ERS statement on chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels <500 µm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions.This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH.It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice.

Radiological differences between chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH).

OBJECTIVES: The aim of this study was to describe the radiological features of chronic thromboembolic pulmonary disease (CTEPD), not yet systematically described in the literature. Furthermore, we compared vascular scores between CTEPD and chronic thromboembolic pulmonary hypertension (CTEPH) patients, trying to explain why pulmonary hypertension does not develop at rest in CTEPD patients. METHODS: Eighty-five patients (40 CTEPD, 45 CTEPH) referred to our centre for pulmonary endarterectomy underwent dual-energy computed tomography pulmonary angiography (DE-CTPA) with iodine perfusion maps; other 6 CTEPD patients underwent single-source CTPA. CT scans were reviewed independently by an experienced cardiothoracic radiologist and a radiology resident to evaluate scores of vascular obstruction, hypoperfusion and mosaic attenuation, signs of pulmonary hypertension and other CT features typical of CTEPH. RESULTS: Vascular obstruction burden was similar in the two groups (p = 0.073), but CTEPD patients have a smaller extension of perfusion defects in the iodine map (p = 0.009) and a smaller number of these patients had mosaic attenuation (p < 0.001) than CTEPH patients, suggesting the absence of microvascular disease. Furthermore, as expected, the two groups were significantly different considering the indirect signs of pulmonary hypertension (p < 0.001). CONCLUSIONS: CTEPD and CTEPH patients have significantly different radiological characteristics, in terms of signs of pulmonary hypertension, mosaic attenuation and iodine map perfusion extension. Importantly, our results suggest that the absence of peripheral microvascular disease, even in presence of an important thrombotic burden, might be the reason for the absence of pulmonary hypertension in CTEPD. KEY POINTS: • CTEPD and CTEPH patients have significantly different radiological characteristics. • The absence of peripheral microvascular disease might be the reason for the absence of pulmonary hypertension in CTEPD.

Acute massive pulmonary embolism during patient repositioning following excision of a thymic carcinoma in a patient affected by cryoglobulinemia.

Acute pulmonary embolism (APE) is a well-described complication following surgical procedures. The incidence of such a complication can be related to the presence of a peculiar patient's condition. Cryoglobulinemia, which consists in the presence of one or more immunoglobulins in the serum that precipitate at temperatures below 37°C and redissolve on warming, seems to increase the risk of thrombotic events. Treatment options of APE, according to clinical severity, include systemic thrombolysis, surgical embolectomy, and systemic anticoagulation. Thrombolysis is considered the first-line treatment, whereas surgery is reserved in case of extremely-compromised hemodynamic conditions related to massive central embolism, and in case of contraindication to thrombolysis. Here, we report a case of acute massive pulmonary embolism occurring at the end of a surgical procedure for a thymic carcinoma resection, in a patient with cryoglobulinemia, which required an emergent surgical pulmonary embolectomy.

Persistent exercise limitation after successful pulmonary endoarterectomy: frequency and determinants.

BACKGROUND: After successful pulmonary endoarterectomy (PEA), patients may still suffer from exercise limitation, despite normal pulmonary vascular resistance. We sought to assess the proportion of these patients after the extension of PEA to frail patients, and the determinants of exercise limitation. METHODS: Out of 553 patients treated with PEA from 2008 to 2016 at our institution, a cohort of 261 patients was followed up at 12 months. They underwent clinical, haemodynamic, echocardiographic, respiratory function tests and treadmill exercise testing. A reduced exercise capacity was defined as Bruce test distance < 400 m. RESULTS: Eighty patients did not had exercise testing because of inability to walk on treadmill and/or ECG abnormalities Exercise limitation 12 months after PEA was present in 74/181 patients (41, 95%CI 34 to 48%). The presence of COPD was more than double in patients with exercise limitation than in the others. Patients with persistent exercise limitation had significantly higher mPAP, PVR, HR and significantly lower RVEF, PCa, CI, VC, TLC, FEV1, FEV1/VC, DLCO, HbSaO2 than patients without. The multivariable model shows that PCa at rest and TAPSE are important predictors of exercise capacity. Age, COPD, respiratory function parameters and unilateral surgery were also retained. CONCLUSIONS: After successful PEA, most of the patients recovered good exercise tolerance. However, about 40% continues to suffer from limitation to a moderate intensity exercise. Besides parameters of right ventricular function, useful information are provided by respiratory function parameters and COPD diagnosis. This could be useful to better address the appropriate therapeutic approach.

Exercise Training After Pulmonary Endarterectomy for Patients with Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: After undergoing a procedure of pulmonary endarterectomy (PEA), patients with chronic thromboembolic pulmonary hypertension (CTEPH) may still experience reduced exercise capacity. Data on effects of exercise training in these patients are scant. OBJECTIVES: To evaluate the effectiveness of exercise training after PEA for CTEPH and if the presence of "residual pulmonary hypertension" may affect the outcome. METHODS: Retrospective data analysis of CTEPH patients undergoing inpatient exercise training after PEA. According to predefined criteria, patients were divided into those with (group 1) and without (group 2) a "good" post-surgery hemodynamic response. Assessments of the 6-min walking distance test (6-min walking distance test [6 MWT]: primary outcome) were performed before and after surgery (before training), after training and at 3-month follow-up. Hemodynamic and lung function data were also analyzed. RESULTS: Data of 84 and 26 patients of groups 1 and 2, respectively, were analyzed. After surgery patients showed a reduction in 6 MWT, which significantly reversed after training and further improved at 3 months (p = 0.0001), without any significant difference between groups. The percentage of patients reaching the minimal clinically important difference in 6 MWT was similar between groups. The sig-nificant (p = 0.0001) post-surgery improvement in hemodynamics was maintained at 3 months without any significant difference between groups. New York Heart Association functional class improved in parallel to the hemodynamic improvement. CONCLUSIONS: Exercise training in patients with CTEPH after PEA, an inpatient exercise training program, improves exercise capacity for up to 3 months, independently of the post-surgery hemodynamic response.

Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: 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.

Analysis of long term CD4+CD25highCD127- T-reg cells kinetics in peripheral blood of lung transplant recipients.

BACKGROUND: The role of CD4+CD25highCD127- T-reg cells in solid-organ Transplant (Tx) acceptance has been extensively studied. In previous studies on kidney and liver recipients, peripheral T-reg cell counts were associated to graft survival, while in lung Tx, there is limited evidence for similar findings. This study aims to analyze long term peripheral kinetics of T-reg-cells in a cohort of lung recipients and tests its association to several clinical variables. METHODS: From jan 2009 to dec 2014, 137 lung Tx recipients were submitted to an immunological follow up (median: 105.9 months (6.7-310.5)). Immunological follow up consisted of a complete blood peripheral immuno-phenotype, inclusive of CD4+CD25highCD127- T and FOXP3+ cells. We tested the association between T-reg and relevant variables by linear OR regression models for repeated measures, adjusting for time from Tx. Also, by ordered logistic models for panel data, the association between Chronic Lung Allograft Dysfuncton (CLAD) onset/progression and T-reg counts in the previous 3 months was tested. RESULTS: Among all variables analyzed at multivariate analysis: Bronchiolitis Obliterans Syndrome (OR -6.51, p < 0.001), Restrictive Allograft Syndrome (OR -5.19, p = 0.04) and Extracorporeal photopheresis (OR -5.65, p < 0.001) were significantly associated to T-reg cell. T-reg cell counts progressively decreased according to the severity of CLAD. Furthermore, patients with higher mean T-reg counts in a trimester had a significantly lower risk (OR 0.97, p = 0.012) of presenting CLAD or progressing in the graft dysfunction in the following trimester. CONCLUSIONS: Our present data confirm animal observations on the possible role of T-reg in the evolution of CLAD.

Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study.

BACKGROUND: Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH. METHODS: We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints. RESULTS: In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups. CONCLUSIONS: Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed. TRIAL REGISTRATION: ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

ANMCO Position Paper: long-term follow-up of patients with pulmonary thromboembolism.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, is the third most common cause of cardiovascular death. The management of the acute phase of VTE has already been described in several guidelines. However, the management of the follow-up (FU) of these patients has been poorly defined. This consensus document, created by the Italian cardiologists, wants to clarify this issue using the currently available evidence in VTE. Clinical and instrumental data acquired during the acute phase of the disease are the cornerstone for planning the FU. Acquired or congenital thrombophilic disorders could be identified in apparently unprovoked VTE during the FU. In other cases, an occult cancer could be discovered after a VTE. The main targets of the post-acute management are to prevent recurrence of VTE and to identify the patients who can develop a chronic thromboembolic pulmonary hypertension. Knowledge of pathophysiology and therapeutic approaches is fundamental to decide the most appropriate long-term treatment. Moreover, prognostic stratification during the FU should be constantly updated on the basis of the new evidence acquired. Currently, the cornerstone of VTE treatment is represented by both the oral and the parenteral anticoagulation. Novel oral anticoagulants should be an interesting alternative in the long-term treatment.

Patent foramen ovale diagnosis: The importance of provocative maneuvers.

Patent foramen ovale (PFO) is a frequent congenital anomaly, but massive right-to-left shunt (RTLS) is normally prevented by higher pressures in left heart chambers. However, mechanical ventilation with positive end-expiratory pressure (PEEP) can significantly increase right atrial pressure, accentuating the RTLS, mainly after major cardiothoracic surgery. We report a patient admitted to the intensive care unit after cardiac surgery. Pre- and intraoperative transesophageal echocardiography only described an aneurysmal interatrial septum with no shunt. However, high-PEEP ventilation induced a paradoxical response with life-threatening hypoxemia, triggering further echocardiographic evaluation, revealing massive RTLS across a stretch PFO. Provocative maneuvers (Valsalva/PEEP) significantly increase echocardiographic sensitivity, unmasking silent PFO. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:58-61, 2017.

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.)

Changes in surface electrocardiogram in patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary endarterectomy. Correlations with hemodynamic and echocardiographic improvements after surgery.

BACKGROUND: The aim of the present study was to evaluate the changes of electrocardiographic (ECG) markers of right ventricular (RV) hypertrophy/overload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). METHODS AND RESULTS: We evaluated 99 CTEPH patients who underwent PEA. P wave amplitude in DII, R wave amplitude in V1 and the number of patients with negative T wave in V1-V3 decreased significantly at 1month after surgery with no further change at 1year, in parallel with the rapid improvement in right heart hemodynamics. S wave amplitude in V1, R:S wave ratio in lead V6 and prevalence of SIQIII pattern improved significantly at 1year, in parallel with the progressive reverse remodeling of the right ventricle at echocardiography. CONCLUSIONS: The study shows that some of the ECG markers of RV hypertrophy/overload better reflect RV hemodynamic overload while others better reflect the pathologic remodeling of the right ventricle.

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.

Functional assessment and quality of life before and after pulmonary endoarterectomy.

PURPOSE: The study investigates Quality of Life (QOL) and correlation with functional status of patients affected by Chronic Thromboembolic Pulmonary Hypertension who undergo Pulmonary Endoarterectomy. METHODS: We investigated with an observational design (before surgery, three and twelve months afterwards) the hemodynamic data (NYHA class, mean pulmonary arterial pressure, cardiac output and pulmonary vascular resistance), the functional status (using the 6-Minute Walk Test) and the QOL, using three questionnaires: Medical Outcome Study Short Form-36 (SF-36), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Saint George Respiratory Questionnaire (SGRQ). We report the results of forty-nine patients. RESULTS: After surgery there was an improvement on functional and hemodynamic parameters and on QOL. The physical domain (PCS) of SF-36 was weakly but significantly associated with all functional parameters. There was no association between functional parameters and mental domain (MCS) of SF-36 or SGRQ. The improvement in 6-Minute Walk Distance was associated with an increase in MLHFQ. CONCLUSIONS: Both QOL and submaximal exercise tolerance improve after surgery. However only the physical domains of SF-36 appear to be significantly associated to the functional data.

Pulmonary arterial compliance and exercise capacity after pulmonary endarterectomy.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH), despite successful pulmonary endarterectomy (PEA), can continue to suffer from a limitation in exercise capacity. The objective of this study was to assess whether pulmonary arterial compliance is a predictor of exercise capacity after PEA. Right heart haemodynamics, treadmill incremental exercise test, spirometry, carbon monoxide transfer factor, arterial blood gas and echocardiographic examinations were retrospectively analysed in a population of CTEPH patients who underwent PEA at a single centre. Baseline and 3-month haemodynamic data were available in 296 patients; 5-year follow-up data were available in 68 patients. In a multivariable model the following parameters were found to be independent predictors of exercise capacity after surgery: age, sex, pulmonary arterial compliance, tricuspid annular plane excursion, arterial oxygen tension and carbon monoxide transfer factor (p<0.0001); the model showed good discrimination (Harrell's c=0.84) and calibration (shrinkage coefficient=0.91). Poor exercise capacity at 3 months was loosely associated with higher death rate during subsequent survival (Harrell's c=0.61). In conclusion, after successful PEA, reduced pulmonary arterial compliance is an important determinant of exercise capacity in association with the age and sex of the patients, and the extent of recovery of both cardiac and respiratory function. However, exercise capacity does not explain a large proportion of the effect of surgery on subsequent survival.

The pathologic basis of recovery.

More patients with end-stage heart failure are now being supported by left ventricular assist devices (LVAD) as a bridge to heart transplant. The LVAD unloads the failing heart and modifies the myocardial structure, with regression of left ventricular hypertrophy. The regression of hypertrophy has been reported histomorphologically in paired samples of myocardial tissues obtained from the same patient at the time of LVAD implantation and the heart excised at transplant. The understanding of the mechanisms of recovery may contribute to strategic development for LVAD weaning and the use of LVAD as a destination therapy.

Does pulmonary endarterectomy improve the clinical conditions of patients with chronic thromboembolic pulmonary disease without pulmonary hypertension?

To verify whether the new hemodynamic definition of pulmonary hypertension (PH) has any implication in treatment of Chronic Thrombo-Embolic Pulmonary Disease (CTEPD) patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds. The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as chronic thromboembolic pulmonary hypertension (CTEPH) patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mean pulmonary artery pressure (mPAP) ≤ 20 mm Hg and pulmonary vascular resistance (PVR) ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mm Hg.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.

Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial.

OBJECTIVE: To evaluate the efficacy of tezosentan in reducing the incidence of right ventricular (RV) failure and associated mortality in patients with pre-existing pulmonary hypertension. The primary endpoint was the proportion of patients with RV failure during weaning from cardiopulmonary bypass (CPB), assessed 30 minutes after the end of CPB. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial. SETTING: Thirty-one cardiac surgical centers in 14 countries. PARTICIPANTS: Two hundred seventy-four patients with pulmonary hypertension aged ≥ 18 years scheduled to undergo cardiac surgery. INTERVENTION: Intravenous tezosentan (5 mg/h) during surgery and up to 24 hours afterwards (1 mg/h), or matched placebo. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-three patients received tezosentan and 141 placebo. RV failure occurred in 30 patients (10.9%), 37% of whom died. There was no difference in the incidence of RV failure between the two treatment groups (relative risk reduction: 0.07 [95% CI-0.83, 0.53; P = 0.8278]). CONCLUSION: A reduction in RV failure with tezosentan was not observed in this study.(Current Controlled Trials, identifier NCT00458276).