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ABSTRACT: ABSTRACT BACKGROUND: The Pulmonary Arterial Hypertension (PAH) Quality Enhancement Research Initiative (PAH-QuERI) was created to help clinicians implement a guideline-based approach to the diagnosis and management of PAH. Patients with PAH represent a heterogeneous population, and physicians' evaluation and treatment paradigms may vary considerably. METHODS: Utilizing an electronic data management system, participating physicians recorded data on diagnostic work-up, disease management, and outcomes of PAH patients. Queries were generated automatically following each of the prescheduled follow-up visits if the tests recommended by the American College of Chest Physicians (ACCP) were not performed at least once. RESULTS: Of 791 patients enrolled in PAH-QuERI, 77% were women, 64% were confirmed prevalent patients (diagnosed >3 months prior to enrollment), 9% were in functional class I, 39% in II, 48% in III, and 5% in IV, and the median (interquartile range) age was 55 years (range, 45-66 years). At enrollment, all ACCP-recommended tests had been performed in only 6% of patients. The automated program generated 1530 reminders for 642 patients (81%) with validated enrollment data. The proportion of recommended tests performed was CBC (91%), LFTs (91%), CTD screen (50%), HIV screen (29%), chest x-ray (88%), ECG (82%), 2-dimensional echocardiogram (97%), PFTs (83%), oximetry (41%), V/Q scan (57%), 6MWD (79%), and RHC (90%). Regarding management, 78% of patients were on disease-specific therapy and the use of these therapies tended to increase with the functional disability of the patient. One hundred seventy patients were on calcium channel blockers, 91 specifically for PAH. Only 6 of 91 patients (7%) who received calcium channel blockers specifically for PAH had met the current guideline for acute vasoreactivity. CONCLUSIONS: When comparing reported clinical practice with ACCP guideline-recommended strategies, a diagnostic care gap is apparent, such that certain essential and recommended diagnostic tests may be underutilized despite the availability of detailed guidelines and reminders.ClinicalTrials.gov Registration Number: N/A 1University of Michigan Health System, Ann Arbor, MI, USA; 2Canadian Heart Research Centre, Toronto, ON, Canada; 3David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 4LA Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA; 5Duke University Medical Center, Durham, NC, USA; 6Massachusetts General Hospital, Boston, MA, USA; 7University of CA, San Diego, La Jolla, CA, USA Corresponding Author: Vallerie V. McLaughlin, MD, Professor of Medicine, Director, Pulmonary Hypertension Program, University of Michigan, CVC Cardiovascular Medicine, 1500 E. Medical Center Drive, SPC 5853, Ann Arbor, MI 48109, USA, E-mail: vmclaugh@umich.edu.
Chest 08/2012; · 5.25 Impact Factor
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ABSTRACT: ABSTRACT RATIONALE: Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: To determine the individual and additive ability of pre- and post-treatment 6MWD and BNP to discriminate 2-year survival in PAH patients. METHODS: We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (n=370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defined subgroups with a high 2-year mortality. Classification and regression tree analysis was employed to determine the incremental prognostic value of combined assessments. MEASUREMENTS AND MAIN RESULTS: 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics = 0.77 [95%CI 0.70-0.84] and 0.82 [95%CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics = 0.68 [95%CI 0.60-0.76] and 0.74 [95%CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point. CONCLUSIONS: 6MWD and BNP values at baseline or week 12 identified a population with an elevated risk of death at two years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.
Chest 07/2012; · 5.25 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension.
Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening.
Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated.
The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events.
Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302).
Journal of the American College of Cardiology 07/2012; 60(8):768-74. · 14.16 Impact Factor
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ABSTRACT: The objective of this report is to compare baseline, management and survival characteristics in idiopathic pulmonary arterial hypertension (IPAH) with systemic sclerosis-associated pulmonary arterial hypertension (SSc-APAH) using data from the prospectively enrolled PAH Quality Enhancement Research Initiative.
Between August 2005 and July 2007, patients with IPAH and SSc-APAH were enrolled across 60 US sites and followed up for 3 years. Data on diagnostic tests, clinical variables, pulmonary arterial hypertension (PAH) medication and outcomes were recorded.
With some exceptions, baseline clinical and laboratory characteristics were similar between the 279 patients with IPAH and the 228 with SSc-APAH. Patients with SSc-APAH were older at the time of PAH diagnosis, were more likely to be female and were antinuclear antibody positive. Patients with SSc-APAH had poorer spirometric results. During the 3-year follow-up, both groups were managed with prostacyclin and prostacyclin analogue treatment, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors (PDE5i) singly or in combination. At 3 years, patients with SSc-APAH were more likely to be treated with PDE5i alone or with an endothelin receptor antagonist. Patients with SSc-APAH had a significantly lower survival rate compared to patients with IPAH (60% vs 77%, p<0.0001).
The cohort with SSc-APAH was older, was more severely ill, was more likely to be female, was managed with PDE5i and had reduced 3-year survival compared with the cohort with IPAH.
Annals of the rheumatic diseases 02/2012; 71(2):249-52. · 8.11 Impact Factor
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David B Badesch,
Jeremy Feldman,
Anne Keogh,
Michael A Mathier, Ronald J Oudiz,
Shelley Shapiro,
Harrison W Farber,
Michael McGoon,
Adaani Frost,
Martine Allard,
Darrin Despain,
Christopher Dufton,
Lewis J Rubin
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ABSTRACT: Ambrisentan is an oral, once daily, endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension (PAH). Previous studies of ambrisentan were limited to patients with Group 1 PAH and often excluded patients receiving other pulmonary hypertension (PH) therapies. Aims: ARIES-3 was an open-label study evaluating efficacy and safety of ambrisentan in patients with various PH etiologies and background PH medications. Patients received 5 mg ambrisentan once daily for 24 weeks. The primary endpoint was change from baseline in 6-minute walk distance (6MWD) at week 24.
A total of 224 patients with PH due to idiopathic and familial PAH (31%), connective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable background PAH therapies. After 24 weeks of therapy, an increase in 6MWD (+21 m; 95% CI: 12-29) and a decrease in B-type natriuretic peptide (-26%; 95% CI: -34 to -16%) was observed in the overall population compared to baseline; however, increases in 6MWD were not observed in several non-Group 1 PH subpopulations. Peripheral edema, headache, and dyspnea were the most common adverse events.
This study reconfirms the results of previous placebo-controlled studies, which demonstrate that ambrisentan is well tolerated and provides benefit in patients with PAH. Definitive conclusions regarding the safety and efficacy of ambrisentan in specific non-Group 1 PH etiologies cannot be determined and larger, controlled studies will be necessary to determine the efficacy and safety of ambrisentan in these populations.
Cardiovascular Therapeutics 06/2011; 30(2):93-9. · 2.35 Impact Factor
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ABSTRACT: The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.
The American journal of cardiology 05/2011; 108(2):302-7. · 3.58 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. There are currently 3 classes of drugs approved for the treatment of PAH: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. All of these therapies have been approved for use on the basis of relatively small, short-term studies, yet it is common for each to be administered (alone or in combination) over the lifetime of a patient with PAH. Very few prospective, well-controlled PAH studies have examined long-term clinical outcomes associated with current medical therapy. Therefore, data that support the long-term therapeutic benefits of these long-term PAH therapies are limited and derived primarily from uncontrolled, observational studies. In this perspective, the authors review the published research to assess the strengths and weaknesses of the data that support the long-term clinical benefit of current PAH therapies. The authors conclude that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence, in the form of meta-analysis and registry data, suggest that patients are living longer compared with untreated patients; the reasons are likely multifactorial. Although definitive evidence will require randomized and properly controlled long-term trials, the current evidence supports the long-term use of these drugs for the treatment of patients with PAH.
Journal of the American College of Cardiology 03/2011; 57(9):1053-61. · 14.16 Impact Factor
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ABSTRACT: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups.
Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW.
At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar.
Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2011; 30(6):632-43. · 3.54 Impact Factor
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ABSTRACT: We hypothesized that the longitudinal changes in peak oxygen uptake, ventilatory efficiency, and exercise-induced right-to-left shunting in patients with pulmonary arterial hypertension (PAH) would predict outcomes better than baseline measurements alone. Patients with PAH die prematurely. Identifying prognostic markers is critical for treating patients with PAH; however, longitudinal prognostic information of PAH is limited. We enrolled 103 patients with PAH into a long-term, prospective outcome study using serial cardiopulmonary exercise testing to measure the peak oxygen uptake, ventilatory efficiency (ratio of ventilation to carbon dioxide output at the anaerobic threshold), right-to-left shunting, and other factors in patients treated with optimal therapy. The patients were followed up for a mean of 4.7 years. During the study period, 20 patients died, and 3 underwent lung transplantation. The baseline peak oxygen uptake and ventilatory efficiency was 0.79 L/min and 49 (normal <34), respectively, reflecting severe disease. Poorer ventilatory efficiency and greater New York Heart Association classification were associated with poor outcome at baseline and at follow-up. On multivariate analysis, the persistence or development of an exercise-induced right-to-left shunt strongly predicted death or transplantation (p <0.0001), independent of the hemodynamics and all other exercise measures, including peak oxygen uptake and ventilatory efficiency. The absence of a shunt at baseline was associated with a 20% rate of nonsurvival, which decreased to 7% at follow-up. A poorer ventilatory efficiency appeared to be associated with a poor outcome in patients without a shunt. In conclusion, a persistent exercise-induced right-to-left shunt and poor ventilatory efficiency were highly predictive of poor outcomes in patients with pulmonary arterial hypertension.
The American journal of cardiology 04/2010; 105(8):1186-91. · 3.58 Impact Factor
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ABSTRACT: Patients with systemic sclerosis (SSc) may develop exercise intolerance due to musculoskeletal involvement, restrictive lung disease, left ventricular dysfunction, or pulmonary vasculopathy (PV). The latter is particularly important since it may lead to lethal pulmonary arterial hypertension (PAH). We hypothesized that abnormalities during cardiopulmonary exercise testing (CPET) in patients with SSc can identify PV leading to overt PAH.
Thirty SSc patients from the Harbor-UCLA Rheumatology clinic, not clinically suspected of having significant pulmonary vascular disease, were referred for this prospective study. Resting pulmonary function and exercise gas exchange were assessed, including peakVO2, anaerobic threshold (AT), heart rate-VO2 relationship (O2-pulse), exercise breathing reserve and parameters of ventilation-perfusion mismatching, as evidenced by elevated ventilatory equivalent for CO2 (VE/VCO2) and reduced end-tidal pCO2 (PETCO2) at the AT.
Gas exchange patterns were abnormal in 16 pts with specific cardiopulmonary disease physiology: Eleven patients had findings consistent with PV, while five had findings consistent with left-ventricular dysfunction (LVD). Although both groups had low peak VO2 and AT, a higher VE/VCO2 at AT and decreasing PETCO2 during early exercise distinguished PV from LVD.
Previously undiagnosed exercise impairments due to LVD or PV were common in our SSc patients. Cardiopulmonary exercise testing may help to differentiate and detect these disorders early in patients with SSc.
PLoS ONE 01/2010; 5(12):e14293. · 4.09 Impact Factor
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Ronald J Oudiz,
Nazzareno Galiè,
Horst Olschewski,
Fernando Torres,
Adaani Frost,
Hossein A Ghofrani,
David B Badesch,
Michael D McGoon,
Vallerie V McLaughlin,
Ellen B Roecker,
Brooke C Harrison,
Darrin Despain,
Christopher Dufton,
Lewis J Rubin
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ABSTRACT: This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH).
Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH.
In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data.
After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was approximately 2% per year; most of these events were mild and did not lead to discontinuation of drug.
Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).
Journal of the American College of Cardiology 11/2009; 54(21):1971-81. · 14.16 Impact Factor
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Nazzareno Galiè,
Bruce H Brundage,
Hossein A Ghofrani, Ronald J Oudiz,
Gerald Simonneau,
Zeenat Safdar,
Shelley Shapiro,
R James White,
Melanie Chan,
Anthony Beardsworth,
Lyn Frumkin,
Robyn J Barst
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ABSTRACT: Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.
In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.
In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.
Circulation 07/2009; 119(22):2894-903. · 14.74 Impact Factor
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David B Badesch,
Hunter C Champion,
Miguel Angel Gomez Sanchez,
Marius M Hoeper,
James E Loyd,
Alessandra Manes,
Michael McGoon,
Robert Naeije,
Horst Olschewski, Ronald J Oudiz,
Adam Torbicki
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ABSTRACT: The diagnosis and assessment of pulmonary arterial hypertension is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging and follow-up assessment. The definition of pulmonary hypertension has been simplified, and is now based on currently available evidence. There has been substantial progress in advancing the imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. The importance of accurate assessment of right ventricular function in following up the clinical course and response to therapy is more fully appreciated. As new therapies are developed for pulmonary arterial hypertension, screening, prompt diagnosis, and accurate assessment of disease severity become increasingly important. A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from our expanding therapeutic armamentarium.
Journal of the American College of Cardiology 06/2009; 54(1 Suppl):S55-66. · 14.16 Impact Factor
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Vallerie V McLaughlin,
David B Badesch,
Marion Delcroix,
Thomas R Fleming,
Sean P Gaine,
Nazzareno Galiè,
J Simon R Gibbs,
Nick H Kim, Ronald J Oudiz,
Andrew Peacock,
Steeve Provencher,
Olivier Sitbon,
Victor F Tapson,
Werner Seeger
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ABSTRACT: New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.
Journal of the American College of Cardiology 06/2009; 54(1 Suppl):S97-107. · 14.16 Impact Factor
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ABSTRACT: Intravenous (IV) prostanoid therapy remains arguably the most effective treatment of advanced pulmonary arterial hypertension (PAH) despite the introduction of newer molecules from different drug classes.
Literature regarding the properties, efficacy, safety, dosing, and cost of IV prostanoids was reviewed. In addition, a survey of physicians who treat PAH in the United States was conducted to assess IV prostanoid use in clinical practice.
Clinical studies have demonstrated that the 2 prostanoids available for IV administration in the United States, epoprostenol and treprostinil, improve exercise capacity, dyspnea, and cardiopulmonary hemodynamics in patients with PAH. Furthermore, epoprostenol has been shown to improve quality of life, functional class, and survival. The safety profiles of epoprostenol and IV treprostinil during short-term therapy appear comparable. Potential differences in the biochemical properties of these 2 drugs may have clinical implications. Whereas long-term data with subcutaneous treprostinil have been published, such data for IV treprostinil are not currently available. The physician survey revealed differences in the common maintenance doses used for both drugs, with IV treprostinil dosing approximately twice that of epoprostenol. These differences in dose have a direct bearing on the cost of therapy.
The unique properties of epoprostenol and treprostinil translate into clinical differences, which can influence the amount of drug used to achieve satisfactory patient improvement in the acute and long-term settings.
American heart journal 05/2009; 157(4):625-35. · 4.65 Impact Factor
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ABSTRACT: A 56-year-old patient with severe pulmonary hypertension developed severe tricuspid regurgitation, right-sided heart failure, and congestive hepatopathy. She was transferred for possible lung transplant and/or tricuspid valve surgery. Clinical and echocardiographic assessment provided confidence that acute tricuspid valve failure was responsible for the decompensation and that tricuspid valve replacement despite pulmonary hypertension could be performed.
Case Reports in Medicine 02/2009; 2009:108295.
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Circulation 12/2008; 118(21):2120-1. · 14.74 Impact Factor
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Michael D McGoon,
Adaani E Frost, Ronald J Oudiz,
David B Badesch,
Nazzareno Galie,
Horst Olschewski,
Vallerie V McLaughlin,
Michael J Gerber,
Chris Dufton,
Darrin J Despain,
Lewis J Rubin
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ABSTRACT: Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population.
Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs.
Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed.
Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Trial registration: Clinicaltrials.gov Identifier NCT00423592.
Chest 09/2008; 135(1):122-9. · 5.25 Impact Factor
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Nazzareno Galiè,
Horst Olschewski, Ronald J Oudiz,
Fernando Torres,
Adaani Frost,
Hossein A Ghofrani,
David B Badesch,
Michael D McGoon,
Vallerie V McLaughlin,
Ellen B Roecker,
Michael J Gerber,
Christopher Dufton,
Brian L Wiens,
Lewis J Rubin
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ABSTRACT: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.
Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m.
Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.
Circulation 06/2008; 117(23):3010-9. · 14.74 Impact Factor
