David B. Badesch

A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension

BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. CONCLUSIONS As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study

BACKGROUND Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Predicting Survival in Pulmonary Arterial Hypertension Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Background— Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Methods and Results— Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. Conclusions— We identified key predictors of survival based on the patients most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

Diagnosis and Assessment of Pulmonary Arterial Hypertension

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.

Definitions and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥ 25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone.

Medical Therapy For Pulmonary Arterial Hypertension* ACCP Evidence-Based Clinical Practice Guidelines

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Ambrisentan for the Treatment of Pulmonary Arterial Hypertension Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2

Background— Ambrisentan is a propanoic acid–based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Methods and Results— 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. Conclusions— 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.

Pulmonary Arterial Hypertension : Baseline Characteristics From the REVEAL Registry

BACKGROUND The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL Registry) was established to provide updated characteristics of patients with pulmonary arterial hypertension (PAH) and to improve diagnosis, treatment, and management. METHODS Fifty-four US centers enrolled consecutively screened patients with World Health Organization group I PAH who met expanded hemodynamic criteria of mean pulmonary arterial pressure (PAP) > 25 mm Hg at rest (30 mm Hg with exercise), pulmonary capillary wedge pressure (PCWP) <or= 18 mm Hg, and pulmonary vascular resistance >or= 240 dynes x s x cm(-5). Patients meeting the traditional hemodynamic definition (PCWP <or= 15 mm Hg) were compared with those with a PCWP of 16 to 18 mm Hg. RESULTS Between March 2006 and September 2007, 2,967 patients enrolled. Among 2,525 adults meeting traditional hemodynamic criteria, the mean age was 53 +/- 14 years, and 2,007 (79.5%) were women. The mean duration between symptom onset and diagnostic catheterization was 2.8 years, and 1,008 (41.3%) patients were treated with more than one pulmonary vascular-targeted medication. Compared with patients meeting the traditional hemodynamic definition of PAH, patients with a PCWP of 16 to 18 mm Hg were older, more obese, had a lower 6-min walk distance, and had a higher incidence of systemic hypertension, sleep apnea, renal insufficiency, and diabetes. CONCLUSIONS Patients in the REVEAL Registry are older and more often female than in previous descriptions. Delays between symptom onset and diagnostic catheterization persist. Many treatment regimens are fundamentally empirical, and data will be required to determine outcomes, improve risk stratification, and develop and validate more precise prognostic tools. Patients with PCWP of 16 to 18 mm Hg differ in a number of important respects from those meeting the traditional hemodynamic definition of PAH.

Beraprost Therapy for Pulmonary Arterial Hypertension

OBJECTIVES The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH). BACKGROUND Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available. METHODS A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life. RESULTS Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events. CONCLUSIONS These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.

Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension: A Randomized Trial

BACKGROUND Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. OBJECTIVE To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. DESIGN A 16-week, double-blind, placebo-controlled, parallel-group study. SETTING Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. PATIENTS 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. INTERVENTION Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. MEASUREMENTS Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). RESULTS A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]). LIMITATIONS The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis. CONCLUSION In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.