APPENDIX 1: LITERATURE SEARCH STRATEGY
$ Truncation symbol adj Adjacent (i.e., terms are near/next to one another, any order) adj# Adjacent within # of words ti Title ab Abstract kw Keyword sh Subject heading/descriptor exp Explode subject heading fs Floating subject heading pt Publication type tn Trade name rn Registry number (i.e., CAS) tw Text word hw Heading word
DATABASES LIMITS KEYWORDS/DESCRIPTORS
Ovid Human Systematic Reviews/Meta-Analyses
- Medline Medline In-Process & Other Non-Indexed Citations - Medline In-Process & Other Non- 1. Octreotid$.ti,ab. Indexed Citations 2. Longastatin$.ti,ab. - EMBASE 3. DRG-0115.ti,ab. - BIOSIS Previews 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 biomedical).ti,ab. 12. (technology adj assessment$ adj2 bio-medical).ti,ab. 13. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 14. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 15. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 16. or/10-15 17. 9 and 16
Medline
1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab.
A-1 DATABASES LIMITS KEYWORDS/DESCRIPTORS 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 biomedical).ti,ab. 12. (technology adj assessment$ adj2 bio-medical).ti,ab. 13. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 14. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 15. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 16. Meta-Analysis.pt. 17. Meta-Analysis.sh. 18. exp Technology Assessment, Biomedical/ 19. or/10-18 20. 9 and 19
EMBASE
1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. Meta-Analysis.sh. 16. Systematic review.sh. 17. Biomedical Technology Assessment.sh. 18. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 19. (technology adj assessment$ adj2 biomedical).ti,ab. 20. (technology adj assessment$ adj2 bio-medical).ti,ab. 21. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 22. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 23. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 24. or/15-23 25. 14 and 24
BIOSIS
1. Octreotid$.hw,ti,ab.
A-2 DATABASES LIMITS KEYWORDS/DESCRIPTORS 2. Longastatin$.hw,ti,ab. 3. DRG-0115.hw,ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).hw,ti,ab. 5. Sandostatin$.hw,ti,ab. 6. SMS-LAR.hw,ti,ab. 7. Sandoz 201-995.hw,ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 (biomedical or bio-medical)).ti,ab. 12. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 13. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 14. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 15. or/10-14 16. 9 and 15
Performed 16 May 2006 99 unique records after de-duping in Reference Manager
Medline In-Process & Other Non-Indexed Citations - 1 Medline – 42 EMBASE - 44 BIOSIS – 12
Ovid Economic Studies
- Medline Medline In-Process & Other Non-Indexed Citations - Medline In-Process & Other Non- 1. Octreotid$.ti,ab. Indexed Citations 2. Longastatin$.ti,ab. - EMBASE 3. DRG-0115.ti,ab. - BIOSIS Previews 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. (cost or costs or costing or cost-effective$).ti,ab. 11. (sensitivity analysis or sensitivity analyses).ti,ab. 12. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 13. budget$.ti,ab. 14. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 15. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 16. (Quality adj1 adjusted life year$).ti,ab. 17. (Quality adj1 adjusted life expectanc$).ti,ab. 18. or/10-17 19. 9 and 18
A-3 DATABASES LIMITS KEYWORDS/DESCRIPTORS Medline
1. Octreotide.sh. 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. 83150-76-9.rn. 10. or/1-9 11. Economics.sh. 12. Economics, medical.sh. 13. Economics, pharmaceutical.sh. 14. exp "Costs and Cost Analysis"/ 15. exp health care costs/ 16. exp decision support techniques/ 17. economics.fs. 18. (cost or costs or costing or cost-effective$).ti,ab. 19. (sensitivity analysis or sensitivity analyses).ti,ab. 20. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 21. budget$.ti,ab. 22. value of life.sh. 23. quality of life.sh. 24. quality-adjusted life years.sh. 25. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 26. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 27. (Quality adj1 adjusted life year$).ti,ab. 28. (Quality adj1 adjusted life expectanc$).ti,ab. 29. or/11-28 30. 10 and 29
EMBASE
1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. exp health economics/ 16. exp economic evaluation/ 17. exp pharmacoeconomics/ 18. exp economic aspect/ 19. (cost or costs or costing or cost-effective$).ti,ab.
A-4 DATABASES LIMITS KEYWORDS/DESCRIPTORS 20. (sensitivity analysis or sensitivity analyses).ti,ab. 21. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 22. budget$.ti,ab. 23. quality adjusted life year.sh. 24. exp quality of life/ 25. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 26. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 27. (Quality adj1 adjusted life year$).ti,ab. 28. (Quality adj1 adjusted life expectanc$).ti,ab. 29. pe.fs. 30. or/15-29 31. 14 and 30
BIOSIS
1. Octreotid$.hw,ti,ab. 2. Longastatin$.tw. 3. DRG-0115.tw. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).tw. 5. Sandostatin$.tw. 6. SMS-LAR.tw. 7. Sandoz 201-995.tw. 8. 83150-76-9.rn. 9. or/1-8 10. Economic$.hw. 11. Pharmacoeconomic$.hw. 12. (cost or costs or costing or cost-effective$).ti,ab. 13. (sensitivity analysis or sensitivity analyses).ti,ab. 14. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 15. budget$.ti,ab. 16. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 17. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 18. (Quality adj1 adjusted life year$).ti,ab. 19. (Quality adj1 adjusted life expectanc$).ti,ab. 20. or/10-19 21. 9 and 20
Search Performed 30 May 2006 362 unique records after de-duping Reference Manager
Medline In-Process & Other Non-Indexed Citations – 4 Medline – 141 EMBASE - 203 BIOSIS – 14
Ovid Human Clinical Trials:
- Medline Medline In-Process & Other Non-Indexed Citations - Medline In-Process & Other Non- 1. Octreotid$.ti,ab. Indexed Citations 2. Longastatin$.ti,ab.
A-5 DATABASES LIMITS KEYWORDS/DESCRIPTORS - EMBASE 3. DRG-0115.ti,ab. - BIOSIS Previews 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 11. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 12. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 13. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 14. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 15. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 16. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 17. or/10-16 18. 9 and 17
Medline
1. Octreotide.sh. 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. 83150-76-9.rn. 10. or/1-9 11. (Multicenter Study or Randomized Controlled Trial or Controlled Clinical Trial).pt. 12. exp Controlled Clinical Trials/ 13. Double-Blind Method.sh. 14. Single-Blind Method.sh. 15. Random allocation.sh. 16. Multicenter studies.sh. 17. Cross-over studies.sh. 18. Cohort studies.sh. 19. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 20. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 21. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 22. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 23. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 24. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 25. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 26. or/11-25 27. 10 and 26
EMBASE
A-6 DATABASES LIMITS KEYWORDS/DESCRIPTORS
1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. Randomized Controlled Trial/ 16. exp controlled study/ 17. Double Blind Procedure.sh. 18. Single Blind Procedure.sh. 19. Multicenter study.sh. 20. Crossover procedure.sh. 21. Cohort Analysis.sh. 22. (major clinical study or multicenter study or randomized controlled trial).ti,ab. 23. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 24. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 25. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 26. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 27. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 28. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 29. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 30. or/15-29 31. 14 and 30
BIOSIS
1. Octreotid$.hw,ti,ab. 2. Longastatin$.tw. 3. DRG-0115.tw. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).tw. 5. Sandostatin$.tw. 6. SMS-LAR.tw. 7. Sandoz 201-995.tw. 8. 83150-76-9.rn. 9. or/1-8 10. (major clinical study or multicenter study or randomized controlled trial).ti,ab,hw. 11. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab,hw. 12. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab,hw. 13. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab,hw.
A-7 DATABASES LIMITS KEYWORDS/DESCRIPTORS 14. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab,hw. 15. ((crossover or cross-over) adj (study or study or trial$)).ti,ab,hw. 16. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab,hw. 17. (Cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab,hw. 18. or/10-17 19. 9 and 18
Performed 26 Jul 2006 1873 unique records after de-duping in Reference Manager
Medline In-Process & Other Non-Indexed Citations - 12 Medline – 727 EMBASE - 1047 BIOSIS – 87
Ovid Human Performed biweekly between May 2006 to February 2008
Alerts: - Medline - Medline In-Process & Other Non- Indexed Citations - EMBASE - BIOSIS Previews
John Wiley & Sons, (octreotid* OR longastatin* OR sandostatin* OR drg-0115 OR (drg NEXT Inc. 0115) OR (sms-201-995) OR (sms NEXT 201 NEXT 995) OR san-201-995 OR (san NEXT 201 NEXT 995) OR sms-lar OR (sms NEXT lar) OR The Cochrane (sandoz NEXT 201-005) OR (sandoz NEXT 201 NEXT 005) – ti,ab,kw Library 2006, Issue 2 23 Records The Cochrane Database of Systematic Reviews = 3 complete reviews; The Database of Abstracts of Reviews of Effects = 9 records; HTA database = 2 records; The NHS Economic Evaluation Database = 9 records
Search re-run in 2006, Issue 3 to obtain clinical trial records
676 records (188 unique records after de-duping in Reference Manager with results of previous systematic review and clinical search)
CENTRAL REGISTER OF CONTROLLED TRIALS = 676 records Regular updates performed to September 2007
OHE-IFPMA All variations of octreotide Database Ltd. 17 records HEED: health economic evaluations database
June 2006 Issue
A-8 Grey Literature: Websites of health technology assessment (HTA), related agencies and other databases
* NOTE: This section lists the main agencies, organizations, and websites searched; it is not a complete list. For a complete list of sources searched, contact CADTH (http://www.cadth.ca).
Health Technology Assessment Agencies
Alberta Heritage Foundation for Medical Research (AHFMR) http://www.ahfmr.ab.ca
Agence d’Evaluation des Technologies et des Modes d’Intervention en Santé (AETMIS). Québec http://www.aetmis.gouv.qc.ca
Canadian Agency for Drugs and Technologies in Health (CADTH) http://www.cadth.ca
Centre for Evaluation of Medicines. Father Sean O'Sullivan Research Centre, St.Joseph's Healthcare,Hamilton, and McMaster University, Faculty of Health Sciences. Hamilton, Ontario http://www.thecem.net/
Centre for Health Services and Policy Research, University of British Columbia http://www.chspr.ubc.ca/cgi-bin/pub
Health Quality Council of Alberta (HQCA) http://www.hqca.ca
Health Quality Council. Saskatchewan. http://www.hqc.sk.ca/
Institute for Clinical Evaluative Sciences (ICES). Ontario http://www.ices.on.ca/
Institute of Health Economics (IHE). Alberta http://www.ihe.ca/
Manitoba Centre for Health Policy (MCHP) http://www.umanitoba.ca/centres/mchp/
Ontario Ministry of Health and Long Term Care. Health Technology Analyses and Recommendations http://www.health.gov.on.ca/english/providers/program/ohtac/tech/techlist_mn.html
The Technology Assessment Unit of the McGill University Health Centre http://www.mcgill.ca/tau/
Therapeutics Initiative. Evidence-Based Drug Therapy. University of British Columbia http://www.ti.ubc.ca
Health Technology Assessment International (HTAi) http://www.htai.org
International Network for Agencies for Health Technology Assessment (INAHTA) http://www.inahta.org
A-9 WHO Health Evidence Network http://www.euro.who.int/HEN
Australian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S) http://www.surgeons.org/Content/NavigationMenu/Research/ASERNIPS/default.htm
Centre for Clinical Effectiveness, Monash University http://www.med.monash.edu.au/healthservices/cce/
Medicare Services Advisory Committee, Department of Health and Aging http://www.msac.gov.au/
NPS RADAR (National Prescribing Service Ltd.) http://www.npsradar.org.au/site.php?page=1&content=/npsradar%2Fcontent%2Farchive_alpha.html
Institute of Technology Assessment (ITA) http://www.oeaw.ac.at/ita/index.htm
Federal Kenniscentrum voor de Gezendheidszorg http://www.kenniscentrum.fgov.be
Danish Centre for Evaluation and Health Technology Assessment (DCEHTA). National Board of Health http://www.dihta.dk/
DSI Danish Institute for Health Services Research and Development http://www.dsi.dk/engelsk.html
Finnish Office for Health Care Technology and Assessment (FinOHTA). National Research and Development Centre for Welfare and Health http://finohta.stakes.fi/EN/index.htm
L’Agence Nationale d’Accréditation et d’Evaluation en Santé (ANAES). Ministere de la Santé, de la Famille, et des Personnes handicappés http://www.anaes.fr/anaes/anaesparametrage.nsf/HomePage?ReadForm
Committee for Evaluation and Diffusion of Innovative Technologies (CEDIT) http://cedit.aphp.fr/english/index_present.html
German Institute for Medical Documentation and Information (DIMDI). Federal Ministry of Health http://www.dimdi.de/static/de/hta/db/index.htm
College voor Zorgverzekeringen/Health Care Insurance Board (CVZ) http://www.cvz.nl
Health Council of the Netherlands http://www.gr.nl
New Zealand Health Technology Assessment Clearing House for Health Outcomes and Health Technology Assessment (NZHTA) http://nzhta.chmeds.ac.nz/
Norwegian Centre for Health Technology Assessment (SMM) http://www.kunnskapssenteret.no/
Basque Office for Health Technology Assessment (OSTEBA). Departemento de Sanidad http://www.osasun.ejgv.euskadi.net/r52-2536/es/
A-10 Catalan Agency for Health Technology Assessment and Research (CAHTA) http://www.gencat.net/salut/depsan/units/aatrm/html/en/Du8/index.html
CMT - Centre for Medical Technology Assessment http://www.cmt.liu.se/pub/jsp/polopoly.jsp?d=6199&l=en
Swedish Council on Technology Assessment in Health Care (SBU) http://www.sbu.se/
Swiss Network for Health Technology Assessment http://www.snhta.ch/about/index.php
European Information Network on New and Changing Health Technologies (EUROSCAN). University of Birmingham. National Horizon Scanning Centre http://www.euroscan.bham.ac.uk
National Horizon Scanning Centre (NHSC) http://www.pcpoh.bham.ac.uk/publichealth/horizon
NHS Health Technology Assessment /National Coordinating Centre for Health Technology Assessment (NCCHTA). Department of Health R&D Division http://www.ncchta.org/
NHS National Institute for Clinical Excellence (NICE) http://www.nice.org.uk
NHS Quality Improvement Scotland http://www.nhshealthquality.org
University of York NHS Centre for Reviews and Dissemination (NHS CRD) http://www.york.ac.uk/inst/crd
The Wessex Institute for Health Research and Development. Succinct and Timely Evaluated Evidence Review (STEER) http://www.wihrd.soton.ac.uk/
West Midlands Health Technology Assessment Collaboration (WMHTAC) http://www.wmhtac.bham.ac.uk/
Agency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov/
VA Technology Assessment Program (VATAP) http://www.va.gov/vatap/
ECRI http://www.ecri.org/
Institute for Clinical Systems Improvement http://www.icsi.org/index.asp
Technology Evaluation Center (Tec). BlueCross BlueShield Association http://www.bluecares.com/tec/index.html
University HealthSystem Consortium (UHC) http://www.uhc.edu/
A-11 Health Economic
Bases Codecs. CODECS (COnnaissances et Décision en EConomie de la Santé) Collège des Economistes de la Santé/INSERM http://infodoc.inserm.fr/codecs/codecs.nsf
Centre for Health Economics and Policy Analysis (CHEPA). Dept. of Clinical Epidemiology and Biostatistics. Faculty of Health Sciences. McMaster University, Canada http://www.chepa.org
Health Economics Research Group (HERG). Brunel University, U.K. http://www.brunel.ac.uk/about/acad/herg
Health Economics Research Unit (HERU). University of Aberdeen http://www.abdn.ac.uk/heru/
The Hospital for Sick Children (Toronto). PEDE Database http://pede.bioinfo.sickkids.on.ca/pede/index.jsp
University of Connecticut. Department of Economics. RePEc database http://ideas.repec.org
Conference Proceedings Searched 2004-2006 when available.
American Association of Clinical Endocrinologists (AACE) American Society of Clinical Oncology (ASCO) Digestive Diseases Week; Endocrine Society European Association for the Study of the Liver (EASL) Society of American Gastrointestinal Endoscopic Surgeons (SAGES)
A-12 APPENDIX 2: EXCLUDED STUDIES
Systematic review search
Andrén-Sandberg Å, Flati G, Büchler M. The role of octreotide in preventing complications after pancreatoduodenectomy for cancer. HPB 2000;2(3):299-312.
Andriulli A, Leandro G, Clemente R, Caruso N, Annese V, Perri F. Meta-analysis of somatostatin, octreotide and gabexate in the therapy of acute pancreatitis [abstract]. Gastroenterology 1997;112(4 Suppl):A425.
Andriulli A, Leandro G, Niro G, Lichino E, Conoscitore P, Clemente R, et al. Prophylactic therapy with octreotide is able to reduce morbidity associated to pancreatic surgery: a meta-analytical evaluation [abstract]. Gastroenterology 1997;112(4 Suppl):A425.
Andriulli A, Festa V, Clemente R, Leandro G, De MG. Il danno pancreatico in corso di colangiopancreatografia retrograda endoscopica: una complicanza prevedibile e prevenibile [Pancreatic damage in endoscopic retrograde cholangiopancreatography: a predictable and preventable complication]. G Ital Endosc Dig 2000;23(1):19-23.
Avgerinos A, Armonis A, Raptis S. Somatostatin or octreotide versus endoscopic sclerotherapy in acute variceal haemorrhage: a meta - analysis study. J Hepatol 1995;22(2):247-8.
Avgerinos A, Armonis A, Raptis S. Somatostatin and octreotide in the management of acute variceal hemorrhage. Hepatogastroenterology 1995;42(2):145-50.
Avgerinos A. Approach to the management of bleeding esophageal varices: role of somatostatin. Digestion 1998;59 Suppl 1:1-22.
Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139(10):843-57.
Bartoli FG, Arnone GB, Ravera G, Bachi V. Pancreatic fistula and relative mortality in malignant disease after pancreaticoduodenectomy. Review and statistical meta-analysis regarding 15 years of literature. Anticancer Res 1991;11(5):1831-48.
Berberat PO, Friess H, Uhl W, Buchler MW. The role of octreotide in the prevention of complications following pancreatic resection. Digestion 1999;60 Suppl 2:15-22.
Bhasin DK, Malhi NJS. Variceal bleeding and portal hypertension: much to learn, much to explore. Endoscopy 2002;34(2):119-28.
Bhasin DK, Siyad I. Variceal bleeding and portal hypertension: new lights on old horizon. Endoscopy 2004;36(2):120-9.
Bretagne JF, Heresbach D. La sclérose endoscopique. Acta Endosc 1995;25(4):347-64.
Burroughs AK. Octreotide in variceal bleeding. Gut 1994;35(3 Suppl):S23-S27.
Burt MG, Ho KKY. Comparison of efficacy and tolerability of somatostatin analogs and other therapies for acromegaly. Endocrine 2003;20(3):299-305.
Büchler MW, Binder M, Friess H. Role of somatostatin and its analogues in the treatment of acute and chronic pancreatitis. Gut 1994;35 Suppl 3:S15-S19.
A-13 Cirillo F. Medical treatment of neuroendocrine gastroenteropancreatic tumors. Med Biol Environ 1997;25(1):3- 7.
Copel L. Place des analogues de la somatostatine en soins palliatifs. Oncol Paris 2002;4(7):419-22.
D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22(1):332-54.
D'Amico G. First meta-analysis of octreotide for variceal bleeding. A lost opportunity. J Hepatol 2002;36(4):574-7.
D'Amico G, Tararantino IG, Pietrosi G, Pagliaro L. Emergency sclerotherapy compared with somatostatin or octreotide therapy for variceal bleeding in cirrhosis: a meta-analysis. Gastroenterology 2001;120(5 Suppl 1):374.
De Franchis R. Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding oesophageal varices. Dig Liver Dis 2004;36 Suppl 1:S93-100. de Mon MÁ. Estado actual y perspectivas futuras en la modulatión de la respuesta inmune en la pancreatitis aguda grave [Modulation of immune response in severe acute pancreatitis. Present and future view]. Gastroenterol Hepatol 2003;26(3):163-5.
Fried M. Octreotide in the treatment of refractory diarrhea. Digestion 1999;60 Suppl 2:42-6.
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A-41 APPENDIX 3: FIGURES
Figure A1: Selected Systematic Reviews or Meta-Analyses
103 citations identified from electronic search and
screened
42 citations excluded
5 citations identified from other sources
66 potentially relevant reports retrieved for scrutiny
1 potentially relevant
report retrieved from other sources
67 potentially relevant reports
52 reports excluded based on: - study design (40)
- population (2) - intervention (4)
- inappropriate outcome measures (2)
- duplicate publication (4)
15 relevant systematic reviews*
*three additional systematic reviews identified after this phase of screening completed and systematic review of RCTs was underway.96-98
A-42 Figure A2: Selected RCTs and CCTs
2180 citations identified from electronic search and screened
1730 citations excluded
34 citations identified from other sources
484 potentially relevant reports retrieved for scrutiny (full text, if available)
1 potentially relevant report retrieved from other sources
485 potentially relevant reports
321 reports excluded based on: study design (113), population (71), intervention (15), comparator (11), duplicate report of same trial data (9), contained insufficient information (14), unable to retrieve full text copy (18), language (16), other (54)
140 relevant RCTs describing 99 unique trials; 24 relevant CCTs
A-43 Emergency management of acute variceal bleeding
Figure A3: Death with OCT-SA versus placebo or no treatment
Review: Emergency Management of Variceal Hemorrhage Comparison: 01 OCT-SA versus placebo/no treatment Outcome: 01 Death
Study OCT-SA Placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA + sclerotherapy versus placebo/no treatment + sclerotherapy Besson 1995 12/98 12/101 6.05 1.03 [0.49, 2.18] A Farooqi 2000 1/72 6/69 3.14 0.16 [0.02, 1.29] B Freitas 2000b 12/44 13/42 6.81 0.88 [0.45, 1.71] B Morales 2007 8/40 5/28 3.01 1.12 [0.41, 3.07] B Shah 2005 10/51 12/54 5.96 0.88 [0.42, 1.86] B Shaikh 2002 4/196 12/188 6.27 0.32 [0.10, 0.97] B Shiha 1996 7/93 8/96 4.03 0.90 [0.34, 2.39] B Silva 2004 1/36 8/43 3.73 0.15 [0.02, 1.14] B Souza 2003 10/56 13/56 6.65 0.77 [0.37, 1.61] B Zuberi 2000 1/35 1/35 0.51 1.00 [0.07, 15.36] A Subtotal (95% CI) 721 712 46.16 0.72 [0.54, 0.96] Total events: 66 (OCT-SA), 90 (Placebo/no treatment) Test for heterogeneity: Chi² = 8.90, df = 9 (P = 0.45), I² = 0% Test for overall effect: Z = 2.20 (P = 0.03)
02 OCT-SA + sclerotherapy (after 48-72 h) versus placebo/no treatment + sclerotherapy Freitas 2000a 13/58 8/53 4.28 1.48 [0.67, 3.30] B Jenkins 1997 23/73 13/77 6.47 1.87 [1.02, 3.40] B Sivri 2000 1/30 1/36 0.47 1.20 [0.08, 18.38] B Sung 1993 14/49 20/49 10.23 0.70 [0.40, 1.22] B Subtotal (95% CI) 210 215 21.45 1.22 [0.86, 1.74] Total events: 51 (OCT-SA), 42 (Placebo/no treatment) Test for heterogeneity: Chi² = 5.99, df = 3 (P = 0.11), I² = 49.9% Test for overall effect: Z = 1.10 (P = 0.27)
03 OCT-SA versus placebl/no treatment Burroughs 1996 42/189 53/194 26.77 0.81 [0.57, 1.16] B Subtotal (95% CI) 189 194 26.77 0.81 [0.57, 1.16] Total events: 42 (OCT-SA), 53 (Placebo/no treatment) Test for heterogeneity: not applicable Test for overall effect: Z = 1.15 (P = 0.25)
04 OCT-SA + ligation versus no treatment + ligation Sung 1995 5/47 11/47 5.63 0.45 [0.17, 1.21] B Subtotal (95% CI) 47 47 5.63 0.45 [0.17, 1.21] Total events: 5 (OCT-SA), 11 (Placebo/no treatment) Test for heterogeneity: not applicable Test for overall effect: Z = 1.58 (P = 0.11)
Total (95% CI) 1167 1168 100.00 0.84 [0.70, 1.01] Total events: 164 (OCT-SA), 196 (Placebo/no treatment) Test for heterogeneity: Chi² = 19.63, df = 15 (P = 0.19), I² = 23.6% Test for overall effect: Z = 1.88 (P = 0.06)
0.01 0.1 1 10 100 Favours OCT-SA Favours placebo/nt CI=confidence interval; OCT-SA=octreotide short-acting; placebo/nt=placebo or no treatment; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A4: Death with OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal Hemorrhage Comparison: 04 OCT-SA versus sclerotherapy Outcome: 01 Death
Study OCT-SA Sclerotherapy RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Bildozola 2000 9/42 3/42 15.74 3.00 [0.87, 10.31] B Lopez 1999 6/31 7/33 21.72 0.91 [0.34, 2.42] B Poo 1996 3/22 5/20 14.64 0.55 [0.15, 2.00] B Shaikh 2002 4/180 12/188 18.23 0.35 [0.11, 1.06] B Silva 2004 2/13 8/43 12.74 0.83 [0.20, 3.42] B Yousuf 2000 5/48 5/48 16.94 1.00 [0.31, 3.23] B
Total (95% CI) 336 374 100.00 0.86 [0.48, 1.52] Total events: 29 (OCT-SA), 40 (Sclerotherapy) Test for heterogeneity: Chi² = 7.02, df = 5 (P = 0.22), I² = 28.8% Test for overall effect: Z = 0.52 (P = 0.60)
0.01 0.1 1 10 100 Favours OCT-SA Favours SCL CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk; SCL=sclerotherapy
A-44 Figure A5: Death with OCT-SA versus terlipressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 02 OCT-SA versus terlipressin Outcome: 01 Death
Study OCT-SA Terlipressin RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Cho 2006 8/45 6/43 23.03 1.27 [0.48, 3.37] B Pedretti 1994 3/30 4/30 15.01 0.75 [0.18, 3.07] B Salih 2005 3/102 5/107 18.31 0.63 [0.15, 2.57] B Silvain 1993 10/46 11/41 43.65 0.81 [0.38, 1.71] B
Total (95% CI) 223 221 100.00 0.87 [0.53, 1.45] Total events: 24 (OCT-SA), 26 (Terlipressin) Test for heterogeneity: Chi² = 0.87, df = 3 (P = 0.83), I² = 0% Test for overall effect: Z = 0.52 (P = 0.61)
0.01 0.1 1 10 100 Favours OCT-SA Favours terlipressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A6: Death with OCT-SA versus vasopressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 03 OCT-SA versus vasopressin Outcome: 01 Death
Study OCT-SA Vasopressin RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Huang 1992 5/20 9/21 42.25 0.58 [0.24, 1.44] B Hwang 1992 11/24 12/24 57.75 0.92 [0.51, 1.66] B
Total (95% CI) 44 45 100.00 0.78 [0.47, 1.28] Total events: 16 (OCT-SA), 21 (Vasopressin) Test for heterogeneity: Chi² = 0.69, df = 1 (P = 0.41), I² = 0% Test for overall effect: Z = 1.00 (P = 0.32)
0.01 0.1 1 10 100 Favours OCT-SA Favours vasopressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A7: Patients who are failing initial hemostasis for OCT-SA versus placebo or no treatment
Review: Emergency Management of Variceal Hemorrhage Comparison: 01 OCT-SA versus placebo/no treatment Outcome: 03 Patients failing initial hemostasis
Study OCT-SA Placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA + sclerotherapy versus placebo/no treatment + sclerotherapy Besson 1995 3/98 15/101 12.60 0.21 [0.06, 0.69] A Farooqi 2000 3/72 11/69 9.58 0.26 [0.08, 0.90] B Freitas 2000b 8/43 16/40 14.13 0.47 [0.22, 0.97] B Morales 2007 8/40 6/28 6.02 0.93 [0.36, 2.39] B Shah 2005 5/51 13/54 10.77 0.41 [0.16, 1.06] B Signorelli 1997 7/44 12/42 10.47 0.56 [0.24, 1.28] B Silva 2004 1/36 3/43 2.33 0.40 [0.04, 3.66] B Souza 2003 19/56 32/56 27.28 0.59 [0.39, 0.91] B Zuberi 2000 2/35 5/35 4.26 0.40 [0.08, 1.93] A Subtotal (95% CI) 475 468 97.44 0.48 [0.36, 0.63] Total events: 56 (OCT-SA), 113 (Placebo/no treatment) Test for heterogeneity: Chi² = 6.05, df = 8 (P = 0.64), I² = 0% Test for overall effect: Z = 5.16 (P < 0.00001)
02 OCT-SA + ligation versus no treatment + ligation Sung 1995 2/47 3/47 2.56 0.67 [0.12, 3.81] B Subtotal (95% CI) 47 47 2.56 0.67 [0.12, 3.81] Total events: 2 (OCT-SA), 3 (Placebo/no treatment) Test for heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.65)
Total (95% CI) 522 515 100.00 0.48 [0.36, 0.63] Total events: 58 (OCT-SA), 116 (Placebo/no treatment) Test for heterogeneity: Chi² = 6.12, df = 9 (P = 0.73), I² = 0% Test for overall effect: Z = 5.16 (P < 0.00001)
0.01 0.1 1 10 100 Favours OCT-SA Favours placebo/nt CI=confidence interval; OCT-SA=octreotide short-acting; placebo/nt=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
A-45 Figure A8: Patients who are failing initial hemostasis for OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal Hemorrhage Comparison: 04 OCT-SA versus sclerotherapy Outcome: 02 Number of patients failing initial hemostasis
Study Treatment Sclerotherapy RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA versus sclerotherapy Bildozola 2000 6/39 2/37 3.98 2.85 [0.61, 13.22] B Lopez 1999 5/31 4/33 7.52 1.33 [0.39, 4.51] B Poo 1996 1/22 2/21 3.97 0.48 [0.05, 4.88] B Silva 2004 4/13 3/43 2.70 4.41 [1.13, 17.22] B Yousuf 2000 4/48 2/48 3.88 2.00 [0.38, 10.41] B Subtotal (95% CI) 153 182 22.05 1.95 [1.02, 3.73] Total events: 20 (Treatment), 13 (Sclerotherapy) Test for heterogeneity: Chi² = 3.40, df = 4 (P = 0.49), I² = 0% Test for overall effect: Z = 2.00 (P = 0.04)
02 OCT-SA + sclerotherapy (after 48-72 hours) versus placebo + sclerotherapy Freitas 2000a 10/56 7/48 14.62 1.22 [0.51, 2.97] B Jenkins 1997 13/73 20/77 37.76 0.69 [0.37, 1.28] B Sivri 2000 8/30 9/36 15.87 1.07 [0.47, 2.42] B Sung 1993 8/49 5/49 9.70 1.60 [0.56, 4.55] B Subtotal (95% CI) 208 210 77.95 0.98 [0.66, 1.45] Total events: 39 (Treatment), 41 (Sclerotherapy) Test for heterogeneity: Chi² = 2.40, df = 3 (P = 0.49), I² = 0% Test for overall effect: Z = 0.11 (P = 0.91)
Total (95% CI) 361 392 100.00 1.19 [0.85, 1.66] Total events: 59 (Treatment), 54 (Sclerotherapy) Test for heterogeneity: Chi² = 9.21, df = 8 (P = 0.32), I² = 13.2% Test for overall effect: Z = 1.03 (P = 0.30)
0.01 0.1 1 10 100 Favours OCT-SA Favours SCL CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk; SCL=sclerotherapy
Figure A9: Patients who are failing initial hemostasis for OCT-SA versus balloon tamponade
Review: Emergency Management of Variceal Hemorrhage Comparison: 05 Octreotide versus balloon tamponade Outcome: 01 Patients failing initial hemostasis
Study OCT-SA Balloon tamponade RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Kusumobroto 1994 3/21 1/18 51.85 2.57 [0.29, 22.61] B McKee 1992 2/20 1/20 48.15 2.00 [0.20, 20.33] B
Total (95% CI) 41 38 100.00 2.30 [0.47, 11.19] Total events: 5 (OCT-SA), 2 (Balloon tamponade) Test for heterogeneity: Chi² = 0.02, df = 1 (P = 0.88), I² = 0% Test for overall effect: Z = 1.03 (P = 0.30)
0.01 0.1 1 10 100 Favours OCT-SA Favours tamponade CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A10: Patients who are failing initial hemostasis for OCT-SA versus terlipressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 02 OCT-SA versus terlipressin Outcome: 02 Patients failing initial hemostasis
Study OCT-SA Terlipressin RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Cho 2006 2/45 1/43 2.85 1.91 [0.18, 20.32] B Pedretti 1994 7/30 14/30 38.97 0.50 [0.24, 1.06] B Salih 2005 1/102 3/107 8.15 0.35 [0.04, 3.31] B Silvain 1993 10/46 17/41 50.04 0.52 [0.27, 1.01] B
Total (95% CI) 223 221 100.00 0.54 [0.34, 0.87] Total events: 20 (OCT-SA), 35 (Terlipressin) Test for heterogeneity: Chi² = 1.29, df = 3 (P = 0.73), I² = 0% Test for overall effect: Z = 2.56 (P = 0.01)
0.01 0.1 1 10 100 Favours OCT-SA Favours terlipressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
A-46 Figure A11: Patients who are failing initial hemostasis for OCT-SA versus vasopressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 03 OCT-SA versus vasopressin Outcome: 02 Patients failing initial hemostasis
Study OCT-SA Vasporessin RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Huang 1992 5/20 8/21 15.35 0.66 [0.26, 1.67] B Hwang 1992 3/24 11/24 21.64 0.27 [0.09, 0.86] B Kusumobroto 1994 3/21 5/22 9.61 0.63 [0.17, 2.31] B Zhang 2002 11/73 29/83 53.40 0.43 [0.23, 0.80] B
Total (95% CI) 138 150 100.00 0.45 [0.29, 0.70] Total events: 22 (OCT-SA), 53 (Vasporessin) Test for heterogeneity: Chi² = 1.63, df = 3 (P = 0.65), I² = 0% Test for overall effect: Z = 3.55 (P = 0.0004)
0.01 0.1 1 10 100 Favours OCT-SA Favours vaspresssin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A12: Patients with rebleeding after OCT-SA versus placebo or no treatment
Review: Emergency Management of Variceal Hemorrhage Comparison: 01 OCT-SA versus placebo/no treatment Outcome: 05 Patients with rebleeding
Study OCT-SA Placebo/no treatment RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA + sclerotherapy versus placebo/no treatment + sclerotherapy Besson 1995 11/98 14/101 12.87 0.81 [0.39, 1.70] A Farooqi 2000 2/72 13/69 5.15 0.15 [0.03, 0.63] B Morales 2007 8/40 6/28 9.70 0.93 [0.36, 2.39] B Shah 2005 2/51 8/54 4.87 0.26 [0.06, 1.19] B Shaikh 2002 20/196 48/188 18.44 0.40 [0.25, 0.65] B Shiha 1996 4/93 24/96 8.74 0.17 [0.06, 0.48] B Silva 2004 3/36 8/43 6.51 0.45 [0.13, 1.56] B Souza 2003 19/56 33/56 19.82 0.58 [0.38, 0.88] B Zuberi 2000 2/35 8/35 5.01 0.25 [0.06, 1.09] A Subtotal (95% CI) 677 670 91.10 0.44 [0.30, 0.64] Total events: 71 (OCT-SA), 162 (Placebo/no treatment) Test for heterogeneity: Chi² = 13.48, df = 8 (P = 0.10), I² = 40.6% Test for overall effect: Z = 4.29 (P < 0.0001)
02 OCT-SA + ligation versus no treatment + ligation Sung 1995 4/47 18/47 8.90 0.22 [0.08, 0.61] B Subtotal (95% CI) 47 47 8.90 0.22 [0.08, 0.61] Total events: 4 (OCT-SA), 18 (Placebo/no treatment) Test for heterogeneity: not applicable Test for overall effect: Z = 2.93 (P = 0.003)
Total (95% CI) 724 717 100.00 0.41 [0.29, 0.60] Total events: 75 (OCT-SA), 180 (Placebo/no treatment) Test for heterogeneity: Chi² = 15.62, df = 9 (P = 0.08), I² = 42.4% Test for overall effect: Z = 4.74 (P < 0.00001)
0.01 0.1 1 10 100 Favours OCT-SA Favours placebo/nt CI=confidence interval; OCT-SA=octreotide short-acting; placebo/nt=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
A-47 Figure A13: Patients with rebleeding after OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal Hemorrhage Comparison: 04 OCT-SA versus sclerotherapy Outcome: 03 Patients with rebleeding
Study OCT-SA Sclerotherapy RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA versus sclerotherapy Bildozola 2000 11/39 8/37 9.02 1.30 [0.59, 2.88] B Poo 1996 2/22 3/21 3.37 0.64 [0.12, 3.44] B Shaikh 2002 24/180 48/188 51.58 0.52 [0.33, 0.82] B Silva 2004 4/13 8/43 4.08 1.65 [0.59, 4.62] B Yousuf 2000 4/48 2/48 2.20 2.00 [0.38, 10.41] B Subtotal (95% CI) 302 337 70.25 0.74 [0.53, 1.04] Total events: 45 (OCT-SA), 69 (Sclerotherapy) Test for heterogeneity: Chi² = 8.10, df = 4 (P = 0.09), I² = 50.6% Test for overall effect: Z = 1.74 (P = 0.08)
02 OCT-SA + sclerotherapy (after 48-72 hours) versus placebo/no treatment + sclerotherapy Jenkins 1997 11/73 14/77 14.97 0.83 [0.40, 1.71] B Sivri 2000 5/30 6/36 5.99 1.00 [0.34, 2.95] B Sung 1993 7/49 8/49 8.79 0.88 [0.34, 2.23] B Subtotal (95% CI) 152 162 29.75 0.88 [0.53, 1.45] Total events: 23 (OCT-SA), 28 (Sclerotherapy) Test for heterogeneity: Chi² = 0.08, df = 2 (P = 0.96), I² = 0% Test for overall effect: Z = 0.51 (P = 0.61)
Total (95% CI) 454 499 100.00 0.78 [0.59, 1.03] Total events: 68 (OCT-SA), 97 (Sclerotherapy) Test for heterogeneity: Chi² = 8.39, df = 7 (P = 0.30), I² = 16.5% Test for overall effect: Z = 1.73 (P = 0.08)
0.01 0.1 1 10 100 Favours OCT-SA Favours SCL CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk; SCL=sclerotherapy
Figure A14: Patients with rebleeding after OCT-SA versus balloon tamponade
Review: Emergency Management of Variceal Hemorrhage Comparison: 05 Octreotide versus balloon tamponade Outcome: 02 Patients with rebleeding
Study OCT-SA Balloon tamponade RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Kusumobroto 1994 4/21 2/18 35.00 1.71 [0.35, 8.29] B McKee 1992 8/20 4/20 65.00 2.00 [0.72, 5.59] B
Total (95% CI) 41 38 100.00 1.90 [0.80, 4.50] Total events: 12 (OCT-SA), 6 (Balloon tamponade) Test for heterogeneity: Chi² = 0.03, df = 1 (P = 0.87), I² = 0% Test for overall effect: Z = 1.46 (P = 0.14)
0.01 0.1 1 10 100 Favours OCT-SA Favours tamponade CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A15: Patients with rebleeding after OCT-SA versus terlipressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 02 OCT-SA versus terlipressin Outcome: 03 Patients with rebleeding
Study OCT-SA Terlipressin RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Cho 2006 11/45 12/43 49.31 0.88 [0.43, 1.77] B Pedretti 1994 2/30 2/30 11.18 1.00 [0.15, 6.64] B Silvain 1993 15/46 6/41 39.52 2.23 [0.95, 5.20] B
Total (95% CI) 121 114 100.00 1.29 [0.66, 2.51] Total events: 28 (OCT-SA), 20 (Terlipressin) Test for heterogeneity: Chi² = 2.84, df = 2 (P = 0.24), I² = 29.5% Test for overall effect: Z = 0.74 (P = 0.46)
0.01 0.1 1 10 100 Favours OCT-SA Favours terlipressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
A-48 Figure A16: Patients with rebleeding after OCT-SA versus vasopressin
Review: Emergency Management of Variceal Hemorrhage Comparison: 03 OCT-SA versus vasopressin Outcome: 03 Patients with rebleeding
Study OCT-SA Vasopressin RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Huang 1992 3/20 6/21 33.74 0.53 [0.15, 1.82] B Hwang 1992 6/24 2/24 27.29 3.00 [0.67, 13.40] B Kusumobroto 1994 4/21 7/22 38.97 0.60 [0.20, 1.75] B
Total (95% CI) 65 67 100.00 0.89 [0.33, 2.41] Total events: 13 (OCT-SA), 15 (Vasopressin) Test for heterogeneity: Chi² = 3.76, df = 2 (P = 0.15), I² = 46.8% Test for overall effect: Z = 0.23 (P = 0.82)
0.01 0.1 1 10 100 Favours OCT-SA Favours vasopressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk
Figure A17: Patients with uncontrolled bleeding who require additional treatments after OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal Hemorrhage Comparison: 04 OCT-SA versus sclerotherapy Outcome: 04 Number of patients with uncontrolled bleeding requiring additional treatments
Study OCT-SA Sclerotherapy RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA versus sclerotherapy Bildozola 2000 14/39 8/37 26.22 1.66 [0.79, 3.49] B Lopez 1999 5/31 4/33 12.37 1.33 [0.39, 4.51] B Poo 1996 1/22 2/21 6.54 0.48 [0.05, 4.88] B Subtotal (95% CI) 92 91 45.13 1.40 [0.76, 2.56] Total events: 20 (OCT-SA), 14 (Sclerotherapy) Test for heterogeneity: Chi² = 1.03, df = 2 (P = 0.60), I² = 0% Test for overall effect: Z = 1.09 (P = 0.28)
02 OCT-SA + sclerotherapy (after 48-72 hours) versus placebo/no treatment + sclerotherapy Sivri 2000 8/30 9/36 26.13 1.07 [0.47, 2.42] B Sung 1993 10/49 9/49 28.74 1.11 [0.49, 2.49] B Subtotal (95% CI) 79 85 54.87 1.09 [0.61, 1.94] Total events: 18 (OCT-SA), 18 (Sclerotherapy) Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.94), I² = 0% Test for overall effect: Z = 0.29 (P = 0.77)
Total (95% CI) 171 176 100.00 1.23 [0.81, 1.86] Total events: 38 (OCT-SA), 32 (Sclerotherapy) Test for heterogeneity: Chi² = 1.46, df = 4 (P = 0.83), I² = 0% Test for overall effect: Z = 0.97 (P = 0.33)
0.01 0.1 1 10 100 Favours OCT-SA Favours SCL CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk; SCL=sclerotherapy
Prevention of complications after pancreatic surgery
Figure A18: Hospital length of stay after OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 01 Length of hospital stay (days)
Study OCT-SA placebo/no treatment WMD (fixed) Weight WMD (fixed) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Quality
Friess 1995 122 17.25(10.31) 125 16.55(8.08) 36.59 0.70 [-1.61, 3.01] B Hesse 2005a 56 23.12(15.08) 49 20.36(8.07) 9.46 2.76 [-1.79, 7.31] B Montorsi 1995 111 19.10(9.60) 107 19.50(12.90) 21.38 -0.40 [-3.43, 2.63] B Yeo 2000 104 13.10(11.20) 107 11.90(6.20) 32.57 1.20 [-1.25, 3.65] A
Total (95% CI) 393 388 100.00 0.82 [-0.58, 2.22] Test for heterogeneity: Chi² = 1.42, df = 3 (P = 0.70), I² = 0% Test for overall effect: Z = 1.15 (P = 0.25)
-10 -5 0 5 10 Favours OCT-SA Favours placebo/nt CI=confidence interval; OCT-SA=octreotide short-acting; placebo/nt=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; SD=standard deviation; WMD=weighted mean difference
A-49 Figure A19: Post-surgical occurrence of abscess with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 02 Abscess
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Briceno Delgado 1998 0/16 3/18 10.26 0.16 [0.01, 2.87] B Buchler 1992 8/125 12/121 37.85 0.65 [0.27, 1.52] B Friess 1995 5/122 2/125 6.13 2.56 [0.51, 12.95] B Lange 1992 1/10 1/11 2.96 1.10 [0.08, 15.36] B Montorsi 1995 4/111 3/107 9.48 1.29 [0.29, 5.61] B Pederzoli 1994 3/122 6/130 18.03 0.53 [0.14, 2.08] B Yeo 2000 9/104 5/107 15.30 1.85 [0.64, 5.34] A
Total (95% CI) 610 619 100.00 0.95 [0.59, 1.54] Total events: 30 (OCT-SA), 32 (placebo/no treatment) Test for heterogeneity: Chi² = 6.07, df = 6 (P = 0.42), I² = 1.1% Test for overall effect: Z = 0.20 (P = 0.84)
0.001 0.01 0.1 1 10 100 1000 Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/ no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A20: Post-surgical occurrence of bleeding with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 05 OCT-SA versus placebo/no treatment Outcome: 06 Bleeding
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Büchler 1992 12/125 10/121 24.60 1.16 [0.52, 2.59] B Pederzoli 1994 3/122 2/130 4.69 1.60 [0.27, 9.40] A Friess 1995 7/122 4/125 9.57 1.79 [0.54, 5.97] B Montorsi 1995 8/111 9/107 22.19 0.86 [0.34, 2.14] B Briceño Delgado 1998 0/16 1/18 3.43 0.37 [0.02, 8.55] B Suc 2004 16/122 10/108 25.68 1.42 [0.67, 2.99] A Hesse 2005a 2/56 1/49 2.58 1.75 [0.16, 18.71] B Hesse 2005b 2/20 3/20 7.26 0.67 [0.12, 3.57] B
Total (95% CI) 694 678 100.00 1.19 [0.80, 1.77] Total events: 50 (OCT-SA), 40 (placebo/no treatment) Test for heterogeneity: Chi² = 2.35, df = 7 (P = 0.94), I² = 0% Test for overall effect: Z = 0.87 (P = 0.38)
0.001 0.01 0.1 1 10 100 1000 Favours OCT-SA Favours placebo/nt CI=confidence interval; OCT-SA=octreotide short-acting; placebo/nt=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A21: Post-surgical occurrence of fluid collection with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 03 Fluid Collection
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 1/7 2.43 0.24 [0.01, 5.21] B Briceno Delgado 1998 0/16 1/18 1.99 0.37 [0.02, 8.55] B Buchler 1992 8/125 9/121 12.82 0.86 [0.34, 2.16] B Friess 1995 4/122 12/125 16.62 0.34 [0.11, 1.03] B Montorsi 1995 2/111 9/107 12.85 0.21 [0.05, 0.97] B Pederzoli 1994 8/122 13/130 17.64 0.66 [0.28, 1.53] B Stratta 1993 1/13 1/12 1.46 0.92 [0.06, 13.18] B Suc 2004 18/122 23/108 34.20 0.69 [0.40, 1.21] A
Total (95% CI) 641 628 100.00 0.57 [0.40, 0.83] Total events: 41 (OCT-SA), 69 (placebo/no treatment) Test for heterogeneity: Chi² = 4.26, df = 7 (P = 0.75), I² = 0% Test for overall effect: Z = 3.00 (P = 0.003)
0.001 0.01 0.1 1 10 100 1000 Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
A-50 Figure A22: Post-surgical occurrence of infection with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 04 Infection
Study OCT-SA placebo/no treatment RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 2/7 4.77 0.15 [0.01, 2.63] B Briceno Delgado 1998 0/16 2/18 4.58 0.22 [0.01, 4.34] B Buchler 1992 3/125 6/121 15.65 0.48 [0.12, 1.89] B Friess 1995 2/122 1/125 6.68 2.05 [0.19, 22.31] B Pederzoli 1994 2/122 8/130 13.39 0.27 [0.06, 1.23] B Stratta 1993 9/13 5/12 28.26 1.66 [0.78, 3.56] B Yeo 2000 9/104 12/107 26.67 0.77 [0.34, 1.75] A
Total (95% CI) 512 520 100.00 0.72 [0.37, 1.41] Total events: 25 (OCT-SA), 36 (placebo/no treatment) Test for heterogeneity: Chi² = 9.36, df = 6 (P = 0.15), I² = 35.9% Test for overall effect: Z = 0.96 (P = 0.34)
0.001 0.01 0.1 1 10 100 1000 OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A23: Post-surgical occurrence of pancreatic fistula with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 05 Pancreatic fistula
Study OCT-SA placebo/no treatment RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Briceno Delgado 1998 0/16 5/18 1.27 0.10 [0.01, 1.70] B Buchler 1992 22/125 46/121 21.31 0.46 [0.30, 0.72] B Friess 1995 12/122 28/125 15.15 0.44 [0.23, 0.82] B Hesse 2005a 5/56 4/49 5.57 1.09 [0.31, 3.85] B Hesse 2005b 2/20 0/20 1.14 5.00 [0.26, 98.00] B Montorsi 1995 10/111 21/107 13.21 0.46 [0.23, 0.93] B Pederzoli 1994 11/122 24/130 14.07 0.49 [0.25, 0.95] B Suc 2004 21/122 20/108 17.34 0.93 [0.53, 1.62] A Yeo 2000 11/104 10/107 10.94 1.13 [0.50, 2.55] A
Total (95% CI) 798 785 100.00 0.61 [0.44, 0.84] Total events: 94 (OCT-SA), 158 (placebo/no treatment) Test for heterogeneity: Chi² = 12.25, df = 8 (P = 0.14), I² = 34.7% Test for overall effect: Z = 3.01 (P = 0.003)
0.001 0.01 0.1 1 10 100 1000 Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A24: Post-surgical occurrence of pancreatitis with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 07 Pancreatitis
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 2/7 12.39 0.15 [0.01, 2.63] B Briceno Delgado 1998 1/16 0/18 2.02 3.35 [0.15, 76.93] B Buchler 1992 0/125 4/121 19.57 0.11 [0.01, 1.98] B Friess 1995 2/122 2/125 8.46 1.02 [0.15, 7.16] B Hesse 2005b 1/20 0/20 2.14 3.00 [0.13, 69.52] B Montorsi 1995 2/111 5/107 21.79 0.39 [0.08, 1.94] B Pederzoli 1994 1/122 6/130 24.87 0.18 [0.02, 1.45] B Suc 2004 2/122 1/108 4.54 1.77 [0.16, 19.25] A Yeo 2000 3/104 1/107 4.22 3.09 [0.33, 29.20] A
Total (95% CI) 752 743 100.00 0.60 [0.31, 1.14] Total events: 12 (OCT-SA), 21 (placebo/no treatment) Test for heterogeneity: Chi² = 9.13, df = 8 (P = 0.33), I² = 12.4% Test for overall effect: Z = 1.55 (P = 0.12)
0.001 0.01 0.1 1 10 100 1000 Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
A-51 Figure A25: Post-surgical deaths with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 08 Death
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed) or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 1/7 5.48 0.24 [0.01, 5.21] B Briceno Delgado 1998 0/16 1/18 4.47 0.37 [0.02, 8.55] B Buchler 1992 4/125 7/121 22.43 0.55 [0.17, 1.84] B Friess 1995 2/122 1/125 3.11 2.05 [0.19, 22.31] B Hesse 2005a 1/56 0/49 1.68 2.63 [0.11, 63.15] B Hesse 2005b 0/20 0/20 Not estimable B Lange 1992 0/10 0/11 Not estimable B Montorsi 1995 9/111 6/107 19.26 1.45 [0.53, 3.92] B Pederzoli 1994 2/122 5/130 15.26 0.43 [0.08, 2.16] B Stratta 1993 0/13 0/12 Not estimable B Suc 2004 15/122 8/108 26.76 1.66 [0.73, 3.76] A Yeo 2000 1/104 0/107 1.55 3.09 [0.13, 74.90] A
Total (95% CI) 831 815 100.00 1.10 [0.69, 1.75] Total events: 34 (OCT-SA), 29 (placebo/no treatment) Test for heterogeneity: Chi² = 6.17, df = 8 (P = 0.63), I² = 0% Test for overall effect: Z = 0.39 (P = 0.70)
0.01 0.1 1 10 100 Favours OCT-SA Favours plac / no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A26: Post-surgical occurrence of complications with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgery Comparison: 01 OCT-SA versus placebo or no treatment Outcome: 06 Overall complication rate
Study OCT-SA placebo/no treatment RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 1/10 3/7 1.23 0.23 [0.03, 1.81] B Briceno Delgado 1998 2/16 7/18 2.44 0.32 [0.08, 1.33] B Buchler 1992 40/125 67/121 18.63 0.58 [0.43, 0.78] B Friess 1995 20/122 37/125 12.49 0.55 [0.34, 0.90] B Hesse 2005a 6/56 6/49 4.06 0.88 [0.30, 2.54] B Lange 1992 2/10 4/11 2.31 0.55 [0.13, 2.38] B Montorsi 1995 24/111 39/107 13.96 0.59 [0.38, 0.92] B Pederzoli 1994 19/122 38/130 12.25 0.53 [0.33, 0.87] B Suc 2004 35/122 40/108 15.99 0.77 [0.53, 1.12] A Yeo 2000 42/104 36/107 16.65 1.20 [0.84, 1.71] A
Total (95% CI) 798 783 100.00 0.67 [0.53, 0.84] Total events: 191 (OCT-SA), 277 (placebo/no treatment) Test for heterogeneity: Chi² = 15.95, df = 9 (P = 0.07), I² = 43.6% Test for overall effect: Z = 3.38 (P = 0.0007)
0.01 0.1 1 10 100 Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Bowel Obstruction
Figure A27: Vomiting with OCT-SA versus hyoscine butylbromide
Review: Bowel Obstruction Comparison: 01 OCT-SA versus hyoscine butylbromide Outcome: 01 Vomiting
Study OCT-SA Hyoscine WMD (fixed) Weight WMD (fixed) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Quality
Mercadante 2000 9 1.00(1.80) 6 2.40(1.70) 11.41 -1.40 [-3.20, 0.40] B Mystakidou 2002 34 0.82(1.09) 34 1.91(1.58) 88.59 -1.09 [-1.74, -0.44] B
Total (95% CI) 43 40 100.00 -1.13 [-1.73, -0.52] Test for heterogeneity: Chi² = 0.10, df = 1 (P = 0.75), I² = 0% Test for overall effect: Z = 3.63 (P = 0.0003)
-4 -2 0 2 4 Favours OCT-SA Favours hyoscine CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; SD=standard deviation; WMD=weighted mean difference
A-52 Figure A28: Severity of nausea with OCT-SA versus hyoscine butylbromide
Review: Bowel Obstruction Comparison: 01 OCT-SA versus hyoscine butylbromide Outcome: 02 Nausea
Study OCT-SA Hyoscine SMD (fixed) Weight SMD (fixed) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Quality
Mercadante 2000 9 0.50(0.60) 6 1.60(1.00) 14.75 -1.33 [-2.50, -0.16] B Mystakidou 2002 34 1.68(2.67) 34 3.85(4.02) 85.25 -0.63 [-1.12, -0.14] B
Total (95% CI) 43 40 100.00 -0.73 [-1.18, -0.28] Test for heterogeneity: Chi² = 1.17, df = 1 (P = 0.28), I² = 14.6% Test for overall effect: Z = 3.19 (P = 0.001)
-4 -2 0 2 4 Favours OCT-SA Favours hyoscine CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; SD=standard deviation; SMD=standardized mean difference
Figure A29: Severity of pain with OCT-SA versus hyoscine butylbromide
Review: Bowel Obstruction Comparison: 01 OCT-SA versus hyoscine butylbromide Outcome: 03 Pain
Study OCT-SA Hyoscine SMD (fixed) Weight SMD (fixed) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Quality
Mercadante 2000 9 0.40(0.60) 6 0.80(0.50) 16.66 -0.67 [-1.74, 0.40] B Mystakidou 2002 34 1.06(0.85) 34 1.32(0.84) 83.34 -0.30 [-0.78, 0.17] B
Total (95% CI) 43 40 100.00 -0.36 [-0.80, 0.07] Test for heterogeneity: Chi² = 0.37, df = 1 (P = 0.54), I² = 0% Test for overall effect: Z = 1.64 (P = 0.10)
-4 -2 0 2 4 Favours OCT-SA Favours hyoscine CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; SD=standard deviation; SMD=standardized mean difference
A-53 Figure A30: selection of economic evidence for review
671 citations identified from electronic search and screened
576 citations excluded
95 potentially relevant reports retrieved for scrutiny (full text, if available)
3 potentially relevant articles from other sources
98 potentially relevant reports
89 reports excluded* based on: Inappropriate study design (62) Inappropriate patient group (14) Inappropriate intervention (11) Inappropriate language (2)
9 reports of 8 studies included
*population, intervention, comparator, and cost elements reviewed simultaneously.
A-54 APPENDIX 4 : TABLES
Table A1: characteristics of trials on acromegaly Study Study design, Patients characteristics Total number Treatment arms Treatment Jadad score, funding of patients duration, allocation sources randomized, follow-up concealment withdrawals OCT-LA versus lanreotide Amato Open-label Newly diagnosed patients 23, 3 OCT-LA10-30 mg 24 months 3, unclear 2002147 RCT, parallel with active acromegaly; IM every 28 days design, mean age=55 years funding (range 40-72); 14 women lanreotide sources NR and 9 men 30 mg IM every 7-10 days
Chanson Open-label patients with acromegaly, 125, NR OCT-LA 20 mg IM 3 months 2, unclear 2000149 RCT, parallel treated with lanreotide (at once monthly design, least 3 injections prior to industry study day 1; mean lanreotide funding duration of treatment 26 30 mg IM every 10- months); mean age =47 14 days years (range 18-76); 67 women and 58 men
Jenkins Open-label patients previously 29, NR OCT-LA 10-30 mg 3 months, 3.5 1, unclear 2000148 RCT, parallel treated with surgery or IM every 4 weeks months design, radiation, with or without funding medical treatment lanreotide sources NR (octreotide or dopamine 30 mg IM every 2 agonists); age and gender weeks NR
A-55 Table A1: characteristics of trials on acromegaly Study Study design, Patients characteristics Total number Treatment arms Treatment Jadad score, funding of patients duration, allocation sources randomized, follow-up concealment withdrawals OCT-SA versus placebo or no treatment Andersen Double-blind active acromegalic 12, 0 OCT-SA 1 month, 4, unclear 1995152 RCT, patients; mean age=51.9 150-300 μg SC total follow-up crossover years (range 26-69); 5 daily dose period NR Hansen design, non- women and 7 men 1994151 industry Placebo funding Colao Open-label acromegalic patients 59, 0 OCT-SA before 3-6 months, 1, unclear 1997150 RCT, parallel undergoing neurosurgical surgery 12 months design, treatment; mean 150-600 μg SC total funding age=40.3 years (range daily dose sources NR 18-62) for treatment group and mean=40.9 No octreotide before years (range 18-66) for surgery control; 32 women and 27 men Ezzat Double-blind serum GH concentration 115, 5 OCT-SA 1 month, 2 3, unclear 1992154 RCT, parallel of >2μg/L throughout a 2 150-300 μg SC total months design, h oral glucose (100g) daily dose industry ingestion; mean funding age=47±2 (SD or SE) Placebo years for treatment group and 45±2 years for placebo; gender NR
A-56 Table A1: characteristics of trials on acromegaly Study Study design, Patients characteristics Total number Treatment arms Treatment Jadad score, funding of patients duration, allocation sources randomized, follow-up concealment withdrawals Ezzat Open-label GH>2μg/L following 69, NR OCT-SA before 4 months, 5 1, unclear 1995153 RCT, parallel oral glucose surgery months design, administration -pituitary 150-300 μg SC total industry mass of >10mm; mean daily dose funding age=46.5 years (range 21-72) for treatment and No octreotide before 45 years (range 23-74) surgery for control; gender NR
Fredstorp Double-blind patients with active 20, 0 OCT-SA 14 days, 20 3, unclear 1990155 RCT, parallel acromegaly (clinical 150-600 μg SC total days design, partial signs and symptoms, daily dose Fredstorp industry elevated GH levels, and 1993156 funding GH levels >2μg/L during Placebo Fredstorp an OGTT). Patients on 1994157 bromocriptine stopped treatment 1 month prior. Mean age=51.5 years (range 25-77); 11 women and 9 men
A-57 Table A1: characteristics of trials on acromegaly Study Study design, Patients characteristics Total number Treatment arms Treatment Jadad score, funding of patients duration, allocation sources randomized, follow-up concealment withdrawals OCT-SA versus bromocriptine Halse Open-label Patients with signs and 26, 3 OCT-SA 2 months, 2.5 3, unclear 1990158 RCT, parallel symptoms of acromegaly 300-600 μg SC total months design, partial and fasting GH level daily dose industry greater than 2μg/L which funding remained elevated during OGTT. No patients had Bromocriptine surgery during the past 6 7.5-22.5 mg PO daily months or received radiation during the past 2 years. None had hypersecretion of any pituitary hormone other than GH. Bromocriptine had been discontinued for at least 30 days. Mean age=48.4 years (range 21-67) OCT-LA versus surgery Colao Open-label previously untreated 104, NR OCT-LA 11 months 1, unclear 2006159 RCT, parallel acromegalic patients; 20-30 mg IM once (conference design, partial mean age=45 years for monthly proceeding) industry treatment group and 51 funding years for control; 60% Surgery males
GH=growth hormone; h=hour; IM=intramuscular; NR=not reported; OGTT=oral glucose tolerance test; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; PO=oral; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; SE=standard error
A-58
Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) OCT-LA versus lanreotide Amato OCT-LA NR NR At 12 At baseline: At baseline: At 12 At 12 2002147 10-30 mg IM months: 52.0±31.4 567.8±179.0 months: months: every 28 days: 31.1±16.1 mU/L ng/mL 3/8* 3/8* 11 At 24 (mean/SD) (mean/SD) At 24 At 24 months: At end- At end- months: months: 34.8±16.5 point: NR point: 4/8* 4/8* NR
lanreotide 30 At 12 At baseline: At baseline: At 12 At 12 mg IM 7-10 months: 60.2±30.6 565.7±198.7 months: months: days: 12 26.5±17.3 mU/L ng/mL 4 6 At 24 (mean/SD) (mean/SD) At 24 At 24 months: At end- At end- months: months: 30.0±17.2 point: NR point: 7 8 NR
A-59 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Chanson OCT-LA 1 during Tool: a 5-point no At baseline: At baseline: NR At 2000149 20 mg IM the first 3 verbal rating scale significant 9.9±1.3 59±3 baseline: monthly: 98 months no significant change mU/L nmol/L 42/90* (treatment change from from At end- At end- At end- group baseline baseline point: point: point: NR) 6.6±0.8 48±3 56/56* mU/L nmol/L (mean/SE) (mean/SE)
lanreotide no significant At baseline: At 30 mg IM 10- change from no 9.4±4.4 baseline: 14 days: 27 baseline significant mU/L At At baseline: 11/21* change end-point: 50±5 At end- from 8.1±3.4 nmol/L point: baseline mU/L At end- 11/21* (mean/SE) point: 49±5 nmol/L (mean/SE)
A-60 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Jenkins OCT-LA NR NR NR At baseline: At baseline: At At 2000148 10-30 mg IM 3.1-68.0 17.25-102.6 baseline: baseline: every 4 mU/L At nmol/L 5 9 weeks: 18 end-point: At end- At 4 weeks At 4 NR point: post- weeks NR treatment: post- 13 treatment: At 6 weeks 12 post- At 6 weeks treatment: post- 12 treatment: 11
lanreotide At baseline: At baseline: At At 30 mg IM 2.2-47.0 86-904 baseline: 4 baseline: 4 every 2 mU/L At ng/mL At 10 days At 10 days weeks: 11 endpoint: At endpoint: post- post- NR NR treatment: treatment: 5 8 At 2 weeks At 2 weeks post- post- treatment: treatment: 4 6 At 3 weeks At 3 weeks post- post- treatment: treatment: 3 5
A-61 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) OCT-SA versus placebo or no treatment Andersen OCT-SA: NR NR NR At baseline: Outcome 3 NR 1995152 150-300 μg 48±15 reported for Hansen SC per day mU/L 10 of 12 1994151 At end- patients at point: week 4 13±2 mU/L however the (mean/SE) number of Placebo patients in NR At baseline: each group NOTE: 48±14 was not number of mU/L reported. patients in At end- each group point: before 47±14 crossing over mU/L NR (mean/SE)
A-62 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Colao OCT-SA 0 NR NR At baseline: At baseline: 15 (after 12 (after 1997150 before surgery 71.4±15.8 518±60 surgery) surgery) 150-600 μg μg/L μg/L SC per day: At end- At end- 22 point: point: 5.5±1 μg/L 223.5±18.8 (mean/SE) μg/L (mean/SE)
1 At baseline: At baseline: 13 (after 11 (after No octreotide (occurred 76.4±15.7 693±86.8 surgery) surgery) before after μg/L μg/L surgery: 37 surgery) (mean/SE) (mean/SE) At end- At end- point: point: 35.4±122.2 351.2±224.8 μg/L (mean/ μg/L (mean/ SD)† SD)†
A-63 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Ezzat OCT-SA NR NR NR At baseline: At baseline: sub-group sub-group 1992154 150-300 μg 39±11 μg/L 5100±400 analysis at analysis at SC per day: At 2 weeks: U/L 2 weeks: 2 weeks: 60 9±2 μg/L At 2 weeks: normalized normalized (mean/SE) 2400±400 in 49% in 58% U/L [95% CI [95%CI (mean/SE) 36-62%] 44-72%] of 39 of patients patients with with initially abnormal abnormal values values At baseline: At baseline: Placebo: 55 19±4 μg/L 4900±500 placebo At 2 weeks: U/L NR 17±4 μg/L At 2 weeks: (mean/SE) 4900±500 U/L (mean/SE)
A-64 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Ezzat OCT-SA NR NR NR At baseline: At baseline: NR NR 1995153 before surgery 49±9 μg/L 6894±971 150-300 μg Prior to U/L SC per day: surgery: Prior to 34 17±4 μg/L surgery: After 2442±406 surgery: U/L After 11±6 μg/L surgery: (mean/SE) 1801±318 U/L (mean/SE)
At baseline: At baseline: No octreotide 42±14 μg/L 8813±1221 before After U/L surgery: 35 surgery: After 22±11 μg/L surgery: (mean/SE) 5188±1649 U/L (mean/SE) Fredstorp OCT-SA NR NR NR After 2 significant At At 1990155 150-600 μg weeks: GH reduction baseline: baseline: Fredstorp SC per day: significantly during (but 0 1 1993156 decreased in not after) 2 At end- At end-
A-65 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) Fredstorp 1994157
A-66 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) OCT-SA versus bromocriptine Halse OCT-SA NR Tool: composite of At baseline: At baseline: 4/12* 8/12‡ 1990158 300-600 μg 19 items scored as 13.8±5.2 3.0 ±0.4 SC per day: 0=absent/subsided, μg/L U/mL 13 1=mild, At 8 weeks: 2=moderate, 2.9±0.7 At 8 weeks: 3=severe μg/L 1.4±0.4, At baseline: 18.6 At 10 p<0.01 At 8 weeks: 10.3 weeks: (n=12) At 10 weeks: 17.0 1.25±4.4 (mean/SE) μgL (mean/SE)
At baseline: 22.4 1 patient At baseline: At baseline: 2/11* 4/11‡ Bromocriptine At 8 weeks: 15.6 showed 18.8±7.5 2.9±0.4 7.5-22.5 mg At 10 weeks: 21.0 reduction in μg/L U/mL PO daily: 13 tumour size At 8 weeks: 5.4±1.2 At 8 weeks: μg/L 2.1±0.3, At 10 p<0.01 weeks: (n=11) 13.8±4.4 (mean/SE) μg/L (mean/SE)
A-67 Table A2: Outcomes for acromegaly Study Number of Death Change in Change in Change in Change in Number Number patients in (n) symptom severity tumour GH level IGF-1 level of patients of patients each size as % attained attained treatment volume normal normal arm reduction GH IGF-1 (mean±SD) OCT-LA versus surgery Colao, OCT-LA NR NR 73% of At baseline: NR NR NR 2006159 20-30 mg IM patients had octreotide (conference monthly: NR >20% group was 2 proceeding) reduction in fold higher tumour size than surgery group. At end-point: NR Surgery: NR 95% of patients had significant tumour shrinkage *Available cases; † The mean and standard deviation were calculated from data provided by Professor Annamaria Colao, Federico II University, Naples: unpublished data, 2007; ‡ reported as somatomedin-C levels, former name for IGF-1; GH=growth hormone; IGF-1=insulin-like growth factor; IM=intramuscular; mU/L=milliunits per litre; nmol/L=nanomoles per litre; NR= not reported; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; PO=oral; SC=subcutaneous; SD=standard deviation; SE=standard error
A-68 Table A3: Withdrawals or drop-outs in acromegaly RCTs Study Sample Treatment Control size, ITT Number Reason Number Reason Amato 23, no 3 lost to follow-up: 1 0 -- 2002147 chose surgery; 2 lost to hospital control Ezzat 115, yes 3 1 left country; 1 had 2 1 had adverse events; 1 was non-compliant 1992154 headache relief and refused to enter wash-out phase; 1 had headaches Halse 26, no 1 Throat spasms and 2 1 developed hypotension after the 1st dose; 1 had a CVI on 1990158 flushing after day 5 injection CVI=cerebrovascular ischemic event; ITT=intention to treat
A-69 Table A4: Harm reported in RCTs of acromegaly Study Treatment Reported harm: Reported harm: control Duration treatment (total patients) OCT-LA versus lanreotide Jenkins 2000148 3 months Discomfort on injection, excess flatulence, diarrhea, mild abdominal pain. (n=29) OCT-SA versus placebo Ezzat, 1992154 1 month One patient discontinued NR (n=115) treatment due to headaches. 88% (53) patients had 33% (18) patients had diarrhea and nausea. diarrhea and nausea. (p<0.001) Fredstorp 14 days Abdominal discomfort Abdominal discomfort and pain, loose stools, pale stools, and diarrhea, 1990155 (n=20) and pain, loose stools, n=1 pale stools, and diarrhea, n=7, p=0.05 OCT-SA versus bromocriptine Halse 1990158 2 months One discontinued One discontinued treatment due to hypotension and one due to (n=26) treatment due to throat hemiparesis. spasms, flushing and shallow breathing. Diarrhea, loose stools, Constipation. One patient had dizziness with high-dose bromocriptine. flatulence.
NR=not reported; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
A-70
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus placebo or no treatment Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Internatio double blind Clinical OCT-SA 50 383 (194 5 d, 2,unclear nal RCT, suspicion of µg/h IV with variceal 90 d Octreotide parallel variceal bleeding), Varices design, bleeding Placebo exclusions Study industry (enrolled prior from analysis Group funded to endoscopy) not clear 1996165 (abstract) Age, sex: NR El Sayed open label acute bleeding OCT-SA 25 100, 2 d, 1, unclear 1995166 RCT, from µg/h IV NR NR (abstract) parallel esophageal design, varices Conservative funding treatment sources NR Age, sex: NR
A-71
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Number Treatment Jadad score, Notes design, characteristics randomized, duration, allocation funding withdrawals Follow-up concealment sources Besson double blind Cirrhotic OCT-SA 25 199, 0 5 d, 5, adequate 1995167 RCT, patients with µg/h IV + 15 d Silvain parallel endoscopically sclerotherapy 1995279 design, confirmed (abstract) partial active or Placebo + industry recently (<24h) sclerotherapy Besson funding bleeding varices (2% 1995280 polidocanol) (abstract) Mean age=56 years All patients: 152 men and 47 repeat women sclerotherapy day 5 to 7
A-72
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Farooqi open label Cirrhotic OCT-SA 50 141, 2 d, 1, unclear 2000169 RCT, patients with µg/h + NR NR parallel endoscopically sclerotherapy design, confirmed acute funding esophageal sclerotherapy sources NR variceal bleed (ethanolamine (<24 h in oleate) duration)
Mean age= OCT-SA 39.4, sclerotherapy 38.9 years
79 men and 62 women
A-73
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Morales open label Cirrhotic OCT-SA 50 µg 70, 2 d, 3, unclear 2007168 RCT, patients with LD then 50 2 (did not 7d parallel active or recent µg/h for 24 h meet design, no esophageal then 25 µg/h IV inclusion industry variceal for 24 h + criteria) funding bleeding sclerotherapy confirmed by endoscopy Placebo + sclerotherapy Mean age=51.8 (5% years (range 20- ethanolamine 80) oleate) 45 men and 23 women Patients underwent ligation starting at day 3 (if indicated)
A-74
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Primignan Double Patient with OCT-SA 100 58, 12 29 d, 5, adequate Not included in i 1995170 blind RCT, cirrhosis and µg 3 times per 120 d meta-analysis (interim parallel first or recurrent day SC + due to report) design, variceal sclerotherapy population funding hemorrhage characteristics sources NR (active or recent Placebo + bleed) if sclerotherapy Study results hemodynamical NS at interim De ly stable for 24 All patients: analysis so trial Franchis hours after emergency was terminated. 1992281 bleeding treatment to (abstract) stopped. achieve hemostasis in Mean age= 59 the first 24 h years (sclerotherapy, 37 men and 21 tamponade, women terlipressin or somatostatin)
Sclerotherapy on day 1, 8, 15 and 29 if varices still present
A-75
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Shah open label Adult patients OCT-SA 50 105, 0 2 d, hospital 3, unclear 2005171 RCT, with cirrhosis and µg/h + stay parallel endoscopically sclerotherapy, design, confirmed active Shah funding or recent variceal placebo + 1996282 sources NR bleeding sclerotherapy (abstract) (5% Mean age= OCT- ethanolamine SA 49.5, oleate) sclerotherapy 50 years 68 men and 37 women Shiha open label Patients with OCT-SA 25 189, NR 5 d, 1, unclear 1996172 RCT, active or recent µg/h + 7 d parallel variceal bleeding sclerotherapy design, at endoscopy funding sclerotherapy sources NR Mean age=OCT- (5% SA 48.6, ethanolamine) sclerotherapy 50.5 154 men and 35 women
A-76
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Signorelli open label Cirrhotic OCT-SA 100 94, NR 5 d, 1, unclear Data excluded 1996173 RCT, patients with µg every 8 h SC 5 d from meta- (abstract) parallel endoscopically + sclerotherapy analysis. design, confirmed acute Some patients funding esophageal somatostatin 3.5 missing from sources NR variceal µg/kg/h + results bleeding sclerotherapy because cannot Age and sex: placebo + correlate NR sclerotherapy absolute (2% numbers with polidocanol) percentages. Signorelli open label cirrhotic OCT-SA 50 µg 86, NR 5 d, 1, unclear 1997174 RCT, patients with LD, then 25 5 d (abstract) parallel acute µg/h + design, hemorrhage due sclerotherapy funding to esophageal sources NR varices Sclerotherapy (2% Age and sex: polidocanol) NR
A-77
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Souza Double Patients with OCT-SA 100 143, NR 3 d, 2, unclear 2003175 blind RCT, cirrhosis or µg LD then 50 (112 in 3 d (abstract) parallel hepatoesplenic µg/h + analysis) design, shistosomiasis sclerotherapy funding with suspected sources NR gastroesophage Placebo + al variceal sclerotherapy bleeding (2.5% (randomized ethanolamine prior to oleate) endoscopy)
Age and sex: NR
A-78
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Zuberi Double First episode of OCT-SA 50 70, NR 5 d, hospital 4, adequate 2000176 blind RCT, variceal µg/h + stay parallel bleeding from sclerotherapy design, esophageal or Zuberi 283 funding gastric Placebo + 1999 sources NR junctional sclerotherapy (abstract) varices. (ethanolamine oleate) Zuberi Excluded Child 1999284 class C patients All patients: (abstract) lansoprazole 30 Mean age= 38.4 mg daily for 14 years days 56 men and 14 women
A-79
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Abd- open label Cirrhotic OCT-SA 60, NR NR, hospital 1, unclear Data excluded Elrazek RCT, patients with infusion (dose stay from meta- 2005177 parallel bleeding varices NR) as initial analysis due (abstract) design, and impaired therapy; to population funding consciousness elective characteristics sources NR due to grade III- endoscopic IV hepatic therapy after encephalopathy. consciousness improved Age and sex: NR emergency endoscopic Data for group therapy at III not extracted presentation (patients were not randomized, n=60)
A-80
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Freitas open label Group I: OCT-SA 25 111, NR 2 d, 2, unclear 2000178 RCT, endoscopically µg/h IV 30 d parallel confirmed design, recent bleeding sclerotherapy funding from (absolute sources NR esophageal ethanol) varices All patients: Mean age=: sclerotherapy or OCT-SA 55, ligation after 48 sclerotherapy hours 56 years 76 men and 35 women Group II: OCT-SA 25 86, NR 2 d, endoscopically µg/h IV + 30 d confirmed sclerotherapy active bleeding from sclerotherapy esophageal (absolute varices ethanol)
Mean age: All patients: OCT-SA 57, sclerotherapy or sclerotherapy ligation after 48 54 years hours 65 men and 21 women
A-81
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Jenkins open label Endoscopically OCT-SA 50 150, NR 2 d, 2, unclear 1997179 RCT, confirmed µg/h + 60 d Jenkins parallel esophageal sclerotherapy 1995285 design, variceal bleed. after 48 hours (abstract) industry Jenkins funded Median age= Sclerotherapy 1992286 OCT-SA 57, (ethanolamine (abstract) sclerotherapy oleate) Shields 52 years 1993287 85 men and 66 (abstract) women
A-82
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Sivri open label Adult patients OCT-SA 50 µg 66 episodes (52 12 h, hospital 2, unclear 2000180 RCT, with active LD then 50 patients), stay parallel bleeding from µg/h + NR design, esophageal or sclerotherapy partial cardial varices after 72 hours industry at endoscopy funding Sclerotherapy Mean age= (1% OCT-SA 46, polidocanol) sclerotherapy 48 years
16 men and 36 women
A-83
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Sung open label Active or recent OCT-SA 50 µg 100, 2 2 d, 3, unclear 1993181 RCT, variceal LD then 50 30 d parallel hemorrhage at µg/h + elective design, endoscopy; age sclerotherapy industry > 16 years after 48 hours Sung funded 288 1993 Mean age= Sclerotherapy (abstract) OCT-SA 54.7, (3% sodium sclerotherapy tetradecyl 56.7 years sulphate) 83 men and 15 women
A-84
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA plus ligation versus placebo or no treatment plus ligation Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Sung open label Endoscopically OCT-SA 50 µg 100, 5 d, 2, unclear 1995182 RCT, confirmed acute LD then 50 6 excluded, 4 1 year parallel or recent µg/h IV + lost to follow- design, esophageal ligation up industry bleeding; ≥16 funded years; portal ligation hypertension. Sung 289 All patients: 1995 Mean age= repeat ligation (abstract) OCT-SA 58, at day 5 ligation 56 years 67 men and 27 women
A-85
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Bildozola open label Adult cirrhotic OCT-SA 100 84, 8 5 d, 3, unclear 2000183 RCT, patients with µg IV LD, then 5 d Kravetz parallel endoscopically 50 µg/h for 48 1996198 design, confirmed hours, then 100 (abstract) partial variceal µg every 8 industry bleeding hours SC for 72 funding hours Mean age= OCT-SA 52.6, Sclerotherapy sclerotherapy (2% 52.5 years polidocanol) 60 men and 16 women
A-86
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources El-Jackie open label Patients with OCT-SA 50 µg 100, NR 2 d, hospital 1, unclear Not included 1998184 RCT, schistosomal LD then 50 stay in meta- (abstract) parallel portal µg/h IV analysis due design, hypertension to population funding and actively sclerotherapy characteristics sources NR bleeding varices (5% at endoscopy ethanolamine oleate) Age and sex: NR Lopez Open label Cirrhotic patient OCT-SA 50 64, NR 24 h, 24 h 1, unclear 1999185 RCT, with acute µg/h IV (abstract) parallel esophageal design, variceal sclerotherapy funding bleeding (polidocanol) sources NR confirmed by endoscopy
Mean age=53 years 27 men and 37 women
A-87 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Poo open label cirrhotic OCT-SA 50 43, 1 2 d, 1, unclear 1996186 RCT, patients with µg/h IV 30 d (abstract) parallel acute design, esophageal Sclerotherapy funding variceal (1% sources NR hemorrhage polidocanol)
Age and sex: NR
A-88 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Shaikh Open label variceal OCT-SA 50 564, NR 5 d, 1, unclear Data extracted 2002187 RCT, bleeding µg/h IV for 48 30 d from abstract. (abstract parallel hours then 50 Unable to only) design, Age and sex: µg every 8 obtain full funding NR hours SC for 3 text sources NR days
OCT-SA + sclerotherapy
sclerotherapy (ethanolamine)
(Sclerotherapy on day 1, 8, 15 and 29. Not clear if all groups received therapy)
A-89
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Silva open label Cirrhotic OCT-SA 50 µg 92, NR 5 d, 1, unclear Data extracted 200499 RCT, patients with LD then 50 42 d from English parallel acute variceal µg/h + abstract and design, bleeding. sclerotherapy or some tables. funding ligation sources NR Not clear if randomized OCT-SA 50 µg before or after LD then 50 endoscopy µg/h
Mean age= sclerotherapy or OCT-SA + ligation sclerotherapy 60, OCT-SA 63, sclerotherapy 61 years 54 men and 38 women
A-90 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Yousuf open label Cirrhotic OCT-SA 50 µg 96, NR NR, 1, unclear 2000188 RCT, patients with every 6 hours 3 d parallel acute SC design, esophageal funding variceal Sclerotherapy sources NR bleeding as (sodium confirmed on tetradecyl endoscopy. sulphate)
Age=OCT-SA 46, sclerotherapy 45 years 75 men and 21 women
A-91
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus Balloon Tamponade Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources McKee open label Active bleeding OCT-SA 25 40 episodes (31 2 d, 2, unclear 1992189 RCT, from µg/h patients), 9 d parallel esophageal 0 design, varices at McKee 203 partial endoscopy Balloon 24-48 h, 9 d 1990 industry tamponade funding Mean age= OCT-SA 49.9, All patients: tamponade 51.6 sclerotherapy years after 48 hours 34 men and 6 women
A-92
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus somatostatin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Vlachogia double blind Adult patients OCT-SA 50 33, NR 5 d, 42 d 2, unclear The source of nnakos RCT, with cirrhosis µg/h IV bleeding for 2007197 parallel and acute upper one patient in design, no gastrointestinal Somatostatin each group industry bleeding 250 µg/h IV was peptic funding ulcer Median age, All patients OCT: 51, received somatostatin: 56 ligation or years sclerotherapy 27 men, 6 (ethanolamine). women Ligation was repeated every 7-10 d as indicated. Bleeding ulcers were injected with epinephrine.
A-93
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus terlipressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Cho open label Cirrhotic OCT-SA 25 88, NR 5 d, 42 d 1, unclear Data extracted 2006100 RCT, patients with µg/h IV + from English parallel acute variceal ligation abstract and design, bleeding tables only funding Terlipressin 2 3 d, 42 d Cho 199 sources NR Not clear if mg LD then 1 2006 patients mg every 4 (abstract) randomized hours IV + before or after ligation endoscopy
Age=OCT-SA 56, terlipressin 53 years 74 men and 14 women
A-94 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus terlipressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Pedretti single blind Cirrhotic OCT-SA 100 60, 0 7 d, 67 d 3, unclear 1994190 (patients) patients with µg LD then 25 RCT, active or recent µg/h IV for 24 parallel bleeding due to hours, then 100 design, no esophageal or µg three times a industry gastric varices day SC funding at endoscopy. terlipressin 2 Mean age= mg IV every 4 octreotide 64.7, hours for 24 terlipressin 66.7 hours, then 2 years mg every 6 35 men and 25 hours for 1 day, women then 1 mg every 6 hours
Salih Single blind Cirrhotic OCT-SA 100 209, NR 3 d, NR 1, unclear 2005191 RCT, patients with µg LD then 50 (abstract) parallel esophageal µg/h IV + design, no variceal ligation industry bleeding funding Terlipressin 2 Age and sex: mg LD then 1 NR mg every 6 hours IV + ligation
A-95 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus terlipressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Silvain open label Patients with OCT-SA 25 87 episodes (84 24 h, 2, unclear Study 1993192 RCT, cirrhosis and µg/h IV for 12 patients), NR 30 d terminated parallel acute variceal hours, then 100 early due to Silvain design, no bleeding at µg SC x 2 doses major adverse 1992200 industry endoscopy events in (abstract) funding (varices in terlipressin 2 terlipressin Fort esophagus or mg LD then 1 group 1991201 esophagogastric mg IV every 4 (abstract) junction) hours + Silvain transdermal 1991202 Mean age= nitroglycerin: (abstract) OCT-SA 57, 10 mg every 12 terlipressin 58 hours years 69 men and 18 women
A-96
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus vasopressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Huang open label cirrhotic OCT-SA 100 41, 0 24 h, hospital 2, unclear 1992193 RCT, patients with µg LD then 25 stay parallel active variceal µg/h IV design, bleeding at funding endoscopy Vasopressin 0.4 sources NR units/min IV mean age= OCT-SA 46.7, vasopressin 51.1 years 33 men and 8 women Hwang open label Cirrhotic OCT-SA 100 48, 0 24 h, 2, unclear 1992194 RCT, patients with µg LD then 25 42 d parallel acute variceal µg/h IV design, bleeding at partial endoscopy Vasopressin 0.4 industry units/min IV funding Mean age= OCT-SA 59, vasopressin 63 years 45 men and 3 women
A-97 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus vasopressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Kusumobr open label endoscopically OCT-SA 100 61, NR 8- 24 h, 24 h 1, unclear oto RCT, confirmed µg LD then 25 1994195 parallel bleeding µg/h IV (abstract) design, esophageal funding varices Vasopressin 0.5 sources NR units/min for age and sex: NR 20-60 min IV, every 3 to 6 hours
Balloon tamponade
A-98 Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus vasopressin Study Study Patient Treatment Number Treatment Jadad score, Notes design, characteristics arms randomized, duration, allocation funding withdrawals Follow-up concealment sources Zhang open label Endoscopically OCT-SA 1.7 224, NR 3 d, 1, unclear 2002196 RCT, confirmed acute µg/kg LD then 3 d parallel esophageal and 0.014 design, no gastric variceal µg/kg/min IV industry bleeding funding associated with Vasopressin hepatitis B 0.005 units/kg cirrhosis. LD then 0.002 units/kg/min IV Mean age=47.5 + glyceryl years trinitrate 0.35 194 men and 30 µg/kg/min IV women Somatostatin 5 µg/kg LD then 0.07 µg/kg/min IV
d = day(s); h = hour(s); IV = intravenous; LD = loading dose; NR = not reported; OCT-SA =octreotide short-acting; RCT=randomized controlled trial; SC = subcutaneous
A-99 Table A6: Outcomes for Variceal bleed OCT-SA versus placebo or no treatment Study Treatment Number Number Number Number Number of Number Length Other arms * of deaths of deaths of patients of patients patients with of blood of (n) (in (> 10 failing with uncontrolled transfusio hospital hospital days) initial rebleeding bleeding n (units)† stay or ≤ 10 hemostasis requiring (days) † days) other treatments International OCT-SA NR 42/189 NR NR 71/123 (all No NR Octreotide 50 µg/h (90 d) bleeds) difference Varices 189 56/87 in blood Study Group (variceal (variceal transfusio 1996165 bleed 87) bleed) (5 d) ns Placebo NR 53/194 NR NR 82/137 (all NR (abstract) 194 bleeds) (variceal 73/106 bleed 106) (variceal bleed), NS El Sayed OCT-SA NS NR NR NR NR NR NR Overall 1995166 25 µg/h difference control of 50 at 2 d bleeding (abstract) 90% Conservative NR NR NR NR NR NR NR 66% treatment p<0.01 50
A-100
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number Number Number of Number of Length Other arms * of of of patients of patients patients blood of (n) deaths deaths failing with with transfusion hospital (in (> 10 initial rebleeding uncontrolled (units)† stay hospital days) hemostasis bleeding (days) † or ≤ 10 requiring days)) other treatments Besson OCT-SA 7 (5 d) 12 (15 3 (24 h) 8 (5d) 11 (5 d) 1.2 (range 0- NR 1995167 25 µg/h + d) 3 (day 5- 7)(24 h) sclerotherapy 15) 98 0.4 (range 0- 5)(2-5 d) Placebo + 10 12 15 10 (5 d) 25 2.0 (range 0- NR sclerotherapy 4 (day 5- 10) (24 h, 101 15) p=0.006)
0.8 (range0- 6)(2-5 d, NS) Farooqi OCT-SA 1 NR 3 2 (10 d) NR NR NR 2000169 50 µg/h + sclerotherapy 72 sclerotherapy 6 NR 11 13 NR NR NR 69
A-101
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Numb Number Number of Number Number of Number of Length Other arms * er of of patients of patients patients with blood of (n) deaths deaths failing with uncontrolled transfusion hospital (in (> 10 initial rebleeding bleeding (units)† stay hospit days) hemostasis requiring (days) † al or ≤ other 10 treatments days) Morales OCT-SA 8/40 NR 8/40 (48 h) 8/40 NR Mean 2.05; NR 2007168 25 - 50 µg/h + (7 d) median 2 sclerotherapy 40 Placebo + 5/28 NR 6/28 6/28 NR Mean 2.08; NR sclerotherapy median 2, 30 (28 p=0.96 analyzed) Primignani OCT-SA NR 4 (15 d) NR 5 (15 d) NR NR NR 1995170 300 µg/d + 7 (30 d) 6 (30 d) sclerotherapy 10 (90 d) 8 (90 d) 26 Placebo + NR 3 (15 d) NR 7 (15 d) NR NR NR sclerotherapy 5 (30 d) 8 (30 d) 32 7 (90 d), 11 (90 d), NS NS
A-102
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of of deaths patients patients with patients with blood hospital (n) deaths (> 10 failing initial rebleeding uncontrolled transfusion stay (days) (in days) hemostasis bleeding (units)† † hospital requiring or ≤ 10 other days) treatments Shah OCT-SA 10 NR 5 (24 h) 2 (2-5 d) 2 (SCL) 3.88 ± 2.80‡ 5.31 ± 2005171 50 µg/h + 0 (surgery) 3.87‡ sclerotherapy 51 Placebo + 12 NR 13 8 8 (SCL) 5.37± 3.15‡ 6.63± sclerotherapy 2 (surgery) p=0.002 3.86‡ 54 p=0.008
A-103
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Numb Numb Number Number Number of Number of Length of Other arms * er of er of of of patients with blood hospital stay (n) deaths deaths patients patients uncontrolled transfusion (days) † (in (> 10 failing with bleeding (units)† hospit days) initial rebleedin requiring al or ≤ hemostas g other 10 is treatments days) Shiha OCT-SA 7 (7 d) NR NR 4 (7d) NR 1.14 ± 0.3‡ NR Survival 1996172 25 µg/h + (range 0-4) without sclerotherapy rebleeding (7 93 d) 89 sclerotherapy 8 NR NR 24 NR 1.40 ± 0.4‡ NR 72 96 (0-6) P<0.001
A-104
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of of deaths patients patients patients with blood hospital (n) deaths (> 10 failing with uncontrolled transfusion stay (days) (in days) initial rebleeding bleeding (units)† † hospital hemostasis requiring or ≤ 10 other days) treatments Signorelli OCT-SA 15% NR NR NR NR Median NR control of 1996173 300 µg/d + (5d) (range) bleeding (5d) sclerotherapy 3 (1-8) 75% (abstract) 31 somatostatin 13% NR NR NR NR 2 (1-6) NR 81% (NS vs. 3.5 µg/kg/h + p<0.05 vs OCT-SA) sclerotherapy octreotide, 33 <0.01 vs P Placebo + 15% NR NR NR NR 3.5 (2-12) NR 62% sclerotherapy NS p<0.01 30 versus octreotide or versus somatostatin
A-105
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of deaths of deaths patients patients patients with blood hospital (n) (in (> 10 failing with uncontrolled transfusion stay (days) hospital days) initial rebleeding bleeding (units)† † or ≤ 10 hemostasis requiring days) other treatments Signorelli OCT-SA No NR 7 (5 d) NR NR 2.28 ± 2.1** NR 1997174 25 µg/h + differenc sclerotherapy e (abstract) 44 between groups at sclerotherapy 5 d NR 12 NR NR 3.96±3.4** NR 42 p<0.01
A-106
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of deaths of deaths patients patients patients with blood hospital (n) (in (> 10 failing with uncontrolled transfusion stay (days) hospital days) initial rebleeding bleeding (units)† † or ≤ 10 hemostasis requiring days) other treatments Souza OCT-SA 10 NR 13 (6 h) 19 (3 d) NR NR NR 2003175 50 µg/h + 19 (24 h) sclerotherapy (abstract) 56 Placebo + 13 NR 17 (6 h) 33 NR NR NR sclerotherapy 32 (24 h) 56
Zuberi OCT-SA 1 (5 d) NR 2 (24 h) 2 (5 d) NR 1.5 ± 0.7 5.9 ± 1.2 2000176 50 µg/h + sclerotherapy 35 Placebo + 1 NR 5 8 NR 2.1 ± 1.2 6.6 ± 1.3 sclerotherapy p=0.03 p=0.04 35
A-107
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy (after 48-72 h) versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of deaths of deaths patients patients patients blood hospital (n) (in (> 10 failing with with transfusion stay (days) hospital days) initial rebleeding uncontrolled (units)† † or ≤ 10 hemostasis bleeding days) requiring other treatments Abd-Elrazek OCT-SA 93.3% NR NR NR NR Similar 11 ± 2.9‡ Control of 2005177 (dose NR) + (28/30) between bleeding, endoscopic (in groups 15% therapy hospital) 30 Endoscopic 70% NR NR NR NR 5 ± 2.3‡ 75% therapy (21/30) 30
A-108
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy (after 48-72 h) versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of deaths of deaths patients patients patients with blood hospital (n) (in (> 10 failing with uncontrolled transfusion stay hospital days) initial rebleeding bleeding (units)† (days) † or ≤ 10 hemostasis requiring days) other treatments Freitas 2000178 OCT-SA 2 (48 h) 13 (30 d) 10/56 (48 h) NR NR Mean 1.8 NR Hemostasis 25 µg/h (48 h) (7 d) Group I recent 58 42/53 bleeding sclerotherapy 2 8 7/48 NR NR 1.6 NS NR 38/47, NS 53 (all patients received sclerotherapy or ligation after 48 h) Freitas 2000178 OCT-SA 1 (48 h) 12 (30 d) 8/43 (48 h) NR The need for Mean 0.9 NR Hemostasis 25 µg/h + further (48 h) (7 d) Group II sclerotherapy interventions 32/43 active 44 was higher in bleeding sclerotherapy 2 13 16/40 NR the 2.9 p=0.01 NR 22/37, NS 42 sclerotherapy (all patients group (p value received NR) sclerotherapy or ligation after 48 h)
A-109
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy (after 48-72 h) versus placebo or no treatment plus sclerotherapy Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of deaths of deaths patients patients patients with blood hospital (n) (in (> 10 failing with uncontrolled transfusion stay hospital days) initial rebleeding bleeding (units)† (days) † or ≤ 10 hemostasis requiring other days) treatments Jenkins OCT-SA 2 (2 d) 22 (42 d) 13 (required 11 (48 h) NR 6.9 ± 4.4 NR Overall 1997179 50 µg/h + 8 (5 d) 23 (60 d) BT as control of sclerotherapy adjunct, bleeding after 48 h <24 h) (48 h) 73 62, 85% sclerotherapy 2 (2 d) 13 (42 d) 20 14 NR 7.5± 5.2 NR 63, 82% 77 9 (5 d) 13 (60 d) NS
Sivri 2000180 OCT-SA 1 (in NR 8 (episodes) 5 8 (episodes) 4.8± SE 2.9 NR 50 µg/h + hospital) (6 h) (episodes) sclerotherapy (72 h) after 72 h 24 (30 episodes) sclerotherapy 1 NR 9 6 9, NS 4.2 ± SE NR 28 (36 1.8, NS episodes)
A-110
Table A6: Outcomes for Variceal bleed OCT-SA plus sclerotherapy (after 48-72 h) versus placebo or no treatment plus sclerotherapy Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of deaths patients patients patients with blood hospital (n) hospital or (> 10 failing with uncontrolled transfusion stay ≤ 10 days) days) initial rebleeding bleeding (units)† (days) † hemostasis requiring other treatments Sung 1993181 OCT-SA 3 (2 d) 14 (30 d) 8 7 (48 h) 10 (48 h) Median 3.5 Median 6 50 µg/h + 10 (in [After SCL 3 (>48 h, (in hospital) (range 1- sclerotherapy hospital) or before after SCL) 31) after 48 h withdrawal 50 (49 of analyzed) endoscope (octreotide group)] Sclerotherapy 4 (2 d) 20 5 8 (48 h) 9, p=1.0 3, p=0.34 5 (range 1- 50 (49 13 (in NR (>48 h) 33), analyzed) hospital) p=0.41
A-111
Table A6: Outcomes for Variceal bleed OCT-SA + ligation versus placebo or no treatment + ligation Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of deaths patients patients patients with blood hospital (n) hospital or ≤ (> 10 failing with uncontrolled transfusion stay 10 days) days) initial rebleeding bleeding (units)† (days) † hemostasis requiring other treatments Sung OCT-SA 4 (in 5 (30 d) 2 (24 h) 4 (48 h) 1 balloon Median 3 NR 1995182 50 µg/h + hospital) tamponade (range 0-13) ligation 0 surgery 50 (47 analyzed) ligation 9 11 3 18 10 balloon Median 4 NR 50 (47 tamponade (0-23) analyzed) 2 surgery p=0.06
A-112
Table A6: Outcomes for Variceal bleed OCT-SA versus Sclerotherapy Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of deaths patients patients patients with blood hospital (n) hospital or (> 10 failing with uncontrolled transfusion stay ≤ 10 days) days) initial rebleeding bleeding (units)† (days) † hemostasis requiring other treatments
Bildozola OCT-SA 9/42 NR 6/39 8/39 (48 h) 14/39 0.7 ± 1.4 NR 2000183 50 µg/h (5 d) (12 h) 11/39 (5 d) (5d) 42 (39 analyzed) sclerotherapy 3/42 NR 2/37 7/37 (48 h) 8/37, NS 0.4 ± 1.0 NR 42 (37 8/37 (5 d) NS analyzed)
A-113
Table A6: Outcomes for Variceal bleed OCT-SA versus Sclerotherapy Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of patients patients patients with blood hospital (n) hospital or deaths failing with uncontrolled transfusion stay ≤ 10 days) (> 10 initial rebleeding bleeding (units)† (days) † days) hemostasis requiring other treatments
El-Jackie OCT-SA Child Class NR 21 (42%) Child Class NR 2.9 ± 17.9 ± 1998184 50 µg/h A/B: 3.2% (48 h) A/B: 14.3% 0.79** 9** 50 (48h) (5d) (abstract) Child Class 10% (in A/B: 9.7% hospital) C: 18/19, 94.7% sclerotherapy Child Class NR 3 (6%) Child Class NR 2.1 ±0.41** 5.12 ± 50 A/B: 0% (48 (p<0.05) A/B: 3.5% p<0.05 1.62** h, NS) (5 d, NS) p<0.05 Child Class Child C: 3.5% (in A/B: 0% 27% hospital, NS) (NS) C: 15% (p<0.01)
A-114
Table A6: Outcomes for Variceal bleed OCT-SA versus Sclerotherapy Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of patients patients patients with blood hospital (n) hospital or ≤ deaths failing with uncontrolled transfusion stay 10 days) (> 10 initial rebleeding bleeding (units)† (days) † days) hemostasis requiring other treatments Lopez OCT-SA 6 NR 5 NR 5 NR NR 1999185 50 µg/h (abstract) 31 sclerotherapy 7 NR 4 NR 4 NR NR 33
Poo 1996186 OCT-SA NR 3/22 (30 1 (48 h) 2 (3-30 d) 1 2.7 ±1.8‡ NR 50 µg/h d) (abstract) 22 sclerotherapy NR 5/20 2 3 2 3.2 ± 1.7‡ NR 21 NS
A-115
Table A6: Outcomes for Variceal bleed OCT-SA versus Sclerotherapy Study Treatment Number of Number Number of Number of Number of Number of Length of Other arms * deaths (in of patients patients patients with blood hospital (n) hospital or ≤ deaths failing with uncontrolled transfusion stay 10 days) (> 10 initial rebleeding bleeding (units)† (days) † days) hemostasis requiring other treatments Shaikh OCT-SA 50 4 NR NR 24 NR NR NR 2002187 µg/h 180 (abstract OCT-SA 50 4 NR NR 20 NR NR NR only) µg/h + sclerotherapy 196 Sclerotherapy 12 NR NR 48 NR NR NR 188 Silva 200499 OCT-SA NR 1 (42 d) 1 (24 h) 3 (5 d) NR 3.2 ± 2.3 10.9± 6.2 50 µg/h + sclerotherapy or ligation 36 OCT-SA NR 2 4 4 NR 3.4± 1.4 11.8± 7.4 13 sclerotherapy or NR 8 3 8 NR 2.8 ± 2.5 10.9± 5.8 ligation p=0.6 p=0.89 43 Yousuf OCT-SA 5 (3 d) NR 4 (12 h) 4 (3 d) NR NR NR 2000188 200 µg/d 48 sclerotherapy 5 NR 2 2 NR NR NR 48
A-116
Table A6: Outcomes for Variceal bleed OCT-SA versus Balloon Tamponade Study Treatment Number of Number of Number of Number of Number of Number of Length of Other arms * deaths (in deaths (> 10 patients patients patients with blood hospital (n) hospital or days) failing with uncontrolled transfusion stay (days) ≤ 10 days) initial rebleeding bleeding (units)† † hemostasis requiring other treatments McKee OCT-SA 0 (48 h), 0 NR 2 (4 h) 8 (48 h) 6 1710 ml ± NR 1992189 25 µg/h + (9 d) SE 252 (7 d) sclerotherapy (after 48 h) 20 (episodes) Balloon 2 (48 h), NR 1 4 5 1680 mL ± NR tamponade + 5 (9 d) SE 295, sclerotherapy p=0.47 p=0.4 (after 48 h) 20 (episodes)
A-117
Table A6: Outcomes for Variceal bleed OCT-SA versus Somatostatin Study Treatment Number Number Number of Number of Number of Number of Length of Other arms * of of patients patients patients with blood hospital (n) deaths deaths failing with uncontrolled transfusion stay (in (> 10 initial rebleeding bleeding (units)† (days) † hospital days) hemostasis requiring or ≤ 10 other days) treatments Vlachogiannakos OCT-SA 0 (5 d) 1 (42 d) NR 4 (42 d) NR Median NR Treatment 2007197† 50 µg/h (range) failure (failed 16 3.3 (0-6) hemostasis, (5 d) rebleeding or death within 5 d) 8 somatostatin 1 2, p=0.98 NR 3, p=0.688 NR 0.5 (0-4.5), NR 2, p=0.025 17 p=0.009
A-118
Table A6: Outcomes for Variceal bleed OCT-SA versus Terlipressin Study Treatment Number of Number of Number of Number of Number of Number of Length of Other arms * deaths (in deaths (> 10 patients patients patients with blood hospital (n) hospital or days) failing with uncontrolled transfusion stay (days) ≤ 10 days) initial rebleeding bleeding (units)† † hemostasis requiring other treatments Cho 2006100 OCT-SA NR 8 (42 d) 2 4 (5d) NR NR 13.1 ± 25 µg/h + 11 (42 d) 9.9** ligation 45 terlipressin NR 6 1 5 (5 d) NR NR 10.0 ± + ligation 12 (42 d) 6.8** (NS) 43
Pedretti OCT-SA 1 (7 d) 3 (67 d) 7 (24 h) 0 (7 d) 1 (balloon 1.7 ± 1.4 NR 1994190 25 µg/h 2 (67 d) tamponade) (24 h) 30 (<24 h) 7 (SCL) (>24 h) terlipressin 2 4 14 0 (7 d) 14 (SCL) (>24 1.8± 1.5, NR 30 2 (67 d) h) NS
A-119
Table A6: Outcomes for Variceal bleed OCT-SA versus Terlipressin Study Treatment Number of Number of Number of Number of Number of Number of Length of Other arms * deaths (in deaths (> 10 patients patients patients with blood hospital (n) hospital or days) failing with uncontrolled transfusion stay (days) ≤ 10 days) initial rebleeding bleeding (units)† † hemostasis requiring other treatments Salih 2005191 OCT-SA 3 NR 1 NR NR 4.0± 2.6** 5.2±2.0** 50 µg/h + (abstract) ligation 102 terlipressin + 5 NR 3 NR NR 3.7± 2.2** 4.5±1.5** ligation NS p=0.004 107 Silvain OCT-SA 3 (48 h) 10 (30 d) 10 (12 h) 10 (48 h) 8 (12 h) Mean 1 NR 1993192 25 µg/h 15 (30 d) 5 (>12-24 h) (range 0-5) 46 (episodes) 3 (>24-48 h) ( 24 h)
terlipressin + 5 11 17 5 (48 h) 12 (12 h) 3 (range 0- NR nitroglycerin 6 (30 d) 0 (>12-24) 13) 41 (episodes) 4 (>24-48 h) P=0.012
A-120
Table A6: Outcomes for Variceal bleed OCT-SA versus Vasopressin Study Treatment Number of Number of Number of Number of Number of Number of Length of Other arms * deaths (in deaths (> 10 patients patients patients with blood hospital (n) hospital or days) failing with uncontrolled transfusion stay (days) ≤ 10 days) initial rebleeding bleeding (units)† † hemostasis requiring other treatments Huang 1992193 OCT-SA 5 (in NR 5 (6 h) 3 (24 h) NR 3.4 ± 3.2 NR 25 µg/h hospital) (24 h) 20 vasopressin 9 NR 8 6 NR 5.2 ± 2.7 NR 21 P<0.05
Hwang OCT-SA 11 (in 11 (42 d) 3 (6 h) 6 (24 h) NR 615 mL ± NR 1992194 25 µg/h hospital) 472 (24 h) 24 vasopressin 11 12 11 2 NR 771 ± 909 NR 24 (NS)
Kusumobroto OCT-SA NR NR 3 (24 h) 4 NR NS NR 1994195 25 µg/h difference 21 between (abstract) groups vasopressin NR NR 5 7 NR NR 22 Balloon NR NR 1 2 NR NR tamponade 18
A-121
Table A6: Outcomes for Variceal bleed OCT-SA versus Vasopressin Study Treatment Number of Number of Number of Number of Number of Number of Length of Other arms * deaths (in deaths (> 10 patients patients patients with blood hospital (n) hospital or days) failing with uncontrolled transfusion stay (days) ≤ 10 days) initial rebleeding bleeding (units)† † hemostasis requiring other treatments Zhang 2002196 OCT-SA NR NR 11 (72 h) NR NR NR NR Bleeding 0.014 control µg/kg/min 75.3% 73 (24 h) 80.8% (48 h) vasopressin + NR NR 29 NR NR NR NR 51.8% glyceryl 59.0% trinitrate 83 somatostatin NR NR 7 NR NR NR NR 80.9% 68 86.8%
* Refer to Appendix 4 Table A2.1 for complete description of treatments † mean ± SD unless otherwise stated ‡ not clearly stated if standard deviation or standard error ** not clearly stated if mean, median, standard deviation or standard error
BT=balloon tamponade; d=day(s); kg=kilogram; min=minute; h=hour(s); NR=not reported; NS= not significant; OCT-SA= octreotide short-acting; SCL=sclerotherapy; SD=standard deviation; SE=standard error;
A-122 Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment Mean age ± Number Child Active bleeding at endoscopy arms SD, years of Class C (n/N) males/ (n/N) females OCT-SA versus placebo or no treatment Internationa OCT-SA NR NR 46/123 NR l Octreotide Varices placebo 45/137 Study Group 1996165 El Sayed OCT-SA NR NR NR NR 166 1995 Conservative treatment OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy
Besson OCT-SA + 56 (range 72/26 26/98 42/98 1995167 sclerotherapy 33-78) Placebo + 56 (range 80/21 47/101 47/101 sclerotherapy 28-79) Farooqi OCT-SA + 39.4 40/32 20/72 NR 2000169 sclerotherapy sclerotherapy 38.9 39/30 18/69 NR Morales OCT-SA + 52.2 27/13 24/40 26/40 2007168 sclerotherapy Placebo + 51.4 18/10 10/28 13/28 sclerotherapy Primignani OCT-SA + 59.1 ± 11.0 19/7 11/26 11/26 1995170 sclerotherapy Placebo + 59.2 ± 10.2 18/14 16/32 8/32 sclerotherapy Shah OCT-SA + 49.5 ± 14.2* 32/19 11/51 23/51 2005171 sclerotherapy Placebo + 50.0 ± 12.3* 36/18 14/54 24/54 sclerotherapy Shiha OCT-SA + 48.6 ± 12.5* 79/14 14/93 NR 1996172 sclerotherapy sclerotherapy 50.5 ± 11.5* 75/21 12/96 OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Signorelli OCT-SA + NR NR NR NR 1996173 sclerotherapy Somatostatin +
A-123 Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment Mean age ± Number Child Active bleeding at endoscopy arms SD, years of Class C (n/N) males/ (n/N) females sclerotherapy Placebo + sclerotherapy Signorelli OCT-SA + NR NR NR NR 1997174 sclerotherapy sclerotherapy Souza OCT-SA + NR NR NR NR 2003175 sclerotherapy Placebo + sclerotherapy Zuberi OCT-SA + 38.7 ± 7.8 NR 0 NR 2000176 sclerotherapy Placebo + 38.2 ±9.4 NR 0 NR sclerotherapy OCT-SA plus sclerotherapy (after 48 to 72 hours) versus placebo or no treatment plus sclerotherapy Abd- OCT-SA + NR NR NR NR Elrazek endoscopic 2005177 therapy Endoscopic therapy Freitas Group I: 55 40/18 20/58 0/58 2000178 OCT-SA + sclerotherapy or ligation (after 48 hours) Sclerotherapy 56 36/17 18/53 0/53 Group II: 57 34/10 14/44 44/44 OCT-SA + sclerotherapy Sclerotherapy 54 31/11 15/42 42/42 Jenkins OCT-SA + Median 57 47/27 39/73 36/73 1997179 sclerotherapy (range 36- (after 83) 48hours) sclerotherapy 52 (30-83) 38/39 41/77 49/77 Sivri OCT-SA+ 46 ± SE 7/17 13/24 30/30 (episodes) 2000180 sclerotherapy 10.4 (after 72
A-124 Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment Mean age ± Number Child Active bleeding at endoscopy arms SD, years of Class C (n/N) males/ (n/N) females hours) sclerotherapy 48 ± SE 9.4 9/19 15/28 36/36 (episodes) Sung OCT-SA + 54.7 (range 44/5 22/49 25/49 1993181 sclerotherapy 16-79) (after 48 hours) sclerotherapy 56.7 (range 39/10 21/49 18/49 30-78) OCT-SA plus ligation versus placebo or no treatment plus ligation Sung OCT-SA + 58 (range 31/16 20/47 16/47 1995182 ligation 17-77) ligation 56 (range 36/11 19/47 21/47 32-78) OCT-SA versus sclerotherapy Bildozola OCT-SA 52.6 ± 9.8 33/6 5/39 15/39 2000183 sclerotherapy 52.5 ± 10.4 27/10 3/37 18/37 El-Jackie OCT-SA NR NR 38% NR 1998184 sclerotherapy 42% Lopez OCT-SA 53 27/37 NR NR 1999185 sclerotherapy Poo 1996186 OCT-SA NR NR 10/21 5/22 sclerotherapy 10/21 8/21 Shaikh OCT-SA NR NR NR NR 2002187 OCT-SA + sclerotherapy Sclerotherapy Silva 200499 OCT-SA + 60.2 ± 10.5 20/16 8/36 NR sclerotherapy or ligation OCT-SA 63.4 ± 13.1 4/9 3/13 Sclerotherapy 61.2 ± 9.4 30/13 16/43 or ligation Yousuf OCT-SA 46 ± 9* 39/9 5/48 NR 2000188 sclerotherapy 45 ± 11 * 36/12 11/48 OCT-SA versus balloon tamponade McKee OCT-SA + 49.9 ± SE 18/2 10/20 20/20 (episodes) 1992189 sclerotherapy 3.5 (after 48 h) Balloon 51.6 ± SE 16/4 15/20 20/20 (episodes) tamponade + 3.3
A-125 Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment Mean age ± Number Child Active bleeding at endoscopy arms SD, years of Class C (n/N) males/ (n/N) females sclerotherapy (after 48 h) OCT-SA versus terlipressin Cho 2006100 OCT-SA + 56 ± 11* 38/7 15/45 16/45 ligation Terlipressin + 53 ± 11* 36/7 14/43 17/43 ligation Pedretti OCT-SA 64.7 ± 10.7 18/12 3/30 NR 1994190 Terlipressin 66.7 ± 10.6 17/13 4/30 Salih OCT-SA + NR NR NR 27/102 2005191 ligation Terlipressin + 17/107 ligation Silvain OCT-SA 57 (37-76) 35/11 21/46 46/46 (episodes) 1993192 Terlipressin + 58 (37-77) 34/7 20/41 41/41 (episodes) nitroglycerin OCT-SA versus vasopressin Huang OCT-SA 46.7 ± 12.0 14/6 12/20 20/20 1992193 vasopressin 51.1 ± 12.1 19/2 11/21 21/21 Hwang OCT-SA 59 ± 11 22/2 15/24 24/24 1992194 vasopressin 63 ± 9 23/1 11/24 24/24 Kusumobrot OCT-SA NR NR NR NR o 1994195 vasopressin balloon tamponade Zhang OCT-SA 48.0 ± 12.5 62/11 19/73 NR 2002196 Vasopressin + 46.9 ± 11.8 73/10 21/83 glyceryl trinitrate somatostatin 47.6 ± 13.2 59/9 15/68
OCT-SA versus somatostatin Vlachogian OCT-SA Median 14/2 4/16 3/16 nakos (range) 2007197 56 (38-87) somatostatin 51 (31-69) 13/4 7/17 1/17
*Not clearly reported as mean ± SD or SE; NR=not reported; OCT-SA=octreotide short-acting; SD=standard deviation; SE=standard error
A-126 Table A8: Study withdrawals or losses to follow-up: Variceal bleeding Study N, Treatment group withdrawals Control group withdrawals ITT # Reason (#) # Reason (#) OCT-SA versus placebo or no treatment Internationa 383, 102 Non-variceal bleed 88 Non-variceal bleed diagnosed at l Octreotide no diagnosed at endoscopy Varices endoscopy Study Group 1996165 Freitas 111, 2 Patients were missing 5 See treatment* 2000178 no from the outcome Group I hemostasis at 48 h. Reason for missing patients NR. Freitas 86, 1 Patients were missing 2 See treatment* 2000178 no from the outcome Group II hemostasis at 48 h. Reason for missing patients NR. Morales 70, 0 2 Entry criteria exclusion 2007168 no (hepatocellular carcinoma) Primignani 58, 3 refused treatment but 9 adverse effects (1), on medical advice 1995170 yes continued follow up (3) (3 of 4 patients continued follow (2), up) withdrew on medical lost to follow up before day 30 (3) advice (1) lost to follow up between day 30 and 90 (2) Souza 143, NR Patients were NR See treatment* 2003175 no randomized prior to endoscopy: 112 patients analyzed, data for 31 patients NR Sung 100, 1 Refused treatment 1 Bleeding source was gastric varices 1993181 no after day 1 Sung 100, 4 hepatocellular 6 hepatocellular carcinoma or bleeding 1995182 no carcinoma or gastric varices (3); lost to follow up bleeding gastric (3) varices (3); Lost to follow up (1) Not completed 1 year of follow up (7) Not completed 1 year of follow up (14)
A-127 Table A8: Study withdrawals or losses to follow-up: Variceal bleeding
OCT-SA versus sclerotherapy Bildozola 84, 3 Portal vein 5 See treatment* 2000183 no thrombosis (5), protocol violation (2), no cirrhotic liver (1)
ITT analysis possible for mortality data (1 of the 8 excluded patients died. The patient was enrolled in the OCT-SA group) Poo 1996186 43, 0 1 One patient missing from the no mortality outcome, reason NR * reason for dropouts were not separated by treatment arms ITT=intention to treat; NR=not reported; OCT-SA=octreotide short acting
A-128 Table A9: Trial characteristics for GEPNETs Study Study design, Patients characteristics Number of Treatment arms Treatment Jadad score, funding patients duration, allocation sources randomized, follow-up concealment withdrawals OCT-SA versus lanreotide O’Toole Open-label Patients with carcinoid 33, 5 OCT-SA 400-600 μg 30 days 2, unclear 2000204 RCT, tumours with symptoms, SC total daily dose Ruszniewski crossover such as diarrhea or 1992205 design, partial flushes. Patients had not lanreotide 30 mg IM (abstract) industry been treated previously every 10 days funding with somatostatin analogues or had discontinued their treatment for a sufficient time to allow the reappearance of symptoms. Age OCT- SA=63±11.1 years; lanreotide=64±10.8 years; 17 women and 16 men OCT-SA versus OCT-LA Rubin 1999206 Double-blind, Men and non-pregnant, 93, 14 OCT-SA 300-900 μg 24 weeks 2, unclear Anthony RCT, parallel non-lactating women at SC total daily dose 1999207 design, least 18 years of age industry with a diagnosis of OCT-LA 10 mg IM funding carcinoid tumour with every 4 weeks carcinoid syndrome. Symptoms of flushes OCT-LA 20 mg IM and diarrhea well every 4weeks controlled by OCT-SA SC during a 2-week OCT-LA 30 mg IM
A-129 Table A9: Trial characteristics for GEPNETs Study Study design, Patients characteristics Number of Treatment arms Treatment Jadad score, funding patients duration, allocation sources randomized, follow-up concealment withdrawals screening period, during every 4 weeks which patients received 0.3-0.9 mg OCT-SA SC daily. Symptoms must have returned during a washout period of 3-5 days. Mean age=59.5 years; 41 women and 52 men OCT-SA versus placebo Jacobsen Double-blind Histologically proven 11, 2 OCT-SA 200 μg SC 4 weeks 5, adequate 1995209 RCT, NET, at least one total daily dose crossover symptom related to the design, partial tumour disease; the Placebo industry symptoms had to funding interfere with daily activity and curtain well-being during the week preceding inclusion. Mean age=56.5 (range 30-72); six women and 5 men Saslow Double-blind Histologically proven 12, 0 OCT-SA 50 μg SC 24 hours 3, unclear 1997208 RCT, parallel metastatic carcinoid every 8 hours design, partial disease due to primary industry mid-gut tumours, funding associated diarrhea (at Placebo least 4 bowel
A-130 Table A9: Trial characteristics for GEPNETs Study Study design, Patients characteristics Number of Treatment arms Treatment Jadad score, funding patients duration, allocation sources randomized, follow-up concealment withdrawals movements per day), and intestinal resections limited to <100 cm of small bowel or ≤ 30 cm of small bowel with proximal ascending colon and ileocecal valve. Mean age=62 years (range 54-71); 5 women and 7 men IM=intramuscular; NET=neuroendocrine tumour; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; RCT=randomized controlled trial; SC=subcutaneous
A-131
Table A10: Outcomes for GEPNETs Number Change in HRQL Deaths Treatment Change in symptom Change in 5-HIAA level of patients success rates severity (mg/ 24 hour urine) in each treatment arm OCT-SA versus lanreotide O’Toole OCT-SA NR NR NR >50% decrease in At baseline: 57.4±102.2 2000204 400-600 frequency of flushes: At end-point: 32.3±82.1 Ruszniewski, μg SC per 36% (5/ 14) (mean/SD) 1992205 day: 16 >50% decrease in (abstract) frequency of stools: 86% (12/ 14)
lanreotide >50% decrease in At baseline: 94.3±124.9 30mg IM frequency of flushes: At end-point: 29.1±123.5 every 10 31% (4/ 14) (mean/SD) days: 17 >50% decrease in frequency of stools: 79% total n=24 (11/ 14) OCT-SA versus OCT-LA Rubin OCT-SA NR 0 At 20 and 24 Number of stools per day At baseline: 48.5 (12.3- 1999206 300-900 weeks: (median) 223.4) (median/range; Anthony μg SC per 59% (14/ 24) At baseline: 6 n=20) 1999207 day: 26 At end-point: 2.8 At end-point: 35.4 (0.1- Number of flushing per 240.0) (median/ range; day (median) n=21) At baseline: 4 At end-point: 0.2
OCT-LA 0 67% (12/ 18) Number of stools per day At baseline: 72.7 (5.4- 10 mg IM (median) 826.9) (median/ range;
A-132 Table A10: Outcomes for GEPNETs Number Change in HRQL Deaths Treatment Change in symptom Change in 5-HIAA level of patients success rates severity (mg/ 24 hour urine) in each treatment arm every 4 At baseline: 5.9 n=14) weeks: 22 At end-point: 3 At end-point: 68.9 (3.2- Number of flushing per 717.8) (median/ range; day (median) n=14) At baseline: 4 At end-point: 1
OCT-LA 1 71% (11/ 15)* Number of stools per day At baseline: 52.6 (3.1- 20 mg IM (median) 513.3) (median/ range; every 4 At baseline: 5.3 n=13) weeks: 20 At end-point: 2 At end-point: 24.0 (2.8- Number of flushing per 223.3) (median/ range; day (median) n=14) At baseline: 4.9 At end-point: 1.1
OCT-LA 2 61% (13/ 22)* Number of stools per day At baseline: 83.0 (10.3- 30 mg IM (median) 230.9) (median/ range; every 4 At baseline: 5.3 n=14) weeks: 25 At end-point: 2.5 At end-point: 77.2 (0.6- Number of flushing per 473.3) (median/ range; day (median) n=20) At baseline: 5.9 At end-point: 0.5
Results were Total n for stool Median 24 hours urinary similar for ITT outcome=47 5-HIAA were equally
A-133 Table A10: Outcomes for GEPNETs Number Change in HRQL Deaths Treatment Change in symptom Change in 5-HIAA level of patients success rates severity (mg/ 24 hour urine) in each treatment arm population Total n for flushing controlled by the outcome=33 different doses of OCT- LA OCT-SA versus placebo Saslow NR NR NR Tool: 10cm analogue 1997208 scale; 0=no flushing/ abdominal pain to 10=worst flushing/ abdominal pain OCT-SA At baseline: 105 (33-194) 50μg SC Flushing: 0.2±0.2 every 8 (mean/SE) hours: 6 Abdominal pain: 0.9±0.8 (mean/SE) Placebo: 6 At baseline: 171 (21-405)
Flushing: 0.9±0.2 (mean/SE) Abdominal pain: 1.5±0.5 (mean/SE) Jacobsen OCT-SA NR NR NR NR For patients who started 1995209 200μg SC with octreotide, pre- per day: nr treatment values were restored during placebo Placebo: nr treatment. *includes partial success 5HIAA=5-hydroxyindoleacetic acid; HRQL=health-related quality of life; IM=intramuscular; NR=not reported; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; SC=subcutaneous; SD=standard deviation; SE=standard error
A-134
Table A11: withdrawals or drop-outs in GEPNETs trials Study Sample Treatment Control size, Number Reason Number Reason ITT
O’Toole 33, no 2 Worsening of 3 2 worsening of symptoms; 1 transient occlusive syndrome 2000*204 symptoms Rubin 93, no† 2 2 consent of 12 (2 in 10 See treatment‡ 1999206 withdrawals; 4 mg group; 5 failed to return in 20 mg for scheduled group and 3 visit; 1 adverse in 30 mg event; 2 group) treatment failure; 1 unknown; 3 deaths; 1 NR Jacobsen 11, no 2 1 allergic 0 -- 1995209 reaction; 1 worsening of nausea *Drop-outs also reported in an abstract published in 1992 by Ruszniewski et al.205 †Authors reported that the results were similar for the ITT population but did not provide absolute numbers ‡reasons for drop-outs were not separated by treatment arms
ITT=intention-to-treat; NR=not reported
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Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study Patient characteristics Number of Treatment arms Treatment Jadad score, design, patients duration, allocation funding randomized, follow-up concealment sources withdrawals, number patients inoperable* Benedetti Open, Pancreas transplantation 17, 1, 0 OCT-SA 100 µg SC 5 days, >6 1, unclear 1998217 RCT, three times daily, months parallel, Mean age= octreotide initiated pre- (average 18 Benedetti funding not 33.5±7.2; Control 37.4±5.5 operatively months) 1998223 reported years (SD or SE) Men: 12; Women: 5 No treatment Briceño Open, Pancreaticoduodenectomy 34, 1, 0 OCT-SA100 µg SC 7 days 1, unclear Delgado, RCT, for malignancy or chronic three times daily, 1998216 parallel, pancreatitis initiated post- funding not operatively reported Age (?mean or median)= octreotide 53 (28-73); Control 52 (20-69) years No treatment Men: 25; Women 9 Büchler Double- Patients suitable for 322, 0, 76 OCT-SA100 µg SC 7 days 4, unclear 1992222 blinded, elective pancreatic three times daily, Büchler & RCT, resection because of initiated pre- Friess, 1993224 parallel, pancreatic or operatively Friess 1994225 partial periampullary tumours, or Büchler & industry chronic pancreatitis Friess, 1993226 funding Median age= octreotide 51 Placebo Büchler, (19-75); Placebo 52 (20- 1991227 80) years Men: 174; Women: 72
A-136 Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study Patient characteristics Number of Treatment arms Treatment Jadad score, design, patients duration, allocation funding randomized, follow-up concealment sources withdrawals, number patients inoperable* Friess 199526 Double- Patients with chronic 280, 0, 33 OCT-SA 100 µg SC 8 days, 90 days 4, unclear blinded, pancreatitis, suitable for three times daily RCT, pancreatic resection or initiated pre- parallel, pancreatic duct operatively partial anastomosis industry Median age= octreotide 48 funding (19-72) and placebo 47 Placebo (20-76) years Men: 194; Women: 53 Hesse 2005a212 Open label, Patients with malignant or 105, 1, 0 OCT-SA 100 µg SC 7 days 2, unclear RCT, benign tumours or three times daily parallel, pancreatitis who initiated peri- funding not underwent pancreatic operatively reported surgery and subsequent pancreatico-jejunostomy Mean age ±SD= octreotide No treatment 59.93±12.5; Control 58.98±13.7 years Men: 78; Women: 27 Hesse Open label, pancreas transplantation 40, 0,0 OCT-SA 100 SC µg, 7 days, mean 2, unclear 2005b213 RCT, Mean age= octreotide three times daily 26.5 parallel, 43.3±7.1; Control 44.1±7.9 initiated peri- months±11.3 funding not years (SD or SE not operatively reported indicated) 7 days, 25.5 Men: 28; Women: 12 months±11.1 No treatment
A-137 Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study Patient characteristics Number of Treatment arms Treatment Jadad score, design, patients duration, allocation funding randomized, follow-up concealment sources withdrawals, number patients inoperable* Lange 1992221 Double- Cancer patients scheduled 21, 2, 0 OCT-SA SC, day 1 Continued until 4, unclear blinded, for surgery for pancreatic post-operatively:50 µg 3 days after RCT, endocrinic tumour three times daily, day drain removal; parallel, 2:100 µg , three times mean days to funding not Median age= octreotide 47 daily; day 3 drain removal: reported (26-69; Placebo: 46 (23- onwards:150 µg, three octreotide:20.2 65) years times daily placebo:25.4 Men: 11; Women: 10
Placebo Montorsi Double- elective pancreatic 278, 6, 54 OCT-SA 100 µg SC 7 days, 60 days 4, unclear 1995218 blinded, resection for neoplastic or (218 considered in three times daily RCT, chronic inflammatory the analysis) initiated pre- parallel, disease of pancreas and operatively funding not periampullary region reported Age (mean±SD)= octreotide: 56.4±10.8; Placebo placebo:56.9±12.5 years Men: 131; Women 87 Pederzoli Double- elective pancreatic surgery 303, 10, 45 OCT-SA 100 µg SC 7 days 5, unclear 1994219 blinded, or drainage procedures for three times daily RCT, tumours of the pancreas or (252 considered in initiated pre- Bassi 1994230 parallel, periampullary region, or the analysis) operatively industry for chronic pancreatitis, funding Age (mean±SE)= octreotide:52.6±1.1; Placebo
A-138 Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study Patient characteristics Number of Treatment arms Treatment Jadad score, design, patients duration, allocation funding randomized, follow-up concealment sources withdrawals, number patients inoperable* placebo:53.6±1.2 years Men: 153; Women 99
Stratta, 1993220 Open, Pancreas transplantation 27, 0, 2 OCT-SA 100 µg SC 8 days±4 days, 2, unclear RCT, Mean age= octreotide twice daily post- follow-up parallel, 35.3±5.7 (SD); Control operatively (months) funding not 35.5±5.5 (SD) years octreotide:10±4; reported Men:15; Women:10 control:10±3 No treatment Suc 2004214 Single- Patients undergoing 230, 0, 0 OCT-SA 100 µg SC 10 days 3, adequate blinded, pancreaticoduodenectomy three times daily RCT, followed by anastomosis initiated peri- parallel or distal pancreatectomy, operatively design, malignant or benign Oberlin 228 funding not disease, or chronic 2000 reported pancreatitis No treatment Mean age=octreotide 56±14(SD) (16-81); Control 57±12(SD) (24- 80) years Men: 131; Women: 99 Yeo 2000215 Double Patients with malignant or 383, 40, 132 OCT-SA 250 µg SC 7 days 5, adequate blinded, benign tumour or three times daily RCT, pancreatitis who (211 considered in initiated pre- parallel, , underwent the analysis) operatively funding not pancreaticoduodenectomy
A-139 Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study Patient characteristics Number of Treatment arms Treatment Jadad score, design, patients duration, allocation funding randomized, follow-up concealment sources withdrawals, number patients inoperable* reported, with pancreatic-enteric anastomosis Placebo Mean age±SE= octreotide 63.9±1.3; Control 65.5±1.1 years Men: 111; Women: 100 *Patients were randomized prior to their surgical procedure. Once in surgery, patients were deemed inoperable if they had an unresectable lesion or because a procedure not anticipated in the protocol was required; OCT-SA=octreotide short-acting; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; SE=standard error
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment Pancreatitis Pancreatic Fluid Bleeding Infection Abscess Death Overall Length of arms, n * fistula collection † (infection complicati hospital stay † type) on rate (days) Benedetti, OCT-SA 0/10 NR 0/10 NR 0/10 NR 0/10 1/10 NR 1998217 300 µg SC per day Benedetti, N=10 1998223 No treatment 2/7 NR 1/7 NR 2/7 NR 1/7 3/7 NR N=7 (intra- abdominal infection)
A-140 Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment Pancreatitis Pancreatic Fluid Bleeding Infection Abscess Death Overall Length of arms, n * fistula collection † (infection complicati hospital stay † type) on rate (days) Briceño OCT-SA 1/16 0/16 0/16 0/16 0/16 0/16 0/16 2/16 Mean=13 Delgado 300 µg SC (range 10- 1998216 per day 17) N=16 0/18 5/18 1/18 1/18 2/18 3/18 1/18 7/18 Mean=26 No treatment ascites Abdomin (Sepsis (range 10- N=18 al n=1 or 90), SS hemorrha infected ge wound n=1) Büchler, OCT-SA 0/125 22/125 8/125 12/125 3/125 8/125 4/125 40/125 Mean= 1992222 300 µg SC 22.1±1.5 Büchler & per day (SD or SE) Friess N=125 1993224 mean= Friess Placebo 4/121 46/121 9/121 10/121 6/121 12/121 7/121 67/121 26.2±1.9 1994225 N=121 (sepsis) (SD or SE) Büchler & Friess 1993226 Büchler 1991227
A-141 Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment Pancreatitis Pancreatic Fluid Bleeding Infection Abscess Death Overall Length of arms, n * fistula collection † (infection complicati hospital stay † type) on rate (days) Friess, OCT-SA 2/122 12/122 4/122 7/122 2/122 5/122 2/122 20/122 Median 199526 300 µg SC (range): per day 14 (8-80); N=122 mean±SD‡: 17.25±10.31
Placebo 2/125 28/125 12/125 4/125 1/125 2/125 1/125 37/125 Median N=125 (sepsis) (range): 15 (7-71) mean±SD‡: 16.55±8.08 Hesse OCT-SA NR 5/56 NR 2/56 NR NR 1/56 6/56 mean±SD 2005a212 300 µg SC 23.12±15.08 per day N=56 NR 4/49 NR 1/49 NR NR 0/49 6/49 20.36±8.07 No treatment N=49 Hesse, OCT-SA 1/20 2/20 NR 2/20 NR NR 0/20 NR NR 2005b213 300 µg SC per day N=20
No treatment 0/20 0/20 NR 3/20 NR NR 0/20 NR NR N=20 Lange, OCT-SA NR NR NR NR NR 1/10 0/10 2/10 NR 1992221 150 µg to 450 µg SC per day
A-142 Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment Pancreatitis Pancreatic Fluid Bleeding Infection Abscess Death Overall Length of arms, n * fistula collection † (infection complicati hospital stay † type) on rate (days) N=10
Placebo NR NR NR NR NR 1/11 0/11 4/11 NR N=11 Montorsi. OCT-SA 2/111 10/111 2/111 8/111 NR 4/111 9/111 24/111 Mean±SD* 1995218 300 µg SC * 19.1± 9.6 per day N=111
Placebo 5/107 21/107 9/107 9/107 NR 3/107 6/107 39/107 19.5 ±12.9 N=107 Pederzoli, OCT-SA 1/122 11/122 8/122 3/122 2/122 3/122 2/122 19/122 NR 1994219 300 µg SC per day Bassi N=122 1994230 Placebo 6/130 24/130 13/130 2/130 8/130 6/130 5/130 38/130 NR N=130 (sepsis) Stratta OCT-SA NR NR 1/13 NR 9/13 NR 0/13 NR NR 1993220 200 µg SC per day N=13
No treatment NR NR 1/12 NR 5/12 NR 0/12 NR NR N=12 (major infection)
A-143 Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment Pancreatitis Pancreatic Fluid Bleeding Infection Abscess Death Overall Length of arms, n * fistula collection † (infection complicati hospital stay † type) on rate (days) Suc OCT-SA 2/122 21/122 18/122 16/122 NR NR 15/122 35/122 median 2004214 300 µg SC (range) per day 17 (7-130) N=122 Oberlin 19 (6-109), 2000228 No treatment 1/108 20/108 23/108 10/108 NR NR 8/108 40/108 NS N=108 Yeo OCT-SA 3/104 11/104 NR NR 9/104 9/104 1/104 42/104 mean±SE 2000215 750 µg SC 13.1±1.1 per day N=104
Placebo 1/107 10/107 NR NR 12/107 5/107 0/107 36/107 11.9±0.6 N=107 (wound infection) * refer to Appendix 4 Table A12 for a complete description of the treatments; † bleeding was described as: hemorrhage; abdominal hemorrhage; or intra-abdominal or digestive tract hemorrhage or both, in four reports; ‡ The mean and standard deviation were provided by Professor Helmut Friess, University of Berne, Switzerland: unpublished data, 2007; ** The mean and standard deviation were provided by Professor Marco Mortorsi, University of Milan, Milan: unpublished data, 2007; NR=not reported; NS=not significant; OCT-SA=octreotide short acting; SC=subcutaneous; SD=standard deviation; SE=standard error; SS=statistically significant
A-144 Table A14: Withdrawals in prophylaxis of complications after pancreatic surgery RCTs Study Sample Treatment Control size, ITT Number Reason Number Reason
Lange 1992221 21, yes 1 Prolonged ileus and 1 Prolonged copious nausea drain output requiring total parenteral nutrition Pederzoli, 303, no 6 patients were withdrawn due to protocol violations (treatment 1994219 group not specified) 4 patients stopped therapy early but were evaluable 230 Bassi, 1994 Of the 4 evaluable Of the 4 evaluable patients, 1 patients, 2 died and discontinued 1 had post- treatment due to operative adverse events. pancreatitis Montorsi 278, no 6 withdrawn due to protocol violations (treatment group not 1995218 reported) Yeo 2000215 383, no 40 Did not receive 0 N/A OCT-SA for at least 5 days
ITT=intention to treat; N/A=not applicable; OCT-SA=octreotide short acting
Table A15: Harms reported in RCTs for prophylaxis of complications after pancreatic surgery Study Treatment Number Pain at Gastro- Other adverse events group, n patients with injection intestinal (OCT-SA, control) adverse events, site tract Dropouts due to adverse events Buchler OCT-SA NR, 2 31 NR 2 patients with itching 1992222 125 and temporary migrant exanthema, treatment placebo NR , 1 25 NR group NR 121 Briceno OCT-SA NR, 1 14 NR cutaneous infection at Delgado 16 injection site (1, NR) 1998216 placebo NR, NR NR NR 18
A-145 Table A15: Harms reported in RCTs for prophylaxis of complications after pancreatic surgery Study Treatment Number Pain at Gastro- Other adverse events group, n patients with injection intestinal (OCT-SA, control) adverse events, site tract Dropouts due to adverse events Fresiss OCT-SA 24, NR 18 4 dysopia (1, 0), 199526 122 disturbance of coagulation (0, 1), placebo 35, NR 25 8 hyperglycemia (1, 1) 125 Hesse OCT-SA 0, 0 NR NR NR 2005b213 20
placebo NR, 0 NR NR NR 20 Lange OCT-SA NR, 1 Several 1 prolonged copious 1992221 10 drain output requiring total parenteral placebo NR, 1 NR NR nutrition (0, 1) 11 Montorsi OCT-SA 3, 0 NR 3 NR 1995218 111
placebo 3, 0 NR 3 NR 107 Pederzoli OCT-SA 4, 1 NR 1 biliary sludge (1, NR), 29936219 122 rash (1, NR)
placebo NR, NR NR NR 130 Suc 2004214 OCT-SA NR, 0 NR NR NR 122
placebo NR, 0 NR NR NR 108 Yeo 2000215 OCT-SA 0, 0 NR NR NR 104
placebo 0, 0 NR NR NR 107 NR=not reported: OCT-SA=octreotide short-acting
A-146 Table A16: Bowel obstruction study characteristics Study Study Patient Treatment Arms Number Treatment Jadad Score, Allocation Design, Characteristics Randomized, Duration, Concealment Funding Withdrawals Follow-up Sources Mercandante open Cancer patients with OCT-SA: 300 µg/day 18, 3 (patients 3 days, 2, unclear 2000232 label inoperable bowel continuous SC infusion died or data 3 days RCT, obstruction was lost; parallel Hyoscine treatment design, mean age= 66.8 years butylbromide: 60 allocation NR) funding (range 52-81) mg/day continuous SC sources 2 men and 13 women infusion NR ECOG score >2: n= 15 Setting: home care, Concurrent treatments: surgical or oncology opioids, anti- ward inflammatory agents, haloperidol, parenteral hydration Mystakidou double advanced metastatic OCT-SA: 600 - 800 68, 15 until death, 2, unclear 2002233 blind cancer with inoperable µg/day continuous SC (treatment until death RCT, bowel obstruction infusion failures at day (median parallel 6) follow up design, OCT-SA= median age Hyoscine time NR) funding 64.5 years (range 42- butylbromide: 60-80 sources 77), mg/day continuous SC NR hyoscine: median age infusion 63 years (47-74) 36 males, 32 females Concurrent treatments: ECOG score >2: n= 46 chlorpromazine, Setting: home care opioids ECOG score= Eastern Cooperative Oncology Group performance score; NR=not reported; OCT-SA=octreotide short acting; RCT-randomized controlled trial; SC=subcutaneous
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Table A17: Bowel obstruction study outcomes Study Treatment Nausea Vomiting Pain- Pain – Anorexia Drowsiness Dry mouth Arms (n) (mean±SE) (mean±SE) continuous colicky (mean±SE) (mean±SE) (mean±SE) Mercandant OCT-SA: Baseline:1.5 Baseline: 5.5 Baseline:0.6 Baseline: 0.4 NR Baseline: Baseline: 1.7 e 2000232 300 µg/day ±0.4 ± 0.9 ± 0.2 ± 0.2 1.3 ± 0.3 ± 0.2 SC (n=9) Day 3: 0.5 ± Day 3: 1.0 ± Day 3: 0.4 ± Day 3: 0.4 ± Day 3: 2.0 Day 3: 1.7 ± 0.2 0.6 0.2 0.3 ± 0.3 0.3
hyoscine: Baseline: 2.0 Baseline: 5.3 Baseline: 1.8 Baseline: 0.4 Baseline: Baseline: 1.8 60 mg/day ± 0.5 ± 0.9 ± 0.3 ± 0.3 1.8 ± 0.3 ± 0.3 SC (n=6) Day 3: 1.6 ± Day 3: 2.4 ± Day 3: 0.8 ± Day 3: 0.2 ± Day 3: 1.6 Day 3: 1.6 ± 0.4 0.7 0.2 0.2 ± 0.5 0.5
Likert scale Number of Likert scale Likert scale Likert scale Likert scale (0-3)* events per (0-3)* (0-3)* (0-3)* (0-3)* day
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Table A17: Bowel obstruction study outcomes Study Treatment Nausea Vomiting Pain- Pain – Anorexia Fatigue (n) Dry mouth Arms (n) (mean±SD) (mean±SD) continuous colicky (n) (mean±SD) Mystakidou OCT-SA: Baseline: Baseline: Baseline: NR Baseline: 28 Baseline: 18 NR 2002233 600 - 800 18.12 ± 3.79 ± 1.07 5.09 ± 1.4 Day 3: 15 Day 3: 10 µg/day SC 9.51 Day 3: 0.82 Day 3: 1.06 (n=34) Day 3: 1.68 ± 1.09 ± 0.85 ± 2.67
hyoscine: Baseline: Baseline: Baseline: Baseline: 30 Baseline: 16 60 - 80 22.5 ± 4.88 ± 1.65 5.38 ± 1.04 Day 3: 23 Day 3: 17 mg/day SC 11.78 Day 3: 1.91 Day 3: 1.32 (n=34) Day 3: 3.85 ± 1.58 ± 0.84 Number of Number of ± 4.02 patients patients Number of VAS‡ reporting reporting Intensity events per symptom symptom score x day severity as severity as duration† major major
* Likert scale (0=none, 1=slight, 2=moderate, 3=severe); † Intensity score (1=mild, 2=average,3=severe) multiplied by duration (hours per day); ‡ Scott-Huskisson VAS (0=no pain, 10=worst pain) NR=not reported; OCT-SA=octreotide short-acting; SC=subcutaneous; SD=standard deviation; SE=standard error; VAS= visual analogue scale
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Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Chemotherapy patients Cascinu Double- previous diarrhea (three OCT-SA 2 doses of 43, 0 6 h, 24 h 3, unclear 199432 blind RCT, or more loose bowel 100 µg SC parallel movements in the 24 design, hour period after a Placebo funding course of cisplatin not (CDDP). White blood reported cell count over 3,000/mm3 Median age= octreotide 61 (38-70); Placebo 60 (43-68) years Men: 23; Women 20
A-150 Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Cascinu, Single- Grade 2 (4 to 6 stools OCT-SA 100 µg 41, 0 3 days 3, unclear 199331 blinded per day or nocturnal SC twice daily (assessor) stools or moderate Cascinu, RCT, cramping) or grade 3 (7 1992241 parallel to 9 stools per day or Loperamide 4 mg (abstract) design, incontinence or severe PO initial dose then funding cramping) diarrhea as 2 mg PO four times not described in the National daily reported Cancer Institute Common Toxicity criteria. WBC count>3,000/µL Median age= octreotide 57 (46-65); Loperamide 59 (42-68) years Men 22; Women 19 Gebbia Open WHO grade 3 or 4 OCT-SA 500 µg 40, 0 If no 2, unclear 1993238 label, diarrhea after SC three times resolution RCT, chemotherapy. daily after 4 d, parallel discontinued design, Mean age= octreotide and hospitalized. funding 58; Loperamide 56 years Loperamide 4 mg If responding not Men 24; Women 16 PO three times to treatment, reported daily continued until complete resolution Geller Open patients receiving OCT-SA 150 µg IV 36, 5 Primary end- 3, unclear 1995239 label, chemotherapy for over 24 h, doubled point at 48 h.
A-151 Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals RCT, leukemia for bone every 48 h if no If major Geller parallel marrow transplant resolution; response, 1993242 design, Stool volume ≥600 mL maximum 2400 µg patient (abstract) Industry in 24 hours continued on funding Loperamide 4 mg dosage level Mean age= octreotide 48 PO four times daily until stool (30-65); Loperamide 45 was non- (26-68) years liquid for 24 Men 19; Women 17 hrs or there was no stool output for 48 h. Loperamide discontinued if no response at 48 h.
A-152 Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Nikou Open at least grade 3 diarrhea OCT-SA 100 µg 16, 0 Until 2, unclear 1994240 label, (7 to 9 stools per day; titrated to 300 µg resolution RCT, NCI toxicity criteria) SC three times (OCT-SA ≤ parallel daily 3 days, design, Mean age= octreotide treatment funding group: 59 (47-76); Loperamide, 2 mg duration not not loperamide: 62 (49-80) PO four times daily reported for reported years loperamide) Men 9; Women 7
A-153 Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals HIV-AIDS patients Garcia open-label AIDS (according to OCT-SA 100 µg 20, 0 10 days 2, unclear Compean RCT, CDC criteria) with SC three times 1994234 parallel uncontrolled diarrhea daily to a maximum design, resistant to usual doses dose of 300 µg Garcia funding of antidiarrheal three times daily on Compean not treatment for at least 4 third day 1994235 reported weeks. (abstract) Placebo SC Age (mean±SD)= injection+ octreotide 36±9 (25-54); Loperamide 2mg Control 38±10 (27-58) PO three times years daily to a maximum Men: 20; Women 0 dose of 6mg PO three times daily on day 3 + Diphenoxylate 2.5 mg PO three times daily to a max dose of 7.5mg PO three times daily on day 3
A-154 Table A18: Trial characteristics for refractory diarrhea Study Study Patient characteristics Treatment arms Total number Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Simon Double- HIV antibody-positive, OCT-SA 100 µg 129, 21 (16 21 days 5, unclear 1995236 blinded, diarrhea for more than 6 SC three times dropouts and 5 RCT, weeks despite 4 weeks daily to a maximum excluded from Simon parallel, of conventional dosing dose 300 µg SC analysis) 1994237 partial regimens of antidiarrheal three times daily (abstract) Industry agents, and for patients funding with gastrointestinal Placebo infection, continued diarrhea despite 2 weeks The mean stool of potentially curative weight in the last therapy 72 hours of the seven day period Mean age=octreotide determined whether 37.0±0.9; Placebo the dose was 37.3±1.0 years increased Men: 123; Women: 6
CDC=Centre for Disease Control; d=day(s); h=hour(s); HIV=human immunodeficiency virus; IV=intravenous; max=maximum; NCI=National Cancer Institute; OCT-SA=octreotide short- acting; PO=oral; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; WBC=white blood count; WHO=World Health Organization
A-155 Table A19: Refractory diarrhea study outcomes Study Treatment arms, n Complete or major resolution of diarrhea (n/N)
Chemotherapy patients OCT-SA versus placebo
Cascinu 199432 OCT-SA 2 doses of 100 µg SC 22/23 n=23 Placebo 5/20 n=20 OCT-SA versus loperamide Cascinu 199331 OCT-SA 100 µg SC twice daily 19/21 n=21 Loperamide 4 mg PO initial dose then 2 mg PO 3/20 four times daily n=20 Gebbia 1993238 OCT-SA 500 µg SC three times daily 19/20 n=20 Loperamide 4 mg PO three times daily 15/20 n=20 Geller 1995239 OCT-SA 150 µg IV over 24 h, doubled every 48 10/22 h if no resolution, maximum 2400 µg n=22 Loperamide 4 mg PO four times daily 12/14 n=14 Nikou 1994240 OCT-SA 100 µg to 300 µg SC three times daily 8/8 n=8 Loperamide 2 mg PO four times daily 2/8 n=8 HIV-AIDS patients OCT-SA versus placebo Simon 1995236 OCT-SA 100 to 300 µg SC three times daily 34/74 n=76
Placebo 18/50 n=53
OCT-SA versus placebo and anti-diarrheal agents Garcia Compean OCT-SA 100 to 300 µg SC three times daily 2/10 1994234 n=10 Placebo + loperamide 2 to 6 mg PO three times 0/10 daily + diphenoxylate 2.5 to 7.5 mg PO three times daily n=10
AIDS=acquired immune deficiency syndrome; HIV=human immunodeficiency virus; h= hour(s); IV=intravenous; OCT-SA=octreotide short-acting; PO=orally; SC=subcutaneous
A-156 Table A20: Withdrawals reported in refractory diarrhea RCTs Study Sampl Treatment Control e size, ITT Number Reason Number Reason Chemotherapy patients Geller 36, yes 4 Did not receive 1 Did not receive 1995239 treatment due to lost IV drug due to access, infusion pump difficulty malfunction, drug not swallowing. administered, or failure Outcomes were to quantify stool. included in ITT Outcomes were analysis included in ITT analysis HIV-AIDS patients Simon 129, no 8 adverse events (3), 13 adverse events (4), 1995236 illness deemed illness deemed unrelated to study unrelated to study medication (1), lack of medication, (3), cooperation (1), lack of cooperation protocol violation (1), (2), protocol either new/experimental violation (1), antimicrobial therapy new/experimental was initiated (3), antimicrobial exclusion criteria for therapy was study identified after initiated (3), completion of study (2) exclusion criteria for study identified after completion of study (3) AIDS=acquired immune deficiency syndrome; HIV=human immunodeficiency virus; ITT=intention to treat; IV=intravenous; RCT=randomized controlled trial
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Table A21: Harm reported in RCTs for refractory diarrhea Study Treatment Number of patients Number of patients with Duration with reported harm: reported harm: control (total treatment patients) Chemotherapy OCT-SA versus placebo Cascinu 199432 1 day No differences in incidence or severity of nausea and (n=43) vomiting. OCT-SA versus loperamide Cascinu 199331 3 days No adverse events No adverse events (n=41) Geller 1995239 2 days Abdominal cramping and No adverse events (n=36) flatulence: 1 Elevated bilirubin:2 Gebia 1993238 4 days Gastrointestinal adverse NR (n=40) events:15% Pain at injection site:15% Nikou 1994240 3 days for NR NR octreotide; NR for loperamide (n=16) HIV-AIDS OCT-SA versus placebo Simon 1995236 21 days 39/76 patients with 20/53 patients with adverse events (n=129) adverse events 4 patients discontinued therapy 3 patients discontinued due to adverse events therapy due to adverse events OCT-SA versus placebo with anti-diarrheal agents Garcia 10 days Abdominal pain:2 Abdominal pain:1 Compean (n=20) Nausea and vomiting:2 Nausea and vomiting:2 1994234 Pain at injection site:5 Pain at injection site:0 Paresthesia:1 Paresthesia:0
AIDS=acquired immune deficiency syndrome; HIV=human immunodeficiency virus NR=not reported, OCT-SA=octreotide short acting; RCT=randomized controlled trial
A-158 Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study Patients characteristics Total number Treatment arms Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals OCT-LA versus placebo Barbare 2005244 Open-label Histologically proven 266, NR OCT-LA 30 mg NR 1, unclear (conference RCT, hepatocellular carcinoma or IM every month proceeding) parallel diagnosis based on the design, association of cirrhosis, Placebo industry serum AFP>500 μg/L and funding typical imaging findings. Advanced hepatocellular carcinoma not suitable for surgery, percutaneous ablation or chemoembolization. Mean age=68 years (range 38- 87); 37 woman and 229 men Becker 2007243 Double- previously untreated patients 119, 1 OCT-LA Treated until 5, adequate blind RCT, with histologically 30 mg IM every death, Allgaier 2003290 parallel confirmed hepatocellular month followed (abstract) design, carcinoma and no indication 30.2±8.6 partial for surgery or any local months industry treatment. (median) funding Median age=67.1±8.9 (?SE or SD) years for treatment Placebo Followed group and 65.1±8.8 years for 32.5±7.5 control; 14 women and 105 months males (median)
A-159 Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study Patients characteristics Total number Treatment arms Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals OCT-LA versus no treatment Yuen 2002245 Open-label patients who were ineligible 70, NR OCT-LA 30 mg 24 weeks, 26 3, unclear RCT, for surgery or TACE, IM every month weeks parallel histological proven design, hepatocellular carcinoma or No treatment partial serum AFP of >400ng/ml industry with typical imaging funding findings of hepatocellular carcinoma by CT or hepatic angiogram, serum bilirubin <100 micromole/L, and PT <18 seconds. Median age=54.8 years (range 26.6- 78.8) for treatment and 61.7 years (range 36-78.4) for control; 5 women and 65 men OCT-LA with tamoxifen versus tamoxifen alone Verset248 Open-label Hepatocellular carcinoma 109, 10 OCT-LA 30 mg Median 3, unclear
A-160 Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study Patients characteristics Total number Treatment arms Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Verslype 2006291 RCT, not amenable to curative IM every month + number of (conference parallel resection, liver tamoxifen 20 mg octreotide proceeding) design, transplantation or local PO daily doses=2 industry treatment; KPS≥60, life (range 1-31), funding expectancy of ≥2 months. tamoxifen 20 mg followed until Median age=64.5 years PO daily death median (range 39-84) for treatment; 3 months 68 years (range 38-83) for (range 0.1-31 control; 21 women and 88 months) men OCT-SA versus no treatment Farooqi 2000247 Open-label histology proven 13, 0 OCT-SA 500 µg 6 weeks, 1, unclear RCT, hepatocellular carcinoma SC total daily 12 weeks parallel and increased levels of dose design, serum AFP. Mean age=53.1 funding years for treatment group source NR and 51.7 years for control, No treatment Followed 12 p>0.05; 4 women and 5 men weeks
A-161 Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study Patients characteristics Total number Treatment arms Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Kouroumalis Open-label liver biopsy diagnosis of 58, 4 OCT-SA 500 µg Treated until 3, unclear 1998246 RCT, hepatocellular carcinoma SC total daily patient parallel and/or increased levels of dose withdrawal or design, AFP >500ng/L with death, funding compatible liver ultrasound, followed source NR CT scan, or hepatic 14.1±2.17 angiography. months Median age=69 years (range (mean/SE) 53-84) for treatment group and 68 years (range 52-87) No treatment Followed for control; 10 women and 6.6±1.36 48 men months (mean/SE) OCT-SA and OCT-LA versus placebo Dimitroulopoulos Double- patients with cirrhosis (stage 61, 7 OCT-SA 0.5 mg Treatment 3, unclear 2007249 blind RCT, A-B) due to hepatitis B or C SC every 8 hours duration until Dimitroulopoulos parallel and advanced hepatocellular for 6 weeks, then patient 2004292 (abstract) design, carcinoma. Those with OCT-LA IM 20 withdrawal or
A-162 Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study Patients characteristics Total number Treatment arms Treatment Jadad score, design, of patients duration, allocation funding randomized, follow-up concealment sources withdrawals Dimitroulopoulos funding intense uptake of mg at the end of death, 2005293 source NR radionuclear compound week 4 and 8, and followed 3 (conference (111-Indium labelled OCT-LA 30 mg years proceeding) octreotide) were IM at the end of randomized. week 12 and Mean age = 69.4±6.3 (SE) every 4 weeks years for treatment group thereafter. For the and 69.5±5.6 years for period between control; week 4 and 6, 18 women and 43 men OCT-SA 0.5 mg SC was given every 8 hours.
Placebo, oral AFP= alpha-fetoprotein; CT=computed tomography; IM=intramuscular; KPS= Karnofsky performance status; NR= not reported; OCT-LA=octreotide long acting; OCT-SA=octreotide short-acting; PO=oral; PT=prothrombin time; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; SE=standard error; TACE=transcatheter arterial chemoembolization
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Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) OCT-LA versus placebo Barbare OCT-LA NR 6.5 (range 4.7- NR NR NR NR 2005244 30 mg IM 7.0) (conference every proceeding) month: 134
placebo: 7.3 (range 5.5- 132 8.6)
A-164 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) Becker OCT-LA 54 4.7 Tool: EORTC QLQ- At baseline: NR At baseline: 2007243 30 mg IM C30 7.6±3.5 cm 49% of patients every p=NS (mean/SD) had <400ng/mL Allgaier month: 60 At end-point: At end-point: 2003290 Tumour regression NR (abstract) did not occur in any patient.
placebo: 59 52 5.3 p=NS At baseline: At baseline: 7.4±4.0 cm 61% of patients RR=1.1 [95%CI: (mean/SD) had <400ng/mL 0.76-1.63], At end-point: At end-point: Tumour regression NR p=0.59 did not occur in any patient.
For stable or progressive disease: no significant difference on tumour growth or response between groups
A-165 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) OCT-LA versus no treatment Yuen OCT-LA 32 1.93 Tool: KPS NR At 14 weeks: At baseline: 2002245 30 mg IM no improvement 1 static median=19,177 every disease; 6 ng/mL (range 2- month: 35 tumour 864,030) progression At endpoint: median=41,897 ng/mL (range 3- 73,707)
No 33 1.97 no improvement 1 tumour At baseline: treatment: regression; 2 median= 35 static disease; 721 ng/mL 5 tumour (range 1- progression 475,271) At end-point: NR
No significant difference in % of patients with AFP reduction between groups. OCT-LA with tamoxifen versus tamoxifen alone Verset248 OCT-LA 55 median 3 At 3 months: NR At 3 months: At 3 months:
A-166 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) Verslype 30 mg IM (95%CI: 1.4-4.5) Median KPS=80 tumour increase>25%: 2006291 every (95%CI: 40-100), progression: 10/18 (conference month + n=25 13/ 20 proceeding) tamoxifen
A-167 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months)
A-168 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) OCT-SA versus no treatment Farooqi NR NR Tool: appetite, pain NR 2000247 in right hypochondrium, body weight, and feeling of well-being
OCT-SA appetite became At baseline: At baseline: 500 µg SC normal: 5; pain in 7.8±1.9 cm 220±17 ng/mL per day: 6 right hypochondrium (mean/SD) (mean/SD) disappeared: 4; At 3 months: At 3 months: Feeling of well- 11.4±1.4 cm 60±21 ng/mL being returned: 4 (mean/SD) (mean/SD)
no appetite: 0; pain in At baseline: At baseline: treatment: 7 right hypochondrium 7.6±1.6 cm 206±14 ng/mL disappeared: 1; (mean/SD) (mean/SD) feeling of well-being At 3 months: At 3 months: returned: 0 19±1.2 cm 1054±21 ng/mL (mean/SD) (mean/SD)
A-169 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) Kouroumal Tool: Appetite, body NR is 1998246 weight, and the general feeling of well being were used as criteria
OCT-SA At 6 13.0±1.90 (SE) improvement in At baseline: tumour 500 µg SC months (95%CI: 9.3- feeling of well 3 small, 5 medium, progression: per day: 28 :7 16.7) being:15 (53.6%); 11 large, 9 multiple 19 At 12 increase in tumours months appetite:24 (85.7%); At 6-12 months: :12 improvement in small tumours body weight:12 disappeared in 5 (42.8%) patients; size in 4 patients remained unchanged; size in all other patients increased gradually No At 6 4.0±1.10 (SE) no difference tumour treatment: months (95%CI: 1.9- At baseline: progression: 30 :19 6.2) 1 small, 6 medium, 30 At 12 10 large, 13 months multiple tumours. : 26 The tumour size gradually increased.
A-170 Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of Death Survival time Change in HRQL Change in tumour Tumour Change in AFP patients in (n) since from baseline size response level each randomization rates treatment (median in arm months) OCT-SA and OCT-LA versus placebo Dimitroulo OCT-SA All 12.3 Tool: QLQ-C30 NR NR At baseline: poulos 1.5 mg SC patient (interquartile At 12 months: 2714±5049 2007249 per day for s had range 7.0-18.0) 22% decrease in (units NR) Dimitroulo 6 weeks, died at score At end-point: poulos then OCT- the end NR 2004292 LA IM 20 of the (abstract) to 30 mg at follow- Dimitroulo week 4 and up poulos every 4 period 2005293 weeks: 31 except (conference one proceeding) (octreo Placebo: 30 tide) 7.0 (interquartile 39% decrease in At baseline: that range 4.8-8.5) score 3096±4500 died 4 (units NR) weeks At end-point: later NR AFP=α fetoprotein; CI=confidence interval; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HRQL= health-related quality of life; IM=intramuscular; KPS= Karnofsky performance status scale; OCT-LA=octreotide long acting; OCT-SA=octreotide short-acting; NR= not reported; NS=not significant; RCT=randomized controlled trial; RR=relative risk; SC=subcutaneous; SD= standard deviation; SE=standard error
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Table A24: Withdrawals or drop-outs in hepatocellular carcinoma RCTs Study Sample treatment control size, Number Reason Number Reason ITT Becker 119, yes 1 Lost to follow-up 0 -- 2007243 Verset248 109, yes 6 4 lost to follow-up; 1 4 2 lost to follow-up; 1 received a transplant; 1 suffered an adverse event; suffered an adverse 1 had transarterial event chemoembolization Kouroum 58, yes 4 NR 0 -- alis 1998246 Dimitroul 61, yes 7 6 had diarrhea; 1 0 -- opoulos refused treatment 2007249 ITT=intention to treat; NR=not reported; RCT=randomized controlled trial
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Table A25: Harm reported in RCTs for hepatocellular carcinoma Study Treatment Reported harm: Reported harm: control Duration (total treatment patients) OCT-LA versus placebo Barbare 2005244 NR (266) 0.7% (1/134) NR hypoglycemia Becker 2007243 30 months (119) 16/60 serious adverse 25/59 serious adverse events events* 7/59 diarrhea 13/60 diarrhea* 3/59 hyperbilirubinemia 3/60 hyperbilirubinemia OCT-LA versus no treatment Yuen 2002245 24 weeks (70) No significant adverse NR events observed OCT-LA with tamoxifen versus tamoxifen alone Verset248 2 months (109) 1/56 discontinued 3/53 discontinued treatment treatment due to due to adverse events diarrhea* (digestive n=1; flush n=1; gynecomastia n=1) OCT-SA versus no treatment Farooqui 2000247 6 weeks (13) 33% (2/6) diarrhea NR Kouroumalis Until death or 40% (11/28) diarrhea NR 1998246 withdrawal (58) *not significant compared to control group NR=not reported, OCT-LA=octreotide long acting, OCT-SA=octreotide short-acting; RCT=randomized controlled trial
A-173 Table A26: Pancreatic cancer study characteristics Study Study design, Patient Number of Treatment arms Treatment Jadad score, funding Characteristics patients duration, allocation sources randomized, follow-up concealment withdrawals Cascinu RCT, parallel, Advanced 107 (32 with OCT-SA 200 µg SC until disease 3, inadequate 199548 open label, gastrointestinal cancer pancreatic three times per day, 5 progression, funding refractory to cancer), days per week unacceptable sources NR chemotherapy, <75 withdrawals toxicity or years of age, ECOG NR no treatment patient refusal performance status of 0- (mean 2, measurable disease treatment Median age=octreotide duration 12 68 (range 39-71) weeks, range Control 66 (44-72) 6 - 32) years Men: 65; Women: 42 Maurer RCT, parallel, Unresectable stage 2, 3 190, 5 OCT-LA 160 mg IM NR 2, unclear 1998252 double blind, or 4 pancreatic cancer monthly (abstract) partial industry Age and sex: NR Placebo Salvia 1998253 funding (abstract)
Pederzoli 1998255
A-174 Table A26: Pancreatic cancer study characteristics Study Study design, Patient Number of Treatment arms Treatment Jadad score, funding Characteristics patients duration, allocation sources randomized, follow-up concealment withdrawals Schlag RCT, parallel, Unresectable stage 3 284, 3 OCT-LA, 160 mg NR 2, unclear 1998254 double blind, and 4 pancreatic cancer dosing interval NR (5-FU was (abstract) partial administered industry Age and sex: NR Placebo for 8 weeks; Roy 1998256 funding length of (abstract) All patients: 5-FU 225 octreotide mg/m2/d IV for 8 treatment NR) weeks, then one week rest. Burch 200045 RCT, parallel Locally unresectable, 96, 12 OCT -SA 200 µg or NR, 2 years 2, unclear open label, no residual, recurrent or 500 µg SC three times industry metastatic ductal per day funding adenocarcinoma of the pancreas; ECOG status 5-FU 500 mg/m2 IV for of 0-1; 5 days, repeated every 5 weeks Median age= octreotide 65 (range 46-83); 5-FU 5-FU 425 mg/m2 IV 61 (37-72); 5-FU+LV plus leucovorin 20 64 (28-83) years mg/m2 for 5 days, Men:64; Women: 30 repeated every 5 weeks 5-FU=5-Fluorouracil; ECOG=Eastern Cooperative Oncology Group; IV=intravenous; LV=leucovorin; NR=not reported; OCT-SA=octreotide short-acting; OCT-LA = octreotide long-acting; RCT=randomized controlled trial; SC=subcutaneous
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Table A27: Pancreatic cancer study outcomes Median survival Median time to Study Treatment Arms, N Tumour response Comments time (weeks) progression Burch 200045 OCT-SA 200 µg or 13.4 NR 42 days The results of 500 µg SC, three both 5-FU groups times per day; were combined 42 (41 analyzed) (200 µg n=12, 500 study was µg n=30) terminated early based on the 5-FU 500 mg/m2 IV; 27.9 105 days, p=0.01 * results of this 27 (21 analyzed) interim analysis Overall survival 5-FU 425 mg/m2 IV p=0.80 plus leucovorin 20 mg/m2 for 5 days; 27 (22 analyzed) Cascinu OCT-SA 200 µg SC, 16 0 objective responses 2 months 107 cancer 199548 three times per day; patients were 16 randomized, 32 of them with No treatment; 8 2 months pancreatic cancer 16 Maurer OCT-LA, 160 mg 16.0 [95%CI 12.4, 0 objective responses NR Interim analysis 1998252 IM monthly; 20.4] 93 Salvia 1998253 Placebo; 16.9 [95%CI 12.4, Pederzoli 92 20.4] 1998255 p=0.744
A-176 Table A27: Pancreatic cancer study outcomes Median survival Median time to Study Treatment Arms, N Tumour response Comments time (weeks) progression Schlag 1998254 OCT-LA, 160 mg + 22.6 [95%CI 18.1, 1 complete, 1 partial NR Interim analysis 5-FU 27.7] remission Roy 1998256 Placebo + 5-FU 21.6 [95%CI 17.9, 1 partial remission 28.3] 284 randomized (number per p=0.649 treatment arm NR) *Time to progression considered appearance of new areas of disease; decrease of >1 level on Eastern Cooperative Oncology Group (ECOG) performance scale, development of new jaundice or ascites, definite increase in areas of existing disease, or >25% increase in measurements of indicator lesions.
5-FU= 5-fluouracil; CI=confidence interval; IV-intravenous; NR=not reported; OCT-SA=octreotide short-acting; OCT-LA= octreotide long-acting; SC=subcutaneous
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Table A28: Harm reported in RCTs for pancreatic cancer Study, Treatment Adverse Event Treatment Control arms, N Burch 200045* Diarrhea 2% 16% OCT-SA versus 5- Nausea 2% 14% FU ± leucovorin Vomiting 0% 9% N=96 Stomatitis 0% 14% Leukopenia 0% 25% Cascinu 199548† Asymptomatic 20/55 NR OCT-SA versus no hyperglycemia treatment Steatorrhea 10/55 NR N=107 Abdominal 3/55 NR cramping *National Cancer Institute Common Toxicity Criteria grade ≥3 †Data for all gastrointestinal cancers (stomach (n=15), pancreas (16), colorectal (24)) 5-FU=5-fluorouracil, NR=not reported; OCT-SA=octreotide short-acting; RCT=randomized controlled trial
A-178 Table A29: Characteristics of included economic studies Author Location and Study design, Perspective Time Intervention Population Data sources funding Outcomes horizon, and source Discounting comparator Acromegaly Novartis Canada, Cost-efficacy Health care 19 months OCT-SA Not described Efficacy and Pharmaceuticals industry analysis system versus OCT- dosages from Canada Inc. funded LA Lancranjan January 1999 Cost per 1996294 and (Unpublished treatment from chart Data) success (GH review. OCT- level < 2μg/L) LA doses assumed. Wilson, 1999 Canada, Cost- Health care Not stated OCT-LA Patients OCT-SA (Unpublished industry effectiveness system versus OCT- diagnosed doses, Data) funded analysis SA with outcomes and (decision acromegaly compliance analytic and treated rates from a model) with surgery longitudinal and chart review Cost per medication (over 4.5 treatment years). Cross success (GH sectional data level < 2μg/L) on doses prescribed or reimbursed from 3 other jurisdictions. OCT-LA doses were inferred.
A-179 Table A29: Characteristics of included economic studies Author Location and Study design, Perspective Time Intervention Population Data sources funding Outcomes horizon, and source Discounting comparator Moore 200283 UK, non- Cost- Not stated Not stated Somatostatin Acromegalic Estimates for industry effectiveness (direct analogues patients using modelling funding and cost medical costs (OCT-LA and medications based on data utility only) lanreotide, as adjuvant to from analysis combined) surgery or observational (decision compared to radiotherapy studies or analytic bromocriptine, from expert model) cabergoline, panel; costs and no therapy from various Cost per LYS sources and QALY. Esophageal variceal bleeding Arcona 1999261 US, industry Cost- Not stated Not stated OCT-LA or Patients Efficacy from (abstract) funded effectiveness propanolol requiring published analysis used in 1o and treatment for meta-analyses (Markov 2 o prevention. 1o and 2 o and RCTs; model) Reference prevention of cost data from case was no esophageal Red Book and Cost per bleed treatment variceal AHCPR prevented (usual care) hemorrhage. HCUP-3 for 1o national data prevention and set. ligation for 2 o prevention.
A-180 Table A29: Characteristics of included economic studies Author Location and Study design, Perspective Time Intervention Population Data sources funding Outcomes horizon, and source Discounting comparator GEPNET Schonfeld US, industry Cost- Payer, insurer Until death OCT-SA and Patients with An expert 1998260 funded effectiveness or patient usual care carcinoid panel was analysis (direct The discount versus usual syndrome used to (Markov medical costs rate was 5% care (i.e., and/or estimate model) only) per annum. OCT-SA not VIPomas, health state available) with disease values and Cost per year extensive quantities of of remission enough to resources gained and warrant liver utilized. The cost per year resection. unit costs for of life saved health professionals, medications, diagnostic and therapeutic procedures, were from different data sources. Novartis Canada, Cost- Drug plans One month, OCT-SA Patients with Efficacy and Pharmaceuticals industry minimization discounting versus OCT- carcinoid dosage based Canada Inc. funded study N/A LA syndrome and on a RCT May 1999 VIPomas (Rubin (Unpublished 1999206). Drug Data) costs supplied by manufacturer.
A-181 Table A29: Characteristics of included economic studies Author Location and Study design, Perspective Time Intervention Population Data sources funding Outcomes horizon, and source Discounting comparator Complications after pancreatic surgery Rosenberg Canada, Cost- Not stated Six months, OCT-SA Patients Complication 199924 partial effectiveness (direct discounting versus placebo undergoing rates based on Rosenberg industry analysis medical costs N/A pancreatic a meta- 199725 funding (decision only) resection analysis of (abstract) analytic double-blind, model) RCTs. Costing model Cost per 1: Per diem patient hospital costs from Statistics Canada. Incremental LOS based on expert opinion. Model 2: costs of hospitalization from Ontario Case Costing Project.
A-182 Table A29: Characteristics of included economic studies Author Location and Study design, Perspective Time Intervention Population Data sources funding Outcomes horizon, and source Discounting comparator Vanounou US, funding Cost-benefit Not stated 1 month, OCT-SA Patients Costs and 2007259 sources not analysis (hospital discounting versus usual undergoing effectiveness reported medical costs N/A care pancreatico- based on a Cost savings, only) duodenectomy cohort of 227 cost benefit patients from ratio a single institution. Costs of index hospitalization plus readmissions within 30 days were included. AHCPR HCUP-3=Agency for Health Care Policy and Research Healthcare Cost and Utilization Project; GH=growth hormone; HRQL=health related quality of life; LOS=length of stay; LYS=life-years saved; N/A=not applicable; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; QALY= quality adjusted life-years; RCT=randomized controlled trial; VIPoma=vasoactive intestinal polypeptide secreting tumour.
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Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Acromegaly Novartis C$ (year not Cost (19 months) Cost per successfully The study authors concluded that Pharmaceuticals stated) OCT-SA = $21,752 treated patient over 19 the cost per successfully treated Canada Inc. OCT-LA = $28,637 months patient tends to be lower with January 1999 OCT-SA = C$56,353 OCT-LA than OCT-SA. (Unpublished Percent of patients who achieved OCT-LA = C$52,448 Data) a GH concentration of less than Treatment success defined using a 2 µg/L (i.e., treatment success) Incremental cost-efficacy short term surrogate marker (GH OCT-SA = 38.6% ratio over the whole 19 level) and success rates were based OCT-LA = 54.6% months is equal to on a single uncontrolled C$43,031 observational study (patients crossed over from OCT-SA to OCT-LA treatment).294
In the analysis, the proportion of patient receiving OCT-LA 10mg, 20mg or 30 mg doses were assumed to be 10%, 70% and 20% respectively. These doses were lower that those reported in Lancranjan et al.294 (89 patients received long-term treatment with OCT-LA 20 and 30 mg, and 12 patients received 40 mg).
No sensitivity analyses were conducted to assess the uncertainty around parameter values.
A-184 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Wilson, 1999 C$ (year not Disaggregated results not OCT-LA would incur Details of the model, data (Unpublished stated) reported. incremental cost of $3,000 parameters and analysis were not Data) to $7,000 per year per provided by the authors, thus additional patient being making it difficult to assess the cured depending on validity of the study. whether patients have macroadenomas or Effectiveness of two treatments microadenomas. Cure assumed to be equivalent except defined as GH level < for improved compliance with 2μg/L). OCT-LA (assumed compliance rates not provided). Doses of OCT-SA obtained mainly from a retrospective chart review of one specialty clinic. Assumptions used when converting OCT-SA doses to equivalent OCT-LA doses were not reported.
A-185 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Moore 200283 GB£ (year Cost for 1st year treatment: IC/LYS: £64,5 M (range Treatment efficacy based on GH not stated) OCT-LA: £11,544 £29M-300M) for levels attained (<2.5 µg/L, 2.5 - (range 9,329-13,728) somatostatin analogues 10.0 µg/L, > 10 µg/L) which were lanreotide: £9,328 over cabergoline and then extrapolated to LYS or (9,046-15,874) £18.6M (£1.3 M - 35.9M) QALY. bromocriptine: £824 (514-1,110) over bromocriptine cabergoline: £996 (649-2,101) Mortality ratios and GH levels no therapy: £0 IC/QALY: £531,000 based on several cohort studies. (£253,000 - 3.2M) for The authors stated that patients Deaths: somatostatin analogues may not be comparable across somatostatin analogues: 0.00238 over cabergoline and these cohorts. HRQL data was cabergoline: 0.00253 £126,000 (£111,000 – assumed. Thus there is uncertainty bromocriptine: 0.00289 126,000) over in the incremental results. no therapy: 0.00306 bromocriptine In the model, the costs for OCT- QALY: LA and lanreotide were averaged somatostatin analogues: 0.838 and analyzed as a class. The cost cabergoline: 0.821 of lanreotide used in the analysis bromocriptine: 0.763 was lower due to a local cost- no therapy: 0.738 sharing program sponsored by manufacturer. Without cost- sharing, annual cost increased to £11,868. Generalizability would be improved if a separate analysis for OCT-LA and lanreotide had been conducted and the full range of costs explored in sensitivity analysis.
A-186 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Esophageal variceal bleeding Arcona 1999261 US$ (year Disaggregated results not stated Cost per bleed prevented The study authors concluded that (abstract) not stated) compared to reference once a month administration of Assumed octreotide was 30%, case. OCT-LA provides a cost-effective 40% or 50% more effective than 1. Propranolol (1o) plus prophylactic option. propranolol ligation and propranolol (2o): US- Abstract provided insufficient $24,600 details to draw any conclusions 2. Propranolol (1o) plus regarding the cost-effectiveness of ligation and OCT-LA octreotide. In addition, there is (2o): US-$22,900 some uncertainty if the study met 3. OCT-LA (1o) plus the inclusion criteria for ligation and population and intervention. propranolol (2o): US$517 to US$5,506 (octreotide 50% to 30% more effective than propranolol, respectively) 4. OCT-LA (1o) plus ligation and OCT-LA (2o): US$593 to US$5,836 (OCT 50% to 30% more effective than propranolol, respectively) GEPNET Schonfeld US$ 1994 Carcinoid tumour: Carcinoid tumour: Study authors concluded that 1998260 (Costs that octreotide: treatment cost is Incremental cost per year octreotide was cost-effective in were US$76,400 from time of initial of remission terms of cost per year of life saved
A-187 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness collected in liver metastases resection to gained=US$736 for carcinoid tumour and was cost earlier death, with 3.88 years in Incremental cost per year saving for VIPoma patients. reference remission and 4.05 years of life. of life saved=US$752 for years were Usual care: US$74,800 with 1.76 octreotide versus usual care Validity of results may be converted to years in remission and 1.98 years questioned considering that all 1994 dollars.) of life. VIPoma: health state values and resources The scenario with utilized were obtained from an VIPoma: octreotide is dominant (less expert panel. Although sensitivity octreotide: treatment cost is expensive and more analysis was conducted, US$76,100 from time of initial effective). considerable uncertainty remains. resection of liver metastases to death, with 2.39 years in octreotide has shown efficacy in remission and 2.60 years of life. altering disease symptoms but it is Usual care: US$80,000 with 1.09 unclear what impact it may have years in remission and 1.32 years on mortality. Years of life saved of life. may not be the most appropriate outcome measure.
A-188 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Novartis C$ 1999 Average monthly cost OCT-SA N/A Equivalent efficacy was assumed Pharmaceuticals C$1,567 based on mean average based on a single RCT of 24 week Canada Inc. daily dose of 567 μg. Range duration (N=93). The dosages used May 1999 varies from C$270 to 4,077 in the analysis were also based on (Unpublished depending on dose. Costs this clinical trial; validation with Data) include $26 per month for doses used in clinical practice syringes. would be informative.
Average monthly cost OCT-LA The perspective was narrow thus C$1,487 assuming 33% patients the cost of administering OCT-LA on 10mg, 30% patients on 20mg was excluded (intramuscular and 37% patients on 30mg injection requires health care (syringe costs included in drug professional). price). Monthly costs range from C$1,102 to 1,840. Study concluded that, on average, OCT-LA was cost neutral to drug plans. The authors also stated that the reduction in the number of injections required with OCT-LA versus OCT-SA was associated with more convenience and quality of life for patients.
A-189 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Complications after pancreatic surgery Rosenberg C$ (year not Complication rates from the meta- Model 1: on average, OCT- The authors concluded that, when 199924 stated) analysis SA use saved C$853 per compared to placebo, the use of OCT- Rosenberg Pancreatic fistulas patient. SA was more effective and less 199725 (abstract) OCT-SA: 10.7% (95% CI 7.9-13.4) In a cohort of 100 patients, 16 costly. Placebo: 23.4% (95% CI 19.7-27.1) incremental patients would One-way and two-way sensitivity avoid complications. analysis showed that the model was Fluid collection (dominant strategy) robust to changes. OCT-SA: 3.6 % (95% CI 1.9-5.2) Placebo: 8.8% (95% CI 6.2-11.3) Model 2: on average, OCT- In model 1 the incremental LOS SA use saved C$1,642 per associated with a fistula was based on Expected cost of therapy (direct patient. expert opinion (21 days). This medical costs) In a cohort of 100 patients, 16 however was tested with sensitivity Model 1 incremental patients would analysis. OCT-SA became cost OCT-SA: C$884 avoid complications. neutral if the incremental LOS was Placebo: C$1,737 (dominant strategy) reduced to 2.9 days. Only the cost of treating fistulas was Model 2 included in the analysis. This OCT-SA: C$12,568 however biased the results in favour Placebo: C$14,210 of placebo.
In model 2 the case costing was based on data from 2 Ontario hospitals (35 patients). Generalizability would be improved if a larger sample was used and if hospitals from other jurisdictions were included.
A-190 Table A30: Results of economic evaluations included in review Author Currency Estimates of cost and Incremental Results Conclusions and Limitations and Year effectiveness Vanounou 2007259 US$ (year not Overall hospital costs (index admission OCT-SA versus no therapy The study authors concluded that the use stated) plus re-admission within 30 days) resulted in US$ 4,249in cost of OCT-SA in patients at low risk of OCT-SA: US$ 18,510 savings per patient with a cost fistulas represents an inefficient No therapy: US$ 18,723, p=0.76 benefit ratio of 5.80. allocation of resources whereas its use in high risk patients is cost-saving. Weighted average cost [median cost Use of OCT-SA in patients at per severity of fistula (grade A, B or low risk resulted in A typical cost-benefit analysis values the C*) multiplied by probability of each overspending of $US 781. change in clinical outcomes in monetary fistula grade.] terms and compares that with the dollar OCT-SA: US$ 24,227 In patients at high risk of value of the change in costs. There was No therapy: US$ 19,978 fistulas, OCT-SA resulted in cost no attempt to put a monetary value on savings of US$11,849 per clinical outcomes in this case. The Incidence of fistulas by grade patient with a cost benefit ratio analysis only involved the cost side, so it OCT-SA: (A) n=8, 8%; (B/C) n=15, of 16.17. cannot be considered a true cost-benefit 15% analysis. No therapy: (A) n=18, 14%; (B/C) Analyses based on weighted n=19, 15%, no significant difference in average costs. All data were based on a retrospective incidence rates cohort from a single institution. Costs were collected from 2001 to 2007 however the method used to correct for inflation was not reported.
Sensitivity analyses were conducted to investigate risk factors for fistulas however no analysis was done for uncertainty related to costs. There were only 6 patients (3%) in total who developed the most severe fistulas which are associated with the most extremes in cost. The limited number of these patients, particularly for the subgroup analyses, contributes to uncertainty in the results.
* International Study Group on Pancreatic Fistula classification scheme: (A) transient asymptomatic fistulas defined by elevated amylase levels in post-operative percutaneous drainage, (B) clinically apparent, symptomatic fistulas that require diagnostic evaluation and intervention, (C) severe manifestations that tend to cause major deviations in clinical recovery and require significant interventions; GH=growth hormone; HRQL=health related quality of life; IC=incremental cost; LYS=life-years saved; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; QALY= quality adjusted life-years
A-191 Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261 Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic Pancreatic surgery Variceal bleed surgery BMJ Economic Evaluations Checklist257 Study design Research question is stated Y N Y Y Y Y Y Y Economic importance of Y NC Y Y Y Y Y N research question is stated Viewpoint(s) of analysis clearly Y N N Y Y N N N stated and justified Rationale for choosing alternative programs or Y N Y Y Y Y Y N interventions compared stated Alternatives being compared Y Y Y Y Y Y Y Y clearly described Form of economic evaluation Y Y Y Y Y Y Y Y used stated Choice of economic evaluation justified in relation to questions Y Y Y Y Y Y N Y addressed Data collection Source(s) of effectiveness Y Y Y Y Y Y Y Y estimates used stated Details of design and results of effectiveness study given (if NA N NA Y N NA Y N based on 1 study) Details of method of synthesis or meta-analysis of estimates NA NA NA N N Y NA N given (if based on overview of effectiveness studies) Primary outcome measure(s) for Y Y Y Y Y Y Y Y economic evaluation stated
A-192 Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261 Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic Pancreatic surgery Variceal bleed surgery Methods to value health states Y NA Y ** NA NA NA NC and other benefits stated Details of subjects from whom NC NA N ** NA NA NA NC valuations obtained given Productivity changes (if NA NA NA ** N NA NA NA included) reported separately Relevance of productivity changes to study question NA NA NA ** NA NA NA NA discussed Quantities of resources reported N NA Y NC Y Y N N separately from unit costs Methods for estimation of quantities and unit costs NC NA Y Y N Y Y NC described Currency and price data Y Y Y Y Y Y Y N recorded Details of price adjustments for inflation or currency conversion N NA N ** N N N N given Details of model used given Y NA Y ** N Y NA NC Choice of model used and key parameters on which it is based Y NA Y ** Y Y NA NC justified Analysis and interpretation of results Time horizon of costs and Y N N ** N Y Y NC benefits stated Discount rate(s) stated Y N N ** N NA NA N Choice of rate(s) justified N NA N ** N NA NA N
A-193 Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261 Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic Pancreatic surgery Variceal bleed surgery Explanation given if costs or NA N N ** N N NA N benefits not discounted Statistical test and confidence intervals given for stochastic N N N ** N Y Y N data Approach to sensitivity analysis Y N Y ** N Y Y NC given Choice of variables for Y N Y ** N Y N N sensitivity analysis justified Ranges over which variables varied stated NC N Y ** N Y N NC
Relevant alternatives compared Y Y Y Y Y Y Y NC
Incremental analysis reported Y N Y Y Y Y Y Y
Major outcomes presented in disaggregated and aggregated Y N Y NC N Y Y N forms
Answer to study question given Y NA Y Y Y Y Y Y
Conclusions follow from data reported Y Y Y Y Y Y Y Y
Conclusions accompanied by appropriate caveats Y Y N Y Y Y Y N
A-194 Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261 Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic Pancreatic surgery Variceal bleed surgery Quality assessment of economic studies – Part 2 Assessment question Schonfeld260 Novartis* Moore83 Wilson L.† Novartis‡ Rosenberg24,25 Vanounou259 Arcona261 Drummond Checklist for Assessing Economic Evaluations (partial)258 3. Was the effectiveness of the program of services established? a) Was this done through a randomized, controlled clinical trial? If so, did the trial protocol N N N N N NA N NC reflect what would happen in regular practice? b) Were effectiveness data collected and summarized through a systematic overview N N N N N Y N NC of clinical studies? If so, were the search strategy and rules for inclusion or exclusion outlined? c) Were observational data or assumptions used to establish N N Y Y Y Y Y NC effectiveness? If so, what are the potential biases in results? *Novartis Pharmaceuticals Canada Inc. Canada, May 1999 (Unpublished Data); †Wilson L. 1999, Canada (Unpublished Data); ‡Novartis Pharmaceuticals Canada Inc. Canada. January 1999 (Unpublished Data); **author was unable to supply the appendices to the report where additional data was reported; GEPNET=gastroenteropancreatic neuroendocrine tumours; N=no; NA=not applicable; NC=not clear; Y=yes;
A-195 Table A32: Prevalence data and sources Prevalence data Source GEPNET GEPNETs are rare, with an estimated U.S. prevalence of < 5.6 cases per 295 100,000 of the population. VIPomas and carcinoid tumours account for approximately 60% of these cases. Data used in prevalence table: 3.36 per 100,000 of population or 0,000034 Acromegaly Prevalence rate for Canada is 60 per million or 0,00006 296 Prevention of complications after pancreatic surgery • 20% of pancreatic cancers can be removed surgically 297
298 • 28,447 individuals 5 year prevalence rate 2004. Pancreatic cancer US Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race
299 • US population in 2004
300 • Morbidity rate after pancreatic surgery of 30% to 40 (this data provide for information purposed only) 301 • Total morbidity rate after pancreatic surgery found to be 38.4%
(N=331 patients) 302 • 80,000 acute pancreatitis each year which is equivalent to 0.027% (No data found on the proportion of patients requiring surgery due to pancreatitis) Bleeding esophageal varices Canadian rate 100 per 100,000 per year 303 Hepatocellular carcinoma 19,429 individuals 5 year prevalence rate 2004. 304 Liver cancer US Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race
US population in 2004 (298,213,000) 299
Hepatocellular carcinoma accounts for 80% to 90% of all liver cancers. 305 Diarrhea related to Chemotherapy The overall prevalence of cancer in the Canadian population is 306 approximately 2% among men and 2.5% among women
Incidence/ Prevalence Numbers: 10% of all advanced cancer patients 307 experience acute or persistent diarrhea. One third of those are severe diarrheas. (Canadian source)
A-196 Table A32: Prevalence data and sources Prevalence data Source
Diarrhea related to Ileostomy Data not found Diarrhea related to HIV-AIDS At the end of 2002, an estimated 56,000 (46,000-66,000) people in 308 Canada were living with HIV infection (including AIDS), which represents an increase of about 12% from the point estimate of 49,800 at the end of 1999. 309 Population in 2002: 31,372,600 Diarrhea related to Crohn’s disease The US prevalence, or overall number of cases, is 198.5 per 100,000 for 310 Crohn's and 169.7 per 100,000 for ulcerative colitis. Prevalence has increased since 1989, when the rates of Crohn's and ulcerative colitis were 152 and 127 respectively
Prevalence of diarrhea in Crohn’s disease in Iran: 77.1% (unable to locate 311 Canadian data) Short Bowel Syndrome 1.8 to 3 per million (Data from Australia and US, an average was used) 312-314 Bowel obstruction Incidence of the disease in US is 0.2%. Approximately 1 in 500 or 0.20% 315 or 544,000 people in US. (Incidence was used in this case, since bowel obstruction is an acute condition).
US - Inoperable cases between 6 and 50% (data used in prevalence table: 316 28%) Pediatric Hyperinsulinism Incidence rate in the US: 1/25,000 to 1/50,000 50 Pancreatic cancer 28,447 individuals 5 year prevalence rate 2004. Pancreatic cancer US 298 Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race
US population in 2004 299 GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus and aquired immune deficiency syndrome; VIPoma=vasoactive intestinal polypeptide secreting tumour
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Table A33: Prevalence of all Approved Indications for octreotide in Canada (All Age Groups) 2006 2007 2008 2009 2010 British Colombia 1092 1103 1114 1123 1132 Alberta 837 846 854 863871 Saskatchewan 252 251 250 249249 Manitoba 300 302 303 304305 Ontario 3220 3252 3282 33103337 Quebec 1940 1949 1957 19641970 New Brunswick 191 191 191 191 192 Nova Scotia 239 239 239 239 239 Prince Edward Island 35 35 35 35 36 Newfoundland and Labrador 131 131 130 130 130 Yukon 8 8 8 88 Northwest Territories 11 11 11 11 12 Nunavut 8 8 8 88 Canada 8263 8325 8383 84378486
Table A34: Prevalence of Unapproved Indications* for octreotide in Canada (All Age Groups) 2006 2007 2008 2009 2010 British Colombia 24296 24539 24769 24986 25191 Alberta 18609 18809 19002 19189 19368 Saskatchewan 5599 5582 5565 5549 5534 Manitoba 6681 6707 6731 6755 6777 Ontario 71621 72337 73008 73635 74218 Quebec 43151 43350 43526 43680 43812 New Brunswick 4252 4255 4257 4259 4260 Nova Scotia 5306 5313 5318 5323 5327 Prince Edward Island 783 785 787 789 790 Newfoundland and Labrador 2910 2905 2899 2893 2888 Yukon 176 176 176 176 177 Northwest Territories 246 249 252 255 257 Nunavut 171 171 172 173 173 Canada 183801 185178 186464 187661 188772
* Pediatric hyperinsulinism and diarrhea related to ileostomy were not included in the prevalence of unapproved indications
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Table A35: Prevalence Data for ambulatory beneficiaries: GEPNET and Acromegaly* for octreotide in Canada (all age groups) 2006 2007 2008 2009 2010 British Colombia 404 408 412 416 419 Alberta 310 313 316 319 322 Saskatchewan 93 93 93 92 92 Manitoba 111 112 112 112 113 Ontario 1192 1203 1215 1225 1235 Quebec 718 721 724 727 729 New Brunswick 71 71 71 71 71 Nova Scotia 88 88 88 89 89 Prince Edward Island 13 13 13 13 13 Newfoundland and Labrador 48 48 48 48 48 Yukon 3333 3 Northwest Territories 4444 4 Nunavut 3333 3 Canada 3058 3081 3102 3122 3141 * Note that emergency management of esophageal variceal bleeding and prophylaxis of complications after pancreatic surgery are solely treated in hospital; GEPNET=gastroenteropancreatic neuroendocrine tumours
Table A36: British Columbia prevalence data per indication per year (all age groups) Indication 2006 2007 2008 2009 2010 GEPNET 146 148 149 150152 Acromegaly 258 261 263 265268 Prevention of complications after pancreatic surgery* 86 87 88 88 89 Bleeding esophageal varices 602 608 614 619 624 Hepatocellular carcinoma 252 254 256 259 261 Chemotherapy-related diarrhea 10751 10858 10960 11056 11147 Ileostomy-related diarrhea† NE NE NE NE NE HIV-AIDS-related diarrhea 3870 3909 3946 3980 4013 Crohn's related diarrhea‡ 6573 6638 6701 67596815 Short bowel syndrome 13 13 13 13 13 Bowel obstruction (inoperable-28%) 2408 2432 2455 2476 2497 Pediatric hyperinsulinism NE NE NE NE NE Pancreatic cancer 430 434 438 442 446 * surgery due to pancreatic cancer, †unable to find prevalence data, ‡ low confidence data; GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus and acquired immune deficiency syndrome; NE=not estimable
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Table A37: Saskatchewan prevalence data per indication per year (all age groups) 2006 2007 2008 2009 2010 GEPNET 34 34 33 33 33 Acromegaly 59 59 59 59 59 Prevention of complications after pancreatic surgery* 20 20 20 20 20 Bleeding esophageal varices 139 138 138 137 137 Hepatocellular carcinoma 58 58 58 57 57 Chemotherapy-related diarrhea 2478 2470 2463 2455 2449 Ileostomy-related diarrhea† NE NE NE NE NE HIV-AIDS-related diarrhea 892 889 887 884 881 Crohn's related diarrhea‡ 1515 1510 1506 1501 1497 Short bowel syndrome 3 3 3 3 3 Bowel obstruction (inoperable-28%) 555 553 552 550 548 Pediatric hyperinsulinism NE NE NE NE NE Pancreatic cancer 99 99 99 98 98 * surgery due to pancreatic cancer, †unable to find prevalence data, ‡ low confidence data; GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus-acquired immune deficiency syndrome; NE=not estimable
Table A38: Manitoba prevalence data per indication per year (all age groups) 2006 2007 2008 2009 2010 GEPNET 40 40 41 41 41 Acromegaly 71 71 71 72 72 Prevention of complications after pancreatic surgery* 24 24 24 24 24 Bleeding esophageal varices 166 166 167 167 168 Hepatocellular carcinoma 69 69 70 70 70 Chemotherapy-related diarrhea 2956 2968 2979 2989 2999 Ileostomy-related diarrhea† NE NE NE NE NE HIV-AIDS-related diarrhea 1064 1068 1072 1076 1079 Crohn's related diarrhea‡ 1807 1814 1821 1827 1833 Short bowel syndrome 4 4 4 4 4 Bowel obstruction (inoperable-28%) 662 665 667 669 672 Pediatric hyperinsulinism NE NE NE NE NE Pancreatic cancer 118 119 119 120 120 * surgery due to pancreatic cancer, †unable to find prevalence data, ‡ low confidence data; GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus and acquired immune deficiency syndrome; NE=not estimable
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Table A39: New Brunswick prevalence data per indication per year (all age groups) 2006 2007 2008 2009 2010 GEPNET 26 26 26 26 26 Acromegaly 45 45 45 45 45 Prevention of complications after pancreatic surgery* 15 15 15 15 15 Bleeding esophageal varices 105 105 105 106 106 Hepatocellular carcinoma 44 44 44 44 44 Chemotherapy-related diarrhea 1882 1883 1884 1885 1885 Ileostomy-related diarrhea† NE NE NE NE NE HIV-AIDS-related diarrhea 677 678 678 678 679 Crohn's related diarrhea‡ 1150 1151 1152 1152 1152 Short bowel syndrome 2 2 2 2 2 Bowel obstruction (inoperable-28%) 421 422 422 422 422 Pediatric hyperinsulinism NE NE NE NE NE Pancreatic cancer 75 75 75 75 75 * surgery due to pancreatic cancer, †unable to find prevalence data, ‡ low confidence data; GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus and acquired immune deficiency syndrome; NE=not estimable
Table A40: Nova Scotia prevalence data per indication per year (all age groups) 2006 2007 2008 2009 2010 GEPNET 32 32 32 32 32 Acromegaly 56 56 56 57 57 Prevention of complications after pancreatic surgery* 19 19 19 19 19 Bleeding esophageal varices 131 132 132 132 132 Hepatocellular carcinoma 55 55 55 55 55 Chemotherapy-related diarrhea 2348 2351 2353 2355 2357 Ileostomy-related diarrhea† NE NE NE NE NE HIV-AIDS-related diarrhea 845 846 847 848 849 Crohn's related diarrhea‡ 1436 1437 1439 1440 1441 Short bowel syndrome 3 3 3 3 3 Bowel obstruction (inoperable-28%) 526 527 527 528 528 Pediatric hyperinsulinism NE NE NE NE NE Pancreatic cancer 94 94 94 94 94 * surgery due to pancreatic cancer, †unable to find prevalence data, ‡ low confidence data; GEPNET=gastroenteropancreatic neuroendocrine tumours; HIV-AIDS=human immunodeficiency virus and acquired immune deficiency syndrome; NE=not estimable
A-201 Table A41: British Columbia Pharmacare budget impact assessment Basecase: British Columbia Pharmacare Projected Sales Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 and 5 mg $395,868 $397,169 $398,420 $399,721 Cabergoline $11,672$8,282 $13,386 $9,454 Diphenoxylate $159,707$146,474 $134,368 $123,247 Loperamide $147,903$136,803 $126,510 $116,991 OCT-SA 50 µg/mL $10,300$10,300 $10,300 $10,300 OCT-SA 100 µg/mL $46,227$48,572 $50,582 $52,927 OCT-SA 200 µg/mL $94,617 $102,927 $110,599 $118,910 OCT-SA 500 µg/mL $50,416$54,918 $59,419 $65,721
OCT-LA 10 mg $0$0 $0 $0 OCT-LA 20 mg $0$0 $0 $0 OCT-LA 30 mg $0$0 $0 $0
TOTAL $916,710$905,446 $903,584 $897,270 Scenario 1: British Columbia Pharmacare Sales after change in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 and 5 mg $395,868 $397,169 $398,420 $399,721 Cabergoline $11,672$8,282 $13,386 $9,454 Diphenoxylate $159,707$146,474 $134,368 $123,247 Loperamide $147,903$136,803 $126,510 $116,991 OCT-SA 50 µg/mL $10,171$10,042 $9,914 $9,785 OCT-SA 100 µg/mL $45,649$47,358 $48,685 $50,281 OCT-SA 200 µg/mL $93,434 $100,354 $106,452 $112,965 OCT-SA 500 µg/mL $49,786$53,545 $57,191 $62,435
OCT-LA 10 mg $3,955$7,910 $11,866 $15,821 OCT-LA 20 mg $65,061$130,121 $195,182 $260,243 OCT-LA 30 mg $56,218$112,436 $168,654 $224,872
A-202 Table A41: British Columbia Pharmacare budget impact assessment Scenario 1: Incremental sales impact for British Columbia Pharmacare Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 and 5 mg $0 $0 $0 $0 Cabergoline $0 $0 $0 $0 Diphenoxylate $0 $0 $0 $0 Loperamide $0 $0 $0 $0 OCT-SA 50 µg/mL -$129-$257 -$386 -$515 OCT-SA 100 µg/mL -$578-$1,214 -$1,897 -$2,646 OCT-SA 200 µg/mL -$1,183 -$2,573 -$4,147 -$5,946 OCT-SA 500 µg/mL -$630-$1,373 -$2,228 -$3,286
OCT-LA 10 mg $3,955$7,910 $11,866 $15,821 OCT-LA 20 mg $65,061$130,121 $195,182 $260,243 OCT-LA 30 mg $56,218$112,436 $168,654 $224,872
TOTAL INCREMENTAL IMPACT $122,714 $245,050 $367,043 $488,542 Scenario 2: British Columbia Pharmacare Sales after change in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 and 5 mg $387,948 $389,006 $390,026 $391,106 Cabergoline $11,438$8,112 $13,104 $9,250 Diphenoxylate $156,512$143,464 $131,537 $120,590 Loperamide $144,944$133,991 $123,845 $114,469 OCT-SA 50 µg/mL $20,600$20,600 $20,600 $20,600 OCT-SA 100 µg/mL $92,454$97,144 $101,164 $105,854 OCT-SA 200 µg/mL $189,233 $205,855 $221,198 $237,820 OCT-SA 500 µg/mL $100,832$109,835 $118,838 $131,442
OCT-LA 10 mg $7,910$15,821 $23,731 $31,642 OCT-LA 20 mg $130,121$260,243 $390,364 $520,485 OCT-LA 30 mg $112,436$224,872 $337,308 $449,744
A-203 Table A41: British Columbia Pharmacare budget impact assessment
Scenario 2: Incremental sales impact for British Columbia Pharmacare Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 and 5 mg -$7,920 -$8,163 -$8,394 -$8,615 Cabergoline -$234-$170 -$282 -$204 Diphenoxylate -$3,195-$3,010 -$2,831 -$2,656 Loperamide -$2,959-$2,812 -$2,665 -$2,522 OCT-SA 50 µg/mL $10,300$10,300 $10,300 $10,300 OCT-SA 100 µg/mL $46,227$48,572 $50,582 $52,927 OCT-SA 200 µg/mL $94,617 $102,927 $110,599 $118,910 OCT-SA 500 µg/mL $50,416$54,918 $59,419 $65,721
OCT-LA 10 mg $7,910$15,821 $23,731 $31,642 OCT-LA 20 mg $130,121$260,243 $390,364 $520,485 OCT-LA 30 mg $112,436$224,872 $337,308 $449,744
TOTAL INCREMENTAL IMPACT $437,720 $703,497 $968,131 $1,235,731 OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
A-204
Table A42: Saskatchewan Drug Plan budget impact assessment Basecase analysis: Saskatchewan Drug Plan Projected Sales before changes in listing criteria Generic name strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $26,696 $25,367$24,104 $22,905 Bromocriptine 5 mg $10,322 $8,877$7,433 $5,988 Cabergoline $16,703 $17,241$17,617 $17,880 Diphenoxylate $56,570 $56,729$56,863 $56,978 Loperamide $101,517 $101,737$101,923 $102,082 OCT-SA 50 µg/mL $13,458 $13,458$13,458 $13,458 OCT-SA 100 µg/mL $24,729 $27,473$30,521 $33,907 OCT-SA 200 µg/mL $66,211 $66,211 $66,211 $66,211 OCT-SA 500 µg/mL $6,198 $6,738$7,278 $7,818
OCT-LA 10 mg $14,329 $14,329$14,329 $14,329 OCT-LA 20 mg $152,479 $166,464$179,050 $190,378 OCT-LA 30 mg $211,549 $222,163$231,357 $239,467
TOTAL $700,760 $726,786$750,144 $771,402 Scenario 1: Saskatchewan Drug Plan Sales after changes in listing criteria Generic name strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $26,696 $25,367$24,104 $22,905 Bromocriptine 5 mg $10,322 $8,877$7,433 $5,988 Cabergoline $16,703 $17,241$17,617 $17,880 Diphenoxylate $56,570 $56,729$56,863 $56,978 Loperamide $101,517 $101,737$101,923 $102,082 OCT-SA 50 µg/mL $14,064 $14,064$14,064 $14,064 OCT-SA 100 µg/mL $25,842 $28,709$31,894 $35,433 OCT-SA 200 µg/mL $69,190 $69,190 $69,190 $69,190 OCT-SA 500 µg/mL $6,477 $7,041$7,606 $8,170
OCT-LA 10 mg $14,974 $14,974$14,974 $14,974
A-205 Table A42: Saskatchewan Drug Plan budget impact assessment OCT-LA 20 mg $159,340 $173,954$187,107 $198,945 OCT-LA 30 mg $221,069 $232,160$241,768 $250,243 Scenario 1: Incremental sales impact for Saskatchewan Drug Plan Generic name strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $0 $0 $0 $0 Bromocriptine 5 mg $0 $0 $0 $0 Cabergoline $0 $0 $0 $0 Diphenoxylate $0 $0 $0 $0 Loperamide $0 $0 $0 $0 OCT-SA 50 µg/mL $606 $606$606 $606 OCT-SA 100 µg/mL $1,113 $1,236$1,373 $1,526 OCT-SA 200 µg/mL $2,979 $2,979 $2,979 $2,979 OCT-SA 500 µg/mL $279 $303$328 $352 $0 $0 $0 $0 OCT-LA 10 mg $645 $645$645 $645 OCT-LA 20 mg $6,862 $7,491$8,057 $8,567 OCT-LA 30 mg $9,520 $9,997$10,411 $10,776
TOTAL INCREMENTAL IMPACT $22,003 $23,258 $24,399 $25,451 Scenario 2: Saskatchewan Drug Plan Sales after changes in listing criteria Generic name strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $25,196 $23,942$22,751 $21,618 Bromocriptine 5 mg $9,742 $8,379$7,015 $5,652 Cabergoline $15,765 $16,272$16,627 $16,876 Diphenoxylate $53,393 $53,543$53,669 $53,778 Loperamide $95,815 $96,022$96,198 $96,348 OCT-SA 50 µg/mL $33,747 $33,747$33,747 $33,747 OCT-SA 100 µg/mL $62,009 $68,888$76,531 $85,022 OCT-SA 200 µg/mL $166,025 $166,025 $166,025 $166,025 OCT-SA 500 µg/mL $15,542 $16,896$18,250 $19,604
A-206 Table A42: Saskatchewan Drug Plan budget impact assessment OCT-LA 10 mg $35,931 $35,931$35,931 $35,931 OCT-LA 20 mg $382,343 $417,411$448,972 $477,377 OCT-LA 30 mg $530,464 $557,078$580,132 $600,468 Scenario 2: Incremental sales impact for Saskatchewan Drug Plan Generic name strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$1,499 -$1,425-$1,354 -$1,287 Bromocriptine 5 mg -$580 -$499-$417 -$336 Cabergoline -$938 -$968-$990 -$1,004 Diphenoxylate -$3,177 -$3,186-$3,194 -$3,200 Loperamide -$5,702 -$5,714-$5,725 -$5,734 OCT-SA 50 µg/mL $20,288 $20,288$20,288 $20,288 OCT-SA 100 µg/mL $37,280 $41,416$46,011 $51,115 OCT-SA 200 µg/mL $99,815 $99,815 $99,815 $99,815 OCT-SA 500 µg/mL $9,344 $10,158$10,972 $11,786
OCT-LA 10 mg $21,602 $21,602$21,602 $21,602 OCT-LA 20 mg $229,865 $250,948$269,922 $286,999 OCT-LA 30 mg $318,915 $334,915$348,776 $361,001
TOTAL INCREMENTAL IMPACT $725,211 $767,349 $805,705 $841,045 OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
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Table A43: Manitoba Pharmacare budget impact assessment Basecase: Manitoba Pharmacare Program Projected Sales before changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $23,888 $22,773$21,710 $20,697 Bromocriptine 5 mg $21,604 $20,891$20,285 $19,769 Cabergoline $7,805 $8,764$9,722 $10,681 Diphenoxylate $12,552 $13,028$13,503 $13,979 Loperamide $77,282 $76,349$75,416 $74,483 OCT-SA 50 µg/mL $1,134 $1,134$1,134 $1,134 OCT-SA 100 µg/mL $6,942 $2,881$5,915 $2,455 OCT-SA 200 µg/mL $10,807 $10,807 $10,807 $10,807 OCT-SA 500 µg/mL $53,560 $55,329$57,099 $58,868
OCT-LA 10 mg $36,550 $39,269$42,190 $45,328 OCT-LA 20 mg $466,845 $494,316$521,787 $549,258 OCT-LA 30 mg $ 521,707 $ 553,907 $ 586,106 $ 618,305
TOTAL $1,240,676 $1,299,447$1,365,674 $1,425,764 Scenario 1: Manitoba Pharmacare Program Sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $23,052 $21,976$20,951 $19,973 Bromocriptine 5 mg $20,848 $20,160$19,575 $19,077 Cabergoline $7,532 $8,457$9,382 $10,307 Diphenoxylate $12,113 $12,572$13,031 $13,490 Loperamide $74,578 $73,677$72,777 $71,876 OCT-SA 50 µg/mL $1,134 $1,134$1,134 $1,134 OCT-SA 100 µg/mL $6,942 $2,881$5,915 $2,455 OCT-SA 200 µg/mL $10,807 $10,807 $10,807 $10,807 OCT-SA 500 µg/mL $53,560 $55,329$57,099 $58,868
OCT-LA 10 mg $43,495 $46,730$50,206 $53,941
A-208 Table A43: Manitoba Pharmacare budget impact assessment OCT-LA 20 mg $555,545 $588,236$620,926 $653,617 OCT-LA 30 mg $620,832 $659,149$697,466 $735,783 Scenario 1: Incremental sales impact for Manitoba Pharmacare Program Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$836 -$797-$760 -$724 Bromocriptine 5 mg -$756 -$731-$710 -$692 Cabergoline -$273 -$307-$340 -$374 Diphenoxylate -$439 -$456-$473 -$489 Loperamide -$2,705 -$2,672-$2,640 -$2,607 OCT-SA 50 µg/mL $0 $0$0 $0 OCT-SA 100 µg/mL $0 $0$0 $0 OCT-SA 200 µg/mL $0 $0 $0 $0 OCT-SA 500 µg/mL $0 $0$0 $0
OCT-LA 10 mg $6,945 $7,461$8,016 $8,612 OCT-LA 20 mg $88,701 $93,920$99,140 $104,359 OCT-LA 30 mg $99,124 $105,242$111,360 $117,478
TOTAL INCREMENTAL IMPACT $189,760 $201,660 $213,593 $225,563 Scenario 2: Manitoba Pharmacare Program Sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $22,383 $21,338$20,343 $19,393 Bromocriptine 5 mg $20,243 $19,575$19,007 $18,524 Cabergoline $7,313 $8,212$9,110 $10,008 Diphenoxylate $11,761 $12,207$12,653 $13,098 Loperamide $72,414 $71,539$70,665 $69,790 OCT-SA 50 µg/mL $1,063 $1,063$1,063 $1,063 OCT-SA 100 µg/mL $6,504 $2,699$5,542 $2,300 OCT-SA 200 µg/mL $10,126 $10,126 $10,126 $10,126 OCT-SA 500 µg/mL $50,186 $51,844$53,501 $55,159
A-209 Table A43: Manitoba Pharmacare budget impact assessment OCT-LA 10 mg $69,445 $74,611$80,161 $86,124 OCT-LA 20 mg $887,005 $939,200$991,395 $1,043,590 OCT-LA 30 mg $991,244 $1,052,423$1,113,601 $1,174,780 Scenario 2: Incremental sales impact for Manitoba Pharmacare Program Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$1,505 -$1,435-$1,368 -$1,304 Bromocriptine 5 mg -$1,361 -$1,316-$1,278 -$1,245 Cabergoline -$492 -$552-$612 -$673 Diphenoxylate -$791 -$821-$851 -$881 Loperamide -$4,869 -$4,810-$4,751 -$4,692 OCT-SA 50 µg/mL -$71 -$71-$71 -$71 OCT-SA 100 µg/mL -$437 -$181-$373 -$155 OCT-SA 200 µg/mL -$681 -$681 -$681 -$681 OCT-SA 500 µg/mL -$3,374 -$3,486-$3,597 -$3,709
OCT-LA 10 mg $32,895 $35,342$37,971 $40,796 OCT-LA 20 mg $420,160 $444,884$469,608 $494,332 OCT-LA 30 mg $469,537 $498,516$527,495 $556,475
TOTAL INCREMENTAL IMPACT $909,011 $965,389 $1,021,492 $1,078,191 OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
A-210
Table A44: Nova Scotia Pharmacare budget impact assessment Basecase analysis: Nova Scotia Pharmacare Projected Sales Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $13,965 $13,965 $13,965 $13,965 Bromocriptine 5 mg $1,215 $1,029 $842 $655 Cabergoline $23,359 $25,122 $26,884 $28,647 Diphenoxylate $34,415 $33,663 $32,910 $32,158 Loperamide $110,481 $108,826 $107,027 $105,084 OCT-SA 50 µg/mL $13,410 $13,663 $13,915 $14,168 OCT-SA 100 µg/mL $54,674 $46,400 $59,007 $49,937 OCT-SA 200 µg/mL $42,362 $45,407 $48,453 $51,498 OCT-SA 500 µg/mL $107,069 $113,453 $119,164 $124,331
OCT-LA 10 mg $0 $0 $0 $0 OCT-LA 20 mg $110,478 $117,153 $122,661 $127,204 OCT-LA 30 mg $93,736 $102,721 $111,705 $120,690
TOTAL $605,166 $621,402 $656,534 $668,337 Scenario 1: Nova Scotia Pharmacare sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $13,421 $13,421$13,421 $13,421 Bromocriptine 5 mg $1,168 $989 $809 $630 Cabergoline $22,448 $24,142$25,836 $27,530 Diphenoxylate $33,073 $32,350$31,627 $30,904 Loperamide $106,172 $104,582$102,853 $100,986 OCT-SA 50 µg/mL $16,092 $16,395$16,698 $17,001 OCT-SA 100 µg/mL $65,609 $55,680$70,808 $59,924
A-211 Table A44: Nova Scotia Pharmacare budget impact assessment OCT-SA 200 µg/mL $50,834 $54,489 $58,143 $61,798 OCT-SA 500 µg/mL $128,482 $136,144$142,997 $149,197
OCT-LA 10 mg $0 $0 $0 $0 OCT-LA 20 mg $132,574 $140,584$147,193 $152,645 OCT-LA 30 mg $112,483 $123,265$134,047 $144,828 Scenario 1: Incremental sales impact for Nova Scotia Pharmacare Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$545 -$545 -$545 -$545 Bromocriptine 5 mg -$47 -$40 -$33 -$26 Cabergoline -$911 -$980-$1,048 -$1,117 Diphenoxylate -$1,342 -$1,313-$1,284 -$1,254 Loperamide -$4,309 -$4,244-$4,174 -$4,098 OCT-SA 50 µg/mL $2,682 $2,733$2,783 $2,834 OCT-SA 100 µg/mL $10,935 $9,280$11,801 $9,987 OCT-SA 200 µg/mL $8,472 $9,081 $9,691 $10,300 OCT-SA 500 µg/mL $21,414 $22,691$23,833 $24,866
OCT-LA 10 mg $0 $0 $0 $0 OCT-LA 20 mg $22,096 $23,431$24,532 $25,441 OCT-LA 30 mg $18,747 $20,544$22,341 $24,138
TOTAL INCREMENTAL IMPACT $77,192 $80,638 $87,897 $90,526 Scenario 2: Nova Scotia Pharmacare sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $13,965 $13,965 $13,965 $13,965 Bromocriptine 5 mg $1,215 $1,029 $842 $655 Cabergoline $23,359 $25,122 $26,884 $28,647 Diphenoxylate $34,415 $33,663 $32,910 $32,158
A-212 Table A44: Nova Scotia Pharmacare budget impact assessment Loperamide $110,481 $108,826 $107,027 $105,084 OCT-SA 50 µg/mL $13,410 $13,663 $13,915 $14,168 OCT-SA 100 µg/mL $54,674 $46,400 $59,007 $49,937 OCT-SA 200 µg/mL $42,362 $45,407 $48,453 $51,498 OCT-SA 500 µg/mL $107,069 $113,453 $119,164 $124,331
OCT-LA 10 mg $0 $0 $0 $0 OCT-LA 20 mg $70,706 $74,978 $78,503 $81,410 OCT-LA 30 mg $59,991 $65,741 $71,492 $77,242 Scenario 2: Incremental sales impact for Nova Scotia Pharmacare Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $0 $0 $0 $0 Bromocriptine 5 mg $0 $0 $0 $0 Cabergoline $0 $0 $0 $0 Diphenoxylate $0 $0 $0 $0 Loperamide $0 $0 $0 $0 OCT-SA 50 µg/mL $0 $0 $0 $0 OCT-SA 100 µg/mL $0 $0 $0 $0 OCT-SA 200 µg/mL $0 $0 $0 $0 OCT-SA 500 µg/mL $0 $0 $0 $0
OCT-LA 10 mg $0 $0 $0 $0 OCT-LA 20 mg -$39,772 -$42,175-$44,158 -$45,793 OCT-LA 30 mg -$33,745 -$36,979-$40,214 -$43,448 TOTAL INCREMENTAL IMPACT -$73,517 -$79,155 -$84,372 -$89,242 OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
A-213
Table A45: New Brunswick Provincial Drug Program budget impact assessment Basecase: New Brunswick Provincial Drug Program Projected Sales before changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $8,798 $8,268 $7,770 $7,302 Bromocriptine 5 mg $4,399 $4,058 $3,768 $3,519 Cabergoline $8,355 $8,946 $9,538 $10,129 Diphenoxylate $42,914 $42,732 $42,587 $42,470 Loperamide $45,998 $45,864 $45,732 $45,599 OCT-SA 50 µg/mL $500$500 $500 $500 OCT-SA 100 µg/mL $49,081$51,732 $54,383 $57,033 OCT-SA 200 µg/mL $22,074 $19,763 $17,694 $15,841 OCT-SA 500 µg/mL $0 $0 $0 $0
OCT-LA 10 mg $2,755$2,755 $2,755 $2,755 OCT-LA 20 mg $70,494$76,934 $83,374 $89,814 OCT-LA 30 mg $38,192$38,192 $38,192 $38,192
TOTAL $293,560$299,746 $306,292 $313,155 Scenario 1: New Brunswick Provincial Drug Program Sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $8,578 $8,061 $7,576 $7,119 Bromocriptine 5 mg $4,289 $3,957 $3,674 $3,431 Cabergoline $8,146 $8,723 $9,300 $9,876 Diphenoxylate $41,841 $41,664 $41,522 $41,409 Loperamide $44,848 $44,718 $44,588 $44,459 OCT-SA 50 µg/mL $1,001$1,001 $1,001 $1,001 OCT-SA 100 µg/mL $98,163$103,464 $108,765 $114,066 OCT-SA 200 µg/mL $44,147 $39,525 $35,387 $31,683 OCT-SA 500 µg/mL $0 $0 $0 $0
OCT-LA 10 mg $5,509$5,509 $5,509 $5,509
A-214 Table A45: New Brunswick Provincial Drug Program budget impact assessment OCT-LA 20 mg $140,988$153,868 $166,748 $179,628 OCT-LA 30 mg $76,385$76,385 $76,385 $76,385 Scenario 1: Incremental sales impact for New Brunswick Provincial Drug Program Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$220 -$207 -$194 -$183 Bromocriptine 5 mg -$110 -$101 -$94 -$88 Cabergoline -$209 -$224 -$238 -$253 Diphenoxylate -$1,073 -$1,068 -$1,065 -$1,062 Loperamide -$1,150 -$1,147 -$1,143 -$1,140 OCT-SA 50 µg/mL $500$500 $500 $500 OCT-SA 100 µg/mL $49,081$51,732 $54,383 $57,033 OCT-SA 200 µg/mL $22,074 $19,763 $17,694 $15,841 OCT-SA 500 µg/mL $0 $0 $0 $0
OCT-LA 10 mg $2,755$2,755 $2,755 $2,755 OCT-LA 20 mg $70,494$76,934 $83,374 $89,814 OCT-LA 30 mg $38,192$38,192 $38,192 $38,192
TOTAL INCREMENTAL IMPACT $180,335 $187,130 $194,163 $201,410 Scenario 2: New Brunswick Provincial Drug Program Sales after changes in listing criteria Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg $8,473 $7,962 $7,483 $7,032 Bromocriptine 5 mg $4,236 $3,908 $3,629 $3,388 Cabergoline $8,046 $8,615 $9,185 $9,755 Diphenoxylate $41,326 $41,151 $41,011 $40,899 Loperamide $44,296 $44,167 $44,039 $43,912 OCT-SA 50 µg/mL $1,251$1,251 $1,251 $1,251 OCT-SA 100 µg/mL $122,704$129,330 $135,956 $142,583 OCT-SA 200 µg/mL $55,184 $49,407 $44,234 $39,603 OCT-SA 500 µg/mL $0 $0 $0 $0
A-215 Table A45: New Brunswick Provincial Drug Program budget impact assessment OCT-LA 10 mg $6,887$6,887 $6,887 $6,887 OCT-LA 20 mg $176,236$192,335 $208,435 $224,535 OCT-LA 30 mg $95,481$95,481 $95,481 $95,481 Scenario 2: Incremental sales impact for New Brunswick Provincial Drug Program Generic name Strength 2006-2007 2007-2008 2008-2009 2009-2010 Bromocriptine 2.5 mg -$326 -$306 -$287 -$270 Bromocriptine 5 mg -$163 -$150 -$139 -$130 Cabergoline -$309 -$331 -$353 -$375 Diphenoxylate -$1,588 -$1,581 -$1,576 -$1,571 Loperamide -$1,702 -$1,697 -$1,692 -$1,687 OCT-SA 50 µg/mL $750$750 $750 $750 OCT-SA 100 µg/mL $73,622$77,598 $81,574 $85,550 OCT-SA 200 µg/mL $33,111 $29,644 $26,541 $23,762 OCT-SA 500 µg/mL $0 $0 $0 $0
OCT-LA 10 mg $4,132$4,132 $4,132 $4,132 OCT-LA 20 mg $105,741$115,401 $125,061 $134,721 OCT-LA 30 mg $57,289$57,289 $57,289 $57,289
TOTAL INCREMENTAL IMPACT $270,558 $280,749 $291,299 $302,170 OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting
A-216