A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension
- Conditions
- Chronic Thromboembolic Pulmonary Hypertension
- Interventions
- Drug: Placebo
- Registration Number
- NCT04271475
- Lead Sponsor
- Actelion
- Brief Summary
The purpose of the study is to evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).
- Detailed Description
CTEPH is one of the leading causes of severe pulmonary hypertension (PH), classified within World Health Organization (WHO) group 4 PH. It is a rare, progressive pulmonary vascular disease that if left untreated, leads to progressively increasing pulmonary vascular resistance (PVR) and eventually right ventricle failure and death. Histopathologic findings including endothelial cell dysfunction and distal pulmonary arterial remodeling are shared between PAH and CTEPH, and PH-specific therapies (that is, riociguat) have shown efficacy in inoperable and persistent/recurrent CTEPH. The endothelin receptor antagonist macitentan offers a different mode of action and addresses an important unmet medical need for an alternative treatment option in this indication. This study will assess the effect of macitentan 75 mg on exercise capacity in CTEPH. The total duration of the study is approximately 6 years. The study comprises of a screening period (at least 14 days and up to 60 days), a double-blind (DB) treatment period (28 weeks \[minimum duration\] up to 3.5 years), an open-label (OL) extension period (starts at end-of-DB-treatment \[EODBT\] and will end for all participants 104 weeks after the last participant has completed DB Week 28). The DB period consists of an 8-week up-titration phase and a maintenance phase. The maintenance phase is divided into a 28-week fixed duration part, at the end of which primary endpoint is assessed, and a variable duration part. The duration of the DB period for an individual participant depends on the timepoint of entry into the study and whether a CEC-confirmed clinical worsening event occurred. Participants who discontinue DB study intervention during the 28-week fixed duration part will be followed until Week 28 in a post-treatment observation period (PTOP).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 127
- Chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization [WHO] Group 4) fulfilling one of the following criteria: a) inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), b) persistent/recurrent CTEPH after balloon pulmonary angioplasty (BPA), and deemed inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), c) persistent/recurrent CTEPH after rescue pulmonary endarterectomy (PEA)
- 6-minute walk distance (6MWD) greater than or equal to (>=) 100 meter (m) and less than or equal to (<=) 450 meters (m), documented by an eligibility and a baseline 6-minute walk test (6MWT). The baseline 6MWD must not differ by more than 15 percent (%) from the eligibility test
- World Health Organization functional class (WHO FC) >= II
- Participants are to receive riociguat as per local standard of care, unless it is contraindicated or unavailable
- Acute pulmonary embolism within 3 months prior to or during Screening
- Planned balloon pulmonary angioplasty (BPA) during the fixed duration part of the double-blind period
- Significant obstructive and restrictive lung disease
- Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (for example, intermittent claudication).
- Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study
- Decompensated cardiac failure if not under close supervision
- Known and documented life-threatening cardiac arrhythmias
- Acute myocardial infarction within 6 months prior to, or during Screening
- Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening
- Known or suspicion of pulmonary veno-occlusive disease (PVOD)
- Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization
- Change in dose or initiation of Phosphodiesterase type-5 (PDE-5) inhibitors, oral, inhaled or subcutaneous (SC) prostacyclins / prostacyclin analogues, prostacyclin receptor agonists or riociguat, a) within 90 days prior to Randomization, or b) anticipated during the fixed duration part of the double-blind [DB] period
- Hypotension, that is, systolic blood pressure (SBP) less than (<) 90 millimeters of mercury (mmHg) or diastolic blood pressure (DBP) <50 mmHg at Screening.
- Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 milliliters per minute per 1.73 meter square (mL/min/1.73 m^2) using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening
- Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history
- Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than or equal to (>=) 1.5*upper limit of normal (ULN) at Screening
- Hemoglobin <100 g/L (<10 gram per deciliter [g/dL]) at Screening
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants will receive placebo tablets matching the macitentan 10 mg, macitentan 37.5mg and macitentan 75 mg tablets, respectively. Participants who completed the DB period as per protocol either on treatment or in PTOP are eligible for transitioning to the OL extension period and will receive macitentan 75 mg after an 8-week double-dummy uptitration (macitentan 10 mg for 4 weeks, followed by 37.5 mg for another 4 weeks). Placebo Macitentan Participants will receive placebo tablets matching the macitentan 10 mg, macitentan 37.5mg and macitentan 75 mg tablets, respectively. Participants who completed the DB period as per protocol either on treatment or in PTOP are eligible for transitioning to the OL extension period and will receive macitentan 75 mg after an 8-week double-dummy uptitration (macitentan 10 mg for 4 weeks, followed by 37.5 mg for another 4 weeks). Macitentan Macitentan Participant will receive macitentan at a dose of 10 milligram (mg) once daily (OD) for 4 weeks, followed by a dose of macitentan 37.5 mg for another 4 weeks and continue with the target dose of macitentan 75 mg. Participants who have reached the target dose of 75 mg, completed the Double-blind (DB) period up to Week 28 (either on treatment or in Post-treatment observation period \[PTOP\]) at minimum, may be eligible for transitioning into the Open label (OL) extension period once all participants have completed the DB part of the study, or earlier if they experienced a Clinical event committee (CEC) confirmed clinical worsening event.
- Primary Outcome Measures
Name Time Method Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28 Baseline (Day 1), Week 28 Change from baseline in 6MWD as measured by 6-minute walk test (6MWT) at Week 28 was reported. The purpose of the 6MWT was to quantify exercise tolerance and capacity. This standardized test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes.
- Secondary Outcome Measures
Name Time Method Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period From Baseline (Day 1) up to EODBT: median 24.5 weeks (min 3.9 weeks; max 160.4 weeks) for macitentan, median 44 weeks (min 4 weeks; max 147.9 weeks) for placebo Time (months) to first CEC-confirmed clinical worsening up to EODBT were reported. Clinical worsening was defined as the occurrence of at least one of the following events: 1) All-cause death; 2) Heart and/or lung transplantation; 3) Unplanned pulmonary hypertension (PH)-related hospitalization; 4) PH-related deterioration from baseline identified by at least one of the following: a) Persistent increase in World Health Organization functional class (WHO FC) that could not be explained by another cause (for example, viral infection); b) Persistent deterioration by at least 15 percent (%) in exercise capacity; as measured by the 6MWD; c) New or worsened signs or symptoms of right heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH.
Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28 From Baseline (Day 1) up to Week 28 Number of participants with improvement in WHO FC from baseline to Week 28 were reported. Improvement (decrease) in WHO FC from baseline to Week 28 was calculated for each participant. WHO FC test was used to assess disease severity. Four functional classes (FC) were defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). For the analysis purpose, these WHO FC class values were transformed to a scale with scores ranged from 1 to 4; where a score of 1 corresponded to WHO FC Class I and a score of 4 corresponded to WHO FC Class IV. The higher scores indicate greater symptom severity or worse impact. Improvement was considered when a participant changed from a higher class to a lower class.
Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score From Baseline (Day 1) up to Week 28 The cardiopulmonary symptoms domain consisted of 6 items: shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough and were reported on a 5-point Likert scale from 0 (no symptom at all) to 4 (very severe symptoms), with higher score indicating more symptom. The symptoms part of the PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. The mean individual symptom item score was determined for each of the 6 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiopulmonary symptoms to 4=severe cardiopulmonary symptoms. A higher score indicated more severe symptoms experienced.
Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score From Baseline (Day 1) up to Week 28 The cardiovascular symptoms domain consisted of 5 items: heart palpitations (fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness and were reported on a 5-point Likert scale ranged from 0 (no symptoms at al) to 4 (very severe symptoms), with high score indicating more symptom. The symptoms part of PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. An average Cardiovascular Symptoms domain score was determined based on the daily scores of the 5 items. The mean individual symptom item score was determined for each of the 5 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiovascular symptoms to 4=severe cardiovascular symptoms. Higher score indicated more severe symptoms experienced.
Change From Baseline to Week 28 in Euro Quality of Life-5-Dimension-5-Level (EQ-5D-5L) Utility Score and Visual Analog Scale (VAS) Score From Baseline (Day 1) up to Week 28 The EQ-5D-5L was a generic measure of health status. The EQ-5D-5L consisted of 2 parts: EQ-5D-5L utility score (descriptive system) and VAS score. EQ-5D-5L descriptive system consisted of 5-item questionnaire that assessed 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each questionnaire had 5 response levels: 1 =no problems, 2 =slight problems, 3 =moderate problems, 4 =severe problems and 5 =extreme problems. The scores for the 5 questionnaires were used to compute a single utility score which ranged from 0 to 1, where higher score indicated better health state and lower score indicated worse health state. EQ-5D-5L VAS rated current health state on a vertical scale with a score ranged from 0 (worst imaginable health state) to 100 (best imaginable health state), higher scores indicated a better health state.
Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity From Baseline (Day 1) up to Week 28 Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity were assessed. Daily life physical activity of participant was assessed using accelerometer which was provided to the participant at screening and was worn daily during waking hours up to Week 28. For each scheduled visit, the 14 days prior to the visit were considered as the assessment period for physical activity. To be considered evaluable for a given timepoint, actigraphy variables should have been measured for at least 7 complete days (consecutive or not). A complete day is defined as a record of at least 7 waking hours of data. Proportion of time spent in moderate to vigorous physical activity was the estimated number of minutes spent in moderate or higher physical activity as calculated using the Staudenmayer '15 technique as proportion of the total minutes of algorithmically detected wear time and excluding the minutes that fall within a sleep period.
Trial Locations
- Locations (168)
Ordensklinikum Linz GmbH Elisabethinen
🇦🇹Linz, Austria
Medizinische Universitat Wien
🇦🇹Vienna, Austria
Military Medical Academy
🇧🇬Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
🇧🇬Sofia, Bulgaria
Hôpital Cardiologique - Chru Lille
🇫🇷Lille Cedex, France
CHU de Montpellier - Arnaud de Villeneuve
🇫🇷Montpellier, France
CHU Saint Etienne Hopital Nord
🇫🇷St Priest en Jarez Cedex, France
Hopital Larrey CHU de Toulouse
🇫🇷Toulouse Cedex 9, France
CHU de Nancy - Hopital de Brabois
🇫🇷Vandoeuvre les Nancy Cedex, France
Universitatsklinikum Bonn
🇩🇪Bonn, Germany
Medizinische Fakultaet Carl Gustav Carus Technische Universitaet Dresden
🇩🇪Dresden, Germany
Universitaetsklinikum Giessen
🇩🇪Giessen, Germany
Universitaetsklinikum Hamburg Eppendorf
🇩🇪Hamburg, Germany
Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie
🇩🇪Hannover, Germany
Thoraxklinik Heidelberg
🇩🇪Heidelberg, Germany
Universitaetsklinikum des Saarlandes
🇩🇪Homburg, Germany
Universitatsklinikum Jena
🇩🇪Jena, Germany
Krankenhaus Neuwittelsbach
🇩🇪München, Germany
Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet Felnott kardiologiai osztaly
🇭🇺Budapest, Hungary
Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelő
🇭🇺Szeged, Hungary
Tel Aviv Medical Center
🇮🇱Tel Aviv, Israel
The Chaim Sheba Medical Center
🇮🇱Tel-Hashomer, Israel
Ospedale SS. Annunziata
🇮🇹Chieti, Italy
Lietuvos sveikatos mokslų universiteto ligoninė Kauno klinik
🇱🇹Kaunas, Lithuania
Vilnius University Hospital Santariskiu Klinikos
🇱🇹Vilnius, Lithuania
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
🇲🇽Ciudad De México, Mexico
Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
🇲🇽Mexico, Mexico
Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
🇲🇽Monterrey, Mexico
Centro de Investigacion Clinica Chapultepec
🇲🇽Morelia, Mexico
CRI Centro Regiomontano de Investigacion SC
🇲🇽Nuevo Leon, Mexico
Krakowski Szpital Specjalistyczny im Jana Pawla II
🇵🇱Krakow, Poland
Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego PZOZ
🇵🇱Lublin, Poland
Europejskie Centrum Zdrowia Otwock Sp z o o
🇵🇱Otwock, Poland
Uls Almada Seixal - Hosp. Garcia de Orta
🇵🇹Almada, Portugal
Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu
🇷🇴Bucuresti, Romania
Spitalul Clinic Judetean de Urgenta
🇷🇴Tg. Mures, Romania
State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'
🇷🇺Kazan, Russian Federation
Moscow City Clinical Hospital No.51
🇷🇺Moscow, Russian Federation
National Medical Research Center of Cardiology of MoH of Russian Federation
🇷🇺Moscow, Russian Federation
National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
🇷🇺Saint-Petersburg, Russian Federation
Volgograd Regional Clinical Cardiology Center
🇷🇺Volgograd, Russian Federation
King Faisal Specialist Hospital & Research Center
🇸🇦Riyadh, Saudi Arabia
King Fahad Medical City
🇸🇦Riyadh, Saudi Arabia
University Clinical Center of Serbia
🇷🇸Belgrade, Serbia
Institute for Pulmonary Disease of Vojvodina
🇷🇸Sremska Kamenica, Serbia
National University Heart Centre, Singapore
🇸🇬Singapore, Singapore
National Heart Centre (NHC) Singapore
🇸🇬Singapore, Singapore
Narodny ustav srdcovych a cievnych chorob
🇸🇰Bratislava, Slovakia
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
Hosp. Univ. 12 de Octubre
🇪🇸Madrid, Spain
Hosp. Univ. La Paz
🇪🇸Madrid, Spain
Hosp. Costa Del Sol
🇪🇸Malaga, Spain
Hosp Virgen de La Victoria
🇪🇸Málaga, Spain
LKH-Univ. Klinikum Graz
🇦🇹Graz, Austria
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
Keck School of Medicine of USC
🇺🇸Los Angeles, California, United States
UC Davis Medical Center
🇺🇸Sacramento, California, United States
University of Colorado Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States
University of Florida Health Jacksonville
🇺🇸Gainesville, Florida, United States
Piedmont Healthcare
🇺🇸Atlanta, Georgia, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
VA Sierra Nevada Health Care System
🇺🇸Reno, Nevada, United States
University of New Mexico School of Medicine
🇺🇸Albuquerque, New Mexico, United States
Syracuse VA Medical Center
🇺🇸Syracuse, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Legacy Hospital
🇺🇸Portland, Oregon, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor Scott White - Plano
🇺🇸Plano, Texas, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
University of Utah Cardiovascular Center
🇺🇸Salt Lake City, Utah, United States
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States
Sanatorio de la Trinidad Mitre
🇦🇷Buenos Aires, Argentina
Sanatorio Guemes
🇦🇷C.a.b.a., Argentina
Nexo Salud Investigacion Clinica
🇦🇷Ciudad Autonoma de Buenos Aires, Argentina
Queensland Lung Transplant Service
🇦🇺Chermside, Australia
St Vincent's hospital
🇦🇺Darlinghurst, Australia
University Of Calgary - Peter Lougheed Centre
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
University Health Network - Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Beijing Chaoyang Hospital
🇨🇳Beijing, China
Beijing Anzhen Hospital
🇨🇳Beijing, China
China Japan Friendship Hospital
🇨🇳Beijing, China
Beijing Shijitan Hospital
🇨🇳Beijing, China
The First Affiliated Hospital of Chongqing Medical University
🇨🇳Chongqing, China
The First Affiliated Hospital of Guangzhou Medical University
🇨🇳Guangzhou, China
Sir Run Run Shaw Hospital Zhejiang University School of Medicine
🇨🇳Hangzhou, China
Zhongda Hospital Southeast University
🇨🇳Nanjing, China
The Affiliated Hospital of Medical College Qingdao University
🇨🇳Qingdao, China
Huashan Hospital of Fudan University
🇨🇳Shanghai, China
Shanghai Pulmonary Hospital
🇨🇳Shanghai, China
Zhongshan Hospital Fudan University
🇨🇳Shanghai, China
The General Hospital of Northern Theater Command
🇨🇳Shenyang, China
Tianjin Medical University General Hospital
🇨🇳Tian Jin, China
The First Affiliated Hospital of Xian Jiaotong University
🇨🇳Xi'An, China
Fundacion Neumologica Colombiana
🇨🇴Bogota, Colombia
Fundación Abood Shaio
🇨🇴Bogota, Colombia
Clínica Imbanaco S.A.S.
🇨🇴Cali, Colombia
Centro Cardiovascular Colombiano Clínica Santa María
🇨🇴Medellin, Colombia
General University Hospital II.department of Internal Medicine-cardiology and angiology
🇨🇿Praha 2, Czechia
Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B
🇩🇰Aarhus N, Denmark
CHU de Brest - Hopital de la Cavale Blanche
🇫🇷Brest, France
CHU de Grenoble Hopital Albert Michallon
🇫🇷Grenoble Cedex 9, France
Hopital Bicetre Aphp Hopitaux Universitaires Paris Sud
🇫🇷Le Kremlin-Bicetre Cedex, France
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Fondazione Toscana Gabriele Monasterio CNR
🇮🇹Pisa, Italy
Policlinico Gemelli Universita Cattolica
🇮🇹Roma, Italy
A.O.U. Città della Salute e della Scienza
🇮🇹Torino, Italy
The University of Tokyo Hospital
🇯🇵Bunkyo, Japan
Kyushu University Hospital
🇯🇵Fukuoka, Japan
Kure Kyosai Hospital
🇯🇵Hiroshima, Japan
St Marianna University Hospital
🇯🇵Kanagawa, Japan
Kobe University Hospital
🇯🇵Kobe, Japan
University Hospital Kyoto Prefectural University of Medicine
🇯🇵Kyoto, Japan
Kyoto University Hospital
🇯🇵Kyoto, Japan
Shinshu University Hospital
🇯🇵Matsumoto, Japan
Toho University Medical Center, Ohashi Hospital
🇯🇵Meguro-ku, Japan
Kyorin University Hospital
🇯🇵Mitaka, Japan
Nagoya University Hospital
🇯🇵Nagoya, Japan
National Hospital Organization Okayama Medical Center
🇯🇵Okayama, Japan
Hokkaido University Hospital
🇯🇵Sapporo-shi, Japan
National Cerebral and Cardiovascular Center
🇯🇵Suita-Shi, Japan
Juntendo University Hospital
🇯🇵Tokyo, Japan
University of Tsukuba Hospital
🇯🇵Tsukuba City, Japan
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea Seoul St Marys Hospital
🇰🇷Seoul, Korea, Republic of
Hosp. Gral. Univ. de Toledo
🇪🇸Toledo, Spain
Kaohsiung Veterans General Hospital
🇨🇳Kaohsiung, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Chang-Gung Memorial Hospital, LinKou Branch
🇨🇳Taoyuan, Taiwan
Maharaj Nakorn Chiang Mai Hospital
🇹🇭Chiang Mai, Thailand
Srinagarind Hospital, Khon Kaen University
🇹🇭Khon Kaen, Thailand
Thammasat Hospital
🇹🇭Pathumthani, Thailand
Adana City Hospital
🇹🇷Adana, Turkey
Cukurova University Medical Faculty
🇹🇷Adana, Turkey
Hacettepe University Medical Faculty
🇹🇷Ankara, Turkey
Ankara Bilkent Sehir Hastanesi
🇹🇷Ankara, Turkey
Pamukkale University Medical Faculty
🇹🇷Denizli, Turkey
Eskisehir Osmangazi University Medical Faculty Hospital
🇹🇷Eskisehir, Turkey
Istanbul University - Cerrahpasa Cardiology Institution
🇹🇷Istanbul, Turkey
Siyami Ersek Training and Research Hospital
🇹🇷Istanbul, Turkey
Marmara University Medical Faculty
🇹🇷Istanbul, Turkey
Ege University Medical Faculty
🇹🇷Izmir, Turkey
Dokuz Eylul University Medical Faculty
🇹🇷Izmir, Turkey
Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
🇹🇷Kartal Istanbul, Turkey
Mersin University Medical Faculty
🇹🇷Mersin, Turkey
CNE 'Cherkasy Regional Cardiological Center of Cherkasy Regional Council'
🇺🇦Cherkasy, Ukraine
CE 'Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiosurgery'
🇺🇦Dnipro, Ukraine
SI National Scientific Center Institute of Cardiology of M.D. Strazhesko of NAMS of Ukraine
🇺🇦Kyiv, Ukraine
State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
🇺🇦Kyiv, Ukraine
Communal Noncommercial Enterprise of Lviv Regional Council 'Lviv Regional Clinical Hospital'
🇺🇦Lviv, Ukraine
Municipal Non-commercial Enterprise Ternopil University Hospital of Ternopil Regional Council
🇺🇦Ternopil, Ukraine
Papworth Hospital NHS Trust
🇬🇧Cambridge, United Kingdom
National Waiting Times Centre Board Golden Jubilee National Hospital
🇬🇧Glasgow, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
Hammersmith Hospital
🇬🇧London, United Kingdom
Freeman Hospital
🇬🇧Newcastle Upon Tyne, United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom