorial and involves various biochemical pathways and cell chronic haemolytic anaemia. types (Figure 2). Excessive vasoconstriction has been related to abnormal function or expression of potassium channels in the smooth muscle cells and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilator Pathogenesis and antiproliferative agents such as nitric oxide and prostacyclin, The exact processes that initiate the pathological changes seen in along with over-expression of vasoconstrictor and proliferative PAH are largely unknown. It is hypothesized that the interaction substances such as thromboxane A and endothelin. Many of between genetic predisposition and environmental risk factors these abnormalities both elevate vascular tone and promote vascu- (Figure 1) may be involved in the initial stages of the disease. lar remodelling by proliferative changes that involve several cell However, even the exact role of the auto-antibodies in connective types, including endothelial and smooth muscle cells as well as tissue diseases or the viral involvement in HIV infection is unclear. fibroblasts. In addition, in the adventitia, there is increased pro- It appears that a specific injury on the vessel wall of distal pulmon- duction of extracellular matrix including collagen, elastin, and fibro- ary arteries may initiate, in predisposed individuals, a pathobiologi- nectin and of matrix-bound smooth muscle cell mitogens, such as cal cascade of events which leads to a common final pathological basic fibroblast growth factor. Other matrix metalloproteases can obstructive condition (Figures 1B and C and 2). In the initial stimulate the production of tenascin, a smooth muscle cell mito- phases of these processes, the disease is asymptomatic, and detect- genic cofactor. Several additional growth factors including vascular able pathophysiological changes and symptoms limiting exercise endothelial growth factor, platelet-derived growth factor, insulin- capacity appear usually when the pathological lesions are fully like growth factor-1, and epidermal growth factor have been impli- developed (Figure 1). cated in the development of remodelling and all have been * Corresponding author. Tel: +39 051 349 858, Fax: +39 051 344 859, Email: [email protected] 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. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected] The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact [email protected]. Pulmonary arterial hypertension 2081 Figure 1 Schematic representation of pathogenesis, pathology, pathophysiology, and symptoms in pulmonary arterial hypertension. (A)Normal small distal pulmonary artery: the thin wall is constituted by a single elastic lamina and a thin layer of smooth muscle cells; a large lumen with red blood cells is also shown. (B) Distal pulmonary artery in pulmonary arterial hypertension: increased thickness of the media due to hypertrophy and hyperplasia of smooth muscle cells and moderate lumen reduction are present. This picture may represent an initial phase of the disease and/or the prevalent changes in patients responding to vasoreactivity tests. (C) Distal pulmonary artery in pulmonary arterial hypertension: increased thickness of the media and also of the intima due to proliferation/migration of myofibroblasts and fibrosis are present. Severe lumen reduction is also shown. This picture may represent an advanced phase of the disease and/or the prevalent changes in patients not responding to vasoreactivity tests. (D) Echocardiographic four-chamber view in pulmonary arterial hypertension: Severe dilatation of the right atrium and ventricle and reduction in size of the left ventricle are shown. ALK1, activin-like kinase-type 1 gene; BNP, brain natriuretic peptide; BMPR2, bone morphogenetic protein receptor type 2 gene; CHA, chronic haemolytic anaemia; CHD, congenital heart disease; CTD, connective tissue diseases; ENG, endoglin gene; HIV, human immunodeficiency virus; CMR, cardiac magnetic resonance; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; WHO, world health organization. The pathological pictures are a courtesy of Dr Carol Farver, Cleveland Clinic. reported to be increased (the molecule and/or the specific recep- thrombi are present in both the small distal pulmonary arteries tors) in the lung and/or in the blood of PAH patients. Reduced and in proximal elastic pulmonary arteries. plasma levels of other vasodilator and antiproliferative substances 9,10 such as vasoactive intestinal peptide have also been demonstrated. Pathophysiology Angiopoietin-1, an angiogenic factor essential for vascular lung development, seems to be up-regulated in cases of PAH correlat- The increase of pulmonary vascular resistance in PAH patients ing directly with the severity of the disease. Receptors of the bone is therefore related to different mechanisms, including vasocon- morphogenetic protein pathway, involved in cellular proliferation striction, proliferative and obstructive remodelling of the pulmon- and apoptosis, are down-regulated and/or malfunctioning in the ary vessel wall, inflammation, and thrombosis (Figure 2). lung vasculature of both heritable and acquired PAH. Inflammatory Vasoconstriction is likely prevalent in the small group of patients cells, cyto- and chemokines, and platelets (through the serotonin responding to the acute vasoreactivity test. pathway) may also play a significant role in PAH. Prothrombotic The increase in pulmonary vascular resistance leads to right abnormalities have been demonstrated in PAH patients and ventricular overload, hypertrophy, and dilatation and eventually ` 2082 N. Galie et al. Figure 2 Obstructive remodelling of a small pulmonary artery in pulmonary arterial hypertension (increased thickness of the three vessel layers and severe lumen reduction are shown) and ongoing pathobiological processes in the different layers of the vessel wall (yellow boxes) and in the blood. Asterisks indicate the potential processes involved. Corrective interactions of the related approved therapeutic inter- † ‡ § ventions are also reported (green boxes). *Vasoconstriction; Proliferation/migration; Inflammation; Thrombosis. B-FGF, basic fibroblast 2+ + growth factor; BMPR, bone morphogenetic protein receptor; [Ca ], intracellular calcium concentration; K ch, membrane potassium channels; SMC, smooth muscle cells; MFB, myofibroblasts; MMP, matrix metalloproteases; PDE-5, phosphodiesterase type 5; PDGF, platelet-derived growth factor; TxA , tromboxane A ; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide. The pathological picture 2 2 is a courtesy of Dr Carol Farver, Cleveland Clinic. to right ventricle failure and death (Figure 1). The importance of obstructive lesions and a reduction of the right ventricular after- the progression of right ventricle failure on the symptoms, exer- load (Figure 2). cise limitation, and outcome of PAH patients is confirmed by the prognostic impact of right atrial pressure, cardiac index and pul- Progress of medical treatment in monary arterial pressure, the three main haemodynamic factors pulmonary arterial hypertension linked to right ventricle pump function. Echocardiography and cardiac magnetic resonance parameters and brain natriuretic Two decades ago, patients with idiopathic PAH were defined as peptide plasma levels can also identify non-invasively the presence the ‘kingdom of the near-dead’ to outline their dismal median and extent of right ventricular dysfunction (Figure 1). Afterload survival rate that, at that time, was 2.8 years from the diagnosis, mismatch remains the leading determinant of right heart failure despite any available supportive treatment. Usually, rare and in patients with PAH because its removal, as follows lung trans- severe conditions are neglected by both the medical community plantation, leads almost invariably to sustained recovery of right and the pharmaceutical industry due to the intrinsic difficulties of ventricle function. It is, therefore, conceivable that the drug thera- performing experimental and clinical research in these fields. In pies tested in PAH patients have included compounds which fact, meaningful randomized controlled trials (RCTs) in these set- could potentially interfere with the pathobiological mechanisms tings require a worldwide collaboration of expert centres operat- of the disease trying to achieve a reverse remodelling of the ing with a similar standard of medical care and relatively large Pulmonary arterial hypertension 2083 financial resources with a rather high risk of study failure. The agree that in rare and severe conditions dramatically impairing recent history of drug development in PAH contradicts this tra- the functional capacity of relatively young patients, exercise ditional perspective and it is worthwhile to analyse the details of capacity improvement can be considered a worthwhile initial this phenomenon. objective. In addition, the usual concordant favourable changes in 12 13,14 Without a doubt, the progress made in the medical treatment of haemodynamics and TtCW observed in some studies PAH in the past 15 years is unique, particularly for a rare and reinforced the results of the 6MWT. The use of this test as a severe condition: almost 30 RCTs have been completed and primary endpoint has allowed reasonable study sample sizes more than 10 are either ongoing or planned. Twenty-five RCTs (from 100 to 500 patients) and randomized study duration have been published as of May 2010 (Figure 3). Eight drugs (ambri- (from 2 to 6 months), which are favourable feasibility character- sentan, bosentan, epoprostenol, iloprost, sildenafil, sitaxentan, istics in a rare and severe disease. On the other hand, these same tadalafil, treprostinil) belonging to three pharmacological classes characteristics have prevented the observation of effects on the (endothelin receptor antagonists, phosphodiesterase type-5 inhibi- mortality rate except for studies enrolling the most severe 15,16 tors, and prostanoids) administered by four different routes (oral, patient population. inhaled, subcutaneous, and intravenous) have been currently approved by the Food and Drug Administration (FDA) and/or by the European Medicines Agency (EMA). All three classes of Meta-analyses to assess the effect drugs exert both vasodilator and antiproliferative effects and inter- on mortality fere with the endothelial dysfunction abnormalities observed in PAH patients (Figure 2). Meta-analysis of multiple studies is a technique that may allow the analysis of parameters or events with a larger sample size and with additional statistical insights. This approach requires the Traditional endpoints for clinical inclusion of homogeneous studies as far as disease aetiology and study designs are concerned. A first meta-analysis on 16 trials in pulmonary arterial RCTs performed in PAH concluded that the treatments ‘pro- hypertension duced limited benefits in clinical end-points and failed to The traditional primary endpoint of the RCTs performed in PAH support a significant survival advantage’. However, the has been the 6 min walk test (6MWT) that assesses the exercise meta-analysis included both acute and long-term studies and capacity, and secondary endpoints have included haemodynamics one study on patients with lung fibrosis and did not consider and time to clinical worsening (TtCW), a composite endpoint six RCTs published before its submission. We performed a 13,14 12 including death, hospitalization, and disease progression. second meta-analysis on 23 RCTs in 3199 PAH patients pub- Based on the primary endpoint, the specific labelling indication lished as of October 2008. This analysis showed a reduction in of all approved medications for PAH usually includes the mortality ranging between 38 and 43% (according to different wording ‘to improve exercise capacity’ followed by the functional inclusion criteria) after an average treatment period of 14.3 classes of the patient population enrolled in the studies. This weeks. A subgroup analysis showed that all three classes of reflects the fact that both regulatory agencies and investigators PAH-approved drugs achieved a similar favourable reduction in Figure 3 Time-course of 25 published randomized controlled studies (identified by acronyms, if any, or drug and year of publication) in pul- monary arterial hypertension as of May 2010. Colour code identifies the design of the study: monotherapy (black): investigational drug vs. placebo in patients naive for pulmonary arterial hypertension approved drugs. Monotherapy and/or sequential combination (red): investigational drug vs. placebo in patients either naive for, or treated with pulmonary arterial hypertension approved drugs. Upfront combination (light blue): single drug vs. combination of two drugs in patients naive for pulmonary arterial hypertension approved drugs. ` 2084 N. Galie et al. Figure 4 Meta-analysis of published randomized controlled studies (identified by first author and year of publication) in pulmonary arterial hypertension as of May 2010. The primary analysis has included 3780 patients of 23 trials. The figure shows the cumulative RR estimate of death in active treatment groups when compared with control groups stratified according to treatment class (inverse variance method). Studies with no events in both groups were excluded. An overall reduction of mortality of 44% (P ¼ 0.016) is shown. The sensitivity analysis, including two additional studies (59 patients) in which two treatment strategies were compared, confirmed a reduction in mortality of 39% (P ¼ 0.041). The subgroup analysis of the three classes of approved drugs achieved a similar favourable reduction in mortality, although no statistical significance was achieved individually. RR, relative risk. Modified from Galie` et al. mortality, although no statistical significance was achieved indivi- patients treated with the targeted therapies currently approved dually. Updating our meta-analysis with two recently published for PAH. The limitations of this conclusion include the short dur- 18,19 studies, the overall reduction in mortality has been confirmed ation of the RCTs whose primary endpoint was not mortality and (Figure 4). These data have recently been validated by the authors the lack of evidence of a favourable long-term effect. of the first meta-analysis, who reported a reduction in mortality Nevertheless, we disagree with the opinion that the above limit- of 39%, analysing the data of 3363 patients. The concordance of ations are the key factors which should induce us to adopt new these results suggests, therefore, an improvement of survival in trial designs, new endpoints, and longer durations of the RCTs. Pulmonary arterial hypertension 2085 Given the higher mortality observed in the placebo groups of the dual endothelin receptor antagonists, prostanoids and non- 12,20 more recent meta-analyses on PAH trials and the higher rate prostanoid prostacyclin receptor agonists, and inhaled vasoactive of clinical deterioration observed in placebo-treated groups of indi- intestinal peptide. The efficacy of these new compounds needs 15,16,18,21 – 25 vidual PAH studies, it is not ethical, in our view, to to be demonstrated ‘on top of’ the available approved PAH drug repeat RCTs in naı¨ve PAH patients in order to satisfy the scientific therapies in order to avoid any delay in the initiation of effective curiosity of ‘desk trialists’. medications. Therefore, a combination approach is required also in this case. The way forward The true issues PAH patients and physicians face in the clinical Future study designs practice is the insufficient efficacy of the present therapeutic resources, despite clear progress and the escape from ‘the The future decisive challenge is the identification of the most kingdom of the near-dead’. The current treatment strategy, opti- appropriate study designs to demonstrate the efficacy-to-safety mized in recent guidelines, remains inadequate because the mor- ratio of combination strategies either with already approved tality rate continues to be high and the functional and drugs or with novel therapies. The replication of the traditional haemodynamic impairments are still extensive in many patients. phase III strategy (placebo-controlled design in treatment-naı¨ve The specific drugs approved for PAH are able to slow the pro- patients, 6MWT as primary endpoint assessed after 3–4 months gression of the disease but cannot be considered a cure for the of treatment) appears not to be suitable for practical and ethical majority of patients. reasons. In fact, the inclusion of patients on background effective Current and future plans devoted to increasing our ability to therapies will reduce our ability to demonstrate a difference treat PAH are facing new challenges which require scientific crea- between the ‘placebo-treated group’ and the ‘actively treated tivity and new research strategies. Possible working hypotheses group’, in particular, if exercise capacity is the primary endpoint. include the drug combination approach and new candidate This phenomenon was observed in the more recently completed classes of drugs. RCTs in which the treatment effect on the 6MWT ranged from 16,18,19,26 15 to 25 m when compared with the traditional 35 to 55 m observed in historical monotherapy studies. A possible sol- Combination therapy ution is the adoption of different primary endpoints, such as The rationale for combining approved PAH compounds is related TtCW, accepted by the regulatory agencies. This approach also to the different pathobiological pathways targeted by the three presents challenges, including the objective and uniform definition classes of approved PAH drugs (Figure 2). This combined approach of this composite endpoint and the sample size and/or duration of has successfully been employed in the treatment of other serious the study, which can be either pre-specified or based on the and chronic diseases such as congestive heart failure, HIV infection, number of observed events. Additional problems of multicentre and cancer. Combination therapy is currently recommended in and international studies are linked to the country-related hetero- PAH patients with suboptimal response to the initial monotherapy geneity of the PAH-approved medications, the different attitudes as an add-on with a compound of an alternative drug class (sequen- for hospitalization in different geographic areas, and the availability tial combination therapy). Different RCTs have currently shown of centres with experience in combination therapy. the efficacy of this strategy on the improvement of exercise Initial appropriate answers to solve these difficulties have been 16,18,19,21,26 16,18,26 capacity and the reduction of TtCW. given by the regulatory agencies and by the investigators. In fact, An emerging concept relates to the use of first-line combination in the recently published ‘Guideline on the Clinical Investigations therapy with two drugs in PAH patients when compared with the of Medicinal Products for the Treatment of PAH’, the Commit- initial monotherapy. This hypothesis was tested in the BREATHE-2 tee for Medicinal Products for Human Use (CHMP) of the EMA trial, but the small sample size of the study did not allow for a clarified the requirements for the approval of PAH medications, definitive conclusion. The appropriate design to assess the effi- indicating the characteristics of acceptable primary endpoints, cacy of this strategy appears to be a three-arm study, comparing including 6MWT and TtCW. Randomized controlled trials adopt- combination therapy with two arms of monotherapy, using the ing novel designs and TtCW as primary endpoint have already single compounds. been initiated. For example, a morbidity and mortality primary end- point has been adopted in the SERAPHIN study (Study with Endothelin Receptor Antagonist in Pulmonary arterial Hyperten- New candidate classes of drugs sion to Improve cliNical outcome), testing the efficacy of a new tis- Paradoxically, there is no shortage of novel candidate therapies for sular dual endothelin receptor antagonist, and in the AMBITION PAH, including drugs, gene, and/or stem-cell treatments. These study (A randomized, double-blind, placebo-controlled, multicen- approaches are intended to address alternative pathobiological tre study of first-line combination therapy with AMBrIsentan and pathways (Figure 2) or explore new strategies such as regenerative Tadalafil vs. monotherapy in subjects with pulmonary arterial medicine. New drugs with ongoing or planned phase III studies in hypertensION), testing the efficacy of the initial combination this field include oral compounds such as NO-independent stimu- therapy of a selective endothelin receptor antagonist and a phos- lators and activators of cyclic guanosine monophosphate, tyrosine phodiesterase type-5 inhibitor when compared with monotherapy kinase inhibitors (platelet-derived growth factor inhibitors), tissular using single compounds. ` 2086 N. Galie et al. 12. Galie N, Manes A, Negro L, Palazzini M, Bacchi Reggiani ML, Branzi A. A Conclusions meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394–403. In conclusion, the clear recent progress in the treatment of PAH 13. Peacock AJ, Naeije R, Galie N, Rubin L. End-points and clinical trial design in pul- supported by the concordant results of recent meta-analyses monary arterial hypertension: have we made progress? Eur Respir J 2009;34: 231–242. need to be further extended because the current treatment strat- 14. McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, egy is still not satisfactory. This requires a joint effort between Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. regulatory agencies, patient associations, investigators, and industry End points and clinical trial design in pulmonary arterial hypertension. J Am Coll for the development and completion of additional new RCTs. Cardiol 2009;54(Suppl. 1):S97–S107. 15. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, There is no time for sterile discussions about the extent of Tapson VF, Bourge RC, Brundage BH. A comparison of continuous intravenous current achievements based on others’ published papers. Let us epoprostenol (prostacyclin) with conventional therapy for primary pulmonary fight the battle against PAH ‘on the field’ together. Our patients hypertension. The Primary Pulmonary Hypertension Study Group [see com- ments]. N Engl J Med 1996;334:296–302. deserve this commitment. 16. Simonneau G, Rubin L, Galie` N, Barst RJ, Fleming T, Frost A, Engel PJ, Kramer MR, Funding Burgess G, Collings L, Cossons N, Sitbon O, Badesch BD, For the Pulmonary Arterial Hypertension combination Study of Epoprostenol and Sildenafil Funding to pay the Open Access publication charges for this article was (PACES) Study Group. Addition of sildenafil to long-term intravenous epoproste- provided by Dipartimento Cardiovascolare, Universita` di Bologna. nol therapy in patients with pulmonary arterial hypertension. Ann Intern Med 2008;149:521–530. Conflict of interest: N.G. has participated in advisory board activi- 17. Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, Tognoni G. ties for Actelion, Pfizer, United Therapeutics, Eli-Lilly, Bayer-Schering, A meta-analysis of trials of pulmonary hypertension: a clinical condition looking Encysive, and GlaxoSmithKline, Mondobiotec, given paid lectures for for drugs and research methodology. Am Heart J 2007;153:1037–1047. 18. Galie` N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, Actelion, Pfizer, Bayer-Schering, and Encysive. 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European Heart Journal – Pubmed Central

Published: May 26, 2010

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