Page 1 of 63 An application to include blood pressure lowering drug fixed dose combinations to the model list of essential medicines lists for the treatment of essential hypertension in adults Author Organization Abdul Salam The George Institute for Global Health India Raju Kanukula The George Institute for Global Health India Hariprasad Esam The George Institute for Global Health India Ehete Bahiru Northwestern University Feinberg School of Medicine Abhishek Sharma Boston University School of Public Health, and Precision Health Economics David Heller Arnhold Institute for Global Health Mark Huffman Northwestern University Feinberg School of Medicine Rajesh Vedanthan Icahn School of Medicine at Mount Sinai Anubha Agarwal Duke University and NIH Fogarty Global Health Fellow Marc G. Jaffe Resolve to Save Lives, Vital Strategies, and Kaiser Permanente Northern California Tom Frieden Resolve to Save Lives, Vital Strategies Sandeep P. Kishore Arnhold Institute for Global Health & Young Professionals Chronic Disease Network Anthony Rodgers The George Institute for Global Health Coordinated and Submitted by: Sandeep P. Kishore, Arnhold Institute for Global Health & Young Professionals Chronic Disease Network Anthony Rodgers, The George Institute for Global Health Marc G. Jaffe, Resolve to Save Lives, Vital Strategies, and Kaiser Permanente Northern California Tom Frieden, Resolve to Save Lives, Vital Strategies Contact: Cherian Varghese, Coordinator, Management of NCDs, WHO Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention Page 2 of 63 Table of Contents General items ....................................................................................................... 5 1. Summary statement of the proposal for inclusion, change or deletion. ..................... 5 Rationale for inclusion ......................................................................................... 5 Hypertension guidelines recommendations for use of two BP lowering drugs and FDCs 5 2. Name of the WHO technical department and focal point supporting the application (where relevant) ................................................................................................... 7 3. Name of organization(s) consulted and/or supporting the application. ...................... 7 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine. ............................................................................................ 7 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate). ........................................................................................................ 7 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class. ........................................................................................... 8 7. Treatment details (requirements for diagnosis, treatment and monitoring) .............. 10 Diagnosis and monitoring of hypertension ............................................................. 10 Treatment strategy with dual BP combinations ...................................................... 11 8. Information supporting the public health relevance. ............................................. 12 Epidemiological information on disease burden and treatment gaps ......................... 12 Comparing Fixed-dose combinations vs. separate pills ............................................ 13 Target population(s) ........................................................................................... 14 Likely impact of treatment on the disease ............................................................. 14 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings. ............................................................................................................. 14 Review of BP lowering efficacy of dual vs mono ..................................................... 14 Review of effects of combination therapy vs. placebo/no treatment on cardiovascular events .............................................................................................................. 15 Review of clinical trials assessing BP lowering efficacy of FDC combinations .............. 16 Review of clinical trials assessing BP lowering efficacy of lisinopril/HCTZ ................... 17 Lisinopril/HCTZ vs. placebo ............................................................................... 17 Lisinopril/HCTZ vs. monotherapy ....................................................................... 17 Lisinopril/HCTZ vs. other dual combination therapies ........................................... 17 Review of clinical trials assessing BP lowering efficacy of telmisartan/amlodipine combination ...................................................................................................... 18 Telmisartan/amlodipine vs. placebo ................................................................... 18 Telmisartan-amlodipine vs. monotherapy............................................................ 18 Telmisartan-amlodipine vs. other dual therapies .................................................. 19 Page 3 of 63 Telmisartan/amlodipine as initial therapy ............................................................ 19 Review of clinical trials assessing BP lowering efficacy of telmisartan/HCTZ combinations ....................................................................................................................... 19 Telmisartan/HCTZ vs. placebo ........................................................................... 19 Telmisartan/HCTZ vs. monotherapy ................................................................... 19 Telmisartan/HCTZ vs. dual therapy .................................................................... 20 Four trials51,55–57 reported data for this comparison. ............................................. 20 Review of clinical trials assessing BP lowering efficacy of lisinopril/amlodipine combination ....................................................................................................................... 20 10. Review of harms and toxicity: summary of evidence on safety. ........................... 21 Safety data for Lisinopril/HCTZ ............................................................................ 21 Safety data for Telmisartan/Amlodipine ................................................................ 24 Safety data for lisinopril/amlodipine ..................................................................... 25 Safety data for Telmisartan/HCTZ ........................................................................ 27 11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. ............................................................ 28 Current price insights with respect to global use .................................................... 28 Procurement prices: fixed dose combinations versus single pills ............................ 29 Retail prices of proposed FDCs .......................................................................... 30 Evergreening strategies and FDC price points ...................................................... 30 Implications on cost of FDC for hypertension if added to WHO EML ........................ 31 12. Summary of regulatory status of the medicine ................................................... 32 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). ................... 33 14. References .................................................................................................... 34 Appendix 1: Gender-specific hypertension awareness, treatment, and control in 2010 in countries with data by world region ................................................................ 40 Appendix 2: Summary of characteristics of RCTs that assessed the effects of combination therapy of BP lowering drugs compared to placebo/no treatment on CV outcomes ....................................................................................................... 43 Appendix 3: Lisinopril + Hctz search strategy, PRISMA and summary of characteristics of included trials .............................................................................................. 45 Appendix 4: Lisinopril + HCTZ PRISMA flow chart ................................................ 46 Appendix 5: Summary of characteristics of included trials for assessing lisinopril + HCTZ ..................................................................................................................... 47 Appendix 6: Telmisartan + Amlodipine search strategy, PRISMA and Summary of characteristics of included trials ......................................................................... 48 Appendix 7: Telmisartan + Amlodipine PRISMA flow chart .................................... 49 Appendix 8: Summary of characteristics of included trials for assessing telmisartan + amlodipine ...................................................................................................... 50 Page 4 of 63 Appendix 9: Telmisartan + Hydrochlorothiazide search strategy, PRISMA and summary of characteristics of included trials ..................................................................... 52 Appendix 10: