Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism

413 Pages·2017·5.63 MB·English

CADTH OPTIMAL USE REPORT
Optimal Strategies for the Diagnosis
of Acute Pulmonary Embolism:
A Health Technology Assessment
January 2018
Volume 6, Issue 3b
PROSPERO Registration Number: 42016046980
Clinical Authors: Alison Sinclair, Kwakye Peprah, Teo Quay, Matthew McInnis, Eddy Lang, Melissa Severn, Sohail Mulla, Laura Weeks
Economic Author: Bernice Tsoi
Patient Perspectives and Experiences Authors: Elijah Herrington, Myuri Manogaran
Implementation Author: Sarah Garland
Ethics Author: Angel Petropaganos
Environmental Authors: Kwakye Peprah, Julie Polisena
Cite As: Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment. Ottawa: CADTH; 2018 Jan. (CADTH optimal
use report; vol.6, no.3b).
ISSN: 1927-0127 (online)
Disclaimer: The information in this document 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. While patients and others may access this document, the
document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose.
The information in this document should not be used as a substitute for professional medical advice or 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. The Canadian Agency for Drugs and Technologies in
Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date
the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the
quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing
this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, 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 contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the
third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on
such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no
responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal,
provincial, or territorial governments or any third party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at
the user’s own 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.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian
Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes
only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to
help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 2
External Reviewers
This document was externally reviewed by content experts. The following individuals
granted permission to be cited.
Dr. Michel Leblanc, MD, RCPSC ABNM
Chief of Staff
Nuclear Medicine, CIUSS-MCQ
University of Sherbrooke, Quebec

Dr. Nandini Dendukuri, PhD
Associate Professor
Department of Epidemiology, Biostatistics and Occupational Health Faculty of Medicine
McGill University, Quebec

Thomas Foreman, DHCE, MA
Ethicist
Health Ethics Alliance, Centre for Addiction and Mental Health
Sunnybrook Health Sciences Centre
Toronto, Ontario

Dr. Martin H. Reed, MD, FRCPSC, FACR
Radiologist
Department of Diagnostic Imaging
Children’s Hospital
Winnipeg, Manitoba

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 3
Authorship
Clinical Review
Dr. Alison Sinclair led the clinical project protocol development and selected studies. She
extracted, tabulated, and analyzed data; wrote the clinical section of the report; and revised
the report based on reviewers’ comments.
Kwakye Peprah contributed to article screening and selection, data extraction, and
tabulation of data for the clinical review, and contributed to the writing of the clinical section
of the report.
Teo Quay also contributed to article screening and selection, data extraction, and tabulation
of data for the clinical review, and contributed to the writing of the clinical section of the
report.
Dr. Matthew McInnis participated in the conceptualization of clinical approaches to imaging
for pulmonary embolism and in the preparation and review of the draft reports.
Dr. Eddy Lang participated in the conceptualization of clinical approaches to imaging for
pulmonary embolism and in the preparation and review of the draft reports.
Melissa Severn designed and executed the literature search strategies, wrote the literature
search methods section and appendix, and managed report referencing.
Dr. Sohail Mulla contributed to the preparation of the clinical section in the protocol and
provided methodological support throughout the project.
Dr. Laura Weeks contributed to the preparation of the clinical section in the protocol and
provided methodological support throughout the project.
Economic Review
Dr. Bernice Tsoi led the economic protocol development, conducted the review of the
economic literature, conducted the economic evaluation, wrote the economic section of the
report, and revised the report based on reviewers’ comments.
Patient Perspectives and Experience Review
Elijah Herrington contributed to the drafting and reviewing of the protocol sections for the
patient perspectives and experience review; performed article selection, coding, and
analysis; and reviewed and contributed to the drafting of the report.
Dr. Myuri Manogaran contributed to the drafting and reviewing of the protocol sections for
the patient perspectives and experience review; performed article selection, coding, and
analysis; and reviewed and contributed to the drafting of the report.
Implementation Review
Sarah Garland led the conception of the methodology for the implementation review and
prepared the protocol sections for the implementation review, performed the analysis, and
contributed to the drafting of the report.

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 4
Ethics Review
Dr. Angel Petropaganos conducted and wrote the ethics analysis of this report, participated
in discussion and interpretation of the results.
Environmental Review
Kwakye Peprah contributed to article screening and selection, and to the writing of the
environmental section of the report.
Dr. Julie Polisena contributed to article screening and selection, and to the writing of the
environmental section of the report.
Acknowledgements
The authors would like to acknowledge the Health Technology Assessment Unit at the
University of Calgary for reviewing the clinical data and draft health technology assessment
report; Dr. Reem Mustafa, Dr. Payal Patel, Itziar Etxeandia Ikobaltzeta, and Dr. Parth Patel
for reviewing and validating the clinical data; Andra Morrison for her contribution to the
scoping of the clinical report; Tamara Radar for providing methodological support to the
patient preferences and experiences review; Ken Bond for his contribution to the ethics
review; and Kim Ghosh for her assistance in project management support.
Conflicts of Interest
There were no declarations of conflict of interest.

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 5
Table of Contents
External Reviewers ..................................................................................................... 3
Authorship .................................................................................................................. 4
Abbreviations ............................................................................................................ 12
Protocol Amendments .............................................................................................. 13
Executive Summary .................................................................................................. 14
Issue ............................................................................................................................................ 14
Objectives .................................................................................................................................... 14
Clinical Evidence .......................................................................................................................... 14
Economic Evidence ...................................................................................................................... 15
Patients’ Perspectives and Experiences ...................................................................................... 16
Implementation Issues ................................................................................................................. 17
Environmental Impact .................................................................................................................. 18
Ethical Issues ............................................................................................................................... 18
Conclusions .................................................................................................................................. 19
Rationale and Policy Issues ...................................................................................... 20
Overview ...................................................................................................................................... 20
Mechanism and Outcomes........................................................................................................... 20
Diagnosis ..................................................................................................................................... 20
Policy Issues ................................................................................................................................ 24
Summary and Project Goals ........................................................................................................ 25
Policy Question ......................................................................................................... 26
Objectives ................................................................................................................. 26
Research Questions ................................................................................................. 26
Clinical.......................................................................................................................................... 26
Cost-Effectiveness ....................................................................................................................... 27
Patients’ Perspectives and Experiences ...................................................................................... 27
Implementation Issues ................................................................................................................. 27
Environmental Impact .................................................................................................................. 27
Methods .................................................................................................................... 28
Clinical Review ............................................................................................................................. 28
Economic Review ....................................................................................................................... 107

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 6
Patient Perspectives and Experiences .................................................................... 144
Study Design .............................................................................................................................. 144
Methods ..................................................................................................................................... 144
Eligibility Criteria ......................................................................................................................... 145
Critical Appraisal of Individual Studies ....................................................................................... 146
Summary of Study Characteristics ............................................................................................. 147
Summary of Critical Appraisal .................................................................................................... 148
Results ....................................................................................................................................... 150
Summary of Findings ................................................................................................................. 153
Implementation Issues ............................................................................................ 154
Methods ..................................................................................................................................... 154
Summary of Results ................................................................................................................... 165
Environmental Impact ............................................................................................. 166
Objective .................................................................................................................................... 166
Literature Search ........................................................................................................................ 166
Study Selection Criteria .............................................................................................................. 166
Data Extraction ........................................................................................................................... 167
Ethics...................................................................................................................... 168
Research Question .................................................................................................................... 168
Methods ..................................................................................................................................... 168
Search Results ........................................................................................................................... 169
Summary of Findings and Ethics Analysis ................................................................................. 170
Discussion .............................................................................................................. 180
Overall Summary of Findings ..................................................................................................... 180
Strengths .................................................................................................................................... 182
Limitations .................................................................................................................................. 183
Conclusions ................................................................................................................................ 187
References ............................................................................................................. 188

Appendix 1: Literature Search Strategy ......................................................................................... 213
Appendix 2: Supplemental Search Strategy .................................................................................. 243
Appendix 3: Clinical Full-Text Screening Checklist ....................................................................... 253
Appendix 4: Clinical Data Extraction Form for Primary Studies ..................................................... 255
Appendix 5: Clinical Data Extraction Form for Systematic Reviews .............................................. 257
Appendix 6: Pulmonary Embolism Diagnosis and Management Strategies
and Subsequent Outcomes ...................................................................................... 259

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 7
Appendix 7: Selection Criteria for Network Meta-Analysis ............................................................. 260
Appendix 8: Study Selection Flowchart (Prisma) for Clinical Review ............................................ 261
Appendix 9: Overlap Among Primary Studies from Included Systematic Reviews ........................ 263
Appendix 10: List of Excluded Studies for Clinical Review (Questions 1, 2, and 3) ....................... 266
Appendix 11: Quality Assessment Questions for Clinical Review ................................................. 273
Appendix 12: Characteristics of Included Systematic Reviews for Clinical Review of Risk
Stratification (Question 1) ....................................................................................... 277
Appendix 13: Diagnostic Accuracy Outcomes Reported by Included Systematic Review
(Question 1) ............................................................................................................ 280
Appendix 14: Utility Outcomes Reported by Included Systematic Reviews (Question 1) ............. 282
Appendix 15: Summary of Quality or Risk of Bias Assessments Conducted by
Included Systematic Reviews For Clinical Review (Question 1) ............................. 283
Appendix 16: Characteristics of Included Primary Studies for Clinical Review
(Questions 2 and 3) ................................................................................................ 285
Appendix 17: Quality Assessment of Included Primary Studies for Clinical Review
(Questions 2 and 3) ................................................................................................ 326
Appendix 18: Individual Study Diagnostic Test Accuracy Data (Questions 2 and 3) .................... 340
Appendix 19: Individual Study Utility and Safety Data (Questions 2 and 3) .................................. 352
Appendix 20: Study Characteristics of Studies in Pregnant Patients ............................................ 358
Appendix 21: Results of Individual Studies Reporting Stratified Results
and Multiple Imaging Conditions ............................................................................. 360
Appendix 22: Statistical Appendix (Questions 2 and 3) ................................................................ 362
Appendix 23: Risk Stratification: Parameters for the Economic Evaluation .................................. 377
Appendix 24: Characteristics of Existing Published Economic Evaluation on Diagnosis of PE .... 378
Appendix 25: Diagnostic Pathway ................................................................................................ 381
Appendix 26: List of Diagnostic Strategies Considered in the Economic Model ........................... 385
Appendix 27: Detailed Results of the Reference Case ................................................................. 389
Appendix 28: Additional Sensitivity Analysis Results .................................................................... 396
Appendix 29: Selection of Studies on Patient Perspectives and Experience ................................ 398
Appendix 30: Study Characteristics Table .................................................................................... 399
Appendix 31: Critical Appraisal of Included Publications .............................................................. 400
Appendix 32: CADTH Survey Questions ...................................................................................... 403
Appendix 33: Survey Respondents – Self Identified Description .................................................. 407
Appendix 34: Study Characteristics Table .................................................................................... 408
Appendix 35: Selection of Studies on Environmental Impact ........................................................ 410
Appendix 36: Selection of Studies on Ethics Analysis .................................................................. 411
Appendix 37: Characteristics of Included Ethics Reports ............................................................. 412

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 8
Tables
Table 1: Economic Analysis Reference-Case Results .................................................................... 16
Table 2: Search and Selection Criteria for Clinical Research Questions ......................................... 29
Table 3: Summary of Modalities, End Points, and Failure Rate Recorded for Pathways for
Diagnosis of PE ................................................................................................................. 47
Table 4: Matrix of Counts for Pairs of Index Tests and Reference Standards Reported in Studies . 48
Table 5: Summary of Study Information for Computed Tomography .............................................. 50
Table 6: Summary of Study Information for Magnetic Resonance Imaging ..................................... 55
Table 7: Summary of Technical and Sequence Information for Magnetic Resonance Imaging
Studies .............................................................................................................................. 56
Table 8: Summary of Study Information for Thoracic Ultrasound .................................................... 62
Table 9: Summary of Study Information for Perfusion Imaging ....................................................... 67
Table 10: Summary of Study Information for Ventilation/Perfusion ................................................. 73
Table 11: Summary of Study Information for Ventilation/Perfusion Single-Photon Emission
Computed TomographyStudies ....................................................................................... 78
Table 12: Summary of Study Information for Ventilation/Perfusion Single-Photon Emission
Computed Tomography–Computed Tomography Studies .............................................. 82
Table 13: Summary of Meta-Analysis Diagnostic Test Accuracy Results ....................................... 84
Table 14: Summary of Narrative Diagnostic Test Accuracy Results ............................................... 84
Table 15: Failure Rate by Modality ................................................................................................ 103
Table 16: Summary of Indeterminate or Nondiagnostic Tests ....................................................... 104
Table 17: Mortality and Radiation Dose Results by Modality ......................................................... 105
Table 18: Diagnostic Tests and Examinations Evaluated in the Reference Case ......................... 110
Table 19: Diagnostic Test Accuracy .............................................................................................. 114
Table 20: Radiation Exposure Associated With Each Diagnostic Test .......................................... 116
Table 21: Pulmonary Embolism–Specific Probabilities .................................................................. 117
Table 22: Utility Values Associated With Each Health State ......................................................... 118
Table 23: Diagnostic Costs (2017 $) ............................................................................................. 119
Table 24: Assumptions Used to Populate the Economic Model
(applied to all diagnostic strategies evaluated) .............................................................. 122
Table 25: Comparison of Markov Model’s Prediction on Disease Progression
With Published Studies .................................................................................................. 124
Table 26: Comparison of Decision Tree Prediction on Diagnostic Results
Against Clinical Studies ................................................................................................. 126
Table 27: Lifetime Costs and QALYs of Different Diagnostic Strategies (Reference Case) —
Sequential Incremental Cost-Utility Ratio ...................................................................... 131
Table 28: Expected Clinical Outcomes — Diagnostic Strategies on the Efficiency Frontier .......... 131
Table 29: Expected Lifetime Costs in Selected Categories — Diagnostic Strategies on the
Efficiency Frontier .......................................................................................................... 132

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 9
Table 30: Lifetime Costs and Life-Years of Different Diagnostic Strategies — Sequential
Incremental Cost-Effectiveness Ratio ............................................................................ 132
Table 31: General Sensitivity Analyses Results (Diagnostic Strategies That Are
Dominated Are Not Shown) ........................................................................................... 135
Table 32: Lifetime Results of Different Scenario Analyses ............................................................ 139
Table 33: Lifetime Results, By Varied Patients’ Age (Diagnostic Strategies That Are
Dominated Are Not Shown) ........................................................................................... 140
Table 34: Lifetime Results for Pregnant Patients (Diagnostic Strategies That Are
Dominated Are Not Shown) ........................................................................................... 140
Table 35: Lifetime Results From an In-Patient Setting (Diagnostic Strategies That Are
Dominated Are Not Shown) ........................................................................................... 141

Figures
Figure 1: Schematic of Pathway Studies ......................................................................................... 45
Figure 2: Risk of Bias for Single-Arm Pathway Studies ................................................................... 46
Figure 3: Risk of Bias and Applicability for All Studies With Computed Tomography
as an Index Test ............................................................................................................... 51
Figure 4: Forest Plot for Studies With Computed Tomography as Index Test ................................. 52
Figure 5: Risk of Bias and Applicability for All Studies With Magnetic Resonance Imaging
as an Index Test ............................................................................................................... 57
Figure 6: Forest Plot for Studies With Magnetic Resonance Imaging as Index Test ....................... 58
Figure 7: Risk of Bias and Applicability for All Studies With US as an Index Test ........................... 63
Figure 8: Forest Plot for Studies With Thoracic Ultrasound as Index Test ...................................... 64
Figure 9: Risk of Bias and Applicability for All Studies With Q as an Index Test ............................. 67
Figure 10: Forest Plot for Studies With Perfusion as Index Test ..................................................... 68
Figure 11: Risk of Bias and Applicability for All Studies With Ventilation/Perfusion
as an Index Test ............................................................................................................. 74
Figure 12: Forest Plot of Studies With Ventilation/Perfusion as Index Test..................................... 75
Figure 13: Risk of Bias and Applicability for All Studies With Ventilation/Perfusion
Single-Photon Emission Computed Tomography as an Index Test ............................... 79
Figure 14: Forest Plot of Studies With Ventilation/Perfusion Single-Photon Emission
Computed Tomography as Index Test ........................................................................... 80
Figure 15: Forest Plot of Studies With Ventilation/Perfusion Single-Photon Emission
Computed Tomography–Computed Tomography as Index Test .................................... 83
Figure 16: Risk of Bias for Comparative Studies of Computed Tomography as Index Test ............ 87
Figure 17: Risk of Bias for Single-Arm Studies of Computed Tomography ..................................... 87

OPTIMAL USE REPORT Optimal Strategies for the Diagnosis of Acute Pulmonary Embolism: A Health Technology Assessment 10