Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Cardiac Surgery
Brief Summary: Endothelin-1 is a powerful substance that may be involved in causing hemodynamic instability (problems related to unstable blood pressure) during and after open heart surgery. Tezosentan is an investigational intravenous drug that blocks the endothelin receptors. This clinical trial will assess the potential benefit of tezosentan compared with placebo in the treatment of patients undergoing open heart surgery with cardiopulmonary bypass (CPB). Treatment time is from the start of surgery up to 24 hours.


Options:
A: Inclusion Criteria:

* Patients ≥ 18 years of age
* Male or female patients (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception).
* Patients undergoing complex\* cardiac surgery on CPB and having systolic PAP \> 40 mmHg or mean PAP \> 30 mmHg (\*surgery on 2 valves, 1 valve and revascularization, or reoperation of a valve)
* Patients undergoing cardiac surgery on CPB and having pre-operative pulmonary hypertension due to left heart disease with systolic PAP \> 60 mmHg
* Signed written informed consent

Exclusion Criteria:

* Systolic blood pressure \< 100 mmHg
* Significant chronic lung disease
* Emergency surgery
* Pregnant/breast-feeding
* Investigational drug use within 28 days prior to randomization
* Complex adult congenital heart disease.
* Severe concomitant illness limiting life expectancy to \< 6 months
* Participation in a device study that will affect the outcome of the study
* Pre-operative use of balloon pump, inotropes/vasopressors, treatment of pulmonary arterial hypertension
* Known hypersensitivity to tezosentan or drugs of the same class, or any of their excipients
* Severe liver impairment
B: Inclusion Criteria:

* Symptomatic pulmonary hypertension in modified NYHA functional class II to IV due to CTEPH as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography.
* CTEPH judged inoperable because of peripheral localization of thrombotic material or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) with no evidence of recurrent thromboembolism and not amenable to repeated surgery.
* 6-minute walk test (6MWT) distance \< 450 m.
* Hemodynamic evaluation showing: Mean pulmonary arterial pressure (mPAP) \>= 25 mmHg; Pulmonary capillary wedge pressure (PCWP) \< 15 mmHg; Pulmonary vascular resistance (PVR) at rest \>= 300 dyn×sec/cm5
* For patients who underwent PEA, hemodynamic evaluation must have been performed more than 6 months after PEA.
* For all patients, hemodynamic evaluation must have been performed with the 3 months immediately preceding inclusion.
* Men or women \>= 18 and =\< 80 years of age (Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception).
* Anticoagulants at efficacious dose for at least 3 months prior to randomization.
* Signed informed consent prior to initiation of any study-mandated procedure.

Exclusion Criteria:

* Other forms of pulmonary hypertension including pulmonary hypertension related to sickle cell disease.
* Obstructive lung disease: FEV1/FVC \< 0.5 after bronchodilator.
* Severe restrictive lung disease: Total Lung Capacity \< 60% of predicted value.
* Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication.
* Symptomatic pulmonary embolism within 6 months prior to randomization.
* Pulmonary endarterectomy within 6 months prior to randomization.
* Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
* Illness with a life expectancy of less than 6 months.
* Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
* AST and/or ALT \> 3 times the upper limit of normal ranges.· Hemoglobin concentration \< 75% the lower limit of normal ranges.
* Pregnancy or breast-feeding.
* Systolic blood pressure (BP) \< 85 mmHg.
* Treatment or planned treatment with another investigational drug and/or pulmonary angioplasty within 3 months prior to randomization.
* Treatment with an endothelin receptor antagonist, a phosphodiesterase inhibitor, L-arginine or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization.
* Treatment for pulmonary hypertension within 1 month prior to randomization, excluding calcium channel blockers if present for at least 1 month before randomization.
* Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, glibenclamide (glyburide) within 1 week prior to randomization.
* Known hypersensitivity to bosentan or any of the excipients.
C: Inclusion Criteria:

* Patients with known sarcoidosis 21.
* Age 18 or greater
* Patients with documented pulmonary hypertension with a PA mean \> 25 mm Hg as measured by cardiac catheterization within six months of entry into the study. Pulmonary artery occluding pressure and or left ventricular end diastolic pressure must be less than 15 mm Hg.
* Patients with WHO class II or III
* Six minute walk distance of between 100 to 500 meters
* Patients on stable immunotherapy for their sarcoidosis, including prednisone, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, thalidomide, and/or infliximab
* Patients able to provide written consent

Exclusion Criteria:

* Patients on pulmonary vasodilator drugs (flolan, remodulin, bosentan, sildenafil) n the prior 28 days. Patients on stable dose of calcium channel blocker for more than 1 month prior to right heart catheterization can be continued on the calcium channel blocker.
* Patients with severe airway obstruction as defined by FEV1/FVC of less than 35%
* Patients with World Health Organization (WHO) class IV status.
* Patients who are pregnant or breast feeding
* Patients with significant left ventricular dysfunction with a left ventricular ejection fraction of less than 35%
* Cardiac index \< 2.0 liters and/or right atrial pressure \>15 mm Hg
* Significant liver dysfunction not due to sarcoidosis.
* Patients with severe other organ disease felt by investigators to impact on survival during the course of the study.
* Patients unable to perform the 6 minute walk study
D: Inclusion Criteria:

* Subjects:

  * not participating in the hemodynamic sub-study: males or females ≥ 12 years of age.
  * participating in the hemodynamic sub-study: males or females ≥ 18 years of age.
* Subjects (including those with Down Syndrome \[DS\]) with confirmed Eisenmenger Syndrome \[ES\] (European Society of Cardiology \[ESC\] and the European Respiratory Society \[ERS\] guidelines):

  1. Established by echocardiography as:

     * Large congenital shunting defect at atrial, ventricular or arterial level\*
     * and right to left shunt or bi-directional shunt with prevalent right to left direction.
  2. Resting peripheral oxygen saturation (SpO2) ≤ 90% and \> 70% (pulse oximetry, room air).

The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level.

\*Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination:

* atrial septal defect (ASD)
* ventricular septal defect (VSD)
* partial or complete atrioventricular septal defect (AVSD)
* patent ductus arteriosus (PDA)
* aortopulmonary window (AP window)
* total or partial anomalous pulmonary venous return (TAPVR, PAPVR) The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains).

The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization.

* Subjects with the following findings at cardiac catheterization:

  * Mean resting pulmonary arterial pressure (mPAP) \> 25 mmHg
  * Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) ≤ 15 mmHg
  * Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units
* Subjects with WHO functional class ≥ II.
* Subjects able to reliably perform the the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.

Exclusion Criteria:

- Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography:

* Pulmonary arterial or venous stenosis \> 25% size of native pulmonary artery (PA) or pulmonary vein
* Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level
* Greater than mild tricuspid stenosis
* Intracavitary RV outflow obstruction
* Greater than mild mitral stenosis
* Intracavitary LV outflow obstruction
* Subvalvular or supravalvular aortic stenosis
* Aortic coarctation
* Greater than moderate mitral regurgitation
* Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation
* Recognized hepatic wedge pressure-inferior vena cava pressure gradient \>12 mm Hg
* PCWP "v" waves \>20 mmHg
* Tetralogy of Fallot
* Truncus arteriosus
* Interrupted aortic arch
* Transposition of great arteries
* Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome
* Ebstein's anomaly
* Severe aortic regurgitation
* Pulmonary atresia
* PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist.

For subjects participating in the hemodynamic sub-study the following will also be considered exclusion criteria:

* SVC stenosis \>25% size of native vessel
* PDA, AP window, TAPVR, PAPVR, or ASD sinus venosus with anomalous pulmonary veins
* Down Syndrome

  * Subjects with deterioration of their clinical status within 3 months prior to Screening or during the Screening period.
  * Known moderate-to-severe restrictive (i.e., total lung capacity \[TLC\] \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 80 % of predicted value, and with FEV1 / forced vital capacity \[FVC\] \< 70%)
  * Treatment with prostanoids within 1 month prior to Randomization
  * Subjects who initiated a PDE-5 inhibitor within 1 month prior to Randomization or those on a PDE-5 inhibitor for whom the dose has not been stable within 1 month prior to Randomization
  * Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization
  * Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable for at least 1 week prior to Randomization
  * Subjects being considered for an organ transplant

Answer: A