European Radiology

, Volume 27, Issue 7, pp 2957–2968 | Cite as

Computed tomography versus invasive coronary angiography: design and methods of the pragmatic randomised multicentre DISCHARGE trial

  • Adriane E. Napp
  • Robert Haase
  • Michael Laule
  • Georg M. Schuetz
  • Matthias Rief
  • Henryk Dreger
  • Gudrun Feuchtner
  • Guy Friedrich
  • Miloslav Špaček
  • Vojtěch Suchánek
  • Klaus Fuglsang Kofoed
  • Thomas Engstroem
  • Stephen Schroeder
  • Tanja Drosch
  • Matthias Gutberlet
  • Michael Woinke
  • Pál Maurovich-Horvat
  • Béla Merkely
  • Patrick Donnelly
  • Peter Ball
  • Jonathan D. Dodd
  • Martin Quinn
  • Luca Saba
  • Maurizio Porcu
  • Marco Francone
  • Massimo Mancone
  • Andrejs Erglis
  • Ligita Zvaigzne
  • Antanas Jankauskas
  • Gintare Sakalyte
  • Tomasz Harań
  • Malgorzata Ilnicka-Suckiel
  • Nuno Bettencourt
  • Vasco Gama-Ribeiro
  • Sebastian Condrea
  • Imre Benedek
  • Nada Čemerlić Adjić
  • Oto Adjić
  • José Rodriguez-Palomares
  • Bruno Garcia del Blanco
  • Giles Roditi
  • Colin Berry
  • Gershan Davis
  • Erica Thwaite
  • Juhani Knuuti
  • Mikko Pietilä
  • Cezary Kępka
  • Mariusz Kruk
  • Radosav Vidakovic
  • Aleksandar N. Neskovic
  • Ignacio Díez
  • Iñigo Lecumberri
  • Jacob Geleijns
  • Christine Kubiak
  • Anke Strenge-Hesse
  • The-Hoang Do
  • Felix Frömel
  • Iñaki Gutiérrez-Ibarluzea
  • Gaizka Benguria-Arrate
  • Hans Keiding
  • Christoph Katzer
  • Jacqueline Müller-Nordhorn
  • Nina Rieckmann
  • Mario Walther
  • Peter Schlattmann
  • Marc Dewey
  • The DISCHARGE Trial Group
Computed Tomography

Abstract

Objectives

More than 3.5 million invasive coronary angiographies (ICA) are performed in Europe annually. Approximately 2 million of these invasive procedures might be reduced by noninvasive tests because no coronary intervention is performed. Computed tomography (CT) is the most accurate noninvasive test for detection and exclusion of coronary artery disease (CAD). To investigate the comparative effectiveness of CT and ICA, we designed the European pragmatic multicentre DISCHARGE trial funded by the 7th Framework Programme of the European Union (EC-GA 603266).

Methods

In this trial, patients with a low-to-intermediate pretest probability (10–60 %) of suspected CAD and a clinical indication for ICA because of stable chest pain will be randomised in a 1-to-1 ratio to CT or ICA. CT and ICA findings guide subsequent management decisions by the local heart teams according to current evidence and European guidelines.

Results

Major adverse cardiovascular events (MACE) defined as cardiovascular death, myocardial infarction and stroke as a composite endpoint will be the primary outcome measure. Secondary and other outcomes include cost-effectiveness, radiation exposure, health-related quality of life (HRQoL), socioeconomic status, lifestyle, adverse events related to CT/ICA, and gender differences.

Conclusions

The DISCHARGE trial will assess the comparative effectiveness of CT and ICA.

Key Points

Coronary artery disease (CAD) is a major cause of morbidity and mortality.

Invasive coronary angiography (ICA) is the reference standard for detection of CAD.

Noninvasive computed tomography angiography excludes CAD with high sensitivity.

CT may effectively reduce the approximately 2 million negative ICAs in Europe.

DISCHARGE addresses this hypothesis in patients with low-to-intermediate pretest probability for CAD.

Keywords

Computed tomography Angiography Invasive coronary angiography Adverse events Comparative effectiveness 

Notes

Acknowledgments

The scientific guarantor of this publication is Prof. Marc Dewey, M.D. Ph.D. The authors of this manuscript declare relationships with the following companies, foundations and government or university grants: Abbott, Academy of Finland, Centre of Excellence programs, Actelion, American Thoracic Society, Amgen, AP Møller og hustru Chastine McKinney Møllers Fond, Astra-Zeneca, Athera Biotechnologies AB, B.Braun Medical, Bayer, Bayer-Schering, Berlin Chemie, Beuth Hochschule für Technik Berlin, Biosensors, Biotie Therapies, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bracco, Braun, Cardiac MR Academy Berlin, CardiRad Ltd, Comac-Medical, Cordis, Covance, Directorate-General for Health and Food Safety, Eckert & Ziegler Radiopharma GmbH, Edwards Lifesciences, Endocyte Inc, European Regional Development Fund, European Society of Cardiology, European Union, F.Hoffmann-La Roche, Finnish Foundation for Cardiovascular Research, Fundação para a Ciência e Tecnologia, Portugal, GE Healthcare, Gedeon Richter, German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG), Guerbet, Guidotti,Intermeetings Padova, Irish Lung Foundation, Jansen-Cilag, Johnson & Johnson, KRKA, Lantheus Inc, Medtronic, Medtronik, Menarini, Merck, Merck Sharp & Dohme, MSD, National Heart, Lung, and Blood Institute (NHLBI), Novartis, Orion Pharma, Pfizer, Pharma Swiss, Philips, Piramal, Portuguese Society of Cardiology, Quintiles, Research Council of Rigshopitalet, Roche, Sandoz, Sanofi Aventis, Schering, Servier, Siemens, Sigma Tau, Southeastern Health and Social Care Trust Innovation Research Development Group Fund, Spanish Society of Cardiology, St. Jude Medical, Stiftung Charité (Berlin Institute of Health), Takeda,TEKES Finland, The Danish Agency for Science Technology and Innovation by The Danish Council for Strategic Research, The Danish Heart Foundation, The John and Birthe Meyer Foundation, The Lundbeck Foundation, Toshiba Medical Systems, Turku University Hospital research funds, VITAL Images Inc., Zealand A/S

This study has received funding by the Seventh Framework Programme of the European Union (EC-GA 603266). Prof. Peter Schlattmann kindly provided statistical advice for this manuscript. Institutional review board approval was obtained. Written informed consent will be obtained from all subjects (patients) for the study. Study subjects or cohorts have not been previously reported in another journal/study. Methodology: prospective/retrospective, randomised controlled trial, multicenter study.

Supplementary material

330_2016_4620_MOESM1_ESM.pdf (1.7 mb)
ESM 1(PDF 1722 kb)
330_2016_4620_MOESM2_ESM.pdf (120 kb)
ESM 2(PDF 120 kb)
330_2016_4620_MOESM3_ESM.pdf (313 kb)
ESM 3(PDF 312 kb)

References

  1. 1.
    WHO (2008) The global burden of disease. WHO, GenevaGoogle Scholar
  2. 2.
    Moschovitis A, Cook S, Meier B (2010) Percutaneous coronary interventions in Europe in 2006. EuroIntervention 6:189–194CrossRefPubMedGoogle Scholar
  3. 3.
    Patel MR, Peterson ED, Dai D et al (2010) Low diagnostic yield of elective coronary angiography. N Engl J Med 362:886–895CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Noto TJ Jr, Johnson LW, Krone R et al (1991) Cardiac catheterization 1990: a report of the registry of the Society for Cardiac Angiography and Interventions (SCA&I). Catheter Cardiovasc Diagn 24:75–83CrossRefGoogle Scholar
  5. 5.
    Scanlon PJ, Faxon DP, Audet AM et al (1999) ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 33:1756–1824CrossRefPubMedGoogle Scholar
  6. 6.
    Schuetz GM, Zacharopoulou NM, Schlattmann P, Dewey M (2010) Meta-analysis: noninvasive coronary angiography using computed tomography versus magnetic resonance imaging. Ann Intern Med 152:167–177CrossRefPubMedGoogle Scholar
  7. 7.
    von Ballmoos MW, Haring B, Juillerat P, Alkadhi H (2011) Meta-analysis: diagnostic performance of low-radiation-dose coronary computed tomography angiography. Ann Intern Med 154:413–420CrossRefGoogle Scholar
  8. 8.
    Montalescot G, Sechtem U, Achenbach S et al (2013) 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 34:2949–3003CrossRefPubMedGoogle Scholar
  9. 9.
    Genders TS, Ferket BS, Dedic A et al (2012) Coronary computed tomography versus exercise testing in patients with stable chest pain: comparative effectiveness and costs. Int J Cardiol. doi:10.1016/j.ijcard.2012.03.151,
  10. 10.
    Dewey M, Hamm B (2007) Cost effectiveness of coronary angiography and calcium scoring using CT and stress MRI for diagnosis of coronary artery disease. Eur Radiol 17:1301–1309CrossRefPubMedGoogle Scholar
  11. 11.
    Schlattmann P, Schuetz GM, Dewey M (2011) Influence of coronary artery disease prevalence on predictive values of coronary CT angiography: a meta-regression analysis. Eur Radiol 21:1904–1913CrossRefPubMedGoogle Scholar
  12. 12.
    Fox K, Garcia MA, Ardissino D et al (2006) Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 27:1341–1381CrossRefPubMedGoogle Scholar
  13. 13.
    Douglas PS, Hoffmann U, Patel MR et al (2015) Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 372:1291–1300CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    The SCOT-HEART Investigators (2015) CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet 385:2383–2391CrossRefGoogle Scholar
  15. 15.
    Chan AW, Tetzlaff JM, Gotzsche PC et al (2013) SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 346:e7586CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Chan AW, Tetzlaff JM, Altman DG et al (2013) SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 158:200–207CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Lawlor DA, Adamson J, Ebrahim S (2003) Performance of the WHO Rose angina questionnaire in post-menopausal women: are all of the questions necessary? J Epidemiol Community Health 57:538–541CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Perk J, De Backer G, Gohlke H et al (2012) European guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 33:1635–1701CrossRefPubMedGoogle Scholar
  19. 19.
    Tunis SR, Stryer DB, Clancy CM (2003) Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 290:1624–1632CrossRefPubMedGoogle Scholar
  20. 20.
    Mullins CD, Whicher D, Reese ES, Tunis S (2010) Generating evidence for comparative effectiveness research using more pragmatic randomized controlled trials. Pharmacoeconomics 28:969–976CrossRefPubMedGoogle Scholar
  21. 21.
    Thorpe KE, Zwarenstein M, Oxman AD et al (2009) A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. CMAJ 180:E47–E57CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Zimmermann E, Germershausen C, Greupner J et al (2010) Improvement of skills and knowledge by a hands-on cardiac CT course: before and after evaluation with a validated questionnaire and self-assessment. Röfo 182:589–593PubMedGoogle Scholar
  23. 23.
    Maruish ME (2012) User’s manual for the SF-12v2 health survey, 3rd edn. QualityMetric, LincolnGoogle Scholar
  24. 24.
    EuroQolGroup (1990) EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 16:199–208CrossRefGoogle Scholar
  25. 25.
    Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370CrossRefPubMedGoogle Scholar
  26. 26.
    Griffin S, Claxton K, Sculpher M (2008) Decision analysis for resource allocation in health care. J Health Serv Res Policy 13:23–30CrossRefPubMedGoogle Scholar
  27. 27.
    Ramsey SD, Willke RJ, Glick H et al (2015) Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report. Value Health 18:161–172CrossRefPubMedGoogle Scholar
  28. 28.
    Schuetz GM, Schlattmann P, Achenbach S et al (2013) Individual patient data meta-analysis for the clinical assessment of coronary computed tomography angiography: protocol of the Collaborative Meta-Analysis of Cardiac CT (CoMe-CCT). Syst Rev 2:13CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Kernan WN, Viscoli CM, Makuch RW, Brass LM, Horwitz RI (1999) Stratified randomization for clinical trials. J Clin Epidemiol 52:19–26CrossRefPubMedGoogle Scholar
  30. 30.
    Therneau TM, Grambsch P, Pankratz VS (2003) Penalized survival models and frailty. J Comput Graph Stat 12:156–175CrossRefGoogle Scholar
  31. 31.
    Therneau T (2012) coxme: mixed effects Cox models. R package version 2.2-3. http://CRAN.R-project.org/package=coxme
  32. 32.
    R Development Core Team (2012) R: a language and environment for statistical computing. http://www.R-project.org. R Foundation for Statistical Computing, Vienna, Austria
  33. 33.
    Schlattmann P (2009) Medical applications of finite mixture models. Springer, BerlinGoogle Scholar
  34. 34.
    Schafer JL (1999) Multiple imputation: a primer. Stat Methods Med Res 8:3–15CrossRefPubMedGoogle Scholar
  35. 35.
    Keaven Anderson (2012) gsDesign: group sequential design. R package version 2.7-04. http://CRAN.R-project.org/package=gsDesign
  36. 36.
    Dewey M, Rief M, Martus P et al (2016) Evaluation of computed tomography in patients with atypical angina or chest pain clinically referred for invasive coronary angiography: randomised controlled trial. BMJ 355:i5441Google Scholar
  37. 37.
    Williams MC, Hunter A, Shah AS et al (2016) Use of coronary computed tomographic angiography to guide management of patients with coronary disease. J Am Coll Cardiol 67:1759–1768CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Kip KE, Hollabaugh K, Marroquin OC, Williams DO (2008) The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol 51:701–707CrossRefPubMedGoogle Scholar
  39. 39.
    The DISCHARGE Trial (2015) www.dischargetrial.eu. Accessed 25 Mar 2015
  40. 40.
    Chow BJ, Small G, Yam Y et al (2015) Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (coronary CT angiography evaluation for clinical outcomes: an international multicenter registry) registry. Arterioscler Thromb Vasc Biol. doi:10.1161/ATVBAHA.114.304351 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Dewey M, Zimmermann E, Deissenrieder F et al (2009) Noninvasive coronary angiography by 320-row CT with lower radiation exposure and maintained diagnostic accuracy: comparison of results with cardiac catheterization in a head-to-head pilot investigation. Circulation 120:867–875CrossRefPubMedGoogle Scholar
  42. 42.
    Pontone G, Andreini D, Bartorelli AL et al (2013) A long-term prognostic value of CT angiography and exercise ECG in patients with suspected CAD. JACC Cardiovasc Imaging 6:641–650CrossRefPubMedGoogle Scholar
  43. 43.
    Linde JJ, Hove JD, Sorgaard M et al (2015) Long-term clinical impact of coronary CT angiography in patients with recent acute-onset chest pain: the randomized controlled CATCH trial. JACC Cardiovasc Imaging 8:1404–1413CrossRefPubMedGoogle Scholar
  44. 44.
    Schuetz GM, Schlattmann P, Dewey M (2012) Use of 3x2 tables with an intention to diagnose approach to assess clinical performance of diagnostic tests: meta-analytical evaluation of coronary CT angiography studies. BMJ 345:e6717CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© European Society of Radiology 2016

Authors and Affiliations

  • Adriane E. Napp
    • 1
  • Robert Haase
    • 1
  • Michael Laule
    • 2
  • Georg M. Schuetz
    • 1
  • Matthias Rief
    • 1
  • Henryk Dreger
    • 2
  • Gudrun Feuchtner
    • 3
  • Guy Friedrich
    • 4
  • Miloslav Špaček
    • 5
  • Vojtěch Suchánek
    • 6
  • Klaus Fuglsang Kofoed
    • 7
  • Thomas Engstroem
    • 8
  • Stephen Schroeder
    • 9
  • Tanja Drosch
    • 9
  • Matthias Gutberlet
    • 10
  • Michael Woinke
    • 11
  • Pál Maurovich-Horvat
    • 12
  • Béla Merkely
    • 12
  • Patrick Donnelly
    • 13
  • Peter Ball
    • 14
  • Jonathan D. Dodd
    • 15
  • Martin Quinn
    • 16
  • Luca Saba
    • 17
  • Maurizio Porcu
    • 18
  • Marco Francone
    • 19
  • Massimo Mancone
    • 20
  • Andrejs Erglis
    • 21
  • Ligita Zvaigzne
    • 22
  • Antanas Jankauskas
    • 23
  • Gintare Sakalyte
    • 24
  • Tomasz Harań
    • 25
  • Malgorzata Ilnicka-Suckiel
    • 26
  • Nuno Bettencourt
    • 27
  • Vasco Gama-Ribeiro
    • 27
  • Sebastian Condrea
    • 28
  • Imre Benedek
    • 28
  • Nada Čemerlić Adjić
    • 29
  • Oto Adjić
    • 30
  • José Rodriguez-Palomares
    • 31
  • Bruno Garcia del Blanco
    • 31
  • Giles Roditi
    • 32
  • Colin Berry
    • 32
  • Gershan Davis
    • 33
  • Erica Thwaite
    • 34
  • Juhani Knuuti
    • 35
  • Mikko Pietilä
    • 36
  • Cezary Kępka
    • 37
  • Mariusz Kruk
    • 38
  • Radosav Vidakovic
    • 39
  • Aleksandar N. Neskovic
    • 39
  • Ignacio Díez
    • 40
  • Iñigo Lecumberri
    • 41
  • Jacob Geleijns
    • 42
  • Christine Kubiak
    • 43
  • Anke Strenge-Hesse
    • 44
  • The-Hoang Do
    • 45
  • Felix Frömel
    • 45
  • Iñaki Gutiérrez-Ibarluzea
    • 46
  • Gaizka Benguria-Arrate
    • 46
  • Hans Keiding
    • 47
  • Christoph Katzer
    • 1
  • Jacqueline Müller-Nordhorn
    • 48
  • Nina Rieckmann
    • 48
  • Mario Walther
    • 49
  • Peter Schlattmann
    • 49
  • Marc Dewey
    • 1
  • The DISCHARGE Trial Group
  1. 1.Department of RadiologyCharité – Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of CardiologyCharité – Universitätsmedizin BerlinBerlinGermany
  3. 3.Department of RadiologyMedical University InnsbruckInnsbruckAustria
  4. 4.Department of CardiologyMedical University InnsbruckInnsbruckAustria
  5. 5.Department of CardiologyUniversity Hospital MotolPrague 5Czech Republic
  6. 6.Department of RadiologyUniversity Hospital MotolPrague 5Czech Republic
  7. 7.Department of Radiology and Department of CardiologyRigshospitalet Region HovedstadenCopenhagenDenmark
  8. 8.Department of CardiologyRigshospitalet Region HovedstadenCopenhagenDenmark
  9. 9.Department of CardiologyALB FILS KLINIKEN GmbHGoeppingenGermany
  10. 10.Department of RadiologyUniversity of Leipzig Heart CentreLeipzigGermany
  11. 11.Department of CardiologyUniversity of Leipzig Heart CentreLeipzigGermany
  12. 12.MTA-SE Cardiovascular Imaging Center, Heart and Vascular CenterSemmelweis UniversityBudapestHungary
  13. 13.Department of CardiologySoutheastern Health and Social Care TrustBelfastUK
  14. 14.Department of RadiologySoutheastern Health and Social Care TrustBelfastUK
  15. 15.Department of RadiologySt. Vincent’s University Hospital and National University of IrelandDublinIreland
  16. 16.Department of CardiologySt. Vincent’s University HospitalDublinIreland
  17. 17.Department of RadiologyAzienda Ospedaliero Universitaria di CagliariMonserratoItaly
  18. 18.Department of CardiologyAzienda Ospedaliera BrotzuCagliariItaly
  19. 19.Department of RadiologySapienza University of RomeRomeItaly
  20. 20.Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric SciencesSapienza University of RomeRomeItaly
  21. 21.Department of CardiologyPaul Stradins Clinical University HospitalRigaLatvia
  22. 22.Department of RadiologyPaul Stradins Clinical University HospitalRigaLatvia
  23. 23.Department of RadiologyLithuanian University of Health SciencesKaunasLithuania
  24. 24.Department of CardiologyLithuanian University of Health SciencesKaunasLithuania
  25. 25.Department of RadiologyWojewodzki Szpital Specjalistyczny We WroclawiuWroclawPoland
  26. 26.Department of CardiologyWojewodzki Szpital Specjalistyczny We WroclawiuWroclawPoland
  27. 27.Department of CardiologyCentro Hospitalar de Vila Nova de GaiaVila Nova de GaiaPortugal
  28. 28.Department of CardiologyCardio Med Medical CenterTargu-MuresRomania
  29. 29.Department of CardiologyInstitute of Cardiovascular Diseases of VojvodinaNovi SadSerbia
  30. 30.Radiology Department Imaging CenterInstitute of Cardiovascular Diseases of VojvodinaNovi SadSerbia
  31. 31.Department of Cardiology (Barcelona Spain), Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR)Universitat Autònoma de BarcelonaBarcelonaSpain
  32. 32.Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
  33. 33.Department of CardiologyAintree University HospitalLiverpoolUK
  34. 34.Department of RadiologyAintree University HospitalLiverpoolUK
  35. 35.Turku PET CentreTurku University Hospital and University of TurkuTurkuFinland
  36. 36.Heart CentreTurku University HospitalTurkuFinland
  37. 37.Department of RadiologyThe Institute of Cardiology in WarsawWarsawPoland
  38. 38.Department of CardiologyThe Institute of Cardiology in WarsawWarsawPoland
  39. 39.Department of CardiologyClinical Hospital Center ZemunBelgrade-ZemunSerbia
  40. 40.Department of CardiologyBasurto University HospitalBilbaoSpain
  41. 41.Department of RadiologyBasurto University HospitalBilbaoSpain
  42. 42.Department of RadiologyLeiden University Medical CenterLeidenNetherlands
  43. 43.European Clinical Research Infrastructure Network (ECRIN-ERIC), Management OfficeParisFrance
  44. 44.European Clinical Research Infrastructure Network (ECRIN-ERIC), National ECRIN office/KKS NetworkUniversity CologneCologneGermany
  45. 45.Clinical Coordinating CentreCharité – Universitätsmedizin BerlinBerlinGermany
  46. 46.Basque Office for Health Technology AssessmentVitoria-GasteizSpain
  47. 47.Department of Economics, Department of EconomicsUniversity of CopenhagenCopenhagenDenmark
  48. 48.Institute of Public HealthCharité - Universitätsmedizin BerlinBerlinGermany
  49. 49.Institute of Medical Statistics, Computer Sciences and DocumentationJena University Hospital, Friedrich Schiller University JenaJenaGermany

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