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ABSTRACT: ABSTRACT BACKGROUND: Novel non-invasive tools may improve the management of patients with pulmonary arterial hypertension (PAH) experiencing heart failure. Major right ventricle overload leads to decreased stroke volume, which shortens left ventricular ejection time (LVET). Our arterial tonometry study tested the hypothesis that LVET carries prognostic value in PAH patients with heart failure. METHODS: Clinical, biological and radial artery tonometry variables were prospectively obtained at admission and at day 3-5 in 53 consecutive PAH patients admitted in our ICU for clinical deterioration. LVET was measured from the reconstructed aortic pressure curve. RESULTS: Overall ICU mortality (median stay 5 days) was 17% and 28%. At admission, the LVET was shorter in patients with unfavourable outcome (median 228 ms (212-278) vs 257 ms (237-277), p=0.032), while other tonometric indices were similar. The LVET at entry (237 ms) had 73% sensitivity and 89% specificity for identifying death in the ICU. Other prognostic factors at admission were higher serum levels of brain natriuretic peptide (BNP) and creatinine, and lower natremia. Dobutamine requirement, higher furosemide dose and higher oxygen flow were associated with unfavourable outcome. At the second evaluation, higher serum level of creatinine and BNP, higher furosemide dose and oxygen flow, and dobutamine or norepinephrine requirement were associated with poor outcome. The change in LVET between admission and follow-up measurement was not associated with outcome. The 90-day mortality was 28%. CONCLUSIONS: Shortened LVET at ICU admission was a prognostic factor in PAH with heart failure. Previously documented prognostic factors were also confirmed in this cohort.
Chest 05/2013; · 5.25 Impact Factor
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Respiration 03/2013; · 2.26 Impact Factor
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ABSTRACT: Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell disease have established the prevalence of pulmonary hypertension in this disease about 6 to 10%. Over half of these correspond to postcapillary pulmonary hypertension. Precapilliary arterial pulmonary hypertension seems to be a relatively infrequent complication of the disease. It is characterized by a different hemodynamic profile of idiopathic PAH with lower levels of pulmonary pressures and pulmonary vascular resistance. However, pulmonary vascular disease appears to have a significant impact on the functional status and vital prognosis of patients with sickle cell disease. The predictive value of echocardiography to detect pulmonary hypertension in this population is low (25-32%) when the threshold of tricuspid regurgitation velocity of 2.5m/s is used. At present, no specific treatments for pulmonary arterial hypertension is currently approved for the treatment of PAH associated with sickle cell disease due to lack of data in this specific population.
La Presse Médicale 06/2012; · 0.67 Impact Factor
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ABSTRACT: Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomized controlled trials with pulmonary arterial hypertension (PAH) specific therapies. This study investigated short- and long-term efficacy/safety of bosentan in these patients, as well as pharmacokinetics.All 34 consecutive patients with PoPH treated first-line with bosentan (December 2002 -July 2009) were retrospectively evaluated. Assessments included: New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-minute walk distance (6MWD) and event-free status. Pharmacokinetics of bosentan in 5 patients with Child-Pugh class B cirrhosis were compared with idiopathic PAH patients.Significant improvements from baseline were observed in NYHA FC, 6MWD, and haemodynamics, and largely maintained during follow up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after 5±2 months. Mean follow-up was 43±19 months; 4 patients died; seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with cirrhosis C-P class B than observed in idiopathic PAH.These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.
European Respiratory Journal 05/2012; · 5.89 Impact Factor
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Circulation 04/2012; 125(16):2045-7. · 14.74 Impact Factor
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Laurent Savale,
Marie-Camille Chaumais,
Vincent Cottin,
Emmanuel Bergot,
Irène Frachon,
Grégoire Prevot,
Christophe Pison,
Claire Dromer,
Patrice Poubeau,
Nicolas Lamblin,
Gilbert Habib,
Martine Reynaud-Gaubert,
Arnaud Bourdin,
Olivier Sanchez,
Pascale Tubert-Bitter,
Xavier Jaïs,
David Montani,
Olivier Sitbon,
Gérald Simonneau,
Marc Humbert
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ABSTRACT: Benfluorex was marketed in France until 2009, despite its similar pharmacological properties with fenfluramine and its derivatives known to be a cause of pulmonary arterial hypertension.The aim of this study is to report clinical and haemodynamic characteristics of patients suffering of pulmonary hypertension associated with benfluorex exposure identified by the French pulmonary hypertension network.Eighty five cases of pulmonary hypertension associated with benfluorex exposure were identified by the French pulmonary hypertension network from June 1999 to March 2011. Of these, 70 patients had confirmed pre-capillary pulmonary hypertension. The median duration of exposure was 30 months, with a median of 108 months between start of exposure and diagnosis of the pulmonary vascular disease. 33% of all patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor for pulmonary hypertension was identified in 20/70 (30%) patients with pre-capillary pulmonary hypertension. A quarter of patients in this current series showed co-existing pulmonary hypertension and mild to moderate cardiac valve involvement.The results of our study, together with the accumulated data regarding the known toxic effects of fenfluramine and dexfenfluramine, strongly suggest that benfluorex exposure is a potent trigger for pulmonary arterial hypertension.
European Respiratory Journal 04/2012; · 5.89 Impact Factor
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Chest 04/2012; 141(4):840-2. · 5.25 Impact Factor
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David Montani,
Emmanuel Bergot,
Sven Günther, Laurent Savale,
Anne Bergeron,
Arnaud Bourdin,
Helene Bouvaist,
Matthieu Canuet,
Christophe Pison,
Margareth Macro, [......],
Delphine Natali,
Christophe Guignabert,
Frédéric Perros,
Dermot S O'Callaghan,
Xavier Jaïs,
Pascale Tubert-Bitter,
Gérard Zalcman,
Olivier Sitbon,
Gérald Simonneau,
Marc Humbert
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ABSTRACT: The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.
This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.
Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
Circulation 03/2012; 125(17):2128-37. · 14.74 Impact Factor
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ABSTRACT: Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure above 25 mmHg. Pulmonary vasoconstriction, cellular proliferation, inflammation, and oxidative stress are involved in the pathophysiology of PH. Since hypomagnesemia was reported to promote endothelial cell dysfunction leading to inflammation and oxidative stress, we investigated the potential involvement of magnesium (Mg) deficiency in experimental and human PH. Our results indicate that Mg deficiency has no impact on hypoxia-induced PH development or severity, and that no reduction in Mg plasma concentration was observed in patients with severe pulmonary arterial hypertension. Thus, hypomagnesemia does not appear to play a role in the pathophysiology of experimental and human pulmonary hypertension.
Magnesium research: official organ of the International Society for the Development of Research on Magnesium 03/2012; 25(1):21-7. · 1.52 Impact Factor
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ABSTRACT: Recent guidelines have proposed first-line combination therapy as a potential strategy for the treatment of functional class IV pulmonary arterial hypertension (PAH).
We analyzed efficacy and safety of upfront epoprostenol and bosentan combination therapy in consecutive patients with idiopathic, heritable, or anorexigen-associated PAH and compared outcomes with matched controls treated by epoprostenol monotherapy.
Data for 16 functional class III patients and 7 functional class IV patients were analyzed. Baseline 6-minute walk distance (6MWD) was 287 ± 133 meters, mean pulmonary artery pressure was 65 ± 12 mm Hg, cardiac index was 1.8 ± 0.3 L/min/m(2), and pulmonary vascular resistance (PVR) was 1493 ± 398 dynes/sec/cm(5). After 4 months, 6MWD and PVR significantly improved to 421 ± 100 meters and 784 ± 364 dynes/sec/cm(5), respectively. These improvements were maintained long-term (30 ± 19 months). At 1, 2, 3, and 4 years, overall survival estimates were 100%, 94%, 94%, and 74%, and transplant-free survival estimates were 96%, 85%, 77%, and 60%, respectively. Compared with matched controls started on epoprostenol monotherapy, there was a trend to an improvement in overall survival (p = 0.07).
Initial combination therapy with epoprostenol and bosentan in patients with severe PAH is associated with improvements in important outcomes such as functional class, exercise capacity, and hemodynamics. This combination strategy might also favorably affect overall and transplant-free survival.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2011; 31(2):150-8. · 3.54 Impact Factor
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Florence Parent,
Dora Bachir,
Jocelyn Inamo,
François Lionnet,
Françoise Driss,
Gylna Loko,
Anoosha Habibi,
Soumiya Bennani, Laurent Savale,
Serge Adnot,
Bernard Maitre,
Azzedine Yaïci,
Leila Hajji,
Dermot S O'Callaghan,
Pierre Clerson,
Robert Girot,
Frederic Galacteros,
Gerald Simonneau
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ABSTRACT: The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established.
In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg.
The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics.
In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).
New England Journal of Medicine 07/2011; 365(1):44-53. · 53.30 Impact Factor
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ABSTRACT: INTRODUCTION: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH. AREAS COVERED: The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested. EXPERT OPINION: The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ 'harder' clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.
Expert Opinion on Pharmacotherapy 07/2011; 12(10):1585-96. · 3.20 Impact Factor
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David Montani,
Florence Coulet,
Barbara Girerd,
Mélanie Eyries,
Emmanuel Bergot,
Hervé Mal,
Giuseppina Biondi,
Claire Dromer,
Thomas Hugues,
Charles Marquette, [......],
Xavier Jaïs,
Peter Dorfmüller,
Hugues Begueret,
Laurent Bertoletti,
Olivier Sitbon,
Christine Bellanné-Chantelot,
Gérard Zalcman,
Gérald Simonneau,
Marc Humbert,
Florent Soubrier
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ABSTRACT: Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH. We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor. In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.
Medicine 05/2011; 90(3):201-11. · 4.35 Impact Factor
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ABSTRACT: The current treatment strategies for pulmonary arterial hypertension, outlined in the ERS/ESC guidelines published in 2009, have led to improvements in life expectancy and patient quality of life. However, a cure for the disease remains elusive. In order to improve the prognosis for patients with PAH, future research will focus on development of new therapeutic agents, identification of novel targets and studies involving combinations of existing treatments An important goal is to refine the efficacy and tolerability of agents that target NO, endothelin and prostacyclin signaling pathways. Novel targeted therapies, such as tyrosine kinase inhibitors that directly act on the abnormal proliferation of pulmonary vascular cells, are under active investigation. Finally, clinical trials evaluating combinations of treatments have shown encouraging results.
La Presse Médicale 04/2011; 40 Suppl 1:1S54-60. · 0.67 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature that results in elevated pulmonary vascular resistance and premature death. Although no cure exists for PAH, improved understanding of the pathobiological mechanisms of this disease has resulted in the development of effective therapies that target specific aberrant pathways. Agents that modulate abnormalities in the prostacyclin, endothelin, and nitric oxide pathways have been shown in randomized, controlled studies to confer improvements in functional status, pulmonary hemodynamics, and possibly even slow disease progression. Several additional pathways believed to play an important role in the pathogenesis of PAH have been identified as potentially useful therapeutic targets and a number of investigative approaches focusing on these targets are in active development. In this Review, we highlight the pharmacological agents currently available for the treatment of PAH and discuss potential novel strategies.
Nature Reviews Cardiology 01/2011; 8(9):526-38. · 8.83 Impact Factor
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Guillaume Gary-Bobo,
Amal Houssaini,
Valerie Amsellem,
Dominique Rideau,
Pierre Pacaud,
Aline Perrin,
Jérémy Brégeon,
Elisabeth Marcos,
Jean-Luc Dubois-Randé,
Olivier Sitbon, Laurent Savale,
Serge Adnot
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ABSTRACT: Pulmonary hypertension (PH) is among the complications of HIV infection. Combination antiretroviral therapy may influence the progression of HIV-related PH. Because Akt signaling is a potential molecular target of HIV protease inhibitors (HPIs), we hypothesized that these drugs altered monocrotaline- and hypoxia-induced PH in rats by downregulating the Akt pathway, thereby inhibiting pulmonary artery smooth muscle cell proliferation.
Daily treatment with each of 3 first-generation HPIs (ritonavir 30 mg/kg, amprenavir 100 mg/kg, and nelfinavir 500 mg/kg) started 3 weeks after a subcutaneous monocrotaline injection (60 mg/kg) substantially diminished pulmonary artery pressure, right ventricular hypertrophy, number of muscularized pulmonary vessels, pulmonary arterial wall thickness, and proliferating pulmonary vascular Ki67-labeled cells without affecting vessel caspase 3 staining. HPI treatment partially prevented the development of hypoxia- and monocrotaline-induced PH. Monocrotaline-induced PH was associated with marked activation of Akt signaling in the lungs and proximal pulmonary arteries, with increases in phosphorylated Akt, phosphorylated glycogen-synthase-kinase-3β (GSK3), and phosphorylated endothelial nitric oxide synthase, all of which decreased markedly after treatment with each HPI. In contrast, PH-associated increases in phosphorylated extracellular signal-related kinase 1/2 and myosin light-chain phosphatase were unaltered by the HPIs. The 3 HPIs and the phosphatidylinositol 3-kinase inhibitor LY294002 inhibited platelet-derived growth factor-induced phosphorylation of Akt and GSK3 in cultured pulmonary artery smooth muscle cells and blocked cell proliferation; this last effect was abolished by the GSK3 inhibitor SB216763.
These results support an effect of HPIs on pulmonary vascular remodeling mediated by inhibition of Akt phosphorylation and consequently of pulmonary artery smooth muscle cell proliferation.
Circulation 10/2010; 122(19):1937-47. · 14.74 Impact Factor
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ABSTRACT: To assess the acute vasodilator response and long-term response to calcium-channel blockers (CCB) in pulmonary arterial hypertension (PAH) with associated conditions.
The response to acute vasodilator testing [>20% decrease in mean pulmonary artery pressure (mPAP) and total pulmonary resistance] was assessed in 663 consecutive PAH patients with connective tissue disease (CTD; n = 168), portal hypertension (PoPH; n = 153), anorexigen use (n = 127), human immunodeficiency virus infection (HIV; n = 124), congenital heart disease (CHD; n = 50), and pulmonary veno-occlusive disease or capillary haemangiomatosis (PVOD/PCH; n = 41). An acute vasodilator response was observed in 13.4% of PAH-anorexigen patients, 12.2% of PVOD/PCH, 10.1% of CTD, 1.6% of HIV, 1.3% of PoPH, and was absent in CHD. A long-term response to CCB (marked haemodynamic improvement at 3-4 months and New York Heart Association functional class I or II after 1 year) was reported in 9.4% of PAH-anorexigen patients but was rare in HIV, PoPH, CTD (1.6, 0.7, and 0.6%, respectively) and absent in PVOD/PCH. All patients with a long-term CCB response were alive after 5 years; two deaths not related to PAH occurred after this time. Recent criteria for acute response based on the fall in mPAP to <40 mmHg are more specific to detect long-term responders to CCB.
A long-term CCB response was reported in patients with PAH associated with anorexigen use, but was rare in patients with PoPH or HIV and absent in PVOD/PCH, CHD, and the vast majority of CTD. The prognosis of long-term responders was favourable and related to the underlying cause of PAH.
European Heart Journal 08/2010; 31(15):1898-907. · 10.48 Impact Factor
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ABSTRACT: A goal-oriented treatment strategy is recommended in patients with pulmonary arterial hypertension (PAH). The current treatment goals are based on regular assessment of clinical parameters that have been demonstrated as prognostic factors at the time of initial evaluation. The prognostic value of the course of these parameters assessed at follow-up on PAH-specific therapies is unknown. The aim of the EFORT clinical study is to analyse the prognostic factors assessed at follow-up in patients with PAH, to provide more accurate information in terms of treatment goals than the simple analysis of prognostic factors at baseline. This clinical research project should help to establish new recommendations for the management of patients with PAH. The impact of these new therapeutic approaches on long-term survival of patients with PAH is a major challenge in the near future.
La Presse Médicale 06/2010; 39 Suppl 1:1S33-40. · 0.67 Impact Factor
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ABSTRACT: At diagnosis of pulmonary arterial hypertension (PAH), some patients are considered to have a "near-normal" 6-min walk distance (6MWD) (ie, > 450 m). Because they are generally excluded from randomized controlled trials, little is known about these patients.
We analyzed the baseline characteristics and treatment responses of 49 consecutive patients with a 6MWD > 450 m at the time of newly diagnosed PAH. Data from this cohort were then compared with data from hemodynamically matched patients with a 6MWD < or = 450 m.
Patients with a 6MWD > 450 m were either in World Health Organization (WHO) functional class (FC) II (n = 23) or III (n = 26) at baseline. Compared with patients in FC II, those in FC III had more severe hemodynamic impairment (ie, a lower cardiac index and higher pulmonary vascular pressures and resistance) but similar 6MWD. At first evaluation after initiation of PAH-specific treatment (3-6 months), FC improved (FC I-II: n = 38; FC III: n = 11, P < .005) and cardiac index increased. However, 6MWD remained unchanged. Compared with matched patients with a 6MWD < or = 450 m (n = 98), individuals with a 6MWD > 450 m were approximately 9 years younger (P = .0006) and had a lower BMI (P = .0009).
Anthropometric characteristics such as younger age and lower BMI may explain higher 6MWD in some PAH patients. In the cohort of patients with a 6MWD > 450 m, hemodynamic indices and WHO FC were more sensitive than 6MWD in detecting changes secondary to PAH-specific treatments.
Chest 06/2010; 137(6):1297-303. · 5.25 Impact Factor
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ABSTRACT: The last decade has witnessed a remarkable increase in the number of effective treatment options available for the management of patients with pulmonary arterial hypertension. In this regard, agents belonging to the therapeutic classes that specifically target the prostacyclin, endothelin and nitric oxide pathways have shown the greatest efficacy in clinical studies to date. These various drug treatments have individually been shown to confer improvements in symptoms, exercise capacity, pulmonary haemodynamics and possibly survival in different patient subgroups. However, pulmonary arterial hypertension is characterised by dysregulation of a variety of pathways. In addition, disease worsening is inevitable for the majority of patients receiving monotherapy. As a consequence, there is increasing interest in the use of treatment combinations in order to target multiple targets with the aim of restoring normal pulmonary vascular function in order to improve clinical status. Indeed, use of multiple specific-treatment regimens is now part of routine clinical practice and is emphasized in recently published therapeutic guidelines. This review details the rationale for the different combination strategies and examines the clinical evidence in favour of some of the approaches that have been evaluated.
Respiratory medicine 04/2010; 104 Suppl 1:S74-80. · 2.33 Impact Factor
