The objective of this therapeutic review is to conduct a systematic review to assess the comparative efficacy and safety and to determine the cost-effectiveness of drug therapies for the treatment of pulmonary arterial hypertension (PAH) in adults.

Contents

• ABBREVIATIONS AND GLOSSARY
• EXECUTIVE SUMMARY
  • Context and Policy Issues
  • Objectives
  • Methods
  • Economic Model
  • Patient Input
  • Key Findings of Systematic Review
  • Key Findings of Economic Analysis
  • Strengths and Limitations
  • Conclusions and Implications for Decision- or Policy-Making
• 1. CONTEXT AND POLICY ISSUES
  • 1.1. Pulmonary Arterial Hypertension
  • 1.2. Therapeutic Options
• 2. POLICY QUESTIONS
• 3. RESEARCH QUESTIONS
• 4. METHODS
  • 4.1. Systematic Review
  • 4.2. Network Meta-analysis Methods
  • 4.3. Pharmacoeconomic Analysis
• 5. RESULTS
  • 5.1. Selection of Primary Studies
  • 5.2. Study and Patient Characteristics
  • 5.3. Critical Appraisal of Included Studies
  • 5.4. Data Synthesis
  • 5.5. Pharmacoeconomic Evaluation
• 6. DISCUSSION
  • 6.1. Summary of the Clinical Evidence
  • 6.2. Interpretation of the Results
  • 6.3. Strengths and Limitations of the Systematic Review
• 7. CONCLUSIONS AND IMPLICATIONS FOR DECISION-OR POLICY-MAKING
• REFERENCES
• APPENDIX 1. PATIENT INPUT INFORMATION
• APPENDIX 2. VALIDITY OF OUTCOMES
• APPENDIX 3. LITERATURE SEARCH STRATEGY
• APPENDIX 4. SELECTION OF INCLUDED STUDIES
• APPENDIX 5. INCLUDED STUDY LIST
• APPENDIX 6. EXCLUDED STUDY LIST
• APPENDIX 7. CHARACTERISTICS OF INCLUDED STUDIES
• APPENDIX 8. CRITICAL APPRAISAL OF INCLUDED STUDIES
• APPENDIX 9. DETAILED DATA OF MONOTHERAPY AND ADD-ON THERAPY TRIALS
• APPENDIX 10. PAIRWISE META-ANALYSES
• APPENDIX 11. COMPARISONS OF PAIRWISE META-ANALYSES AND NETWORK META-ANALYSES
• APPENDIX 12. COMPLETE RESULTS OF NETWORK META-ANALYSIS
• APPENDIX 13. QUALITY OF LIFE
• APPENDIX 14. COMBINATION THERAPY IN PULMONARY ARTERIAL HYPERTENSION — STUDIES NOT INCLUDED IN THERAPEUTIC REVIEW
• APPENDIX 15. REVIEW OF PREVIOUS PHARMACOECONOMIC ANALYSES
• APPENDIX 16. SCHEMATIC OF MARKOV MODEL
• APPENDIX 17. CLINICAL PARAMETERS FOR THE ECONOMIC MODEL
• APPENDIX 18. RESOURCE USE ESTIMATES FOR THE ECONOMIC MODEL
• APPENDIX 19. BREAKDOWN OF COSTS BY COST CATEGORY

Note Regarding Changes to the Report Following Stakeholder Feedback:

Following feedback received in response to the previous draft of this report, modifications were made to the text and data tables. These modifications did not alter the results of the main analyses or the conclusions of the report.

In the clinical review, changes were made mainly in the discussion section to include a summary of three combination therapy trials (COMPASS-2, AMBITION, and PACES-1). The results of the first two trials were recently made public, while the last one was excluded from the review because the sildenafil dose in the trial did not meet the Health Canada–approved dose. Clinical context of the results from the short-term trials and the lack of long-term controlled data on efficacy and safety of many pulmonary arterial hypertension (PAH) therapies, including sildenafil 20 mg three times daily, were also added in the discussion. In the critical appraisal section, limitations regarding differences in clinical trials with respect to study and patient characteristics were further clarified.

In the pharmacoeconomic analyses, the most notable changes include two additional deterministic sensitivity analyses: the incorporation of unadjusted values for relative risk of improvement and worsening in functional class with PAH therapies obtained from the CADTH network meta-analysis, instead of the values adjusted for baseline functional class status, and incorporation of survival estimates from the National Institutes of Health registry instead of the Pulmonary Hypertension Connection registry.

Authorship: Khai Tran led the project protocol development; selected studies; extracted, tabulated, and analyzed data; wrote the clinical section of the report; and revised the report based on reviewers’ comments.

Kathryn Coyle led the conception and design of the economic model, performed cost-effectiveness analyses and interpretation of results, wrote the economic section of the report, and revised the report based on reviewers’ comments.

Mohammed Jabr led the design and conduct of the network meta-analyses, reviewed and interpreted the results of the network meta-analyses, wrote the clinical section of the report pertaining to the indirect comparisons, and revised the report based on reviewers’ comments.

Doug Coyle contributed to the design of the economic model and provided step-by-step supervision of economic analysis.

Michel Boucher developed the topic proposal and led the project development phase, contributed to the conception of project scope and protocol, contributed to writing the clinical section of the report, and reviewed and revised the clinical section of the report.

Lisa Mielniczuk contributed to the project protocol development, provided content expertise, and reviewed drafts of the report.

John Swiston contributed to the project protocol development, provided content expertise, and reviewed drafts of the report.

Danielle Rabb designed and executed the literature search strategies, wrote the literature search section, and managed report referencing.

Karen Cimon selected studies; extracted, tabulated, and analyzed data; contributed to writing the supplemental issues in the appendices of the report; and revised the report based on reviewers’ comments.

Julie Blouin participated in the design of the economic analysis, assisted in the interpretation of results, and reviewed and revised the economic section of the report.

Michael Innes contributed to the conception of scope and protocol for the clinical review, provided guidance regarding the choice of methods for the analysis of clinical data, reviewed and revised the clinical section of the report, and assisted in the interpretation of clinical data.

All authors approved the final draft report.

Contributors: The authors would like to acknowledge Chris Cameron for advice on the network meta-analysis component.

CADTH staff for their contributions:: Hongbo Yuan for advice on the protocol design, data analysis, and review of reports; Elaine MacPhail for feedback support and advice related to patient input; Sarah Jennings for feedback on project scope and final report, support for patient groups and patient input summaries, and advice on knowledge translation; Janice Mann for feedback on project scope and support for patient groups and patient input summaries; Karen Lee for advice regarding the economic analysis; Chander Sehgal and Kristen Chelak for input on project scope; and Patricia Reynard for project management support.

This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). The report contains a comprehensive review of the existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) available to CADTH at the time of report preparation.

The information in this report, when finalized, is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. The information in this report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this document to ensure that its contents are accurate, complete, and up to date as of the date of publication, CADTH does not make any guarantee to that effect. CADTH is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation.

This document and the information provided are prepared and intended for use in the context of the Canadian health care system. Other health care systems are different; the issues and information related to the subject matter of this document may be different in other jurisdictions and, if used outside of Canada, it is at the user’s risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

CADTH takes sole responsibility for the final form and content of this document, subject to the limitations noted above. The statements and conclusions in this document are those of CADTH and not of its advisory committees and reviewers. The statements, conclusions, and views expressed herein do not necessarily represent the views of Health Canada or any Canadian provincial or territorial government. Production of this document is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon.

This report is shared for feedback and comments and should not be used for any purposes other than for consultation. The report may change following this consultation.