Marius M. Hoeper

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.

Chronic Thromboembolic Pulmonary Hypertension

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France.

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.

Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial

BACKGROUND Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the effect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension. METHODS Patients with WHO FC II pulmonary arterial hypertension aged 12 years or over with 6-min walk distance of less than 80% of the normal predicted value or less than 500 m associated with a Borg dyspnoea index of 2 or greater were enrolled in this double-blind, placebo-controlled, multicentre trial. 185 patients were randomly assigned to receive bosentan (n=93) or placebo (n=92) for the 6-month double-blind treatment period via a centralised integrated voice recognition system. Primary endpoints were pulmonary vascular resistance at month 6 expressed as percentage of baseline and change from baseline to month 6 in 6-min walk distance. Analyses of the primary endpoints were done with all randomised patients who had a valid baseline assessment and an assessment or an imputed value for month 6. This trial was registered with ClinicalTrials.gov, number NCT00091715. FINDINGS Analyses were done with 168 patients (80 in the bosentan group, 88 in the placebo group) for pulmonary vascular resistance and with 177 (86 and 91) for 6-min walking distance. At month 6, geometric mean pulmonary vascular resistance was 83.2% (95% CI 73.8-93.7) of the baseline value in the bosentan group and 107.5% (97.6-118.4) of the baseline value in the placebo group (treatment effect -22.6%, 95% CI -33.5 to -10.0; p<0.0001). Mean 6-min walk distance increased from baseline in the bosentan group (11.2 m, 95% CI -4.6 to 27.0) and decreased in the placebo group (-7.9 m, -24.3 to 8.5), with a mean treatment effect of 19.1 m (95% CI 3.6-41.8; p=0.0758). 12 (13%) patients in the bosentan group and eight (9%) in the placebo group reported serious adverse events, the most common of which were syncope in the bosentan group and right ventricular failure in the placebo group. INTERPRETATION Bosentan treatment could be beneficial for patients with WHO FC II pulmonary arterial hypertension.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)

Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. 2015 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management http://ow.ly/RiDLb

Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial ☆

OBJECTIVES The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). BACKGROUND Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. METHODS In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. RESULTS Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. CONCLUSIONS Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), Intern…

Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. 2015 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management http://ow.ly/RiDLb

Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. METHODS In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. RESULTS By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CONCLUSIONS Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)

Long-Term Treatment of Primary Pulmonary Hypertension with Aerosolized Iloprost, a Prostacyclin Analogue

BACKGROUND Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension. RESULTS Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients. CONCLUSIONS Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients With Severe Chronic Pulmonary Hypertension

Background— Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. Methods and Results— Thirty patients with PH (21 women; mean age, 50±13 years; mean pulmonary artery pressure, 50±15 mm Hg; mean World Health Organization [WHO] class, 2.9±0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61±18 to 54±18 mm Hg) within the training group. Conclusions— This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.