Pavel Jansa

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension

BACKGROUND Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

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.)

Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a Randomized, Placebo-Controlled Trial

OBJECTIVES Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA. METHODS The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters. RESULTS One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to bosentan. A statistically significant treatment effect (TE) of bosentan over placebo on PVR was demonstrated: -24.1% of baseline (95% confidence interval [CI]: -31.5% to -16.0%; p < 0.0001). Total pulmonary resistance (TE: -193 dynxsxcm(-5); 95% CI: -283 to -104 dyn.s.cm(-5); p < 0.0001) and cardiac index (TE: 0.3 lxmin(-1)xm(-2); 95% CI: 0.14 to 0.46 lxmin(-1)xm(-2); p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: -22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated. CONCLUSIONS This study demonstrated a positive TE of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222).

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Results From an International Prospective Registry

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments. # Clinical Perspective {#article-title-40}Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (⩽6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments.

Risk factors for chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by nonresolving pulmonary thromboemboli that can be treated by surgical pulmonary endarterectomy (PEA). The authors of the present study sought to confirm known and to identify novel CTEPH risk factors in a controlled retrospective cohort study of prevalent CTEPH cases collected in three European centres offering PEA. Data from CTEPH patients were compared with nonthromboembolic pre-capillary pulmonary arterial hypertension cohorts at the participating institutions. The study population comprised 687 patients assessed at the time of diagnosis between 1996 and 2007. Ventriculo-atrial shunts and infected pacemakers (odds ratio (OR) 76.40, 95% confidence interval (CI) 7.67–10,351), splenectomy (OR 17.87, 95% CI 1.56–2,438), previous venous thromboembolism (VTE; OR 4.52, 95% CI 2.35–9.12), recurrent VTE (OR 14.49, 95% CI 5.40–43.08), blood groups other than 0 (2.09, 95% CI 1.12–3.94), and lupus anticoagulant/antiphospholipid antibodies (OR 4.20, 95% CI 1.56–12.21) were more often associated with CTEPH. Thyroid replacement therapy (OR 6.10, 95% CI 2.73–15.05) and a history of malignancy (OR 3.76, 95% CI 1.47–10.43) emerged as novel CTEPH risk factors. In conclusion, the European database study confirmed previous knowledge of chronic thromboembolic pulmonary hypertension risk factors, and identified thyroid replacement therapy and a history of malignancy as new medical conditions associated with chronic thromboembolic pulmonary hypertension.

Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Study

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (−12 mm Hg [95% CI, −22 to −1]; P = .03) and right ventricular end-diastolic area (−5.6 cm2 [95% CI, −11 to −0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit–risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit–risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Riociguat shows favourable benefit–risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year http://ow.ly/Co04L

Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Results From an International Prospective Registry

Background— Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results— A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90–95), 91% (95% CI, 87–93), and 89% (95% CI, 86–92) in operated patients (n=404), and only 88% (95% CI, 83–91), 79% (95% CI, 74–83), and 70% (95% CI, 64–76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension–targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49–11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76–12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95–1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20–1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36–6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18–3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension–targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions— The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.

Chronic thromboembolic pulmonary hypertension: role of medical therapy

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease with poor prognosis if not treated. The treatment of choice is surgery with pulmonary endarterectomy. However, a significant percentage of patients are deemed non-operable due to distal distribution of the disease and arteriopathy in the non-occluded areas that is indistinguishable from pulmonary arterial hypertension (PAH). The overlap in clinical presentation, pathological features and pathogenesis between PAH and CTEPH provides a compelling rationale for exploring the efficacy of PAH-targeted therapies in CTEPH. These therapies are often considered for non-operable patients and are also used in operable patients as a bridge to surgery or as post-pulmonary endarterectomy therapy for persistent pulmonary hypertension, despite the fact they are not licensed for CTEPH. Two randomised clinical trials have been performed in non-operable CTEPH patients. The BENEFiT study, with the endothelin receptor antagonist bosentan, did not show improvement in walking distance. Recently, the CHEST-1 trial, with the soluble guanylate cyclase stimulator riociguat, met study end-point and demonstrated significant improvement in walking distance in patients with non-operable CTEPH. There is an urgent need for more randomised clinical trials designed to clarify whether administration of PAH-targeted therapies improves clinically meaningful end-points in various CTEPH populations.

Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years. METHODS Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429. FINDINGS 237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events. INTERPRETATION Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers. FUNDING Bayer Pharma AG.