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Recombinant Activated Factor VII for HTA Prevention of Bleeding Unrelated to Issue 124 Hemophilia: Clinical and Economic February 2010 Systematic Review
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Cite as: Murphy G, Tsakonas E, Ndegwa S, Anderson D, Barkun J, Mierzwinski-Urban M. Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010. (Technology Report; no. 124). [cited 2010 Feb 4]. Available from: http://www.cadth.ca/index.php/en/publication/960
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Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
Gaetanne Murphy, BSc Pharm1 Eva Tsakonas, BA MSc2 Sarah Ndegwa, BSc Pharm MSc1 David Anderson, MD FRCPC3 Jeffrey Barkun, MD MSc FRCPC4 Monika Mierzwinski-Urban, MLIS1
February 2010
1 Canadian Agency for Drugs and Technologies in Health, Ottawa, ON 2 Independent Consultant 3 Division of Hematology, Department of Medicine, Pathology and Community Health and Epidemiology, Dalhousie University, Halifax, NS 4 Division of General Surgery, McGill University, Montreal, QC
Reviewers These individuals kindly provided comments on this report.
External Reviewers Craig Mitton, PhD Man-Chiu Poon, MD MSc FRCPC FACP Associate Professor Professor of Medicine, Pediatrics and Oncology, University of British Columbia University of Calgary Vancouver, BC Director, Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Alberta Health Services Calgary, AB
Richard Audas, BBA MBA MA PhD Peter Ghali, MD FRCPC MSc(Epi) Assistant Professor Assistant Professor Faculty of Medicine, McGill University Health Centre Memorial University Montreal, QC St. John’s, NL
Brian Muirhead, MD FRCPC University of Manitoba Winnipeg, MB
CADTH Peer Review Group Reviewers Jocalyn Clark, BSc MSc PhD Stuart Peacock, DPhil Assistant Professor of Medicine, Co-Director University of Toronto National Centre for Health Economics, Services, Senior Editor Policy and Ethics in Cancer PLoS Medicine Vancouver, BC Toronto, ON
Industry: Novo Nordisk Canada Inc. was provided with an opportunity to comment on an earlier version of this report.
This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH, and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation.
CADTH takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CADTH and not of its Panel members or reviewers.
i Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review Authorship Gaetanne Murphy, research lead for the project, led the protocol development and clinical review, wrote the clinical draft, revised the report, and prepared the report for publication.
Eva Tsakonas led the economic review, designed the economic portion of the protocol, and wrote the health services impact and economic sections of the report. She revised the report and prepared it for publication.
Sarah Ndegwa provided guidance on the protocol development and drafting of the report. She assisted with abstract screening, assisted with extracting and verifying data, and reviewed drafts for clarity and accuracy.
David Anderson and Jeffrey Barkun provided clinical expertise and guidance on protocol development, interpretation of evidence, drafting of the report, and revision of the report.
Monika Mierzwinski-Urban developed the literature search strategies, performed the literature searches, provided updates to the searches, wrote the literature search methods section, verified references, and formatted the bibliographies.
Acknowledgements The authors are grateful to Sheri Pohar, who provided background information for the protocol and the introduction, and to Hussein Noorani, who wrote the ethics section. We thank Melissa Severn for completing the final verification of references and formatting the bibliography.
Conflicts of Interest None of the co-authors has any conflicts of interest to declare.
Dr. Man-Chiu Poon was a member of the Expert Panel for Glanzmann’s Thrombasthenia Registry, sponsored by Novo Nordisk, and received honorariums from Novo Nordisk in 2006 and 2009. He was also a speaker on “Management of bleeding in congenital platelet disorders” at the Asian Regional Hemostasis Update Meeting (July 2008) sponsored by the Thai Society of Hematology and International Hemophilia Training Center in Bangkok (received honorarium provided by Novo Nordisk). Dr. Man-Chiu Poon was also a speaker on “Management of patients with refractory platelet function disorders” at the 3rd Asian Regional Hemostasis Update meeting (April 18 to 19, 2009) sponsored by the Malaysian Society of Hematology and the Malaysian Society of Transfusion Medicine in Kuala Lumpur (received honorarium provided by Novo Nordisk).
Dr. Brian Muirhead has received honorariums from Novo Nordisk, Fresenius Kobe, Bristol- Myers Squibb, and Bayer.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: ii Clinical and Economic Systematic Review iii Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review EXECUTIVE SUMMARY
The Issue Recombinant activated factor VII (rFVIIa) is a hemostatic agent that is approved for the treatment of bleeding episodes in hemophilia A or B patients with clotting factor inhibitors. It is being used beyond the approved indications by non-hemophilia patients undergoing surgery. Recombinant FVIIa is costly, and it is unclear if the benefit of the off-label use of rFVIIa outweighs the potential harms and costs.
Objectives This report assesses the impact of using rFVIIa for the prevention of bleeding in patients without hemophilia or other inherited bleeding disorders.
The research questions are: 1. What is the clinical effectiveness of evaluated doses and regimens of rFVIIa compared with placebo, no treatment, or other standard therapies for the prevention of bleeding associated with liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies? 2. What are the practice guidelines for monitoring safety and efficacy of rFVIIa when used for the prevention of bleeding associated with liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies? 3. What is the cost-effectiveness of rFVIIa compared with placebo, no treatment, or other standard therapies when used for liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies?
Methods A systematic review of the clinical and economic literature was conducted. Randomized controlled trials (RCTs), non-randomized controlled clinical trials, prospective controlled observational studies, evidence based guidelines, and economic analyses that met the inclusion criteria were included in the review. The selection of studies and extraction of data were completed independently by two researchers.
Clinical Effectiveness Eight RCTs and two cohort studies focused on surgical patients who received rFVIIa, placebo, or usual care for the prevention of bleeding. No studies evaluated rFVIIa for the prevention of bleeding in patients receiving anticoagulation agents. Two evidence-based guidelines stated that there is no specific method to monitor the efficacy of rFVIIa treatment for the prevention of bleeding.
Because of the heterogeneity among the small numbers of studies that were identified for each indication, a narrative synthesis was conducted. Most trials did not report the mean differences
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: iv Clinical and Economic Systematic Review between groups or associated 95% confidence intervals. Instead, they summarized the comparisons between groups using descriptive statistics and P values resulting from hypothesis testing. When the estimates of between-group differences were unavailable, the interpretations of findings as presented by study authors were summarized.
In an RCT involving 82 pediatric cardiac surgery patients, no statistically significant difference was detected favouring rFVIIa therapy compared with placebo for the volume of red blood cells or platelets transfused, or operative time. In one RCT involving 20 adults undergoing cardiac surgery, no statistically significant difference was found between rFVIIa and placebo in any outcome that was measured (volume of blood products, length of stay, or adverse events). A second placebo-controlled RCT (22 patients) reported statistically significant reductions favouring rFVIIa in the volume of red blood cells or platelets transfused and in the length of intensive care unit stay.
In adult patients undergoing liver transplantation, two small RCTs (25 or fewer patients in each trial) reported that rFVIIa statistically significantly reduced the volume of red blood cells and fresh frozen plasma that was transfused compared with placebo or usual care. No statistically significant differences in the volume of blood products that was transfused were detected among patients who received rFVIIa during one placebo-controlled trial involving 87 patients and during another placebo-controlled trial involving 209 patients. The length of hospital or intensive care unit stay was similar between rFVIIa and control groups. One of four RCTs reported that the use of rFVIIa statistically significantly lowered the duration of the surgical transplantation procedure.
An RCT involving 36 patients undergoing prostatectomy concluded that the use of rFVIIa reduced the need for red blood cell transfusion and reduced the operative time compared with placebo. No statistically significant differences were detected between groups in the length of hospital stay, number of adverse events, or number of deaths.
It was not possible to adequately evaluate the risk of adverse events that was associated with the prophylactic use of rFVIIa during surgery. Adverse event data were poorly reported in the clinical trials, and the studies were not designed to detect differences in the incidence of uncommon events. Most studies excluded patients at risk of thromboembolic events. The strength of evidence was limited by the quality and quantity of the literature available. There was a low risk of bias in two of eight RCTs. In six studies, the risk of bias was unclear.
Economic Review Three studies reported the costs and consequences of treatment in three different indications. The findings of these studies were presented in a narrative synthesis. A retrospective study of liver transplantation found no difference in costs or outcomes between patients who were treated using rFVIIa and those receiving usual care. A randomized, placebo-controlled trial in cardiac valve replacement reported less use of blood products, shorter intensive care unit stays, and higher costs for patients who were randomized to receive therapy using rFVIIa. A randomized, placebo-controlled trial of abdominal prostatectomy reported a dose-response effect in the number of packed cell units transfused and a shorter operating time for patients receiving rFVIIa. There was no evaluation of outcomes beyond the hospital stay in the three studies. Total hospital
v Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review costs were lower for patients receiving the higher dose of rFVIIa compared with placebo. All three studies had limitations in that data were obtained from one hospital centre, the studies on which they were based had small sample sizes, the assessments of outcomes and costs were limited to the duration of the inpatient stay, and the health states were not evaluated. The three studies were not reported in sufficient detail to permit a complete assessment of the methods and results, and generalizability to a Canadian setting was limited.
Health Services Impact There is little use of rFVIIa for the prevention of bleeding in Canada, because of concerns about thromboembolic adverse events relative to potential benefit. For this reason, a formal budget impact analysis was not conducted. If future clinical research finds rFVIIa to be efficacious and to be associated with a low risk of thromboembolic events, as many as 33,000 cardiac surgery, liver transplant surgery, and prostatectomy patients, combined, may be eligible for this treatment in Canada each year.
Conclusions No consistent benefit of rFVIIa therapy was detected among studies evaluating the prevention of bleeding in patients undergoing prostatectomy, liver transplantation, or cardiac surgery. The risk of adverse events after the prophylactic use of rFVIIa in surgical patients is unknown. No conclusions can be drawn on the effectiveness or safety of using rFVIIa in the prevention of bleeding in patients who have received supra-therapeutic doses of anticoagulant agents. When used for prevention of bleeding, no specific method is available to monitor the effectiveness of rFVIIa.
Given the small number of economic studies available and limitations in the reporting, methods, and generalizability of these studies, conclusions about the cost-effectiveness of using rFVIIa to prevent bleeding in a Canadian setting cannot be made. An informative primary economic evaluation might be more appropriate when consistent effectiveness evidence is available and preventive use of this treatment more commonplace. As a result, the cost-effectiveness of using rFVIIa in the prevention of bleeding unrelated to hemophilia remains unknown. If rFVIIa is used preventively on a wider scale by clinicians in the future, the potentially eligible population for this treatment is substantial.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: vi Clinical and Economic Systematic Review ABBREVIATIONS
CI confidence interval FFP fresh frozen plasma ICU intensive care unit INR international normalized ratio RBCs red blood cells (packed cells) RCT randomized controlled trial rFVIIa recombinant activated factor VII RMB Chinese Yuan SD standard deviation
vii Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review TABLE OF CONTENTS
EXECUTIVE SUMMARY ...... iv
ABBREVIATIONS ...... vii
1 INTRODUCTION...... 1 1.1 Background and Setting in Canada...... 1 1.2 Overview of Technology...... 3
2 ISSUE ...... 4
3 OBJECTIVES ...... 4
4 CLINICAL REVIEW ...... 5 4.1 Methods...... 5 4.1.1 Literature searches...... 5 4.1.2 Selection criteria...... 5 4.1.3 Selection method...... 6 4.1.4 Data extraction strategy...... 7 4.1.5 Strategy for validity assessment...... 7 4.1.6 Data analysis methods ...... 7 4.2 Results ...... 8 4.2.1 Quantity of research available ...... 8 4.2.2 Study characteristics...... 8 4.2.3 Data analyses and synthesis...... 11
5 ECONOMIC ANALYSIS ...... 15 5.1 Review of Economic Studies: Methods ...... 15 5.1.1 Literature searches...... 15 5.1.2 Selection criteria...... 15 5.1.3 Selection method...... 16 5.1.4 Data extraction strategy...... 16 5.1.5 Strategy for validity assessment...... 16 5.1.6 Data analysis methods ...... 17 5.2 Review of Economic Studies: Results...... 17 5.2.1 Quantity of research available ...... 17 5.2.2 Study characteristics...... 17 5.2.3 Study results...... 19 5.2.4 Summary ...... 21
6 HEALTH SERVICES IMPACT...... 22 6.1 Planning, Implementation, Utilization, and Legal or Regulatory Considerations...... 24 6.2 Ethical Considerations...... 24 6.2.1 Methods...... 24 6.2.2 Discussion ...... 24
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: viii Clinical and Economic Systematic Review 7 DISCUSSION...... 25 7.1 Summary of Results...... 25 7.2 Strengths and Weaknesses of this Assessment ...... 26 7.3 Generalizability of Findings ...... 27 7.4 Knowledge Gaps...... 27
8 CONCLUSIONS...... 28
9 REFERENCES...... 29
APPENDIX 1: Literature Seach APPENDIX 2: Excluded Studies Classified by Research for Exclusion APPENDIX 3: Clinical Data Extraction Form APPENDIX 4: Quality Assessment Form for RCTs APPENDIX 5: Cochrane Risk of Bias Tool for RCTs APPENDIX 6: Quality Assessment Form for Cohort Studies APPENDIX 7: Summary of Studies in Clinical Review APPENDIX 8: Data Extraction Form for Economic Studies APPENDIX 9: Excluded Economic Studies APPENDIX 10: Quality Assessment Using BMJ 35-Item Checklist for Economic Evaluations APPENDIX 11: External Validity of Economic Studies APPENDIX 12: Summary of Studies in Economic Review
ix Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review 1 INTRODUCTION
This is the second report in the Canadian Agency for Drugs and Technologies in Health’s (CADTH’s) review of the clinical and economic impact of using recombinant activated factor VII (rFVIIa) in patients without hemophilia or other coagulopathies. The first report evaluated the use of rFVIIa for the treatment of uncontrolled bleeding in trauma, surgery, upper gastrointestinal hemorrhage, or intracerebral hemorrhage.1 It found that there was no demonstrated benefit or harm from using rFVIIa relative to usual care in these populations. The potential cost-effectiveness of using rFVIIa for severe blunt trauma, which was uncertain because of the inconclusive clinical data, can be confirmed based on more research. The routine use of rFVIIa for severe blunt trauma could lead to potential costs to Canadian Blood Services.1
This second report focuses on the prevention of bleeding in patients undergoing liver transplantation, prostatectomy, or cardiac surgery or in patients not actively bleeding but who require a reversal of supra-therapeutic anticoagulation.
1.1 Background and Setting in Canada
When tissue injury and bleeding occur, a sequence of enzymatic reactions (known as the coagulation cascade) is initiated to stop bleeding. The result of this sequence of reactions is the formation of a stable fibrin plug or blood clot at the site of tissue injury. It is believed that clotting starts with the contact of factor VII with tissue factor. This converts factor VII to activated factor VII (known as factor VIIa). In turn, factor VIIa activates factors IX and X. This ultimately results in the formation of a hemostatic plug.2,3
When the coagulation cascade is disrupted because of a genetic condition (for example, hemophilia) or an acquired clotting disorder (for example, trauma or the use of anticoagulant agents), hemostasis does not occur as expected.2 Acquired clotting disorders can be difficult to manage because they often arise from several underlying problems and can be complicated by other medical illnesses.2 Perioperative bleeding may be the result of the surgical technique that is used, defective hemostasis, or a combination of the two.2
Some surgical procedures are associated with higher perioperative blood loss. This report will focus on three such surgical populations. In patients undergoing complex cardiac surgery that requires cardiopulmonary bypass, the risk of hemorrhage is increased because of platelet dysfunction caused by the bypass procedure, thrombocytopenia, dilution of coagulation factors, hyperfibrinolysis, hypothermia, or acidosis.2 Excessive bleeding after cardiac surgery has been linked to an increased risk of death during the perioperative period.4 Patients with end-stage liver disease undergoing liver transplantation have an increased risk of morbidity and mortality due to severe hemorrhage secondary to pre-existing coagulopathy.2,5 Radical prostatectomy is a surgical procedure with a potential for substantial blood loss due to the rich venous supply to the prostate6 and from the presence of an intrinsic anticoagulant in prostatic tissue. The average volume of blood loss during radical prostatectomy varies from 550 mL to 2,774 mL, and approximately 2% to 27% of patients need a blood transfusion.6-13
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 1 Clinical and Economic Systematic Review Minimizing surgical blood loss can reduce a patient’s risk of exposure to the use of blood products. Adverse effects occur in approximately 0.5% to 3% of transfusions, and most are minor with no consequences.14 In Canada, the risk of transmission of HIV, hepatitis B virus, and hepatitis C virus have been reduced to one in 7.8 million, one in 153,000, and one in 2.3 million donations respectively.15 Reactions due to the transmission of bacteria are rare.14 Most of the non-infectious adverse events, which are more common, are immune-mediated. Acute hemolytic transfusion reaction, which is the most frequent severe reaction, is a leading cause of death associated with blood transfusions. Eighty per cent of deaths related to acute hemolytic transfusion reactions are due to ABO incompatibility resulting from administrator error.14 Transfusion-related acute lung injury (TRALI), which is rare, has a high case fatality rate and is a leading cause of transfusion related death.14
Antifibrinolytics (for example, tranexamic acid, aminocaproic acid), desmopressin, or the replacement of depleted clotting components with fresh frozen plasma (FFP) or platelet transfusion may be used to minimize perioperative blood loss.2 Aprotinin, an antifibrinolytic commonly used in cardiac surgery, has been removed from the Canadian market based on evidence of increased mortality risk.16 Fresh frozen plasma and prothrombin complex concentrates, which may be used to manage hemostatic disorders in liver disease, are associated with risks such as fluid overload and thromboembolism.2 Surgical blood conservation strategies include preoperative autologous blood donation, acute normovolemic hemodilution, and salvage of blood cells from the operative field (the area that is open during surgery) using a cell saver device.8,10,11,13 The availability of alternative hemostatic agents, such as rFVIIa, that could be used to prevent severe surgical bleeding would be beneficial to patients.
The fourth indication relevant to this report is the prevention of bleeding in patients who have received a supra-therapeutic dose of an anticoagulant agent (those with elevated clotting times and not bleeding). Patients who are treated chronically using anticoagulant agents, such as warfarin, have an increased risk of bleeding.2 The risk increases as international normalized ratio (INR) levels rise to supra-therapeutic levels, and at times, the rapid reversal of anticoagulation is needed. Depending on the anticoagulant that is administered, the effects can be reversed (at varying rates) using agents such as vitamin K, protamine, fresh frozen plasma, or prothrombin complex concentrates.17-19 Recombinant factor VIIa has been shown to normalize laboratory clotting tests in healthy individuals receiving anticoagulants.2,20-22 The efficacy and safety of rFVIIa as a reversal agent in anticoagulated patients is unknown.20-22
Based on published reports and unpublished rFVIIa registry data, most of the off-label rFVIIa use in Canada seems to be for the treatment of uncontrolled bleeding instead of for prevention (Source: Muirhead B, Dickson T, Freeman J. Recombinant Factor VIIa Use in Canada. Physicians and Nurses for Blood Conservation [PNBC] Database: 2005-2006).23-25 Preventive therapy, if adopted widely, could be used in many patients. Complex cardiac surgeries that require cardiopulmonary bypass (on-pump procedures) include heart transplantation, valve replacement, and cardiac bypass. In 2007, more than 18,200 on-pump cardiac procedures were performed in Canada excluding Quebec (Source: Canadian Institute for Health Information, Ottawa, ON, Canada. Discharge Abstract Database [DAD] 2007-2008). From 1997 to 2006, 3,976 liver transplants were performed in Canada.26 On average, 6,280 radical prostatectomy procedures are performed each year in all provinces excluding Quebec (Source: Canadian
2 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review Institute for Health Information, Ottawa, ON, Canada. Discharge Abstract Database [DAD] 2005-2006 to 2007-2008). It is difficult to estimate the number of patients who may receive a supra-therapeutic dose of anticoagulant requiring reversal with rFVIIa. To approximate the potential population, there are more than 200,000 patients receiving warfarin through publicly funded drug plans in Canada.27
1.2 Overview of Technology
Recombinant activated factor VII (eptacog alfa or rFVIIa) is a hemostatic agent that was approved for use in Canada in 1999.28 It is marketed in Canada by Novo Nordisk of Denmark under the trade name NiaStase. Approved indications in Canada include the treatment of bleeding episodes in individuals with hemophilia A or B with inhibitors to clotting factors VIII or IX.3 This indication includes the treatment and prevention of surgical bleeding in individuals with hemophilia who have inhibitors. Recombinant FVIIa was licensed for the same indication in the US in 199929 and in the European Union in 1996 under the trade name NovoSeven.30
Recombinant FVIIa is a genetically engineered form of activated factor VII. It is created by cloning human factor VII and expressing it in baby hamster kidney cells, which then secrete recombinant factor VII.3 Recombinant FVII is converted to its active form during purification. This product is indistinguishable from the activated factor VII that is produced naturally in the plasma. At pharmacologic doses, rFVIIa binds to tissue factor (a protein that is exposed to the blood when a blood vessel is injured) at the site of injury and activates factors IX and X locally, promoting thrombin and clot formation.3 It activates factor X on the surface of activated platelets, stimulating thrombin release independent of tissue factor.3
In practice, the use of rFVIIa has extended beyond its approved indications. It has been used as a hemostatic agent in the treatment or prevention of bleeding in surgery, coagulopathy associated with liver dysfunction, intra-cerebral hemorrhage, blunt or penetrating trauma, postpartum bleeding, hemorrhagic complications after stem cell transplantation or liver transplantation, thrombocytopenia, and reversal of anticoagulant therapy.24,31,32
The safety of rFVIIa when it is used off-label has been questioned, and concern has been raised about the risk of thrombosis.33-35 It has been theorized that the action of rFVIIa may be limited to the site of injury. This could reduce the risk of initiating coagulation at other sites in the body.2,3 This may not be the case, because several studies have found relatively high rates of thrombosis in at-risk patients.33 In 2005, the labelling of rFVIIa was changed to reflect the fact that the risk of thromboembolism in patients without hemophilia is unknown and that these patients may be at increased risk of thromboembolic complications.36
The cost of rFVIIa for off-label indications varies because the dosing is not clearly defined. The estimated cost of one 90 μg/kg rFVIIa dose for an 80 kg person ranges from C$6,600 to C$8,200.24 Recombinant FVIIa is funded through provincial and territorial budgets for blood products and distributed free to hospitals through Canadian Blood Services. This leaves no cost incentive for utilization control at the hospital level.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 3 Clinical and Economic Systematic Review 2 ISSUE
The off-label use of rFVIIa to prevent hemorrhage in high-risk patients may be appealing considering the potential risks of other hemostatic agents and the desire to avoid or minimize patients’ exposure to blood products. Excessive bleeding has been associated with an increased risk of death during the perioperative period among cardiac surgery and liver transplant patients. However, rFVIIa is costly, and it is unclear if the benefits of rFVIIa use for off-label indications outweigh the potential harms and costs.
A previous CADTH report evaluated the clinical and cost-effectiveness of rFVIIa for the treatment of intracerebral hemorrhage, upper gastrointestinal bleeding, and uncontrolled bleeding associated with trauma or surgery.1 This report will focus on the use of rFVIIa for the prevention of bleeding in high-risk patients without hemophilia or other inherited bleeding disorders.
3 OBJECTIVES
This review evaluated the use of rFVIIa for the prevention of bleeding in selected indications among individuals without hemophilia or other inherited bleeding disorders. Based on input from Canadian Blood Services, the scope of this report was limited to the use of rFVIIa in the prevention of bleeding that is associated with liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation. Supra-therapeutic anticoagulation was defined as any use of an anticoagulant that resulted in excessive anticoagulation and placed the patient at risk of major bleeding. Anticoagulated patients with bleeding were excluded.
Specific research questions include: 1) What is the clinical effectiveness of evaluated doses and regimens of rFVIIa compared with placebo, no treatment, or other standard therapies for the prevention of bleeding associated with liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies? 2) What are the practice guidelines for monitoring safety and efficacy of rFVIIa when used for the prevention of bleeding associated with liver transplantation, prostatectomy, cardiac surgery, or supra-therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies? 3) What is the cost-effectiveness of rFVIIa compared with placebo, no treatment, or other standard therapies when used for liver transplantation, prostatectomy, cardiac surgery, or supra- therapeutic anticoagulation in individuals without hemophilia, inherited platelet disorders, or other coagulopathies?
4 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review 4 CLINICAL REVIEW 4.1 Methods
The research was conducted according to a protocol written before the research was started and reported in accordance with CADTH’s Technology Report Requirements.37
4.1.1 Literature searches
Peer-reviewed literature searches were conducted for the clinical review and economic evaluation, and the results were combined. All search strategies were developed by the information specialist with input from the project team.
The following bibliographic databases were searched through the Ovid interface: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, and BIOSIS Previews. Parallel searches were run in PubMed, the Cochrane library, the Centre for Reviews and Dissemination (CRD) databases, and the Health Economic Evaluations Database (HEED). The search strategy comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings) and keywords. The main search concepts focused on rFVIIa for cardiac surgery, liver transplantation, prostatectomy, and the use of anticoagulants. Methodological filters were applied to limit retrieval to randomized controlled trials (RCTs), non-randomized controlled clinical trials, observational studies, health technology assessments, systematic reviews, practice guidelines, and economic studies. Appendix 1 includes the detailed search strategies.
The searches were not restricted by publication date or language. OVID AutoAlerts were set up to send monthly updates with new literature. Updates were performed on HEED, CRD, PubMed, and Cochrane Library databases.
Grey literature (literature that is not commercially published) was identified by searching the websites of health technology assessment and related agencies, professional associations, relevant conference proceedings, and other specialized databases. Google and other Internet search engines were used to search for additional information. These searches were supplemented by hand-searching the bibliographies and abstracts of key papers and through contacts with appropriate experts and agencies. The manufacturer of rFVIIa was contacted and asked to provide the following data for the populations relevant to this report: product description; regulatory approvals; unit cost; ongoing, published, and unpublished clinical studies; clinical practice guidelines; Canadian clinical practice patterns and off-label utilization of rFVIIa; economic evaluations of rFVIIa; or cost of illness studies.
4.1.2 Selection criteria
a) Population Studies that enrolled patients undergoing liver transplantation, prostatectomy, or cardiac surgery or those with supra-therapeutic anticoagulation at risk for major bleeding were relevant to this
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 5 Clinical and Economic Systematic Review report. Studies including individuals with hemophilia, inherited platelet disorders, or other coagulopathies were excluded. No restrictions were placed on sample size or age of participants.
b) Intervention Studies evaluating any dose or duration of rFVIIa treatment used for the prevention of bleeding were relevant to this report. In the surgical populations, this included rFVIIa as part of the “routine” surgical procedure and excluded rescue therapy in patients with uncontrolled perioperative hemorrhage. Studies evaluating rFVIIa when used to stop bleeding in non-surgical anticoagulated patients were excluded.
c) Comparator Studies using another dose of rFVIIa, placebo, no treatment, or other indication-specific standard therapies (including antifibrinolytics, desmopressin, anticoagulant reversal agents, or blood products) that were considered to be relevant comparators were included.
d) Outcomes The following clinical outcomes were relevant to this report: all-cause mortality; health-related quality of life; serious adverse events and thromboembolic adverse events; need for blood transfusion; volume of red blood cells (RBCs), fresh frozen plasma, cryoprecipitate, platelets, or plasma volume expander solutions transfused; operation times; and length of hospital stay. In the supra-therapeutic anticoagulated patient population, the number of patients with bleeding was included as a relevant outcome.
The volume of blood lost during surgery was not included as an outcome relevant to this report because this measure lacks accuracy. The volume of RBCs and the number of patients transfused was used as a proxy for surgical blood loss.
e) Study design RCTs, non-randomized controlled clinical trials, and prospective controlled observational studies were included for research question 1. Clinical practice guidelines were included for research question 2. Systematic reviews and health technology assessments were selected and used in the discussion. No formal evaluation or summary of systematic reviews or health technology assessments were conducted as part of the clinical review.
f) Publication characteristics No restriction was placed on publication language or publication date. Foreign language articles were translated. Authors were contacted in an attempt to obtain more information about studies that were available only as abstracts or conference proceedings. This included clarification of unclear or missing information on study methods, patient characteristics, treatments administered, and outcomes relevant to this report. A copy of the complete study manuscript was requested. Abstracts and conference proceedings were accepted if they contained sufficient detail.
4.1.3 Selection method
The initial screening of titles and abstracts was conducted independently by two CADTH research officers (GM, SN) using the inclusion and exclusion criteria that were specified before
6 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review the research was started. The full study was retrieved for all selected articles and for those on which the researchers disagreed. After the studies were retrieved, two reviewers (GM, SN) independently screened full-text articles for inclusion based on the inclusion and exclusion criteria, using a relevance form that was designed for this review. Disagreements were resolved by consensus or by consulting a third researcher (CP). The list of excluded articles and reason for exclusion appears in Appendix 2. The process for the selection of studies appears in Figure 1.
4.1.4 Data extraction strategy
From the RCTs and non-randomized studies that were selected for inclusion in the review, two CADTH research officers (GM, SN) independently extracted information on study design, population, intervention, comparators, and outcomes, using a data extraction form that was designed before the research was started (Appendix 3). Completed data extraction forms were compared, and any differences were resolved by consensus or by consulting a third researcher (CP). After extracting data, the research officers reassessed whether the studies met the inclusion criteria.
For research question 2, the following information was extracted from the practice guidelines: objectives; country; methods for identifying, evaluating, and summarizing literature; methods to obtain consensus or to develop practice statements; the method to determine the grade of recommendation; statements on the monitoring of rFVIIa when used for the prevention of bleeding; grade of the recommendation; funding source; and potential conflicts of interest reported by the authors.
4.1.5 Strategy for validity assessment
The validity of each included study was assessed independently by two CADTH research officers (GM, SN), and the results were compared. Any disagreements were discussed until consensus was reached.
For each RCT, the quality of study reporting was assessed using the Jadad instrument and Schulz’s allocation concealment instrument (Appendix 4).38,39 Studies were categorized as lower quality (Jadad score of 0 to 2) or higher quality (Jadad score of 3 to 5). Based on the Cochrane Collaboration’s tool for assessing risk of bias (Appendix 5),40 studies were categorized as being at low risk of bias, unclear, or at high risk of bias. The potential for bias was considered when interpreting each study’s findings.
The quality of prospective-controlled observational studies was assessed according to the Newcastle-Ottawa scale (Appendix 6).41 This tool is used to assess cohort selection and comparability, the methods that were used to assess outcomes, and the adequacy of follow-up.
4.1.6 Data analysis methods
A narrative synthesis was used to describe the non-randomized studies and the guidelines, as specified in the protocol. After an assessment of the RCTs, a decision was made to use a narrative synthesis to describe these studies too. As outlined in the protocol, the data were analyzed separately according to indication and dose of rFVIIa. There were an insufficient
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 7 Clinical and Economic Systematic Review number of studies reporting outcomes for the same indication and dose of rFVIIa to allow for meta-analysis, subgroup analyses, or sensitivity analyses.
In our narrative synthesis, the measures of association that describe between-group differences and the corresponding 95% confidence intervals (CIs) were sought for interpretation. When a trial did not report comparisons in this manner, information on between-group comparisons that were described in other forms (for example, P values and associated conclusions of statistical significance, or group-specific descriptive statistics such as mean and standard deviation (SD) or median and interquartile range) was summarized. Where possible, between-group differences were calculated using STATA 11.0.42
4.2 Results
4.2.1 Quantity of research available
Of 4,458 articles that were identified from electronic databases, grey literature, and hand- searching, 132 were retrieved as full text after preliminary screening. Of these, 17 articles were initially included. These included 12 articles about eight unique RCTs,43-54 three cohort studies,55-57 and two guidelines.58,59 On review, it was decided that one cohort study was retrospective, and it was excluded.57 The selection of articles appears in Figure 1. The list of excluded articles and reasons for exclusion appear in Appendix 2.
The authors of the studies that were available as abstracts were asked to provide additional details.49,55,57 None of the authors replied to our request. The manufacturer of rFVIIa declined to provide any data. All included reports were written in English, except one in Chinese, which we translated.45
4.2.2 Study characteristics
The use of rFVIIa for the prevention of bleeding was evaluated in patients undergoing cardiac surgery (three RCTs),43-45 liver transplantation (four RCTs),46-49 and radical prostatectomy (one RCT).50 Two prospective cohort studies of patients undergoing liver transplantation were included.55,56 No studies assessed the use of rFVIIa for the prevention of bleeding in anticoagulated patients. The RCT characteristics, clinical results, and quality assessments of the included studies appear in Appendix 7 Tables A1 to A5.
8 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review Figure 1: Selected Reports
4,458 citations identified from electronic search and screened
4,337 citations excluded
121 potentially relevant reports retrieved for scrutiny (full text, if available)
11 potentially relevant reports retrieved from other sources
132 potentially relevant reports
116 reports excluded: inappropriate population (10) inappropriate intervention (1) inappropriate indication for rFVIIa (2) trial design inappropriate for review (99) guidelines without monitoring information (4)
16 reports describing 8 RCTs, 3 prospective cohort studies, and 2 guidelines
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 9 Clinical and Economic Systematic Review
a) Cardiac surgery The patient populations undergoing cardiac surgery differed among the three RCTs.43-45 In one study, 82 children younger than one year of age with congenital heart disease were enrolled (mean age four months).44 One study included 22 adult patients undergoing cardiac valve replacement (mean age 48 years to 50 years),45 and one study included 20 patients undergoing non-coronary complex cardiac surgery (median age 63 years to 70 years).43 All studies excluded patients with a thromboembolic disorder. Two studies excluded patients with liver disease or other coagulopathy44,45 or who refused blood products.43,45 Other exclusion criteria were prior treatment with rFVIIa or antifibrinolytic agents,44 the use of Aspirin,45 indications for a Norwood procedure, or an expected lifespan of fewer than three months.44
The three studies were double-blinded trials that compared rFVIIa with placebo. In two studies, patients in the rFVIIa group received one dose of 40 μg/kg45 or one dose of 90 μg/kg43 after cardiopulmonary bypass and reversal of heparin treatment. In one RCT, patients were given a dose of the study drug (40 μg/kg rFVIIa or placebo) after reversal of heparin treatment. Doses could be repeated twice if excessive bleeding occurred.44 One patient (5%) in the rFVIIa group was excluded from some analyses in Diprose et al.’s43 study. This patient had severe bleeding caused by an aortic tear. All patients were assumed to have completed Ma et al.’s45 study. Six patients (7%) were excluded from the treated-case analysis (patients who received the study drug and were followed until hospital discharge) in Ekert et al.’s44 study. In this study, 50% of patients received the study drug and completed the planned six-week follow-up. The manufacturer of rFVIIa provided partial funding to two studies,43,44 and funding sources were not reported in one trial.45 The authors of one study reported having worked as consultants for Novo Nordisk.43
b) Liver transplantation surgery Four RCTs that assessed adult patients undergoing orthotopic liver transplantation surgery46-49 were included in this review. The studies enrolled a total of 341 patients (range 20 to 209). The characteristics of the patients who were enrolled were not reported in two studies.47,49 Exclusion criteria in the other two studies included previous liver transplant; split liver, multi-organ, or living donor transplant; renal insufficiency requiring dialysis; coagulation disorder; or a history or presence of portal vein thrombosis.46,48 The patients’ mean ages were approximately 50 years48 and 53 years,46 and most of the patients were male.
Three studies were double-blinded and placebo-controlled.46-48 A fourth trial compared usual care plus rFVIIa (1.2 mg) with usual care. Usual care included the use of blood products to correct coagulopathy of end-stage liver disease.49 In two RCTs, patients in the rFVIIa group received one dose of 20 μg/kg,48 one dose of 40 μg/kg,47,48 or one dose of 80 μg/kg48 just before the first incision. In one RCT, patients were given repeat doses of 60 μg/kg or 120 μg/kg rFVIIa every two hours during surgery.46 In the largest trial, 27 patients (13%) did not meet the inclusion criteria and were withdrawn from the treated-case analysis.46 Another three patients were withdrawn from the per-protocol analysis, including two patients treated with rFVIIa who died within the first 24 hours.46 In Planinsic et al.’s48 study, five patients (6%) had surgery cancelled and were withdrawn from the study. One trial had no withdrawals,47 and the other RCT did not specify the reason for two patients’ withdrawals (8%).49 The manufacturer funded two studies and listed Novo Nordisk employees as co-authors.46,48 The source of funding or potential conflicts of interest were not reported in two studies.47,49
10 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
Two prospective cohort studies assessed patients undergoing orthotopic liver transplantation.55,56 In one study, six patients who received one dose of 80 µg/kg rFVIIa were compared with 10 patients who received usual care.56 The methods that were used to select patients were not reported. The median age was 43 years in the rFVIIa group and 39 years in the control group (range 22 to 61). Approximately two-thirds of patients were male. There were imbalances between groups in the severity of liver disease. The study reported the number of patients who were transfused and the volume of blood products transfused.56 The second cohort study included 24 patients undergoing liver transplantation.55 Some patients (number not reported) were given a 30 µg/kg loading dose of rFVIIa when anesthesia was induced, followed by a 5 µg/kg maintenance dose until the end of the dissection phase of surgery. Control patients received usual care. No description of the methods that were used to select patients and no description of patients’ age, gender, or severity of liver disease were provided in the abstract. The study reported the difference in the volume of blood products that was administered.55
c) Prostatectomy One RCT assessed the efficacy of using rFVIIa to prevent bleeding in patients undergoing prostatectomy.50 A total of 36 patients were enrolled in the double-blind trial. In this dose- escalating study, patients were randomized to receive one dose of 20 μg/kg rFVIIa, one dose of 40 μg/kg rFVIIa, or placebo. The mean age per treatment group was between 61 years and 64 years (overall range 49 years to 79 years). Patients with unstable coronary artery disease, angina, or other thromboembolic disorder; coagulopathy; or thrombophilic state were excluded. Other exclusion criteria included recent treatment with an anticoagulant or Aspirin, advanced liver disease, cirrhosis, or acute hepatitis. Approximately half the patients underwent a radical retropubic prostatectomy for prostate cancer, and half had a Millin procedure for prostate hypertrophy. All patients underwent the 10-day follow-up. Novo Nordisk provided the study drug for the RCT, and two of the study’s authors have been invited by Novo Nordisk to speak at symposia.50
d) Guidelines for monitoring rFVIIa Two guidelines met the inclusion criteria.58,59 Both guidelines were described in a previous CADTH review of rFVIIa for the treatment of uncontrolled bleeding.1
4.2.3 Data analyses and synthesis
Table 1 shows the outcomes relevant to this health technology assessment. These outcomes were reported in RCTs and prospective cohort studies. Few studies evaluated the use of rFVIIa for the prevention of surgical bleeding. No studies tested the efficacy of using rFVIIa for the prevention of bleeding in anticoagulated patients. Health-related quality of life was not assessed for any indication.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 11 Clinical and Economic Systematic Review
Table 1: Outcomes Reported in Clinical Trials and Cohort Studies Indication Number and Type of Study Reporting Outcome Data (total number of patients analyzed) Mortality Adverse Events HRQL Blood Product LOS or Operative Transfusion Time Cardiac 2 RCTs 3 RCTs (117); NR 3 RCTs (118) 3 RCTs (116) surgery (41) incomplete reporting in 2 studies Liver 3 RCTs 3 RCTs (224); NR 4 RCTs (308); 4 RCTs (308); transplantation (224) incomplete reporting 2 cohort studies incomplete in 1 study (40) reporting in 2 studies Prostatectomy 1 RCT 1 RCT (36); NR 1 RCT (36) 1 RCT (36) (36) incomplete reporting Reversal of no clinical trials met inclusion criteria anticoagulation
HRQL = health-related quality of life; LOS = length of stay; NR = not reported; RCTs = randomized controlled trials.
The number of patients who were enrolled was small in most RCTs (range 20 to 209, median 31). In most studies, the length of follow-up was not clearly stated and seemed to be limited to the duration of hospitalization. Five studies reported specific criteria for blood product transfusion based on laboratory values.43,46-48,50
For most RCTs, the reporting of methods and results was incomplete.44-49 One study was available only as an abstract, and thus it was not possible to adequately assess reporting or methodological quality.49 Of the seven RCTs43-48,50 that were reported as being double-blind, two43,50 reported the methods that were used to blind patients and investigators. Six studies did not report the methods that were used to randomize patients or to conceal treatment allocation.44- 49 In these RCTs, the risk of bias was rated as unclear. The proportion of patients who were excluded from the studies ranged from 0 % to 13%. The description of patient withdrawals or dropouts was inadequate or missing in three studies.45,49,52 In the two RCTs where the allocation of patients to treatment groups was adequately concealed, the Jadad score was five (indicating higher quality of reporting), and the risk of bias was judged to be low (Appendix 7 Table A5).43,50 Minimal or no information was provided on the methods for collecting adverse event data. One study provided no information on adverse events.49 Limited or blanket statements of adverse events appeared in five RCTs.43-45,47,50 Two studies provided more detailed information on the number and type of adverse events that were observed, but the data in the tables and text did not always agree.46,48
All the included trials summarized between-group comparisons by reporting P values and did not estimate between-group differences and corresponding 95% CIs. The P values are reported here with the associated interpretations of statistical significance and reported descriptive measures of clinical outcomes relevant to this report (for example, mean [SD] or median [interquartile range]). Three trials provided sufficient detail that the between-group differences and CIs could be calculated.
12 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
a) Cardiac surgery Appendix 7 Table A2 summarizes the results from three RCTs of patients undergoing cardiac surgery for the clinical outcomes relevant to this report. Both studies in adult patients were small with enrolments of 2043 and 2245 patients respectively. In Diprose et al.’s43 study, no statistically significant difference was detected when comparing the 90 μg/kg rFVIIa and placebo groups in terms of the volume of RBCs, platelets, or FFP transfused; the number of patients who received blood product transfusion; the length of intensive care unit (ICU) or hospital stay; and the number of strokes, myocardial infarctions, or deaths. One stroke and one myocardial infarct occurred in each treatment group. There were no deaths in the rFVIIa group and one death in the placebo group.
Ma et al.’s45 study found that the use of 40 μg/kg rFVIIa statistically significantly reduced the volume of RBCs and platelets transfused. The mean difference in the volume of RBCs transfused was −2.8 units (95% CI −5.2 to −0.4) for the rFVIIa group compared with the placebo group. The mean difference in the volume of platelets that was administered was −4.1 units (95% CI −6.5 to −1.7). No statistically significant differences were detected in the volume of FFP or cryoprecipitate transfused. The ICU stay was statistically significantly longer in the placebo group than in the rFVIIa group (3.3 days versus 2.7 days, mean difference −0.6 days (95% CI −1.1 to −0.1). The authors reported that no cerebral infarction, myocardial infarction, deep vein thrombosis, or pulmonary emboli events occurred in either group. There were no deaths during the study.
In the study of 76 pediatric patients with congenital heart disease, no statistically significant difference was detected between the 40 μg/kg rFVIIa and placebo groups in the number of patients receiving RBCs or the mean millilitres of RBCs transfused.44 The mean millilitres of platelets or FFP transfused was reported, but the number of patients transfused was small, and no inferences were formally tested. The study’s authors reported that there were no differences between groups in treatment emergent adverse events. No thromboembolic adverse events occurred in either group. The number of deaths or serious adverse events was not reported. The mean time from heparin reversal to chest closure was statistically significantly longer in the rFVIIa group than in the placebo group (98.8 minutes versus 55.3 minutes respectively, P = 0.026). In this study, 55% of patients in the rFVIIa group and 33% of patients in the placebo group received a second dose of the study drug to control excessive bleeding.
b) Liver transplantation surgery Appendix 7 Table A3 summarizes the results from the four RCTs of patients undergoing liver transplantation surgery for the clinical outcomes relevant to this report. In two of the smallest studies (25 or fewer patients enrolled), a statistically significant difference was detected between rFVIIa and placebo47 or usual care49 in the volume of RBC or FFP infused. Patients in the rFVIIa groups needed fewer blood products. In one study, the mean difference in the volume of RBCs transfused was calculated to be −270 mL (95% CI −385 to −155) for the rFVIIa versus placebo group.47 In a third single-dose study,48 no statistically significant difference was detected between the rFVIIa 20 μg/kg, 40 μg/kg, or 80 μg/kg groups and placebo in the volume of RBC, platelets, FFP, crystalloid, or colloid solution infused. These results were similar in the trial comparing several doses of 60 μg/kg or 120 μg/kg rFVIIa to placebo.46 No statistically significant differences were detected in the volume of blood products, crystalloid, or colloid
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 13 Clinical and Economic Systematic Review
solutions administered.46 A post-hoc analysis showed that fewer patients who were treated with rFVIIa needed RBC transfusion during the first 24 hours after surgery compared with placebo.46
The length of ICU or hospital stay was not statistically significantly different between the rFVIIa and placebo groups in all three trials reporting this outcome.46-48 Operative time was similar between groups in three studies46-48 and statistically significantly lower in the rFVIIa group compared with the usual care group in one study (352 minutes versus 415 minutes, P = 0.02).49
No information on the number of deaths or other adverse events appeared in Zimmerer et al.’s49 abstract. One RCT reported no deaths or thromboembolic adverse events during the study.47 In two RCTs, six (3.3%)46 and seven (8.4%)48 patients died; the authors did not report the treatment group of all patients who died. One study reported no statistical difference in the number of deaths between treatment groups.46 In the second study, the results of statistical tests were not reported.48 The number of patients with serious adverse events was similar in the treatment and control groups of both trials.46,48 Nineteen per cent of patients in the placebo group and 27% and 28% of patients in the rFVIIa groups experienced a serious adverse event in one study.46 These differences were not statistically significant. The incidence of thromboembolic adverse events was similar between the groups (rFVIIa 60 μg/kg, 19%; rFVIIa 120 μg/kg, 12%; placebo, 10%; P > 0.05).46 In the second study, the proportion of patients with serious adverse events ranged from 28% to 42% in the rFVIIa groups compared with 32% in the placebo group. The proportion of patients with arterial thromboses was similar between groups (rFVIIa 4% to 11%; placebo 11%).48 No dose response was apparent.
Two prospective cohort studies compared the use of single56 or several55 doses of rFVIIa to usual care in patients undergoing orthotopic liver transplantation. In Meijer et al.’s56 cohort study, the transfusion of RBCs or adverse events were not reported. In the rFVIIa group, three patients (50%) received FFP (median one unit, range 0 to 7), two patients (33%) received platelets (median 0 units, range 0 to 1), and one patient (17%) received fibrinogen (median 0 g, range 0 to 2). In the control group, nine patients (90%) received FFP (median 3.5 units, range 0 to 8), two patients (20%) received platelets (median 0 units, range 0 to 1), and four patients (40%) received fibrinogen (median 0 g, range 0 to 4). No statistical tests were conducted because of the small sample size and because this pilot study was not designed to test for differences in clinical outcomes.
In the second cohort study, a statistically significant decrease in the volume of RBCs (P = 0.014), FFP (P = 0.01), and platelets (P = 0.0005) transfused were reported in the rFVIIa group compared with the control group.55 No other details about the outcomes relevant to this report appeared in the abstract.
c) Prostatectomy In a double-blind study, Friederich et al.50 reported that treatment using rFVIIa reduced the need for RBC transfusion compared with placebo in patients undergoing prostatectomy (Appendix 7 Table A4). Fewer patients received RBCs in the rFVIIa 20 μg/kg (37.5%) and rFVIIa 40 μg/kg (0%) groups than in the placebo (58.3%) group. These differences were statistically significant for the 40 μg/kg group only (P = 0.0001). The mean volume of RBCs transfused was statistically significantly lower in the rFVIIa groups compared with the placebo group (rFVIIa 20 μg/kg: 0.6 units, P = 0.047 versus placebo; rFVIIa 40 μg/kg: 0 units, P = 0.0003; placebo 1.5 units). None
14 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
of the 36 patients enrolled received FFP or platelets. The operative time was statistically significantly lower in the rFVIIa groups than placebo (mean difference 20 μg/kg versus placebo: −54 minutes [95% CI −71 to −37]; 40 μg/kg versus placebo: −60 minutes [95% CI −72 to −48]). No differences in the length of hospital stay were detected between groups. No deaths or adverse events occurred during the 10-day follow-up. One patient who received rFVIIa had an acute myocardial infarct 14 days after surgery.50
d) Guidelines for monitoring rFVIIa Two guidelines met the inclusion criteria.58,59 The CADTH report on using rFVIIa for the treatment of bleeding includes a summary of these guidelines,1 which indicate that there is no specific method to monitor the efficacy of rFVIIa when it is used for the prevention of bleeding.1
5 ECONOMIC ANALYSIS 5.1 Review of Economic Studies: Methods
The review of the economic literature that was conducted was aimed at assessing the reported cost-effectiveness of using rFVIIa in the prevention of bleeding in each of the four indications.
5.1.1 Literature searches
The results of the peer-reviewed literature searches that were conducted for the clinical review and economic evaluation were combined. The search strategy appears in section 4.1.1, and the full strategy appears in Appendix 1.
5.1.2 Selection criteria
a) Study design Full or partial economic studies (including cost-minimization, cost-effectiveness, cost-utility, cost-benefit, costing, cost-comparison, cost-consequences) were sought.
b) Population Studies enrolling patients without hemophilia, inherited platelet disorders, or other coagulopathies who received rFVIIa for the prevention of bleeding associated with prostatectomy, cardiac surgery, liver transplant, or supra-therapeutic anticoagulation were sought. No restrictions were placed on sample size or age of participants.
c) Intervention Studies evaluating any dose or duration of rFVIIa therapy used for the prevention of bleeding were relevant to this report. The use of rFVIIa as part of the “routine” surgical procedure for surgical populations was included, and rescue therapy in patients with uncontrolled massive perioperative hemorrhage was excluded. Using recombinant FVIIa to stop bleeding in non- surgical anticoagulated patients was also excluded.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 15 Clinical and Economic Systematic Review
d) Comparator Another dose of rFVIIa, placebo, no treatment, or other indication-specific standard therapies (for example, anticoagulant reversal agents, blood products, desmopressin, or antifibrinolytics) were included.
e) Outcomes All-cause mortality, other clinical events (including but not exclusive to serious adverse events, thromboembolic events, transfusion rates), cost of rFVIIa treatment, impact on health care resource use, increased quality-adjusted life-years (QALYs), and incremental cost per QALY gained were relevant to this report.
No restrictions were placed on foreign language articles.
5.1.3 Selection method
Citations were independently selected by two reviewers (ET, SN) according to criteria that were specified before the research was started. After studies were retrieved, two reviewers (ET, SN) independently screened them for inclusion based on the selection criteria, using a relevance form that was designed for this review. Disagreements were resolved by consensus. A list of excluded studies and reasons for exclusion appear in Appendix 9.
5.1.4 Data extraction strategy
A data extraction form that was used in previous CADTH assessments was used to extract data from the selected economic evaluations. Data were extracted by two reviewers (ET, SN). Any differences were resolved by consensus. A template of the data extraction form appears in Appendix 8.
5.1.5 Strategy for validity assessment
a) Quality assessment The 35-item BMJ checklist60 was used to assess the quality of reporting in the economic studies. The checklist criteria are grouped in three categories: study design, data collection, and analysis and interpretation of results. Studies that fulfill fewer criteria may be interpreted with greater caution. The criteria were applied independently by two reviewers (ET, SN), and any differences were resolved by consensus.
b) External validity Four questions were used to assess the extent to which the results of the reviewed studies were generalizable to the Canadian health care system. The questions have been used in CADTH reports and are based on CADTH’s Guidelines for the Economic Evaluation of Health Technologies.61 The four questions focus on how well the study reflected the issue, whether the clinical data reflected what might be seen in a Canadian setting, whether the resource use and cost data reflected what might be seen in a Canadian setting, and whether uncertainty was adequately accounted for. Two reviewers (ET, SN) independently assessed each study based on the four questions, and differences were resolved by consensus.
16 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
5.1.6 Data analysis methods
The characteristics and main findings of the three studies, the strength of evidence, and the study limitations were noted in a narrative analysis.
5.2 Review of Economic Studies: Results
5.2.1 Quantity of research available
Of the 458 citations that were identified from the economic literature search and the 105 citations from the grey literature, 555 were excluded. The most common reason for exclusion was that the citation did not seem to be an economic evaluation. On review of the eight remaining articles, five were excluded. The reasons for exclusion were the use in prevention was unclear (four articles) and the study is not an economic evaluation (one article). A list of the excluded studies appears in Appendix 9.
Of the three economic assessments that were selected for this review, one focused on orthotopic liver transplantation,62-64 one on cardiac valve replacement under cardiopulmonary bypass,45 and one on abdominal prostatectomy.65 No studies focusing on supra-therapeutic anticoagulation were identified. One study was reported in a slide presentation,62 one in a poster presentation,63 and one in an abstract.64 Two studies were reported in English62-65 and one was reported in Chinese.45 None of the studies was conducted from a Canadian perspective.
5.2.2 Study characteristics
a) Study quality The assessment of quality of reporting using the BMJ checklist60 appear in Appendix 10. Odeyemi et al.’s65 study was the only one that was published as an economic report. Ma et al.’s45 study was a clinical report that included an economic assessment of findings. Schoenhaus et al.’s62-64 study was obtained only in abstract and presentation formats. Ma et al.’s45 study and Schoenhaus et al.’s62-64 study fulfilled 33% and 43% respectively of the reporting criteria. Odeyemi et al.’s65 study fulfilled 62% of the reporting criteria. In general, all three studies had limitations in the quality of reporting, but Odeyemi et al.’s65 study fulfilled most criteria in its reporting of study design.
b) External validity The results of the external validity assessment appear in Appendix 11. All three studies reflected the research question. The three studies partially reflected what might be achieved in clinical practice in Canada, and all were partially generalizable to a Canadian setting in terms of resource use patterns and costs. Odeyemi et al.’s65 study partially accounted for uncertainty in its analysis. Neither Ma et al.’s45 study nor Schoenhaus et al.’s62-64 study conducted sensitivity analyses.
c) Study designs All three studies presented results in terms of the costs and consequences of treatment (cost- consequences).
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 17 Clinical and Economic Systematic Review
d) Time horizon The time horizon in all three studies was duration of hospital stay. In Schoenhaus et al.’s62-64 study, the median duration of hospital stay was 12 days for rFVIIa patients and 10 days for control patients. In Odeyemi et al.’s65 study, the mean duration of hospital stay was 11.3 days. The duration of hospital stay was not reported in Ma et al.’s45 study.
e) Study perspective The perspective was not stated in Ma et al.’s45 study or in Schoenhaus et al.’s62-64 study. It seemed to be that of a university hospital centre. The stated perspective in Odeyemi et al.’s65 study was that of the Dutch National Health System. This study considered inpatient outcomes and costs that were due only to the unavailability of post-discharge data.
f) Study populations Orthotopic liver transplant: The data in Schoenhaus et al.’s62-64 study were obtained from retrospectively analyzed electronic health records of 119 patients (68 rFVIIa and 51 control) who underwent liver transplantation between January 2003 and November 2006 at the University of California at San Diego Medical Center. Patients who were younger than 18 years of age, who were retransplantation patients, who were multi-organ transplant patients, or who were extracorporeal membrane oxygenation (ECMO) patients, were excluded. The between-group baseline characteristics were comparable. Males composed 63% of rFVIIa patients and 69% of control patients. The median age of rFVIIa patients was 50.5 years and the median age of control patients was 51.0 years. The median weight in the rFVIIa and control groups was 80 kg and 83 kg respectively. The preoperative Model for End-Stage Liver Disease (MELD) score was 16 in rFVIIa patients and 16.9 in control patients. The MELD score ranges from six to 40, with a score of six indicating the least ill patient and a score of 40 indicating the sickest patient. The median preoperative INR in the rFVIIa and control groups was 1.4 and 1.5 respectively. The median preoperative serum creatinine was 1.1 mg/dL in the rFVIIa group and 1.0 mg/dL in the control group. Of rFVIIa patients, 3% were dialysis-dependent, compared with 14% in the control group.
Cardiac valve replacement: The population in Ma et al.’s45 study was obtained from a double- blind randomized control trial of 22 patients (11 rFVIIa and 11 placebo) who underwent cardiac valve replacement under cardiopulmonary bypass at Shanghai Hospital (China) in 2005. Patients with a history of thrombotic events in the last six months, with coagulation disorders, or with hepatic diseases were excluded. Also excluded were patients who used Aspirin in the seven days before the operation or patients who refused donated blood or other blood products. The distribution of baseline characteristics was similar in the two groups: 59% of patients were male, and the mean age of patients was 48.9 years. Of patients, 68% underwent an aortic or mitral valve replacement, 41% underwent a tricuspid valvuloplasty, and 32% underwent a double valve replacement. The mean preoperative INR was 1.1 in rFVIIa patients and 1.2 in placebo patients.
Abdominal prostatectomy: Odeyemi et al.’s65 study was based on clinical data that were obtained from a three-arm, double-blind randomized control trial of 36 patients reported by Friedrich et al.50 This Dutch study included patients aged between 18 years and 85 years who were scheduled to undergo radical retropubic prostatectomy for prostate cancer or prostatectomy using Millin and MacAllister’s method for prostate hypertrophy. The exclusion criteria were treatment with any anticoagulant within 48 hours of operation; treatment with Aspirin within
18 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
seven days of the operation; known congenital or acquired hemostatic disorder; unstable coronary artery disease or angina pectoris class III-IV (New York Heart Association classification); history of venous thromboembolism or known thrombophilic state; known advanced liver disease, cirrhosis, or acute hepatitis; and participation in another trial 30 days before the operation. The patient baseline characteristics were comparable in the three groups. The mean age of all patients was 63 years, and the mean weight of patients was 80.9 kg. The mean preoperative hemoglobin was 8.3 mmol/L. Of patients, 44% underwent radical prostatectomy, and 56% underwent prostatectomy using Millin and MacAllister’s method.
g) Intervention and comparator In Schoenhaus et al.’s62-64 study, treatment with rFVIIa (median dose of 1.2 mg per patient, range 0.6 mg to 8.4 mg) was compared with standard care. Ma et al.45 compared rFVIIa 40 μg/kg with placebo. Odeyemi et al.65 compared rFVIIa 20 μg/kg with rFVIIa 40 μg/kg and with placebo.
h) Economic outcomes All three studies presented their results as the costs of treatment and the clinical and health care utilization consequences of treatment. No ratios of costs versus outcomes were estimated. Schoenhaus et al.62-64 reported blood product replacement, thrombosis events, and length of stay. Ma et al.45 reported postoperative blood transfusions, duration of ICU stay, rates of thrombotic events, mortality, prothrombin time, INR, and hemoglobin. The outcomes reported by Odeyemi et al.65 included packed cells transfused, duration of operation (in minutes), and hospital stay duration (in days).
i) Economic costs The total costs of care in Schoenhaus et al.’s62-64 study included accommodations, pharmacy, laboratory, blood products, radiology, operating room time, and transplant. Ma et al.45 did not specify the items that were included in the estimated total cost of hospitalization. Odeyemi et al.65 included the cost of packed cells transfused, the cost of rFVIIa, the duration of hospital stay, operating time and costs, postsurgical medication, and diagnostic tests.
j) Funding sources The funding source was not stated for any of the three studies. Odeyemi et al.’s65 study disclosed that Odeyemi had been previously employed by Novo Nordisk.
A summary of study characteristics appears in Appendix 12 Table A6.
5.2.3 Study results
a) Base-case results Orthotopic liver transplant: Schoenhaus et al.62-64 reported that patients in the rFVIIa and control groups used similar amounts of packed RBCs (median 8 [range 0 to 120] and median 8 [range 0 to 58] respectively), FFP (median 6 [range 0 to 59] and median 7 [range 0 to 91] respectively), and platelets (median 3 [range 0 to 20] and median 4 [range 0 to 50] respectively). The median length of stay was 12 days (range 0 to 289 days) in the rFVIIa group and 10 days (range 1 to 55 days) in the control group. The between-group differences were not statistically significant for any outcome. Two thromboembolic events (3%) occurred in the rFVIIa group, and one (2%) occurred in the control group. The median blood costs were US$6,154 (range $563
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 19 Clinical and Economic Systematic Review
to $55,742) in the rFVIIa group and US$5,954 (range $517 to $42,254) in the control group. The median surgical costs were US$6,667 (range $541 to $27,509) in the rFVIIa group and US$6,821 (range $1,088 to $19,756) in the control group. The median total medical costs were US$55,811 (range $32,567 to $479,735) in the rFVIIa group and US$57,279 (range $33,096 to $166,673) in the control group.
Cardiac valve replacement: Ma et al.45 reported that patients with cardiac valve replacements who had been randomized to be in the rFVIIa group received fewer units of RBC than those who had been randomized to be in the placebo group (mean 3.5 [SD 2.2] versus mean 6.3 [SD 3.1], P < 0.01). The rFVIIa group received statistically significantly fewer units of platelets (mean 3.4 [SD 2.2] versus mean 7.5 [SD 3.2], P < 0.01) and spent statistically significantly fewer days in an ICU (mean 2.7 [SD 0.5] versus mean 3.3 [SD 0.7], P < 0.05). There were no statistically significant differences between the rFVIIa and placebo groups in the number of units of plasma received (mean 5.5 [SD 3.4] versus mean 4.8 [SD 7.6] respectively) or units of cryoprecipitate received (mean 0.9 [SD 1.0] versus mean 1.1 [SD 1.7] respectively). No cases of cerebral infarction, myocardial infarction, deep-vein thrombosis, pulmonary embolism, or death from any cause were observed. The authors estimated the average total cost of hospitalization in the rFVIIa group to be RMB 71,356 (SD 11,438). In the placebo group, the mean total cost of hospitalization was RMB 66,772 (SD 19,272).
Abdominal prostatectomy: The outcomes data that were reported by Odeyemi et al.65 were obtained from Friederich et al.’s50 study, which was reviewed in the clinical section of this report. Odeyemi et al.65 reported a dose-response effect in packed cell units transfused (P = 0.001) and operation duration (P = 0.014). There were no between-group differences in admission duration (P = 0.35). The mean per-patient medical costs resulting from abdominal prostatectomy were €9,602 in the placebo group, €9,958 in the 20 μg/kg group, and €9,522 in the 40 μg/kg group. The lower total costs in the 40 μg/kg group were attributed to lower costs for transfused packed cells, surgery, hospitalization, and post-surgical medications.
b) Sensitivity analysis results Neither Schoenhaus et al.62-64 nor Ma et al.45 conducted sensitivity analyses on their base-case results.
Odeyemi et al.65 reported a univariate break-even analysis that found the study results to be sensitive to the cost of a packed cell unit of blood, the unit cost of rFVIIa, and the number of packed cells transfused to the placebo group. The authors suggested that changes in the acquisition costs of packed cells would affect the overall treatment costs of the study groups relative to each other and that the administration of 40 μg/kg rFVIIa may result in greater cost savings in countries with greater health care costs. It was unclear whether other health care costs had been considered in the sensitivity analysis.
A summary of study results appears in Appendix 12 Table A7.
20 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
5.2.4 Summary
This review describes three economic assessments that were conducted regarding three of the four indications relevant to this report.
Schoenhaus et al.62-64 reported a cost-consequences analysis of retrospectively obtained administrative data on patients undergoing orthotopic liver transplant. This study was available only in abstract and presentation forms, and thus, details about the methods and results were limited. The sample size was small, and only inpatient hospital costs from one centre were considered. No assessment of patient health-related quality of life was reported nor were any mortality data. The authors found no between-group differences in outcomes and costs. They concluded that the use of rFVIIa for the reduction of blood product needs during this procedure was not shown to be cost-effective and that this treatment may be associated with a risk of thromboembolic events. Based on this study, the authors no longer recommended rFVIIa for preoperative use at their centre and recommended it be used only as rescue therapy.
Ma et al.’s45 study was published as a clinical report based on an RCT of cardiac valve replacement under cardiopulmonary bypass. It also reported a costing of the hospital resources that were used in providing this procedure. Because it was mainly a clinical report, there was limited information on economic methods and results. This study had a small sample size and considered only inpatient hospital costs from one centre. The health-related quality of life was not assessed, and there were no reported deaths during the study. The authors reported statistically significantly decreased use of RBCs and platelets, decreased ICU days, and lower INR up to two hours post-administration in the rFVIIa group. The average total costs were higher in the rFVIIa group. The authors concluded that the use of rFVIIa effectively improved the coagulation function in the study population, reduced the need for blood transfusion without important side effects, and did not greatly increase hospital expenses.
Odeyemi et al.65 reported a cost-consequences study that was based on clinical data from Friederich et al.’s50 single-centre RCT. There were inconsistencies between the two studies in the reporting of outcomes. This analysis was based on a small sample size, and although its stated perspective was that of the Dutch National Health System, it considered only inpatient costs. The health-related quality of life was not reported, and there were no adverse events during the trial. The authors reported statistically significantly fewer packed cell transfusions and a shorter operation duration in the rFVIIa group. The total hospitalization costs were lower in the 40 μg/kg group compared with placebo. The authors concluded that the use of rFVIIa 40 μg/kg as a hemostatic agent during abdominal prostatectomy lowers the overall treatment costs and reduces surgery time by reducing transfusion requirements.
5.3 Primary Economic Evaluation
During the development of the project protocol, a scoping search of published and unpublished RCTs and prospective clinical trials was conducted to determine if a primary economic analysis could be conducted for one of the indications relevant to this report. Based on this review, the available data appeared insufficient to support an economic model. No differences were found between rFVIIa and placebo based on clinically important outcomes, and any differences in
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 21 Clinical and Economic Systematic Review
blood product utilization were minimal. In addition, utilization data of rFVIIa in prevention (Source: Muirhead B, Dickson T, Freeman J. Recombinant Factor VIIa Use in Canada. Physicians and Nurses for Blood Conservation [PNBC] Database: 2005-2006)66 and expert opinion indicate that there is little use of this drug in the prevention of bleeding and that this is unlikely to change, because of a perceived risk of thromboembolic events relative to potential benefits. For these reasons, a decision was made by the co-authors of this report to forgo the primary economic evaluation.
6 HEALTH SERVICES IMPACT
Based on Canadian data on the use of rFVIIa (Source: Muirhead B, Dickson T, Freeman J. Recombinant Factor VII Use in Canada. Physicians and Nurses for Blood Conservation [PNBC] Database: 2005-2006) and based on consultation with clinical experts on the prophylactic use of rFVIIa in cardiac surgery (Dr. Keyvan Karkouti, Associate Professor, Anesthesia, Toronto General Hospital, University Health Network, Toronto: personal communications, February 13, 2009 and July 7, 2009), liver transplantation (JB, unpublished observations, 2009), open retropubic prostatectomy (Dr. Chris Morash, Medical Director, Prostate Cancer Assessment Centre, The Ottawa Hospital, Ottawa: personal communication, February 10, 2009), and its use in general (Dr. Brian Muirhead, Medical Manager, Winnipeg Regional Health Authority [WRHA] Blood Conservation Service, Winnipeg Health Sciences Centre, Winnipeg: personal communication, February 9, 2009), there is little routine preventive use of rFVIIa for these surgical procedures in Canada. None of the experts indicated seeing the widespread use of rFVIIa in prophylaxis for bleeding during surgery.
The data provided by Dr. Muirhead showed one definite request (of 499) for the prophylactic use of rFVIIa in an unspecified surgery. Data from Karkouti et al.’s23 article suggest that the preventive use of rFVIIa in cardiac surgery may be as low as eight cases per year in Canada, with a median cost of approximately $5,000 per patient (approximate total Canadian budget impact of $40,000 per year). The prophylactic use in cardiac surgery may be more likely among Jehovah’s Witness patients (Dr. Keyvan Karkouti: personal communications, February 13, 2009 and July 7, 2009),67 and Canadian guidelines do not recommend its use for bleeding prophylaxis in cardiac surgery in general.66
Given the low level of apparent use for each of the four indications and the expectation that widespread use is unlikely, a budget impact analysis was not conducted. The preventive use of rFVIIa may become a possibility. As a result, an estimate of the annual potentially eligible populations for three of the four indications, based on Canadian surgical procedure data, appears in Tables 2 and 3.
22 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
Table 2: Annual Potentially Eligible Populations for Preventive Use of Recombinant Activated Factor VII in Three Indications Province Liver Transplant Cardiac Procedures Prostatectomy Newfoundland 0 477 156 Prince Edward Island 0 0 53 Nova Scotia 28 991 369 New Brunswick 0 609 248 Ontario 213 9,237 3,577 Manitoba 0 1,027 257 Saskatchewan 0 876 187 Alberta 75 2,032 691 British Columbia 43 3,024 1,033
Note: All cardiac procedures are on-pump only; cardiac procedures include cardiac bypass surgery, cardiac valve replacement, or both; heart transplant; and heart and lung transplant. Source: Canadian Institute for Health Information, Ottawa, ON, Canada. Discharge Abstract Database (DAD) 2007-2008.
Table 3: Annual Potentially Eligible Populations for Preventive Use of Recombinant Activated Factor VII in Three Indications Province Liver Transplant Cardiac Procedures Prostatectomy Quebec 92 5,696 2,083
Note: All cardiac procedures are on-pump only; cardiac procedures include cardiac bypass surgery, cardiac valve replacement, or both; heart transplant; and heart and lung transplant. Source: Canadian Institute for Health Information, Ottawa, ON, Canada. Hospital Morbidity Database (HMDB) 2005-2006.
All estimated cardiac procedures were performed on-pump, because rFVIIa is unlikely to be used in off-pump cardiac procedures. Among the included cardiac procedures are cardiac bypass surgery, cardiac valve replacement, or both; heart transplant; and heart and lung transplant. The number of patients who may receive a supra-therapeutic dose of anticoagulant requiring reversal with rFVIIa could not be estimated based on available data sources, but it may be approximated based on the more than 200,000 patients receiving warfarin in Canada through publicly funded drug plans per year.27 The price of rFVIIa is estimated to be C$1,100.27 per mg.1 Assuming an average patient weight of 70 kg, the cost of prevention using rFVIIa among the patients who are described in the clinical review ranges from C$1,540.38 per patient (20 µg/kg dose) to C$9,242.27 per patient (120 µg/kg dose).
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 23 Clinical and Economic Systematic Review
6.1 Planning, Implementation, Utilization, and Legal or Regulatory Considerations
As discussed in the CADTH review of rFVIIa for the treatment of uncontrolled hemorrhage,1 there is no standard framework in place to ensure the appropriate use of rFVIIa in Canada.68 The Canadian National Advisory Committee on Blood and Blood Products is implementing a common policy framework for the compassionate use of rFVIIa. This framework includes a list of medical and prerequisite conditions for the use of rFVIIa, a medical screening system where physicians with expertise in transfusion medicine or hemostasis review all requests for rFVIIa, and a review of standardized utilization data on rFVIIa.68 Implementation of the framework requires an alignment with local protocols to facilitate expert review and collection and sharing of utilization data.
6.2 Ethical Considerations
6.2.1 Methods
There were no specific research questions on the ethical, psychosocial, and legal considerations of using rFVIIa for off-label indications. The project team conducted an overview of these components based on a review of reports that were retrieved. Experts on the project team helped identify the issues surrounding the use of this therapeutic agent.
6.2.2 Discussion
It is a principle of ethics and law that medical treatment may be administered only with the patient’s informed consent and that a health care provider who treats a patient without consent faces legal liability.69,70 Ethically and legally valid consent is given voluntarily by a competent person who has been fully informed about the nature of the treatment and its relevant risks and benefits.69
The requirement to disclose information to patients so that they can make an informed choice about consent to treatment is complicated when products such as rFVIIa are involved.71 A key issue relates to the appropriateness of using a therapeutic agent with potential serious risks without proof of benefit for the specified indications. In general, specific consent would not be sought, and it is unlikely that patients would be aware they were being placed at increased potential risk for complications. The surgical team ordering this product may be more concerned about the risk of bleeding during the procedure. There are also societal cost implications that are associated with this therapy.
A patient who is harmed through the use of rFVIIa may argue that he or she should have been informed that a therapeutic agent would be used. Under Canadian law, a health care provider must disclose to a patient all information that a reasonable person in the patient’s position would want to know.70 The standard of disclosure is higher in the research context. To give legally valid consent to participate in research, for example, an individual must be informed of all risks, regardless of how remote or rare.72 This leads to the question of whether a reasonable patient would want to know if rFVIIa will be used in his or her treatment. Some argue that patients have
24 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
a right to know if off-label use of medications and biologics will occur during treatment and a concomitant right to refuse treatment: “Patients need information about off-label uses to make well-informed health care decisions. The legal doctrine of informed consent should be expanded to require disclosure of off-label prescribing where the drug has not proven safe and effective for the condition, especially where scientific evidence is inadequate and risks are substantial or unknown.”73
Because there are no regulations governing the off-label use of rFVIIa in Canada, health care providers considering its use cannot turn to regulations in determining what information must be disclosed to a patient during informed consent. If available evidence suggests that rFVIIa use may increase the risk of harm, health care providers may have a legal obligation to disclose this information to the patient before treatment. If evidence indicates increased risk, however, it is legally and ethically tenuous to ask patients to accept this risk during informed consent. In this case, patients should be informed of the known risks and benefits of rFVIIa or alternative therapies and have the right to accept or refuse the use of this agent. Any valid advance directive should be respected. If, on the other hand, concerns about the safety risks of using rFVIIa are largely theoretical, questions arise about the ethics of informing patients of hypothetical risks. Advising patients that rFVIIa will be used during a surgical procedure and that such therapy could expose the patient to adverse events will likely cause anxiety, and many patients may request that rFVIIa not be used. Offering theoretical information to patients may, in general, undermine trust in health care providers and institutions.
7 DISCUSSION 7.1 Summary of Results
Eight RCTs43-50 and two cohort studies55,56 involved surgical patients who received rFVIIa, placebo, or usual care. No studies were found evaluating the use of rFVIIa for the prevention of bleeding in anticoagulated patients. Two evidence-based guidelines stated that there is no specific method to monitor the efficacy of rFVIIa treatment when used for the prevention of bleeding.58,59
In one trial enrolling 82 pediatric cardiac surgery patients, no statistically significant difference favouring rFVIIa therapy compared with placebo was detected for the volume of RBCs transfused, volume of platelets transfused, or operative time.44 Among adults undergoing cardiac surgery, one RCT (20 participants) detected no statistically significant difference between rFVIIa and placebo in any outcome that was measured (volume of blood products, length of stay, or adverse events).43 A second placebo-controlled trial (22 participants) reported statistically significant reductions in the volume of RBCs transfused or volume of platelets transfused and in the length of ICU stay, favouring rFVIIa.45
In adult patients undergoing liver transplantation, two small (25 participants or fewer) RCTs reported that the use of rFVIIa statistically significantly reduced the volume of RBCs transfused or volume of FFP transfused compared with placebo47 or usual care.49 No statistically significant reductions in the volume of blood products transfused were detected among patients who
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 25 Clinical and Economic Systematic Review
received rFVIIa in two larger placebo-controlled trials (87 and 209 participants).46,48 The length of hospital stay or length of ICU stay was similar between rFVIIa and control groups.46-48 One49 of four RCTs reported that the use of rFVIIa statistically significantly lowered the length of the surgical transplantation procedure.
One RCT of 36 patients undergoing prostatectomy concluded that the use of rFVIIa reduced the need for RBC transfusion and reduced the operative time compared with placebo.50 No statistically significant differences were detected between groups on the length of hospital stay, adverse events, or deaths.50
It was not possible to adequately evaluate the risk of adverse events associated with the prophylactic use of rFVIIa during surgery. Adverse event data were poorly reported in the clinical trials, and these studies were not designed to detect differences in the incidence of uncommon events. Most studies excluded patients at risk of thromboembolic events.
In the economic review, there were three studies on three of the four indications that were relevant to this report. All three studies obtained data from one hospital centre and were based on small samples. In addition, the assessments of outcomes and costs were limited to the duration of the inpatient stay, and health states were not evaluated. Schoenhaus et al.’s62-64 study was based on retrospectively obtained data. Only Odeyemi’s study reported sensitivity analyses, but there were inconsistencies in its reported outcomes compared with the clinical data.50 This study reported a small reduction in the total average health care costs of using 40 µg/kg rFVIIa compared with placebo. The three studies were not reported in sufficient detail to complete an assessment of the methods and results, and generalizability to a Canadian setting was limited.
There seems to be little use of rFVIIa for the prevention of bleeding in Canada. The main reason for this lack of use is concern about the thromboembolic adverse events relative to any potential benefit. If future clinical research finds the use of rFVIIa to be efficacious and associated with a low risk of thromboembolic events, there may be as many as 33,000 cardiac surgery, liver transplant surgery, and prostatectomy patients who would be eligible to receive this treatment in Canada each year.
7.2 Strengths and Weaknesses of this Assessment
The clinical and economic review was conducted according to CADTH guidelines. The strength of this approach is that it reduced the introduction of bias by including a comprehensive literature search for published and unpublished RCTs, non-randomized controlled clinical trials, observational studies, and economic studies. To reduce the potential for bias even further, studies were screened, and data were extracted independently by two researchers.
The assessment is limited by the number of studies that met the inclusion criteria, which do not provide clear evidence because of the small numbers of patients, a risk of bias due to unclear allocation concealment, incomplete reporting of methods for blinding, and incomplete or selective outcome reporting. Limited information was provided on the number and type of adverse events that were observed or the approach to collecting these. The reports relied on the use of P values in the interpretation of findings and did not report between-group differences and
26 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
95% CIs. Interpretation based on P values does not provide information on the magnitude or direction of the treatment effect.74 None of the studies defined minimally important clinical differences for the outcomes that were measured.75 No studies based on the supra-therapeutic anticoagulated patient population met the inclusion criteria. The economic studies were based on small sample sizes and had limitations in clarity and completeness of reporting of methods and results as well as generalizability to a Canadian health care setting.
7.3 Generalizability of Findings
The patient populations who were enrolled in the clinical trials were specific, and in most cases, patients with a history of thromboembolic disease were excluded. The generalizability of the findings may be limited based on the studies’ exclusion criteria and the small numbers of patients who were tested. The RCTs were conducted outside Canada (US, Europe, Australia). The economic evaluations that were reviewed were conducted in the US, Netherlands, and China, which limits the applicability to a Canadian context.
Several systematic reviews evaluated the prophylactic use of rFVIIa during surgery.2,76-80 It is difficult to compare the results of our report with these reviews because of differences in the selection criteria and analysis methods.
7.4 Knowledge Gaps
The efficacy of using rFVIIa for the prevention of bleeding in patients with supra-therapeutic anticoagulation could not be determined, because of a lack of clinical trials. Although the use of rFVIIa has been shown to be effective in normalizing INR or activated partial thromboplastin time (aPTT) results, the clinical importance of these effects is unknown.2,20-22 In Canada, with the introduction of a prothrombin complex concentrate (Octaplex) that is approved for the reversal of vitamin K antagonists,18,19 interest in using rFVIIa as a reversal agent may be limited. The evaluation of rFVIIa as a reversal agent for other anticoagulants, such as low molecular weight heparins, direct thrombin inhibitors, and selective factor Xa inhibitors that lack a specific reversal agent, may be a topic for future RCTs.
In the surgical patient groups who were assessed for this report, the use of rFVIIa reduced blood product needs in some of the small RCTs. These benefits were not detected in other studies. Considering the generally small number of patients who were enrolled in the RCTs (median 31 participants), the differences that were detected may have occurred by chance, or a type II error may have occurred, and real differences between the rFVIIa and control groups may not have been detected. Even if future adequately powered RCTs show that rFVIIa reduces the volume of blood products used, these effects should be interpreted relative to predefined minimal clinically important differences, after exploring the link between this surrogate and patient important outcomes.
The risk of adverse events with the use of rFVIIa by surgical patients is unknown, but the potential for serious morbidity or mortality should be considered. Data from the Food and Drug Administration’s Adverse Event Reporting System showed that most of the thromboembolic adverse events that occurred in patients who received rFVIIa were associated with off-label use
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 27 Clinical and Economic Systematic Review
and often resulted in serious morbidity and mortality.33 Frequent use of rFVIIa as a preventive therapy may expose many patients with a low bleeding risk (and hence a low risk of allogeneic blood product transfusion) to additional harms unnecessarily. To determine the safety and efficacy of rFVIIa, large and adequately powered RCTs with clinically important patient outcomes would be needed for each indication. The risk-benefit profile of a therapy cannot be quantified using small, underpowered studies. For example, aprotinin, an antifibrinolytic agent that was used for years to minimize surgical blood loss, was removed from the Canadian market based on a large RCT showing an increase in risk of death.16 Previous meta-analyses of mainly small RCTs suggested that the risk-benefit profile of aprotinin was favourable.81
The ongoing collection of utilization data on rFVIIa may be useful in providing information about preventive versus rescue use, with a link between these data and patient outcomes.
8 CONCLUSIONS
No consistent benefit of rFVIIa therapy was detected among studies evaluating the prevention of bleeding in patients undergoing prostatectomy, liver transplantation, or cardiac surgery. The risk of adverse events after the prophylactic use of rFVIIa in surgical patients is unknown. No conclusions can be drawn on the effectiveness or safety of using rFVIIa in the prevention of bleeding in patients who have received supra-therapeutic doses of anticoagulant agents. When used for prevention of bleeding, no specific method is available to monitor the effectiveness of rFVIIa.
Given the small number of economic studies available and limitations in the reporting, methods, and generalizability of these studies, conclusions about the cost-effectiveness of using rFVIIa to prevent bleeding in a Canadian setting cannot be made. An informative primary economic evaluation might be more appropriate when consistent effectiveness evidence is available and preventive use of this treatment more commonplace. As a result, the cost-effectiveness of using rFVIIa in the prevention of bleeding unrelated to hemophilia remains unknown. If rFVIIa is used preventively on a wider scale by clinicians in the future, the potentially eligible population for this treatment is substantial.
28 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review 9 REFERENCES
1. Pohar SL, Tsakonas E, Murphy G, Anderson D, Carney D, Moltzan C, et al. Recombinant activated factor VII in the treatment of hemorrhage unrelated to hemophillia: a systematic review and economic review [Technology report 118]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009. Available: http://www.cadth.ca/index.php/en/hta/reports-publications/search/publication/904 (accessed 2009 Jun 24). 2. Technology Evaluation Center. Special report: recombinant activated factor VII for uncontrolled bleeding in non-hemophiliac patients [Assessment program vol. 21 no. 10]. Chicago: The BlueCross BlueShield Association; 2006. Available: http://www.bcbs.com/blueresources/tec/vols/21/21_10.pdf (accessed 2008 Jan 4). 3. Novo Nordisk. Niastase: eptacog alfa (activated) activated recombinant human blood coagulation factor VII [Product monograph (schedule D)]. Mississauga: Novo Nordisk Canada; 2009. Available: http://www.novonordisk.ca/PDF_Files/NiaStasePM012809_En.pdf (accessed 2009 Oct 23). 4. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004;44(10):1453-62. 5. Ramos E, Dalmau A, Sabate A, Lama C, Llado L, Figueras J, et al. Intraoperative red blood cell transfusion in liver transplantation: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 2003;9(12):1320-7. 6. Farnham SB, Webster TM, Herrell SD, Smith JA, Jr. Intraoperative blood loss and transfusion requirements for robotic-assisted radical prostatectomy versus radical retropubic prostatectomy. Urology 2006;67(2):360-3. 7. McCullough TC, Roth JV, Ginsberg PC, Harkaway RC. Estimated blood loss underestimates calculated blood loss during radical retropubic prostatectomy. Urol Int 2004;72(1):13-6. 8. Gilbert JB, Malkowicz SB, Wein AJ. Cell saver and radical retropubic prostatectomy: analysis of cost- effectiveness. Urology 1995;46(4):542-4. 9. Koch MO, Smith JA, Jr. Blood loss during radical retropubic prostatectomy: is preoperative autologous blood donation indicated? J Urol 1996;156(3):1077-9. 10. Goh M, Kleer CG, Kielczewski P, Wojno KJ, Kim K, Oesterling JE. Autologous blood donation prior to anatomical radical retropubic prostatectomy: is it necessary? Urology 1997;49(4):569-73. 11. Monk TG, Goodnough LT, Brecher ME, Colberg JW, Andriole GL, Catalona WJ. A prospective randomized comparison of three blood conservation strategies for radical prostatectomy. Anesthesiology 1999;91(1):24- 33. 12. Thiel DD, Igel TC, Brisson TE, Heckman MG. Outcomes with an alternative anastomotic technique after radical retropubic prostatectomy: 10-year experience. Urology 2006;68(1):132-6. 13. Gaylis FD, Friedel WE, Armas OA. Radical retropubic prostatectomy outcomes at a community hospital. J Urol 1998;159(1):167-71. 14. Public Health Agency of Canada. Transfusion transmitted injuries section. Ottawa: The Agency; 2004. Available: http://www.phac-aspc.gc.ca/hcai-iamss/tti-it/risks-eng.php (accessed 2009 Jan 28). 15. O'Brien SF, Yi QL, Fan W, Scalia V, Kleinman SH, Vamvakas EC. Current incidence and estimated residual risk of transfusion-transmitted infections in donations made to Canadian Blood Services. Transfusion 2007;47(2):316-25. 16. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358(22):2319-31. 17. Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006;4(9):1853-63.
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 29 Clinical and Economic Systematic Review
18. Health Canada. Octaplex (Human Prothrombin Complex). In: Drug Product Database [database online]. Ottawa: Health Canada; 2009. Available: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index- eng.php (accessed 2010 Jan 11). 19. National Advisory Committee on Blood and Blood Products. Recommendations for use of Octaplex in Canada. Edmonton: The Committee; 2008 Sep 16. Available: http://www.transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%2020 08.pdf (accessed 2009 Jun 25). 20. Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998;9(8):741-8. 21. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002;106(20):2550-4. 22. Bijsterveld NR, Vink R, van Aken BE, Fennema H, Peters RJ, Meijers JC, et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004;124(5):653-8. 23. Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL, et al. Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation 2008;118(4):331-8. 24. Webert KE, Arnold DM, Carruthers J, Molnar L, Almonte T, Decker K, et al. Utilization of recombinant activated factor VII in southern Ontario in 85 patients with and without haemophilia. Haemophilia 2007;13(5):518-26. 25. Heller M, Lau W, Pazmino-Canizares J, Brandao LR, Carcao M. A comprehensive review of rFVIIa use in a tertiary care pediatric center. Pediatr Blood Cancer 2007;50(5):1013-17. 26. Canadian Institute for Health Information (CIHI). 2008 annual report - treatment of end-stage organ failure in Canada, 1997 to 2006. Ottawa: CIHI; 2008. Available: http://secure.cihi.ca/cihiweb/products/corr_annual_report_2008_en.pdf (accessed 2009 Jan 28). 27. Brown A, Wells P, Jaffey J, McGahan L, Poon MC, Cimon K, et al. Point-of-Care monitoring devices for long-term oral anticoagulation therapy: clinical and cost effectiveness [Technology report no 72]. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH); 2007. Available: http://www.cadth.ca/media/pdf/H0299_anticoagulation-therapy_tr_e.pdf (accessed 2007 Jun 21). 28. Health Canada. NiaStase. In: Notice of Compliance with conditions (NOC/c) [database online]. Ottawa: Health Canada; 2007. Available: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices- avis/conditions/index_e.html (accessed 2008 Jan 4). 29. Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. NovoSeven® product approval information. Rockville (MD): The Center; 1999 Mar 25. 30. European Medicines Agency. NovoSeven: European public assessment report. London: the Agency; 2008. 31. Ratko TA, Cummings JP, Matuszewski KA. Off-label use of recombinant activated factor VII (NovoSeven). P & T 2004;29(11):712-3, 717-9,-720. 32. Mathew P, Simon TL, Hunt KE, Crookston KP. How we manage requests for recombinant factor VIIa (NovoSeven). Transfusion 2007;47(1):8-14. 33. O'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293-8. Available: http://jama.ama- assn.org/cgi/reprint/295/3/293 (accessed 2009 Apr 24). 34. Enomoto TM, Thorborg P. Emerging off-label uses for recombinant activated factor VII: grading the evidence. Crit Care Clin 2005;21(3 Spec Iss):611-32.
30 Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: Clinical and Economic Systematic Review
35. DeLoughery TG. Management of bleeding emergencies: when to use recombinant activated factor VII. Expert Opin Pharmacother 2006;7(1):25-34. 36. VA MedSafe, Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. Review and recommendations for the off label use of recombinant activated human coagulation factor VII (Novoseven®). Washington (DC): Veteran Affairs; 2007. Available: http://www.pbm.va.gov/Clinical%20Guidance/Drug%20Monographs/Factor%20VII,%20Recombinant%20A ctivated%20(NovoSeven%C2%AE),%20Drug%20Monograph.pdf (accessed 2007 Sep 21). 37. Canadian Agency for Drugs and Technologies in Health. CADTH Report Requirements for Health Technology Assessment. Ottawa: The Agency; 2008 Apr 1. 38. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17(1):1-12. 39. Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet 2002;359(9306):614-8. 40. Cochrane Oral Health Group. The Cochrane Collaboration's tool for assessing risk of bias. Manchester(UK): The Group; 2008. Available: http://www.ohg.cochrane.org/forms/Risk%20of%20bias%20assessment%20tool.pdf (accessed 2008 Aug 19). 41. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Health Research Institute; 1999. Available: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm (accessed 2004 Feb 9). 42. STATA [computer program]. Version 11.0. College Station (TX): StataCorp LP; 2009. 43. Diprose P, Herbertson MJ, O'Shaughnessy DO, Gill RS. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005;95(5):596-602. 44. Ekert H, Brizard C, Eyers R, Cochrane A, Henning R. Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double- blind, parallel group, placebo-controlled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy. Blood Coagul Fibrinolysis 2006;17(5):389-95. 45. Ma B, Wang ZN, Zhang BR, Xu ZY, Yang LX, Chen KB, et al. Effect of recombinant activated factor VII a on early recovery of patients undergoing cardiac valve replacement under cardiopulmonary bypass: a randomized double-blind placebo-controlled trial [Chinese]. Academic Journal of Second Military Medical University 2006;27(10):1110-3. 46. Lodge JP, Jonas S, Jones RM, Olausson M, Mir-Pallardo J, Soefelt S, et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11(8):973-9. 47. Pugliese F, Ruberto F, Summonti D, Perrella S, Cappannoli A, Tosi A, et al. Activated recombinant factor VII in orthotopic liver transplantation. Transplant Proc 2007;39(6):1883-5. 48. Planinsic RM, van der MJ, Testa G, Grande L, Candela A, Porte RJ, et al. Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005;11(8):895-900. 49. Zimmerer SE, Lee V, Brink JA, Jackowski J, Chen C, Khanna A, et al. Activated recombinant factor VII: a prospective randomized clinical trial in liver transplantation [abstract no: 1547]. Am J Transplant 2005;5(Suppl 11):549. Available: http://www3.interscience.wiley.com/cgi- bin/fulltext/118717915/PDFSTART. 50. Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, Kurth KH, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double- blind placebo-controlled randomised trial. Lancet 2003;361(9353):201-5.
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51. Lodge JPA, Jonas S, Jones RM, Olausson M, Mir-Pallardo J, Soefelt S, et al. Efficcy and safety of recombinant factor VIIa (RFVIIa) on transfusion reduction in orthotopic liver transplantation (OLT) - a randomised, double-blind, placebo-controlled trial. Transplantation 2004;78(2):93. 52. Planinsic RM, Testa G, Emre S, Grande L, Candela A, van der Meer J, et al. Safety and efficacy of single bolus dose of recombinant factor VIIa in patients undergoing orthotopic liver transplantation: a randomized multi-center study [abstract]. Hepatology 2002;36(4 Part 2):660A. 53. Friederich PW, Geerdink MG, Spataro M, Messelink EJ, Henny CP, Büller HR, et al. The effect of the administration of recombinant activated factor VII (NovoSeven®) on perioperative blood loss in patients undergoing transabdominal retropubic prostatectomy: the PROSE study. Blood Coagul Fibrinolysis 2000;11 Suppl 1:S129-S132. 54. Friederich PW, Geerdink MGF, Keller TT, Messelink EJ, Henny CP, Levi M. Novel applications of recombinant factor VIIa: the effect of the administration of recombinant activated factor VII ( NovoSeven ) on perioperative blood loss in patients undergoing transabdominal retropubic prostatectomy: the PROSE study. Infusionsther Transfusionsmed 2001;28(2):112-3. 55. Fetouh FA, Salah M, Sedeek K. The efficacy of low dose recombinant factor viia in the prophylaxis of bleeding during orthotropic liver transplantation [abstract]. Can J Anaesth 2008;55(Suppl 1):471974. Available: http://springerlink.com/content/n6h3746426026339/fulltext.pdf (accessed 2009 Sep 10). 56. Meijer K, Hendriks HG, De Wolf JT, Klompmaker IJ, Lisman T, Hagenaars AA, et al. Recombinant factor VIIa in orthotopic liver transplantation: influence on parameters of coagulation and fibrinolysis. Blood Coagul Fibrinolysis 2003;14(2):169-74. 57. Zimmerer SE, Precht AF, Khanna A, Hart MA. Activated recombinant factor VIIa: a novel approach to conserve blood loss in liver transplantation [poster no 1136]. Am J Transplant 2008;2(Suppl 3):424. 58. Shander A, Goodnough LT, Ratko T, Matuszewski KA, Cohn S, Diringer M, et al. Consensus recommendations for the off-label use of recombinant human factor VIIa (NovoSeven) therapy. P & T 2005;30(11):644-50, 652-4, 656-7, 658. 59. Vincent JL, Rossaint R, Riou B, Ozier Y, Zideman D, Spahn DR. Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding--a European perspective. Crit Care 2006;10(4):R120. 60. Drummond MF, Jefferson TO, BMJ Economic Evaluation Working Party. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ 1996;313(7052):275-83. Available: http://www.bmj.com/cgi/content/full/313/7052/275 (accessed 2007 Feb 19). 61. Canadian Agency for Drugs and Technologies in Health. Guidelines for the economic evaluation of health technologies: Canada. 3rd ed. Ottawa: the Agency; 2006. Available: http://www.cadth.ca/media/pdf/186_EconomicGuidelines_e.pdf (accessed 2008 Jan 31). 62. Schoenhaus R, Awdishu L, Martinez S, Hart M, Lane T. A single centre experience with recombinant factor VIIa in orthotopic liver transplantation [PowerPoint presentation]. San Diego: University of California; 2009. Available: http://pharmacy.ucsd.edu/faculty/AppliedPEForum/Schoenhaus%20PE%20forum%20Databases.pdf (accessed 2009 Jun 2). 63. Schoenhaus RH, Awdishu L, Hart M, Martinez S, Daniels CE. Cost effectiveness of factor VIIa use in orthotopic liver transplant. Toronto: Society for Pharmacoeconomics and Outcomes Research (ISPOR); 2008. 64. Schoenhaus R, Awdishu L, Daniels C. Cost-effectiveness recombinant factor VIIa use in orthotopic liver transplant. Value Health 2008;11(3):A5. 65. Odeymei IA, Friedrich PW, Levi M. Economic impact of recombinant activated factor VII in the control of bleeds associated with abdominal prostatectomy. J Med Econ 2004;7:107-15.
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66. Karkouti K, Beattie WS, Crowther MA, Callum JL, Chun R, Fremes SE, et al. The role of recombinant factor VIIa in on-pump cardiac surgery: proceedings of the Canadian Consensus Conference. Can J Anaesth 2007;54(7):573-82. 67. Ballen J, Raabe M, Muirhead B. Aortic dissection and hypothermic arrest in a Jehovah's Witness patient: a case for recombinant factor VIIa? Can J Anaesth 2006;53(4):353-6. 68. Moltzan CJ, Anderson DA, Callum J, Fremes S, Hume H, Mazer CD, et al. The evidence for the use of recombinant factor VIIa in massive bleeding: development of a transfusion policy framework. Transfus Med 2008;18(2):112-20. 69. Beauchamp TL, Childress JF. Principles of biomedical ethics. 5th ed. New York: Oxford University Press; 2001. 70. Picard EI, Robertson GB. Legal liability of doctors and hospitals in Canada. Toronto: Carswell; 2007. 71. Dzik WH. Off-label reports of new biologics: exciting new therapy or dubious research? Examples from recombinant activated factor VII. J Intensive Care Med 2006;21(1):54-9. Available: http://jic.sagepub.com/cgi/reprint/21/1/54 (accessed 2009 Sep 3). 72. Reibl v. Hughes, [1980] 2 S.C.R. 880 (Supreme Court of Canada). Available: http://csc.lexum.umontreal.ca/en/1980/1980rcs2-880/1980rcs2-880.pdf (accessed 2010 Jan 11). 73. Wilkes M, Johns M. Informed consent and shared decision-making: a requirement to disclose to patients off- label prescriptions. PLoS Med 2008;5(11):e223. Available: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050223 (accessed 2009 Sep 3). 74. Lang JM, Rothman KJ, Cann CI. That confounded P-value. Epidemiology 1998;9(1):7-8. 75. Beaton DE, Boers M, Wells GA. Many faces of the minimal clinically important difference (MCID): a literature review and directions for future research. Curr Opin Rheumatol 2002;14(2):109-14. 76. Ranucci M, Isgro G, Soro G, Conti D, De Toffol B. Efficacy and safety of recombinant activated factor VII in major surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg 2008;143(3):296-304. 77. Stanworth SJ, Birchall J, Doree CJ, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev 2007;(2):CD005011. Available: http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005011/pdf_fs.html (accessed 2009 Apr 24). 78. Birchall J, Stanworth SJ, Duffy MR, Doree CJ, Hyde C. Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia. Transfus Med Rev 2008;22(3):177- 87. 79. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 2008;248(1):61-8. 80. Warren O, Mandal K, Hadjianastassiou V, Knowlton L, Panesar S, John K, et al. Recombinant activated factor VII in cardiac surgery: a systematic review. Ann Thorac Surg 2007;83(2):707-14. 81. Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, et al. Anti Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007;(4):CD001886. Available: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001886/frame.html (accessed 2009 Jul 21).
Recombinant Activated Factor VII for Prevention of Bleeding Unrelated to Hemophilia: 33 Clinical and Economic Systematic Review APPENDIX 1: LITERATURE SEARCH
OVERVIEW Interface: Ovid Databases: BIOSIS Previews 1989 to 2009 Week 18 EMBASE 1980 to 2009 Week 14 MEDLINE(R) 1950 to April Week 1 2009 MEDLINE(R) In-Process & Other Non-Indexed Citations April 8, 2009
Note: Subject headings have been customized for each database. Duplicates between databases were removed in Reference Manager Version 11 database. Date of Search: April 8, 2009 Alerts: Monthly search updates began in April 09, 2009 and ran until October 2009 Study Types: Systematic reviews; meta-analyses; technology assessments; randomized controlled trials; controlled clinical trials; observational studies, clinical practice guidelines, economic studies Limits: Human (non-animal), no publication date or language limits
SYNTAX GUIDE / At the end of a phrase, searches the phrase as a subject heading .sh At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading fs Floating subheading exp Explode a subject heading $ Truncation symbol, or wildcard: retrieves plural or variations of a word * Indicates that the marked subject heading is a primary topic OR Truncation symbol, or wildcard: retrieves plural or variations of a word ? Truncation symbol for one or no characters only ADJ Requires words are adjacent to each other (in any order)
A-1
ADJ# Adjacency within # number of words (in any order) .ti Title .ab Abstract .hw Heading Word; usually includes subject headings and controlled vocabulary .pt Publication type .rn CAS registry number use b9o89 Limit search line to the Biosis Previews database use emez " Embase use mesz " Medline use prem " Medline In-Process & Other Non-Indexed Citations Ovid MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations STRATEGY # Searches Results Concept: Niastase 1 Recombinant Blood Clotting Factor 7a/ 2646 2 Factor VII/ 7655 3 factor VIIa/ 3980 4 Blood Clotting Factor 7/ 4014 5 Blood Clotting Factor 7a/ 1513 ("factor VII" or "factor VIIa" or "factor 7" or 6 factor7 or "factor 7a" or factor7a or 17259 fVIIa).ti,ab. 7 or/2-6 21290 8 exp Recombinant Proteins/ 375129 9 exp Recombinant Protein/ 149435 (recombinant* or coagulation* or activated 10 2473699 or activation).ti,ab. 11 or/8-10 2674360 12 7 and 11 14476 (recombinant* or coagulation* or activated 13 320978 or activation).hw. use b9o89 ("factor VII" or "factor VIIa" or "factor 7" or 14 factor7 or "factor 7a" or factor7a or 5587 fVIIa).hw. use b9o89 15 13 and 14 2799 (rFVIIa or rFactor VIIa or rFactor viia or 16 2506 rFactor 7a or rFactor7a or rfviia).ti,ab,hw,cb.
A-2
(Proconvertin* or biosynthetic protein* or 17 recombinant DNA protein* or DNA 528 recombinant protein*).ti,ab. (Proconvertin* or biosynthetic protein* or 18 recombinant DNA protein* or DNA 84 recombinant protein*).hw. use b9o89 19 "EC 3.4.21.21".rn,nm,cb. 2514 20 "9001-25-6".rn,nm,cb. 8378 21 "65312.43.8".rn,nm,cb. 742 22 "102786-61-8".rn,nm,cb. 67 23 or/1,12,15-22 20686 Concept: Cardiac surgery 24 Thoracic Surgery/ 15732 25 exp Cardiac Surgical Procedures/ 252386 26 exp Cardiovascular Surgical Procedures/ 442321 27 exp Thoracic Surgical Procedures/ 386786 28 exp Heart surgery/ 135667 29 cardiovascular surgery/ 2306 ((thoracic or heart or cardiac or cardia or cardiovascular or cardio-vascular or cardio or myocardial or myo-cardial or chest or cardiothoracic or cardio-thoracic or 30 coronary) adj2 (surger* or surgical 189959 procedure* or operation* or resection* or bypass or fontan or cardiomyoplast* or massage or angioplasty* or atherectom*)).ti,ab. (thoracic or heart or cardiac or cardia or cardiovascular or cardio-vascular or cardio or myocardial or myo-cardial or chest or cardiothoracic or cardio-thoracic or 31 coronary).ti,ab. adj2 (surger* or surgical 1953634 procedure* or operation* or resection* or bypass or fontan or cardiomyoplast* or massage or angioplasty* or atherectom*).hw. use b9o89 (cardiosurger* or cardio-surger* or 32 3249 pericardiocentesis or pericardietom*).ti,ab. (cardiosurger* or cardio-surger* or 33 pericardiocentesis or pericardietom*).hw. 460 use b9o89 34 Cardiopulmonary bypass/ 33303 35 Cardiopulmonary bypass/ 33303
A-3
(cardiopulmonary bypass* or cardio- pulmonary bypass* or CPB or 36 cardiopulmonary shunt* or cardio- 49610 pulmonary shunt* or heart-lung bypass or heart-lung shunt*).ti,ab. (cardiopulmonary bypass* or cardio- pulmonary bypass* or CPB or 37 cardiopulmonary shunt* or cardio- 6255 pulmonary shunt* or heart-lung bypass or heart-lung shunt*).hw. use b9o89 38 or/24-37 2304197 Concept: Liver transplantation 39 Liver transplantation/ 67190 40 exp Liver Transplantation/ 68106 ((liver or hepatic or hepar) adj3 (transplant* 41 or graft* or replacement* or 107299 resection*)).ti,ab. ((liver or hepatic or hepar) adj3 (transplant* 42 or graft* or replacement* or resection*)).hw. 20194 use b9o89 (Transplantation/ or organ transplantation/ or 43 transplantation*.ti,ab.) and (liver/ or (liver or 96631 hepatic or hepar).ti,ab.) 44 or/39-43 145978 Concept: Prostatectomy 45 exp Prostatectomy/ 30881 46 exp Prostate surgery/ 20970 (prostatectom* or 47 prostatoseminovesiculectom* or prostate 39301 adenectom* or prostate resection*).ti,ab. (prostatectom* or prostatoseminovesiculectom* or prostate 48 12723 adenectom* or prostate resection*).hw. use b9o89 (TURP or TURPs or TUVP or TUVPs or VLAP or VLAPs or TUEVP or TUEVPs or TUIP or TUIPs or TUMPT or TUMPTs or 49 TEVAP or TEVAPs or TUEVAP or 9795 TUEVAPs or HOLRP or HOLRPs or HOLEP or HOLEPs or TUNA or TUNAs).ti,ab. (TURP or TURPs or TUVP or TUVPs or 50 VLAP or VLAPs or TUEVP or TUEVPs or 3162 TUIP or TUIPs or TUMPT or TUMPTs or
A-4
TEVAP or TEVAPs or TUEVAP or TUEVAPs or HOLRP or HOLRPs or HOLEP or HOLEPs or TUNA or TUNAs).hw. use b9o89 ((transurethral or trans-urethral or transurethra or trans-urethra) and (ablat* or thermotherap* or prostate* or 51 20888 vaporesection* or electrovapori* or electroresection* or vapori* or coagulat* or resection*)).ti,ab. ((transurethral or trans-urethral or transurethra or trans-urethra) and (ablat* or thermotherap* or prostate* or 52 4978 vaporesection* or electrovapori* or electroresection* or vapori* or coagulat* or resection*)).hw. use b9o89 53 or/45-52 58158 Concept: Anticoagulants 54 exp anticoagulants/ 417968 55 anticoagulation/ 15938 56 exp anticoagulant agent/ 419102 (anti-coagula* or anticoagula* or 57 antithrombotic or anti-thrombotic or para 128917 coagulation*).ti,ab. (anti-coagula* or anticoagula* or 58 antithrombotic or anti-thrombotic or para 47956 coagulation*).hw. use b9o89 59 or/54-58 516193 60 Warfarin/ 45354 61 81-81-2.rn,nm,cb. 52211 (warfarin* or aldocumar or marevan or coumadin* or warfant or tedicumar or warfilone or jantoven or coumarin* or 62 circuvit or warfilone or lawarin or panwarfin 84792 or uniwarfin or warf or orfarin or waran or befarin or maforan or jantoven or anasmol or varfine or befarin).ti,ab,hw,tn,nm,cb. (warfarat or athrombin-K or Athrombinek or "Athrombin K" or "compound 42" or solfarin or adoisine or carfin or coumaphene 63 or kumatox or panwarfarin or prothromadin 140 or tintorane or wafarin or waran or warfilone or warnerin or rodex or co-rax or coumafene).ti,ab,hw,tn,nm,cb.
A-5
64 or/60-63 84842 65 4-Hydroxycoumarins/ 691 66 4 Hydroxycoumarin Derivative/ 100 67 1076-38-6.rn,nm,cb. 275 (4-hydrocoumadrin* or 4-Coumarinol or "AI3-52393" or "BRN 0129768" or 68 0 Benzotetronic acid or "EINECS 214-060-2" or "NSC 11889").ti,ab,hw,tn,nm,cb. 69 or/65-68 930 70 Abciximab/ 6092 71 143653-53-6.rn,nm,cb. 9576 (abciximab or "c7E3 Fab" or "chimeric 7E3 72 Fab" or clotinab or CentoRx or ReoPro or 11001 peonpo or c7e3 or 7e3).ti,ab,hw,tn,nm,cb. 73 or/70-72 11001 74 Acenocoumarol/ 3664 75 152-72-7.rn,nm,cb. 4068 (acenocoumarol* or fortonol or sintrom* or acenox or coarol or isquelium or syncumar or sinkumar or syncoumar or syntrhrom or sinthrom* or acitrom or acenocoumarin or 76 4422 nicoumalone or trombostop or sintron or sintrom or sincoumar or sincumar or neosintrom or minisintrom).ti,ab,hw,tn,nm,cb. 77 or/74-76 4437 78 Citrates/ 22576 79 Citric Acid/ 14995 80 13838-07-8.rn,nm,cb. 306 (acid citrate dextrose or "ACD solution" or 81 811 "ACD-A solution").ti,ab,hw,tn,nm,cb. 82 or/78-81 25825 83 Ancrod/ 1029 84 "EC 3.4.21".rn,nm,cb. 13573 (ancrod or "Arvin IRC 50" or "arvin IRC50" 85 or venacil or arvin or arwin or 1546 viprinex).ti,ab,hw,tn,nm,cb. 86 or/83-85 15118 ("limulus anti-LPS" or 87 antilipopolysaccharide factor or anti- 211 lipopolysaccharide factor or "anti-LPS
A-6
(limulus)" or "anti-LPS factor" or endotoxin- neutralizing protein, Limulus or ENP Limulus).ti,ab,hw,tn,nm,cb. 88 Antistasin/ 76 89 "110119-38-5".rn,nm,cb. 164 90 Antistasin*.ti,ab,hw,tn,nm,cb. 240 91 or/88-90 240 92 antivitamin K/ 2743 93 exp vitamin K/ai 939 ("Anti Vitamin K" or menadione antagonist 94 or "vitamin K 1038 antagonist").ti,ab,hw,tn,nm,cb. 95 or/92-94 4377 96 Aprosulate/ 47 97 "123072-45-7".rn,nm,cb. 90 (aprosulate or "LW 98 114 10082").ti,ab,hw,tn,nm,cb. 99 or/96-98 114 100 Ardeparin/ 291 101 (ardeparin or normiflo).ti,ab,hw,tn,nm,cb. 379 102 or/100-101 379 103 Argatroban/ 2026 104 74863-84-6.rn,nm,cb. 3360 (argatroban* or novastan or MMTQAP or MPQA or "MCI 9038" or acova or "MD 105 3799 805" or MD805 or argatra or argipidine or slonnon).ti,ab,hw,tn,nm,cb. 106 or/103-105 3799 107 beta 2 Glycoprotein 1/ 1521 ("beta2 Glycoprotein I" or "beta(2)GPI" or 108 "Apo H" or "Apolipoprotein H" or "EC 3774 VMFa").ti,ab,hw,tn,nm,cb. 109 or/107-108 4430 110 Hirulog/ 1931 111 "128270-60-0".rn,nm,cb. 2854 (bivalirudin or angiomax or angiox or "BG 112 8967" or BG8967 or 3340 Hirulog).ti,ab,hw,tn,nm,cb. 113 or/110-112 3341 114 Bromadiolone/ 85
A-7
115 "28772-56-7".rn,nm,cb. 288 116 bromadiolone.ti,ab,tn,nm,cb. 301 117 or/114-116 345 118 "56073-10-0".rn,nm,cb. 502 (bromfenacoum or "talon-G" or 119 superwarfarin or ratak or talon or "WBA 612 8119").ti,ab,hw,tn,nm,cb. 120 or/118-119 908 121 Certoparin/ 446 (certoparin or mono-embolex or alphaparin 122 or sandoparin* or 675 troparin).ti,ab,hw,tn,nm,cb. 123 or/121-122 675 124 Chlorophacinone/ 69 125 "3691-35-8".rn,nm,cb. 165 (chlorophacinone or 126 187 redentin).ti,ab,hw,tn,nm,cb. 127 or/124-126 193 128 "51404-37-6".rn,nm,cb. 101 (citroglucophosphate or 129 18 redentin).ti,ab,hw,tn,nm,cb. 130 or/128-129 114 131 citric acid/ 14995 132 "77-92-9".rn,nm,cb. 19478 (citric acid* or "Uralyt U" or citrate or 133 106850 Renacid or hemiacidrin).ti,ab,hw,tn,nm,cb. 134 or/131-133 106850 135 exp coumarins/ 80643 136 exp Coumarin Derivative/ 49142 (coumarin* or "Benzopyran 2 ones" or "1,2 Benzo Pyrones" or "1,2 Benzopyrones" or 137 26914 esberiven or "venalot mono").ti,ab,hw,tn,nm,cb. 138 or/135-137 90311 (CPDA solution* or "CPDA-1" or "CPDA- 139 3" or "CPD-A2" or "CPDA- 446 2").ti,ab,hw,tn,nm,cb. 140 Dabigatran/ 183 141 211915-06-9.rn. 54 142 (dabigatran or "BIBR 1048" or "Bibr 953" or 460
A-8
Bibr953).ti,ab,hw,tn,nm,cb. 143 or/140-142 460 144 Dalteparin/ 4791 145 "9041-08-1".rn,nm,cb. 8955 (dalteparin or tedelparin or "Kabi-2165" or Kabi2165 or fragmin* or "FR 860" or 146 6495 FR860 or ligofragmin or boxol).ti,ab,hw,tn,nm,cb. 147 or/144-146 12780 148 Danaproid/ 1597 149 "83513-48-8".rn,nm,cb. 1963 (danaproid or lomoparan or danaparoid or 150 "Org 10172" or ORG10172 or "Organon 2320 10172" or orgaran).ti,an,hw,tn,nm,cb. 151 or/148-150 2320 152 Dermatan Sulfate/ 4303 153 "24967-94-0".rn,nm,cb. 5508 (beta Heparin or "Chondroitin Sulfate 154 365 B").ti,ab,hw,tn,nm,cb. 155 or/152-154 5713 156 Desulfatohirudin/ 501 157 "120993-53-5".rn,nm,cb. 651 (desirudin or revasc or iprivask or desulfatohirudin or desulphatohirudin or 158 822 "IK-HIR02" or "CGP 39393").ti,ab,hw,tn,nm,cb. 159 or/156-158 822 160 Dextrans/ 28168 161 Dextran/ 28168 162 "9004-54-0".rn,nm,cb. 22578 (dextran* or rheopolyglucin or hemodex or hyskon or infukoll or macrodex or 163 polyglucin or promit* or rheodextran or 76433 rheoisodex or rheomacrodex or rondex or saviosol or praedex).ti,ab,hw,tn,nm,cb. 164 or/160-163 76438 165 Dicumarol/ 3132 166 Dicoumarol/ 3132 167 "66-76-2".rn,nm,cb. 3472 168 (dicumarol or dicoumarol or 4639
A-9
bishydroxycoumarin or dicoumarin).ti,ab,hw,tn,nm,cb. 169 or/165-168 4643 170 Difenacoum/ 68 171 "56073-07-5".rn,nm,cb. 159 (difenacoum or 172 201 neosorexa).ti,ab,hw,tn,nm,cb. 173 or/170-172 205 "2 [4 [(1 Acetimidoyl 3 174 Pyrrolidinyl)Oxy]Phenyl] 3 (7 Amidino 2 304 Naphthyl)Propionic Acid"/ 175 "155204-81-2".rn,nm,cb. 470 176 "DX 9065a".ti,ab,hw,tn,nm,cb. 518 177 or/174-176 561 178 Edetic Acid/ 35082 179 "60-00-4".rn,nm,cb. 42319 (edetic acid* or edathamil or EDTA or tetracemate or ethylene dinitrilotetraacetate or versenate or versene or "chelaton 3" or 180 84373 coprin or edetates or endrate or versenic acid* or tetracemin or tetracemic acid*).ti,ab,hw,tn,nm,cb. 181 or/178-180 84556 182 Efegatran/ 170 183 "105806-65-3".rn,nm,cb. 247 (efegatran or "GYKI 14766" or "LY 184 286 294468").ti,ab,hw,tn,nm,cb. 185 or/182-184 286 186 Enoxaparin/ 10146 (enoxaparin* or "PK 10,169" or PK10,169 or "PK 10169" or PK10169 or "EMT 967" 187 13489 or EMT967 or lovenox or clexane or "EMT 966" or EMT966).ti,ab,hw,tn,nm,cb. 188 or/186-187 13489 189 Ethyl Biscoumacetate/ 449 190 "548-00-5".ti,ab,hw,tn,nm,cb. 16 (ethyl biscoumacetate or ethyldicoumarol or 191 carbethoxydicoumarol or tromexan or 604 pelentan).ti,ab,hw,tn,nm,cb. 192 or/189-191 608
A-10
193 ferulic acid/ 1767 194 "1135-24-6".ti,ab,hw,tn,nm,cb. 2207 (ferulic acid or sodium 195 6588 ferulate).ti,ab,hw,tn,nm,cb. 196 or/193-195 6660 197 Fibrin fibrinogen degradation products/ 6484 198 Fibrin Degradation Product/ 6484 (fibrin degradation product* or fibrin fibrinogen split product* or "antithrombin 199 4552 VI" or fibrinolytic split product* or fibrin split product*).ti,ab,hw,tn,nm,cb. 200 or/197-199 9175 201 "fragment X".ti,ab,hw,tn,nm,cb. 284 202 Fluindione/ 410 203 "957-56-2".rn,nm,cb. 542 204 (fluindione or previscan).ti,ab,hw,tn,nm,cb. 564 205 or/202-204 564 206 Fondaparinux/ 2075 (fondaparinux or quixidar or 207 3348 arixtra).ti,ab,hw,tn,nm,cb. 208 or/206-207 3348 209 Fucoidan/ 656 210 "9072-19-9".rn,nm,cb. 1752 (fucoidan or fucoidin or sulfated fucans or 211 2718 fucan sulphate).ti,ab,hw,tn,nm,cb. 212 or/209-211 2721 213 Gabexate/ 775 214 Gabexate Mesilate/ 1396 215 "39492-01-8".rn,nm,cb. 815 (gabexate or foy or gabexate 216 methanesulfonate or gabexate mesylate or 2410 gabexate mesilate).ti,ab,hw,tn,nm,cb. 217 or/213-216 2410 218 Sulodexide/ 261 219 "58915-48-3".rn,nm,cb. 124 (sulodexide or glucuronyl glucosamine glycan sulfate or glucuronyl glucosamine 220 glycan sulphate or "3-glucosaminoglycan 1050923 sulphate" or sulodexide or glucuronyl glucosaminoglycan sulphate or
A-11
glucuronylglucosaminoglycan sulphate or "3 GS" or 3GS or luzone or vessel or aterina).ti,ab,hw,tn,nm,cb. 221 or/218-220 1050923 222 exp heparin/ 117591 223 exp heparin derivative/ 80319 224 "37270-89-6".rn,nm,cb. 1407 (heparin* or calciparin* or cervep or croneparina or parinix or riveparin or serianon or sobrius or sodiparin or calcihep or calciparin* or uniparin or lipohep or 225 liquemin* or thrombophob or venoruton or 214882 viatromb or calparine or liquemine or actparin or disotron or heptar or parinorth or trombofob or hepalean or hepa-gel or hepa- salbe or lioton).ti,ab,hw,tn,nm,cb. (lipohep or trombex or hepaflex or "essaven 60 000" or hemeran or hepaplus or hepathromb* or juwoment sport or liquemin N or perivar venensalbe or sportino or thrombareduct or traumalitan or venalitan or 226 153 venoruton emulgel or vetren or croneparina or hep lok or hepsal or monoparin or multiparin or pump-hep or beparine or hep- rinse or heplok or minihep or unihep or ateroclar or bioclaril).ti,ab,hw,tn,nm,cb. (calciparin* or calcipor or chemyparin or clarisco or croneparina or disebrin or ecabil or ecafast or ecasolv or emoklar or epacalcica or eparical or eparinlider or eparinovis or eparven or epsoclar or epsodil or epsodilave or eudipar or flusolv or hemoflss or hepacal or isoclar or mica or 227 6810 normoparin or pharepa or reoflus or sosefluss or trombolisin or zepac or hep-tec or inhepar or proparin or nycoheparin or menaven or demovarin or gelparin* or hepasol lipogel or hepaspray or canusal or hep-lock or hepflush or hirox).ti,ab,hw,tn,nm,cb. (LMWH or low molecular weight 228 27883 heparin).ti,ab,hw,tn,nm,cb. (heparinoids or exhirud or hirucreme or 229 1392 atheroid or ateroid).ti,ab,hw,tn,nm,cb. 230 or/222-229 225177 231 Inogatran/ 151
A-12
(inogatran or "H 314-27" or "H314-27" or 232 264 "H-314-27").ti,ab,hw,tn,nm,cb. 233 or/231-232 264 234 Lamifiban/ 537 235 "144412-49-7".rn,nm,cb. 708 (lamifiban or "Ro 44-9883" or "Ro 236 765 449883").ti,ab,hw,tn,nm,cb. 237 or/234-236 767 238 Laminaran/ 293 239 "9008-22-4".rn,nm,cb. 869 240 (laminaran or laminarin).ti,ab,hw,tn,nm,cb. 1708 241 or/238-240 1712 242 Lepirudin/ 1741 (lepirudin or refludan or refludin or "HBW 243 2599 023").ti,ab,hw,tn,nm,cb. 244 or/242-243 2599 245 Tissue Factor Pathway Inhibitor/ 1595 (lipoprotein-assocciated coagulation inhibitor or antithromboplastin or "extrinsic pathway inhibitor I" or "EPI I" or "TFI 246 HepG2" or TFPI-beta or TFPIbeta or tissue 5500 factor pathway inhibitor or TFPI or anticonvertin or LACI inhibitor).ti,ab,hw,tn,nm,cb. 247 or/245-246 5500 248 Melagatran/ 673 249 "159776-70-2".rn,nm,cb. 1065 250 (melagatran or exanta).ti,ab,hw,tn,nm,cb. 1429 251 or/248-250 1429 "N (2 Naphthylsulfonyl)Glycyl 4 252 31 Amidinophenylalanine Piperidide"/ 253 "86125-48-6".rn,nm,cb. 80 ("N-alpha-(2-naphthylsulfonylglycyl)-4- amidinophenylalanine piperidide" or "N (2 254 Naphthylsulfonyl)Glycyl 4 223 Amidinophenylalanine Piperidide" or NAPAP or thromstop).ti,ab,hw,tn,nm,cb. 255 or/252-254 223 256 Nadroparin/ 3075 257 (nadroparin* or fraxiparin* or "CY 216" or 3964
A-13
CY216 or "LMF CY 216" or LMF CY216 or fraxodi or seledie or seleparina or fraxiforte).ti,ab,hw,tn,nm,cb. 258 or/256-257 3964 259 Nafamostat/ 124 260 Nafamstat/ 124 261 "81525-10-2".ti,ab,hw,tn,nm,cb. 50 (nafamostat or "FUT 175" or 262 1789 nafamstat*).ti,ab,hw,tn,nm,cb. 263 or/259-262 1791 (nitrophorin or "prolixin 264 195 S").ti,ab,hw,tn,nm,cb. 265 Fondaparinux/ 2075 266 "104993-28-4".rn,nm,cb. 2479 (fondaparin* or "Org 31540" or penta or "SR 90107" or natural heparin 267 10816 pentasaccharide or arixtra).ti,ab,hw,tn,nm,cb. 268 or/265-267 10818 269 Pentosan Sulfuric Polyester/ 1769 270 Pentosan Polysulfate/ 1769 271 "37300-21-3".rn,nm,cb. 1859 (pentosan sulfuric polyester or Polypentose Sulfate or Xylan Sulfate or Pentosane Sulfuric Polyester or Polysulfated Xylan or fibrocid or hemoclar or "HOE-BAY-946" or "HOE BAY 946" or "HOE-946" or "BAY 272 946" or "Xylan SP54" or "PZ 68" or PZ68 or 5516 "SP-54" or "SP 54" or SP54 or elmiron or pentosan polysulfate or polyanion or hemoclar or fibrezym or fibrase or fibrocide or "tavan-SP 54" or fibrocid or thrombocid).ti,ab,hw,tn,nm,cb. 273 or/269-272 5525 274 Phenindione/ 1191 275 "83-12-5".rn,nm,cb. 1217 (phenindione or phenylindanedione or 276 phenyline or pindione or fenilin or 1275 dindevan).ti,ab,hw,tn,nm,cb. 277 or/274-276 1276 278 Phenprocoumon/ 3364 279 "435-97-2".ti,ab,hw,tn,nm,cb. 356
A-14
(phenprocoumon or phenprocoumarol or phenprocoumalol or phenprogramma or marcoumar or marcumar or falithrom or 280 4199 liquamar or fenprocoumon or phenprocouman or phenprocumarol).ti,ab,hw,tn,nm,cb. 281 or/278-280 4199 282 Plumbagin/ 1519 283 "481-42-5".rn,nm,cb. 698 284 (plumbagin or plumbagol).ti,ab,hw,tn,nm,cb. 916 285 or/282-284 2019 286 Protein C/ 11943 287 "protein C".ti,ab,hw,tn,nm,cb. 57830 288 or/286-287 57830 289 Protein S/ 5653 290 "protein S".ti,ab,hw,tn,nm,cb. 63875 291 or/289-290 63875 292 Protocatechualdehyde/ 187 293 "139-85-5".rn,nm,cb. 418 (protocatechualdehyde or protocatechuic 294 aldehyde or "rancinamycin 490 IV").ti,ab,hw,tn,nm,cb. 295 or/292-294 526 296 Reviparin/ 699 (reviparin* or "LU 47311" or clivarin* or 297 996 clivarine).ti,ab,hw,tn,nm,cb. 298 or/296-297 996 299 Rivaroxaban/ 301 (rivaroxaban or "Bay 59 7939" or "Bay 59- 300 7939" or "Bay 597939" or "Bay59 7939" or 607 Bay597939).ti,ab,hw,tn,nm,cb. 301 or/299-300 607 302 Tanshinone/ 315 303 "568-73-0".rn,nm,cb. 338 304 (tanshinone or "TTE-50").ti,ab,hw,tn,nm,cb. 1140 305 or/302-304 1140 306 Alpha Tocopherylquinone/ 184 307 "7559-04-8".rn,nm,cb. 410 308 (tocopherylquinone or alpha-tocoquinone or 618
A-15
alpha-tocopherol quinone or alpha- tocopheryl quinone or "vitamin E quinone" or eutrophyl).ti,ab,hw,tn,nm,cb. 309 or/306-308 651 310 Troxerutin/ 353 311 "7085-55-4".rn,nm,cb. 561 (troxerutin or "vitamin P4" or venoruton or posorutin or "Veno SL" or relvene or rheoflux or eboven or troxeven or vastribil or veinamitol or veniten retard or venorutin or venotrulan trox or oxerutin or paroven or 312 flebon or flebotropin or flerox or jatamansin 3202 or rutilina or terbenol or venosmil or ven- detrex or daflon or flavonid or flebopex or insuven or cilkanol or diamoril or diosmil or diovenor or endium or flavan).ti,ab,hw,tn,nm,cb. (flebosmil or intercyton or mediveine or veinotonic or veineva or venirene or drisi- ven or rutinion or tovene or veinamitol or venusmin or vridol or alven or arvenum or diosven or doven or flebil or pericel or venolen or venosmine or teboven or 313 130 hepaclmina or venex or veroven or troxevazin or diosminil or pentovena or venolep or hemerven or neorutin or pur-rutin or venutabs or heteroid or varemoid or citro- flav or limbrel or flavol or hyflon or verutil).ti,ab,hw,tn,nm,cb. 314 or/310-313 3274 315 Ximelagatran/ 1389 (ximelagatran or "xi-melagatran" or "H 376 316 95" or "H 376-95" or 2315 exanta).ti,ab,hw,tn,nm,cb. 317 or/315-316 2315 318 Tinzaparin/ 1617 319 "9041-08-1".rn,nm,cb. 8955 (tinzaparin or Innohep or 320 2306 logiparin).ti,ab,hw,tn,nm,cb. 321 or/318-320 10076 59 or 64 or 69 or 73 or 77 or 82 or 86 or 87 or 91 or 95 or 99 or 102 or 106 or 109 or 322 113 or 117 or 120 or 123 or 127 or 130 or 1949333 134 or 138 or 139 or 143 or 147 or 151 or 155 or 159 or 164 or 169 or 173 or 177 or
A-16
181 or 185 or 188 or 192 or 196 or 200 or 201 or 205 or 208 or 212 or 217 or 221 or 230 or 233 or 237 or 241 or 244 or 247 or 251 or 255 or 258 or 263 or 264 or 268 or 273 or 277 or 281 or 285 or 288 or 291 or 295 or 298 or 301 or 305 or 309 or 314 or 317 or 321 Results: Niastase & 4 indications 323 23 and (38 or 44 or 53 or 322) 10839 Concept: Human filter 324 exp animals/ 22681723 325 exp animal experimentation/ 1293201 326 exp models animal/ 791992 327 nonhuman/ 3206519 328 exp vertebrate/ 30060876 329 or/324-328 32231541 330 exp humans/ 22328665 331 329 not 330 9902876 Results: Niastase, 4 indications, & human
filter 332 323 not 331 9928 Concept: MA/SR/HTA filter 333 meta-analysis.pt. 20962 meta-analysis/ or systematic review/ or 334 meta-analysis as topic/ or exp technology 89522 assessment, biomedical/ ((systematic* adj3 (review* or overview*)) 335 or (methodologic* adj3 (review* or 53513 overview*))).ti,ab. ((quantitative adj3 (review* or overview* or 336 synthes*)) or (research adj3 (integrati* or 9005 overview*))).ti,ab. ((integrative adj3 (review* or overview*)) or 337 (collaborative adj3 (review* or overview*)) 14813 or (pool* adj3 analy*)).ti,ab. (data synthes* or data extraction* or data 338 18852 abstraction*).ti,ab. 339 (handsearch* or hand search*).ti,ab. 5436 (mantel haenszel or peto or der simonian or 340 dersimonian or fixed effect* or latin 20603 square*).ti,ab.
A-17
(met analy* or metanaly* or health 341 technology assessment* or HTA or 3030 HTAs).ti,ab. (meta regression* or metaregression* or 342 1938 mega regression*).ti,ab. (meta-analy* or metaanaly* or systematic review* or biomedical technology 343 143275 assessment* or bio-medical technology assessment*).mp,hw. (medline or Cochrane or pubmed or 344 93261 medlars).ti,ab,hw. (cochrane or health technology assessment 345 9637 or evidence report).jw. 346 (meta-analysis or systematic review).md. 0 Results: MA/SR/HTA filter 347 or/333-346 258088 Results: Niastase, 4 indications, human
and MA/SR/HTA filters 348 332 and 347 254 349 332 and 347 254 350 remove duplicates from 349 211 Concept: Niastase Same as above Concept: Heart surgery Same as above Concept: Liver transplantation Same as above Concept: Prostatectomy Same as above Concept: Anticoagulants Same as above Concept: Clinical studies filter
(Randomized Controlled Trial or Controlled 333 343550 Clinical Trial).pt.
(Clinical Trial or Clinical Trial, Phase II or 334 Clinical Trial, Phase III or Clinical Trial, 457384 Phase IV).pt.
335 Multicenter Study.pt. 106382
A-18
336 Randomized Controlled Trial/ 436780
337 Randomized Controlled Trials as Topic/ 59464
338 Controlled Clinical Trial/ 138143
339 Controlled Clinical Trials as Topic/ 3897
Clinical Trial/ or Phase 2 Clinical Trial/ or 340 Phase 3 Clinical Trial/ or Phase 4 Clinical 1020136 Trial/
Clinical Trials as Topic/ or Clinical Trials, Phase II as Topic/ or Clinical Trials, Phase 341 148263 III as Topic/ or Clinical Trials, Phase IV as Topic/
Multicenter Study/ or Multicenter Study as 342 151849 Topic/
343 Randomization/ 90338
344 Random Allocation/ 90338
345 Double-Blind Method/ 172531
346 Double Blind Procedure/ 72007
347 Double-Blind Studies/ 172531
348 Single-Blind Method/ 20811
349 Single Blind Procedure/ 8083
350 Single-Blind Studies/ 20811
351 Placebos/ 153123
352 Placebo/ 125370
353 Control Groups/ 4387
354 Control Group/ 4387
355 Cross-Over Studies/ or Crossover Procedure/ 44846
356 (random* or sham or placebo*).ti,ab,hw. 1636906
((singl* or doubl*) adj (blind* or dumm* or 357 318842 mask*)).ti,ab,hw.
A-19
((tripl* or trebl*) adj (blind* or dumm* or 358 520 mask*)).ti,ab,hw.
(control* adj3 (study or studies or 359 3677736 trial*)).ti,ab,hw.
(clinical adj3 (study or studies or 360 2698572 trial*)).ti,ab,hw.
(Nonrandom* or non random* or non- 361 46589 random* or quasi-random*).ti,ab,hw.
(phase adj3 (study or studies or 362 168589 trial*)).ti,ab,hw.
((crossover or cross-over) adj3 (study or 363 75490 studies or trial*)).ti,ab,hw.
((multicent* or multi-cent*) adj3 (study or 364 232043 studies or trial*)).ti,ab,hw.
365 (allocated adj1 to).ti,ab,hw. 49027
((open label or open-label) adj5 (study or 366 31152 studies or trial*)).ti,ab,hw.
367 trial.ti. 211395
Results: clinical trials filter
368 or/333-367 6097508
Concept: Human filter
369 exp animals/ 22697822
370 exp animal experimentation/ 1293201
371 exp models animal/ 791992
372 exp animal experiment/ 1293201
373 nonhuman/ 3206519
374 exp vertebrate/ 30075829
375 animal.po. 0
376 or/369-375 32247640
A-20
377 exp humans/ 22339911
378 exp human experiment/ 255655
379 human.po. 0
380 or/377-379 22340779
381 376 not 380 9907293
Results: clinical trials and human filters
382 368 not 381 4667346
Results: Niastase, 4 indications, clinical
trials and human filters
383 323 and 382 3532
384 remove duplicates from 383 2817
Concept: Niastase
Same as above
Concept: Heart surgery
Same as above
Concept: Liver transplantation
Same as above
Concept: Prostatectomy
Same as above
Concept: Anticoagulants
Same as above
Concept: Human filter
Same as above
Concept: Observational studies filter 333 exp clinical study/ 3744251 334 exp Epidemiologic studies/ 1926869 335 exp case control study/ 437819 336 Case control.ti,ab,hw. 203131 337 Cohort analysis/ 147672
A-21
(cohort adj (study or studies or design or 338 216733 analysis or analyses)).ti,ab,hw. 339 Longitudinal.ti,ab,hw. 246634 340 (Follow up adj (study or studies)).ti,ab,hw. 428728 341 Cross-sectional study/ 100969 342 Cross sectional.ti,ab,hw. 264295 343 Comparative Study/ 1544919 (comparative$ adj (study or studies or 344 2430276 studied or trial$)).ti,ab,hw. (prospectiv$ adj (study or studies or trial or 345 491705 trials or cohort)).ti,ab,hw. (observational adj (study or studies or trial 346 54917 or trials)).ti,ab,hw. (follow adj up adj (study or studies or trial or 347 429049 trials)).ti,ab,hw. (followup adj2 (study or studies or trial or 348 1814 trials)).ti,ab,hw. (open adj label adj (study or studies or trial 349 12406 or trials)).ti,ab,hw. (((head adj to adj head) or crossover or 350 (cross adj over)) adj (design$ or study or 86091 studies or trial$)).ti,ab,hw. 351 population-based analy*.ti,ab,hw. 1093 ((population or descriptive or 352 multidimentional) adj (study or 807828 studies)).ti,ab,hw. 353 Comparative Study.pt. 1428163 354 (comparative adj (study or studies)).ti,ab,hw. 2423749 (retrospectiv$ adj (study or studies or trial or 355 489702 trials or cohort)).ti,ab,hw. Results: observational studies filter 356 or/333-355 8636333 Results: Niastase, 4 indications, human
and observational studies filters 357 332 and 356 4227 359 remove duplicates from 357 3580 Concept: Niastase Same as above Concept: Heart surgery Same as above
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Concept: Liver transplantation Same as above Concept: Prostatectomy Same as above Concept: Anticoagulants Same as above Concept: Human filter Same as above Concept: Practice guidelines filter 333 Guidelines as topic/ 22225 334 Guideline/ 14670 335 Practice guideline/ 116634 336 exp Consensus Development Conference/ 8915 337 Consensus Development.sh. 2489 338 Health Planning Guidelines/ 24636 339 Practice Guidelines as Topic/ 49055 340 Clinical Protocols/ 56467 (Guideline or Practice Guideline or 341 23612 Consensus Development Conference).pt. 342 Standards.fs. 414451 343 Practice Guideline/ 116634 344 Clinical Practice/ 80367 345 Clinical Protocol/ 56467 346 Health Care Planning/ 21814 347 (guideline* or standards or best practice).ti. 97007 (guideline* or standards or best 348 18369 practice).hw. use b9o89 (expert consensus or consensus statement or consensus conference* or practice 349 51466 parameter* or position statement* or policy statement* or CPG or CPGs).ti,ab. (expert consensus or consensus statement or consensus conference* or practice 350 7491 parameter* or position statement* or policy statement* or CPG or CPGs).hw. use b9o89 Results: Practice guidelines 351 or/333-350 813017 Results: Niastase, 4 indications, human
and practice guidelines filters
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352 332 and 351 290 353 remove duplicates from 352 277 Concept: Niastase Same as above Concept: Heart surgery Same as above Concept: Liver transplantation Same as above Concept: Prostatectomy Same as above Concept: Anticoagulants Same as above Concept: Human filter Same as above Concept: Economic studies filter 333 *Economics/ 11588 334 *Economics, Medical/ 7613 335 *Economics, Pharmaceutical/ 1470 336 exp "Costs and Cost Analysis"/ 266934 337 exp Health Care Costs/ 138265 338 exp decision support techniques/ 41458 339 value of life.sh. 5003 340 exp models, economic/ 26661 341 markov chains.sh. 5365 342 monte carlo method.sh. 19473 343 uncertainty.sh. 4022 344 quality of life.sh. 169186 345 quality-adjusted life years.sh. 3729 346 exp health economics/ 232275 347 exp economic evaluation/ 103317 348 exp pharmacoeconomics/ 58355 349 exp economic aspect/ 386811 350 quality adjusted life year/ 7865 351 quality of life/ 169186 352 exp "costs and cost analyses"/ 141099 353 cost control.sh. 35154
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(economic impact or economic value or pharmacoeconomics or health care cost or economic factors or cost analysis or economic analysis or cost or cost- 354 321708 effectiveness or cost effectiveness or costs or health care cost or cost savings or cost- benefit analysis or hospital costs or medical costs or quality-of-life).sh. 355 health care rationing.sh. 8998 (econom$ or cost or costly or costing or costed or price or prices or pricing or priced or discount or discounts or discounted or 356 812306 discounting or expenditure or expenditures or budget$ or afford$ or pharmacoeconomic or pharmaco-economic$).ti,ab. (cost$ adj1 (util$ or effective$ or efficac$ or benefit$ or consequence$ or analy$ or minimi$ or saving$ or breakdown or lowering or estimate$ or variable$ or 357 168072 allocation or control or illness or sharing or life or lives or affordabl$ or instrument$ or technolog$ or day$ or fee or fees or charge or charges)).ti,ab. (decision adj1 (tree$ or analy$ or 358 16376 model$)).ti,ab. ((value or values or valuation) adj2 (money 359 or monetary or life or lives or costs or 7775 cost)).ti,ab. (qol or qoly or qolys or hrqol or qaly or 360 36380 qalys or qale or qales).ti,ab. (sensitivity analys$s or "willingness to pay" or quality-adjusted life year$ or quality 361 adjusted life year$ or quality-adjusted life 9530 expectanc$ or quality adjusted life expectanc$).ti,ab. (unit cost or unit-cost or unit-costs or unit costs or drug cost or drug costs or hospital 362 30329 costs or health-care costs or health care cost or medical cost or medical costs).ti,ab. (decision adj1 (tree$ or analy$ or 363 16376 model$)).ti,ab. 364 exp "Costs and Cost Analysis"/ 266934 (economic value of life or economics, medical or economics, pharmaceutical or 365 39484 models, economic or markov chains or monte carlo method or uncertainty).sh.
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366 economics.fs. 250798 (quality of life or quality-adjusted life 367 172302 years).sh. ((econom$ or cost or costly or costing or costed or prices or pricing or discount or 368 discounts or discounted or discounting or 243329 budget$ or afford$ or pharmacoeconomic$ or pharmaco) adj1 economic$).ti,ab. Results: economic studies filter 369 or/333-368 1526306 Results: Niastase, 4 indications, human
and economic studies filters 370 323 and 369 509 371 remove duplicates from 370 433
Other Databases Searched
Cochrane Library Databases Same MeSH, keywords, limits, and study types used as per Issue 2 2009 Medline search, with appropriate syntax used. Centre for Reviews and Same keywords and date limits used as per Medline search, Dissemination Databases excluding study types and Human restrictions. Syntax adjusted for (CRD) HEED database. University of York 2009
Grey Literature and Hand Searches
Date of Search: April 20-28, 2009 Keywords: Recombinant factor VIIa, rFVIIa, Novo Seven, novoseven, niastase, novo7, eptacog alfa, provertin Limits: No publication or language limits
* 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
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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.ab.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
WHO Health Evidence Network http://www.euro.who.int/HEN
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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.h tml
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
Health Service Executive http://www.hebe.ie/ProgrammesProjects/HealthTechnologyAssessment
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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/index.php?show=38&expand=14,38
Agencia de Evaluación de Tecnologias Sanitarias (AETS), Instituto de Salud “Carlos III”/ Health Technology Assessment Agency http://www.isciii.es/htdocs/investigacion/Agencia_quees.jsp
Basque Office for Health Technology Assessment (OSTEBA). Departemento de Sanidad http://www.osasun.ejgv.euskadi.net/r52-2536/es/
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.hta.nhsweb.nhs.uk
NHS National Institute for Clinical Excellence (NICE) http://www.nice.org.uk
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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.publichealth.bham.ac.uk/wmhtac/
Agency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov/
Dept. of Veterans Affairs Research & Development, general publications http://www1.va.gov/resdev/prt/pubs_individual.cfm?webpage=pubs_ta_reports.htm
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/
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
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Health Economics Research Unit (HERU). University of Aberdeen http://www.abdn.ac.uk/heru/ Health Economic Evaluations Database (HEED) http://heed.wiley.com
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
Search Engines
Google http://www.google.ca/
Yahoo! http://www.yahoo.com
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APPENDIX 2: EXCLUDED STUDIES CLASSIFIED BY REASON FOR EXCLUSION
Inappropriate Indication for rFVIIa
1. Rudisill CN, Hockman RH, DeGregory KA, Mutnick AH, Macik BG. Implementing guidelines for the institutional use of factor VIIa (recombinant): a multidisciplinary solution. Am J Health Syst Pharm 2006;63(17):1641-6.
2. Gaarder C, Naess PA, Frischknecht Christensen E, Hakala P, Handolin L, Heier HE, et al. Scandinavian guidelines - "The massively bleeding patient". Scand J Surg 2008;97(1):15-36.
Inappropriate Intervention
3. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines on behalf of the Australasian society of thrombosis and haemostasis. Med J Aust 2004;181(9):492-7. Available: http://www.mja.com.au/public/issues/181_09_011104/bak10441_fm.pdf (accessed 2009 Apr 24).
Guideline without monitoring information
4. Karkouti K, Beattie WS, Crowther MA, Callum JL, Chun R, Fremes SE, et al. The role of recombinant factor VIIa in on-pump cardiac surgery: proceedings of the Canadian Consensus Conference. Can J Anaesth 2007;54(7):573-82.
5. Nuttall GA, Brost BC, Connis RT, Gessner JS, Harrison CR, Miller RD, et al. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on perioperative blood transfusion and adjuvant therapies. Anesthesiology 2006;105(1):198-208.
6. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):160S-98S.
7. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):141S-59S.
Inappropriate Population
8. Bijsterveld N, Moons A, Boekholdt M, van Aken B, Fennema H, Peters R, et al. Neutralization of the anticoagulant effect of fondaparinux by recombinant activated factor VII in healthy male volunteers. Circulation 2002;106(19 Supplement):II-119, November.
9. Lodge JP, Jonas S, Oussoultzoglou E, Malagó M, Jayr C, Cherqui D, et al. Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial. Anesthesiology 2005;102(2):269-75.
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10. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002;106(20):2550-4.
11. Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998;9(8):741-8.
12. Alavi AA, Jalali SM, Rasouli MR, Eghtesadi-Araghi P. Administration of recombinant activated factor VII in major thoracic operations [letter]. Arch Surg 2008;143(10):1021.
13. Wolzt M, Levi M, Sarich TC, Bostrom SL, Eriksson UG, Eriksson-Lepkowska M, et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004;91(6):1090-6.
14. Vink R, Bijsterveld NR, van Aken BE, Fennema H, Peters RJG, Meijers JCM, et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting anticoagulant idraparinux in healthy volunteers [abstract]. Blood 2003;102(11):812a.
15. Bijsterveld NR, Moons AH, Boekholdt M, van Aken BE, de Greef HJ, Meijers JC, et al. Neutralization of the anticoagulant effect of fondaparinux by recombinant activated factor VII in healthy volunteers. Blood 2002;100(11).
16. Bijsterveld NR, Vink R, van Aken BE, Fennema H, Peters RJ, Meijers JC, et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004;124(5):653-8.
17. Erhardtsen E, Nilsson P, Johannessen M, Thomsen MS. Pharmacokinetics and safety of FFR- rFVIIa after single doses in healthy subjects. J Clin Pharmacol 2001;41(8):880-5.
Trial Design Inappropriate for Review
18. Guidelines and Protocols Advisory Committee. Management of warfarin therapy during invasive procedures and surgery. Victoria: B.C. Ministry of Health Services; 2004. Available: http://www.bcguidelines.ca/gpac/pdf/warfarin_manage.pdf (accessed 2009 Apr 22).
19. Drug Information Center. MUSC guidelines for the off-label use of factor VIIa (rFVIIa) in patients undergoing liver transplant. Charleston (SC): Medical University of South Carolina; 2008.
20. Risko P. NovoSeven: Cleveland clinic guidelines. Pharmacotherapy Update 2007;10(4). Available: http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/pdf/Pharmaco_X-IV.pdf (accessed 2009 Apr 27).
21. VHA Pharmacy Benefits Management Strategic Healthcare Group, the Medical Advisory Panel. Recommendations concerning (nonformulary) off-label use of recombinant activated human coagulation factor seven (rFVIIa) (NovoSeven®). Washington: U.S. Department of Veterans Affairs; 2007. Available: http://www.pbm.va.gov/Clinical%20Guidance/Criteria%20For%20Use/Factor%20VII,%20Recomb inant%20Activated%20(NovoSeven%C2%AE),%20Criteria%20for%20Non- Formulary%20Use.pdf (accessed 2009 Apr 28).
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22. Reiter PD, Valuck RJ, Taylor RS. Evaluation of off-label recombinant activated factor VII for multiple indications in children. Clin Appl Thromb Hemost 2007;13(3):233-40.
23. Lam MS, Sims-McCallum RP. Recombinant factor VIIa in the treatment of non-hemophiliac bleeding. Ann Pharmacother 2005;39(5):885-91.
24. De Gasperi A, Baudo F, De Carlis L. Recombinant fVII in orthotopic liver transplantation (OLT): a preliminary single centre experience [letter]. Intensive Care Med 2005;31(2):315-6.
25. Herbertson M. Recombinant activated factor VII in cardiac surgery. Blood Coagul Fibrinolysis 2004;15(Suppl 1):S31-S32.
26. Hendriks HG, Meijer K, De Wolf JT, Porte RJ, Klompmaker IJ, Lip H, et al. Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002;13(4):309-13.
27. Bernstein DE, Jeffers L, Erhardtsen E, Reddy KR, Glazer S, Squiban P, et al. Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study. Gastroenterology 1997;113(6):1930-7.
28. Gibbs NM. The place of recombinant activated factor VII in liver transplantation. Int Anesthesiol Clin 2006;44(3):99-110.
29. Ramsey G. Treating coagulopathy in liver disease with plasma transfusions or recombinant factor VIIa: an evidence-based review. Best Pract Res Clin Haematol 2006;19(1):113-26.
30. O'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293-8. Available: http://jama.ama-assn.org/cgi/reprint/295/3/293 (accessed 2009 Apr 24).
31. Porte RJ, Caldwell SH. The role of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11(8):872-4.
32. Magnetti S, Oinonen M, Matuszewski KA. An evaluation of off-label use of recombinant activated human factor VII (NovoSeven): patient characteristics, utilization trends, and outcomes from an electronic database of U S academic health centers. P & T 2007;32(4):218-20-227-230.
33. Heller M, Lau W, Pazmino-Canizares J, Brandao LR, Carcao M. A comprehensive review of rFVIIa use in a tertiary care pediatric center. Pediatr Blood Cancer 2007;50(5):1013-17.
34. Webert KE, Arnold DM, Carruthers J, Molnar L, Almonte T, Decker K, et al. Utilization of recombinant activated factor VII in southern Ontario in 85 patients with and without haemophilia. Haemophilia 2007;13(5):518-26.
35. Technology Evaluation Center. Special report: recombinant activated factor VII for uncontrolled bleeding in non-hemophiliac patients [Assessment program vol. 21 no. 10]. Chicago: BlueCross BlueShield Association; 2006. Available: http://www.bcbs.com/blueresources/tec/vols/21/21_10.pdf (accessed 2008 Jan 4).
36. Stanworth SJ, Birchall J, Doree CJ, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev
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2007;(2):CD005011. Available: http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005011/pdf_fs.html (accessed 2009 Apr 24).
37. Ranucci M, Isgrò G. Recombinant activated factor VII in cardiac surgery. Eur J Anaesthesiol 2007;24(Suppl 40):83-8.
38. Roitberg B, Emechebe-Kennedy O, Amin-Hanjani S, Mucksavage J, Tesoro E. Human recombinant factor VII for emergency reversal of coagulopathy in neurosurgical patients: a retrospective comparative study. Neurosurgery 2005;57(5):832-6.
39. Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ, Macik BG. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 2003;9(2):138-43.
40. Baker DS, Shenoy S. Treatment of non-hemophiliac disorders in children with recombinant FVIIa - a review of dosing, safety, and efficacy [abstract]. Blood 2005;106(11, Part 2):122B.
41. Levy JH, Fingerhut A, Brott T, Langbakke IH, Erhardtsen E, Porte RJ. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 2006;46(6):919-33.
42. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2(10):1700-8.
43. Ranucci M, Isgro G, Soro G, Conti D, De Toffol B. Efficacy and safety of recombinant activated factor VII in major surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg 2008;143(3):296-304.
44. von Heymann C, Jonas S, Spies C, Wernecke KD, Ziemer S, Janssen D, et al. Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data. Crit Care 2008;12(1). Available: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2374636&blobtype=pdf (accessed 2008).
45. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 2008;248(1):61-8.
46. Birchall J, Stanworth SJ, Duffy MR, Doree CJ, Hyde C. Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia. Transfus Med Rev 2008;22(3):177-87.
47. Mallarkey G, Brighton T, Thomson A, Kaye K, Seale P, Gazarian M. An evaluation of eptacog alfa in nonhaemophiliac conditions. Drugs 2008;68(12):1665-89.
48. Owen PS, Golightly LK, MacLaren R, Ferretti KA, Badesch DB. Formulary management of recombinant factor VIIa at an academic medical center. Ann Pharmacother 2008;42(6):771-6.
49. Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL, et al. Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation 2008;118(4):331-8.
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50. Fraser IS, Porte RJ, Kouides PA, Lukes AS. A benefit-risk review of systemic haemostatic agents: part 1: in major surgery. Drug Saf 2008;31(3):217-30.
51. Warren OJ, Alcock EM, Choong AM, Leff DR, Van H, I, Darzi AW, et al. Recombinant activated factor VII: a solution to refractory haemorrhage in vascular surgery? Eur J Vasc Endovasc Surg 2008;35(2):145-52.
52. Warren O, Mandal K, Hadjianastassiou V, Knowlton L, Panesar S, John K, et al. Recombinant activated factor VII in cardiac surgery: a systematic review. Ann Thorac Surg 2007;83(2):707-14.
53. Zangrillo A, Mizzi A, Biondi-Zoccai G, Bignami E, Calabro MG, Pappalardo F, et al. Recombinant activated factor VII in cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2009;23(1):34- 40.
54. Hardy JF, Bélisle S, Van Der LP. Efficacy and safety of activated recombinant factor VII in cardiac surgical patients. Curr Opin Anaesthesiol 2009;22(1):95-9.
55. Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006;4(9):1853-63.
56. Mathew P. The use of rFVIIa in non-haemophilia bleeding conditions in paediatrics - a systematic review. Thromb Haemost 2004;92(4):738-46.
57. Goldstein JN, Rosand J, Schwamm LH. Warfarin reversal in anticoagulant-associated intracerebral hemorrhage. Neurocrit Care 2008;9(2):277-83.
58. Delannoy B, Levrat A, Chamouard V, Aulagner G, Perdrix JP, Negrier C, et al. Off label use of recombinant activated factor VII: a practice survey. Ann Fr Anesth Reanim 2007;26(9):774-9.
59. Rodriguez-Merchan EC. Proceedings From the 9th Novo Nordisk Symposium on Haemostasis Management. Semin Hematol 2008;45(Suppl 1):S1-S2.
60. Jeffrey GP, McCall J, Gane E, Mitchell AW, Gibbs NM, Beavis V, et al. Liver transplantation in Jehovah's Witness patients in Australasia. Med J Aust 2007;187(3):188-9. Available: http://www.mja.com.au/public/issues/187_03_060807/jef10070_fm.pdf (accessed 2029 Apr 24).
61. Labattaglia MP, Ihle B. Recombinant activated factor VII: current perspectives and epworth experience. Heart Lung Circ 2007;16(Suppl 3):S96-S101.
62. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology (Hagerstown) 2008;109(5):918-26.
63. Levi M. Use of recombinant factor VIIa in the perioperative period. Hamostaseologie 2009;29(1):68-70.
64. De Santis V, Vitale D, Tritapepe L, Pietropaoli P. Recombinant activated factor VII and cardiac surgery [letter]. Ann Thorac Surg 2008;86(6):2025.
65. Blanloeil Y, Rigal JC, Bastien O, Carteau JP, Toussaint-Hacquard M, Lecompte T. Facteur VII recombinant et active pour le controle du saignement en chirurgie cardiovasculaire: valider l'efficacite et la securite d'emploi. Ann Fr Anesth Reanim 2006;25(1):2-5.
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66. Kalicinski P, Markiewicz M, Kaminski A, Laniewski P, Ismail H, Drewniak T, et al. Single pretransplant bolus of recombinant activated factor VII ameliorates influence of risk factors for blood loss during orthotopic liver transplantation. Pediatr Transplant 2005;9(3):299-304.
67. Kubisz P, Stasko J. Recombinant activated factor VII in patients at high risk of bleeding. Hematology 2004;9(5-6):317-32.
68. Levi M, Bijsterveld NR, Keller TT. Recombinant factor VIIa as an antidote for anticoagulant treatment. Semin Hematol 2004;41(1 Suppl 1):65-9.
69. Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003;53(1):34-8.
70. Jen H, Shew S. Recombinant activated factor VII use in critically ill infants with active hemorrhage. J Pediatr Surg 2008;43(12):2235-8.
71. Levy JH, Tanaka KA. Prohemostatic agents to prevent perioperative blood loss. Semin Thromb Hemost 2008;34(5):439-44.
72. Karkouti K, Beattie WS. Pro: the role of recombinant factor VIIa in cardiac surgery. J Cardiothorac Vasc Anesth 2008;22(5):779-82.
73. Hardy JF, Belisle S, Van der Linden P. Efficacy and safety of recombinant activated factor VII to control bleeding in nonhemophiliac patients: a review of 17 randomized controlled trials. Ann Thorac Surg 2008;86(3):1038-48.
74. Johansson PI. Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials. Vox Sang 2008;95(1):1-7.
75. Levy JH, Tanaka KA. Management of surgical hemostasis: systemic agents. Vascular 2008;16(Suppl 1):S14-S21.
76. Young G, Yonekawa KE, Nakagawa PA, Blain RC, Lovejoy AE, Nugent DJ. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis 2007;18(6):547-53.
77. Ingerslev J, Vanek T, Culic S. Use of recombinant factor VIIa for emergency reversal of anticoagulation. J Postgrad Med 2007;53(1):17-22. Available: http://www.jpgmonline.com/article.asp?issn=0022- 3859;year=2007;volume=53;issue=1;spage=17;epage=22;aulast=Ingerslev (accessed 2009 Apr 24).
78. Planinsic RM. Use of recombinant factor VIIa (rFVIIa) in liver transportation. Liver Transpl 2006;12(7):1178-9.
79. De Gasperi A, Baudo F. Use of recombinant factor VIIa during orthotopic liver transplantation [letter]. Liver Transpl 2006;12(7):1176-7.
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80. De Gasperi A. Intraoperative use of recombinant activated factor VII (rFVIIa). Minerva Anestesiologica 2006;72(6):489-94.
81. Gala B, Quintela J, Aguirrezabalaga J, Fernandez C, Fraguela J, Suarez F, et al. Benefits of recombinant activated factor VII in complicated liver transplantation. Transplant Proc 2005;37(9):3919-21.
82. Gabriel DA, Carr M, Roberts HR. Monitoring Coagulation and the Clinical Effects of Recombinant Factor VIIa. Semin Hematol 2004;41(1 Suppl 1):20-4.
83. Surudo T, Wojcicki M, Milkiewicz P, Czuprynska M, Lubikowski J, Jarosz K, et al. Rapid correction of prothrombin time after low-dose recombinant factor VIIA in patients undergoing orthotopic liver transplantation. Transplant Proc 2003;35(6):2323-5.
84. Markiewicz M, Kalicinski P, Kaminski A, Laniewski P, Ismail H, Drewniak T, et al. Acute coagulopathy after reperfusion of the liver graft in children correction with recombinant activated factor VII. Transplant Proc 2003;35(6):2318-9.
85. Levy JH. Novel pharmacologic approaches to reduce bleeding. Can J Anaesth 2003;50(6 Suppl):S26-S30.
86. Escobar MA, Chong K, Hoots KW. Experience with the "Off label" use of recombinant factor VIIa in a university hospital [abstract 4017]. Blood 2004;104(11, Part 2):90B-1B. Available: http://abstracts.hematologylibrary.org/cgi/content/abstract/104/11/4017?maxtoshow=&HITS=10&h its=10&RESULTFORMAT=&fulltext=Escobar&searchid=1&FIRSTINDEX=0&volume=104&iss ue=11&resourcetype=HWCIT (accessed 2009 Apr 23).
87. Pettersson M, Fischler B, Petrini P, Schulman S, Nemeth A. Recombinant FVIIa in children with liver disease. Thromb Res 2005;116(3):185-97.
88. Bowman LJ, Uber WE, Stroud MR, Christiansen LR, Lazarchick J, Crumbley AJ, III, et al. Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery. Ann Thorac Surg 2008;85(5):1669-76.
89. Wojcicki M, Lubikowski J, Wrzesinski M, Post M, Jarosz K, Hydzik P, et al. Outcome of emergency liver transplantation including mortality on the waiting list: a single-center experience. Transplant Proc 2007;39(9):2781-4.
90. Dager WE, King JH, Regalia RC, Williamson D, Gosselin RC, White RH, et al. Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy 2006;26(8):1091-8.
91. Niemann CU, Behrends M, Quan D, Eilers H, Gropper MA, Roberts JP, et al. Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med 2006;16(2):93-100.
92. Hendriks HG, van der Meer J, Klompmaker IJ, Choudhury N, Hagenaars JA, Porte RJ, et al. Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S87-S93.
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93. Goldberg R, Drummond KJ. Recombinant activated factor VII for a warfarinised Jehovah's Witness with an acute subdural haematoma. J Clin Neurosci 2008;15(10):1164-6.
94. Pichon N, Bellec F, Sekkal S, Marsaud JP, Laskar M, Francois B, et al. Fatal thrombotic event after infusion of recombinant activated factor VII after cardiac surgery. J Thorac Cardiovasc Surg 2008;136(1):220-1.
95. Beldowicz BC, McDonald JM, Needham CS. Confirmed graft flow following use of recombinant factor VIIa in coronary artery bypass grafting: a case report and literature review. J Card Surg 2006;21(5):483-6.
96. Morante L, Guasch EV, Palacio F, Gilsanz F. Activated recombinant factor VII to reverse oral anticoagulants for emergent cesarean delivery [letter]. Anesth Analg 2006;102(6):1902-3. Available: http://www.anesthesia-analgesia.org/cgi/reprint/102/6/1902 (accessed 2009 Sep 11).
97. Jabbour N, Gagandeep S, Cheng PA, Boland B, Mateo R, Genyk Y, et al. Recombinant human coagulation factor VIIa in Jehovah's witness patients undergoing liver transplantation. Am Surg 2005;71(2):175-9.
98. Dao A, Tuan B, Carlson N. Reversal of a potent investigational anticoagulant: idraparinux with recombinant factor VIIa [letter]. Am J Med 2005;118(10):1172-3.
99. Zupancic-Salek S, Kovacevic-Metelko J, Radman I. Succesful reversal of anticoagulant effect of superwarfarin poisoning with recombinant activated factor VII. Blood Coagul Fibrinolysis 2005;16(4):239-44.
100. Jabbour N, Gagandeep S, Thomas D, Stapfer M, Mateo R, Sher L, et al. Transfusion-free techniques in pediatric live donor liver transplantation. J Pediatr Gastroenterol Nutr 2005;40(4):521-3.
101. Pavese P, Bonadona A, Beaubien J, Labrecque P, Pernod G, Letoublon C, et al. FVIIa corrects the coagulopathy of fulminant hepatic failure but may be associated with thrombosis: a report of four cases. Can J Anaesth 2005;52(1):26-9.
102. Stepinska J, Banaszewski M, Konopka A, Szajewski T. Activated recombinant factor VII (rFVIIa) in bleeding management after therapy with IIb/IIIa-inhibitor Tirofiban [letter]. Thromb Haemost 2002;87(2):355-6.
103. Berntorp E, Stigendal L, Lethagen S, Olofsson L, Hedner U. NovoSeven in warfarin-treated patients. Blood Coagul Fibrinolysis 2000;11(4 Suppl 1):S113-S115.
104. Muleo G, Santoro R, Iannaccaro PG, Papaleo P, Leo F, Zappala D, et al. Small doses of recombinant factor VIIa in acquired deficiencies of vitamin K dependent factors. Blood Coagul Fibrinolysis 1999;10(8):521-2.
105. Puetz J, Darling G, Brabec P, Blatny J, Mathew P. The risk of thrombotic events in neonates treated with recombinant factor VIIa [abstract]. Blood 2007;110(11, Part 1):938A. Available: http://abstracts.hematologylibrary.org/cgi/content/abstract/110/11/3193?maxtoshow=&HITS=10&h its=10&RESULTFORMAT=&fulltext=puetz%2C&searchid=1&FIRSTINDEX=0&volume=110&i ssue=11&resourcetype=HWCIT (accessed 2009 Apr 23).
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106. Gatt A, van Veen J, Cooper P, Kitchen S, Makris M. Reversal of anticoagulation as assessed by thrombin generation measurement [abstract]. Blood 2006;108(11, Part 1):263A. Available: http://abstracts.hematologylibrary.org/cgi/content/abstract/108/11/876?maxtoshow=&HITS=10&hit s=10&RESULTFORMAT=&fulltext=Gatt&searchid=1&FIRSTINDEX=0&volume=108&issue=1 1&resourcetype=HWCIT (accessed 2009 Apr 23).
107. Samama CM. Preemptive use of recombinant activated factor VII: many questions but few answers. Can J Anaesth 2006;53(4):336-8.
108. Hanna WT. Recombinant activated factor VII (rFVIIa)-mediated normalization of INR levels post- coumadin overdose [abstract]. Blood 2005;106(11, Part 2):106B. Available: http://abstracts.hematologylibrary.org/cgi/content/abstract/106/11/4102?maxtoshow=&HITS=10&h its=10&RESULTFORMAT=&fulltext=Hanna&searchid=1&FIRSTINDEX=0&volume=106&issu e=11&resourcetype=HWCIT (accessed 2009 Sep 11).
109. Squizzato A, Ageno W. Recombinant activated factor VII as a general haemostatic agent: evidence- based efficacy and safety. Curr Drug Saf 2007;2(2):155-61.
110. Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002;137(11):884-8.
111. Hendriks HG, Meijer K, De Wolf JT, Klompmaker IJ, Porte RJ, de Kam PJ, et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001;71(3):402-5.
112. Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999;59(3):635-46.
113. Mathew P, Young G. Recombinant factor VIIa in paediatric bleeding disorders--a 2006 review. Haemophilia 2006;12(5):457-72.
114. Dunkley S, Phillips L, McCall P, Brereton J, Lindeman R, Jankelowitz G, et al. Recombinant activated factor VII in cardiac surgery: experience from the Australian and New Zealand Haemostasis Registry. Ann Thorac Surg 2008;85(3):836-44.
115. Zimmerer SE, Precht AF, Khanna A, Hart MA. Activated recombinant factor VIIa: a novel approach to conserve blood loss in liver transplantation [poster no 1136]. Am J Transplant 2008;2(Suppl 3):424.
116. Desmurs-Clavel H, Huchon C, Chatard B, Negrier C, Dargaud Y. Reversal of the inhibitory effect of fondaparinux on thrombin generation by rFVIIa, aCCP and PCC. Thromb Res 2009;123(5):796- 8.
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APPENDIX 3: CLINICAL DATA EXTRACTION FORM
Date: Reviewer initials: Indication RefID First author, year, publication type List any related articles’ refIDs Study characteristics Geographic location Number of Centres Time period Setting: (e.g. hospital-based, clinic-based, community- based, referral criteria/process, other) Declared conflict of interest of one or more author/investigator Source(s) of funding Design: (RCT, prospective cohort study) Inclusion criteria Exclusion criteria Duration of follow up Total number randomized Sampling method (cohort studies) Method used to collect and report adverse events
Intervention, Comparator rFVIIa Control Dose(s), route of administration, duration of treatment Timing of Administration: Description of usual care Co-interventions (frequency, dose) Other (specify)
Definitions Transfusion criteria: RBCs FFP Platelets Plasma volume expanders SAE TAE
Baseline patient characteristics rFVIIa Control Total, all groups Number of patients assessed Number randomized Number included in ITT analysis Number included in per protocol analysis Number of withdrawals and reason Age: (years – mean, SD)
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Weight: (kg - mean SD) Gender: (male - n, %) Ethnicity: (%) Dose of study drug received (μg/kg, mean, SD) Type of surgery: (n, %) Anticoagulant administered * Other treatments received Other relevant patient characteristics: (specify) * supra-therapeutic anticoagulation population only
Outcomes Please extract data pertaining to all outcomes including sample size, point and variance estimates, units of measure and p-values for comparisons across groups Timing of rFVIIa* Control assessment n= n= Number of deaths Number of patients with SAE Number of SAE Number of patients with thromboembolic AE Number of thromboembolic AE Arterial thromboembolic AE Venous thromboembolic AE HRQL measure (specify) Number of patients who received RBCs Average number of units of RBCs transfused† Average units of FFP transfused† Average units of platelets transfused† Average units of cryoprecipitate transfused† Average mL of plasma volume expander transfused† (specify solution) Operative time (minutes) † Length of hospital stay (days) † Number of patients who bled ‡ * report drug, dose, and total number of patients per group. If the number of patients with data for a specific outcome varies, indicate the total n with each outcome measure. † specify mean, median, IQR, range, SD SE ‡ For supra-therapeutic anticoagulation population only
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APPENDIX 4: QUALITY ASSESSMENT FORM FOR RCTS
Assessment of RCT study quality38,39 Randomization Yes, No, or Unclear Was the study described as randomized? Was the method of randomization appropriate (table of random numbers, computer generated)? Was the trial described as randomized, but used an inappropriate method of randomization (date of birth, hospital numbers)? Blinding Yes, No, or Unclear Was the study described as double-blind? Did the trial describing an appropriate method of double-blinding (identical placebo, active placebo)? Is the trial described as double-blind, but used an inappropriate method (comparison of tablets versus injection with no dummy)? Withdrawals and dropouts Yes, No, or Unclear Was there a description of withdrawals and dropouts? Jadad Score *
Allocation concealment Adequate, Inadequate, or Unclear Adequate: central randomization; numbered or coded bottles or containers; drugs prepared by a pharmacy, serially numbered, opaque, sealed envelopes. Inadequate: alternation; reference to case record number or date of birth, etc. Unclear: allocation concealment is not reported, or fits neither category. Notes: Limitations of study: * A trial reporting that it is “randomized” is to receive one point. Trials describing an appropriate method of randomization receive an additional point. However, if the report describes the trial as randomized and uses an inappropriate method of randomization a point is deducted. A trial reporting that is “double blind”, it is to receive one point. Trials that describe an appropriate method of double blinding are to receive an additional point. However, if the report describes the trial as double blind and uses an inappropriate method, a point is deducted. A trial reporting the number and reason for withdrawals are to receive one point. If there is no statement, no point is given.
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APPENDIX 5: COCHRANE RISK OF BIAS TOOL FOR RCTS40
Domain Description of Item Data Extraction Review authors’ judgement from study: (High, Unclear or Low Risk of Bias) Sequence Describe the method used to generate the allocation sequence in Was the allocation sequence generation. sufficient detail to allow an assessment of whether it should produce adequately generated? comparable groups. Allocation Describe the method used to conceal the allocation sequence in Was allocation adequately concealment. sufficient detail to determine whether intervention allocations could have concealed? been foreseen in advance of, or during, enrolment. Blinding of Describe all measures used, if any, to blind study participants and Was knowledge of the participants, personnel from knowledge of which intervention a participant received. allocated intervention personnel and Provide any information relating to whether the intended blinding was adequately prevented during outcome assessors effective. the study? Assessments should be made for each main outcome (or class of outcomes). Incomplete Describe the completeness of outcome data for each main outcome, Were incomplete outcome outcome data including attrition and exclusions from the analysis. State whether data adequately addressed? attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors. Assessments should be made for each main outcome (or class of outcomes). Selective outcome State how the possibility of selective outcome reporting was examined reporting. by the review authors, and what was found. Other sources of State any important concerns about bias not addressed in the other Was the study apparently free bias. domains in the tool. of other problems that could put it at a high risk of bias? If particular questions/entries were pre-specified in the review’s
protocol, responses should be provided for each question/entry Overall Assessment of risk of bias:
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APPENDIX 6: QUALITY ASSESSMENT FORM FOR COHORT STUDIES
Newcastle – Ottawa Scale41 Note: a study can be awarded a maximum of one star* for each numbered item within the Selection and Outcome categories. A maximum of two stars** can be given for Comparability. Reference ID # Selection 1. Representativeness of the exposed cohort Truly representative of the average (describe) in the community* Somewhat representative of the average in the community* Selected group of users (e.g., nurses, volunteers) No description of the derivation of the cohort 2. Selection of the non exposed cohort Drawn from the same community as the exposed cohort* Drawn from a different source No description of the derivation of the non exposed cohort 3. Ascertainment of exposure Secure record (e.g., surgical records)* Structured interview* Written self report No description 4. Demonstration that outcome of interest was not present at start of study Yes* No Comparability 1. Comparability of cohorts on the basis of the design or analysis Study controls for (select the most important factor)* Study controls for any additional factor* (This criteria could be modified to indicate specific control for a second important factor.) Outcome 1. Assessment of outcome Independent blind assessment* Record linkage* Self report No description 2. Was follow-up long enough for outcomes to occur? Yes (select an adequate follow up period for outcome of interest)* No 3. Adequacy of follow up of cohorts Complete follow-up – all subjects accounted for* Subjects lost to follow-up unlikely to introduce bias – small number lost > % (select an adequate %) follow up or description provided of those lost* Follow up rate < % (select an adequate %) and no description of those lost No statement Limitations/comments
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APPENDIX 7: SUMMARY OF STUDIES IN CLINICAL REVIEW
Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Diprose 200543 Patients ≥18 years Recent thrombotic rFVIIa 90 μg/kg Median (IQR) age, Standard anaesthesia, of age undergoing disease or refusal of years and perioperative care R, DB, SC complex cardiac blood products Placebo (0.9% saline) rFVIIa: 63 (59 to 66) including aprotinin, surgery requiring placebo: 69.5 (63.5 to anticoagulation and N=20 (20 ITT, 19 CPB (repeat non- Single dose after 76.5) cell-salvage device. per-protocol coronary cardiac CPB and reversal of analysis) surgery, multiple heparin. % male: NR RBC were transfused if valve surgery, haemoglobin <70 g/dL Follow up:NR aortic root or arch Median (IQR) weight, during surgery or < 85 replacements, kg g/L post-surgery. Other Partial funding operations for rFVIIa: 80.8 (76.8 to coagulation products from Novo endocarditis and 89.2) administered as per Nordisk aortic dissection) placebo: 65.5 (56.5 to standard protocol. 76.0), p=0.02
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Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Ekert 200644 Children <1year Liver failure, rFVIIa 40 μg/kg Mean age, months Bleeding was treated with complex thromboembolic rFVIIa: 4.0 with conventional R, DB, SC congenital heart disorder, prior Placebo Placebo: 3.9 replacement therapy disease requiring treatment with rFVIIa using platelets, FFP and N=82 (76 treated- surgery with CPB. or antifibrinolytic First dose after CPB % male: NR blood (packed cells or case analysis, 41 agents, indications and reversal of whole blood) at the per-protocol for a Norwood heparin. Up to two Mean weight, kg discretion of the cardiac analysis) procedure, patients repeat doses could be rFVIIa: 5.2 team. on ventilation administered if Placebo: 5.3 Follow-up:6 weeks assistance, pre- bleeding was operative sepsis, excessive (20 minutes Partial funding coagulopathy or other after first dose or in from Novo disease that could post surgery recovery Nordisk interfere with trial, period) expected lifespan ≤3 months, allergy to rFVIIa Ma 200645 Patients undergoing Thrombotic events in rFVIIa 40 μg/kg IV Mean (SD) age, years NR (article in Chinese) cardiac valve last 6 months, rFVIIa: 50.3 (9.6) replacement coagulation disorders, Placebo placebo: 47.5 (10.9) R, DB, SC surgery under CBP hepatic disease, use of aspirin within 7 Single dose after % male N=22 (no days prior to surgery, protamine reversal rFVIIa: 55% withdrawals) or those who refuse placebo: 64% blood products. Follow-up and Weight: NR funding source: NR
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Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Lodge 200546 Patients undergoing Previous liver rFVIIa 60 μg/kg Mean (SD) age, years Transplantation was OLT because of transplant, split liver rFVIIa 60 μg/kg: 53.3 conducted according to R, DB, MC cirrhosis (Child- transplantation, rFVIIa 120 μg/kg (11.2) institutional standard Turcotte-Pugh class scheduled multiorgan rFVIIa 120 μg/kg: 52.6 procedures. N= 209 (182 B or C), ≥18 years or living related placebo (9.2) Prophylactic treated-case of age donor transplant, placebo: 52.3 (11.5) administration of analysis; 179 per- renal insufficiency First dose was hemostatic agents was protocol analysis) requiring dialysis, administered within % male not allowed during coagulation disorder, 10 minutes of rFVIIa 60 μg/kg: 57 surgery but could be Funding source: history or presence of incision and repeated rFVIIa 120 μg/kg: 71 given if clinically Novo Nordisk portal vein every 2 hours until 30 placebo: 54 indicated. RBCs thrombosis. minutes prior to liver infused if hematocrit Follow up: NR reperfusion. Final Weight: NR was <25%; FFP if INR dose administered at >1.5, aPTT >1.5 times wound closure. % Child-Turcotte-Pugh control or based on score C thromboelastogram; rFVIIa 60 μg/kg: 41 platelets if count was rFVIIa 120 μg/kg: 33 <30,000/mm2; placebo: 46 cryoprecipitate or fibrinogen concentrate if fibrinogen level <1.0 g/L, or based on thromboelastogram tracings.
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Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Pugliese 200747 Patients undergoing NR rFVIIa 40 μg/kg NR Criteria for orthotopic liver transfusions: RBC if R, DB transplantation with placebo haemoglobin <10 g/dL; haemoglobin >8 FFP if INR >1.5. N=20 (no mg/dL, INR>1.5, single dose prior to withdrawals) fibrinogen >100 anesthesia induction mg/dL Follow-up: 6 hours after study drug
Funding source: NR
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Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Planinsic 200548 Patients ≥18 years of Previous liver rFVIIa 20 μg/kg Mean (SD) age, years Prophylactic hemostatic age with end-stage transplant, multi-organ rFVIIa 20 μg/kg: 49.4 agents not permitted but R, DB, MC liver disease (Child- transplant, living rFVIIa 40 μg/kg (13.4) could be administered Turcotte-Pugh class related-donor rFVIIa 40 μg/kg: 49.7 during the OLT if N=87 (83 ITT, 82 B or C) undergoing transplant, renal rFVIIa 80 μg/kg (10.1) clinically indicated. per-protocol orthotopic liver insufficiency requiring rFVIIa 80 μg/kg: 51.9 Criteria for transfusions: analysis) transplantation dialysis, inherited placebo (8.8) RBC if hematocrit <25%; coagulation disorder, placebo: 49.9 (11.0) FFP if INR >1.5 or aPTT Follow-up: NR history of or presence Single dose within 10 >1.5 times control; of portal vein minutes of first skin % male platelets if count below Funding source: thrombosis incision rFVIIa 20 μg/kg:67 30,000/mm2; Novo Nordisk rFVIIa 40 μg/kg:63 cryoprecipitate or rFVIIa 80 μg/kg:73 fibrinogen if fibrinogen placebo:74 level <1.0 g/L; or if indicated by Weight: NR thromboelastogram tracings. % Child-Turcotte-Pugh score C rFVIIa 20 μg/kg:56 rFVIIa 40 μg/kg:58 rFVIIa 80 μg/kg:45 placebo:63 Zimmerer 200549 Adults undergoing NR rFVIIa 1.2 mg + usual NR NR (abstract) orthotopic liver care R, SC transplantation usual care N=25 (23 per- protocol analysis) usual care described as conventional Follow-up and replacement therapy funding sources NR with blood products to correct coagulopathy of end-stage liver disease
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Table A1: Characteristics of RCTs Study, design, Inclusion criteria Exclusion criteria Treatment groups Patient Other treatments and total N, characteristics clinical practice withdrawals, details follow-up, funding Friederich 200350 Patients 18 to 85 Treatment with an rFVIIa 20 μg/kg Mean (SD) age, years RBC if hemoglobin <4.5 years old undergoing anticoagulant within 48 rFVIIa 20 μg/kg: 61 (8.9) mmol/L intraoperatively R, DB, SC radical retropubic hours of surgery, rFVIIa 40 μg/kg rFVIIa 40 μg/kg: 64 (8.5) or <5.5 mmol/L post- prostatectomy for aspirin within 7 days, placebo: 63 (8.3) operatively. Other blood N=36 (no prostate cancer or congenital or acquired placebo products at physician’s withdrawals) prostatectomy (Millin hemostatic disorder, Mean (SD) weight, kg discretion. & MacAlister unstable coronary artery single dose during rFVIIa 20 μg/kg: 76.8 Partial funding from method) for prostate disease or angina procedure (9.2) Novo Nordisk hypertrophy pectoris NYHA class rFVIIa 40 μg/kg: 82.0 III/IV, history of Dose escalating study: (13.1) Follow up 10 days venous thrombo- recruitment to 80 μg/kg placebo: 82.1 (11.8) embolism or dose was stopped based thrombophilic state, on interim data analysis advanced liver disease, cirrhosis, or acute hepatitis, or participation in another study within 30 days. aPTT= activated partial thromboplastin time; CPB= cardiopulmonary bypass; DB=double blind; FFP=fresh frozen plasma; INR= international normalized ratio; IQR=interquartile range; MC=multicentre; NR=not reported; NYHA=New York Heart Association; R=randomized; RBC=red blood cells; rFVIIa=recombinant activated factor VII; SC=single centre
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Table A2: Results of Cardiac Surgery RCTs Study Treatment N patients RBCs Platelets FFP Length of Serious Deaths Other outcomes arms (n) transfused transfused transfused transfuse stay adverse (n) measured (RBC) d events, TAE Diprose rFVIIa 90 3* Median Median Median Median Post-op 0/9 200543 μg/kg units (IQR) units (IQR) units (IQR) days stroke: 1 (n=10) 0 (0 to 0 (0) (IQR) in ICU: 2.5 MI: 1 0.75) 0 (0 to (1 to 3.5) 0.75) [n=9] Hospital: 11.5 (8.8 to 19.8) [n=9] Placebo 8*, p=0.07 2 (1 to 3.5) 1 (0 to 2), 4 (0 to ICU: 1 (1 to Stroke: 1 1/10, (n=10) p=0.11 p=0.23 12.75), 4), p=0.43 MI: 1 p=1.0 p=0.18 [n=10], p=1.0 Hospital: 8 (8 to 14), p=0.41 [n=9] Ekert 200644 rFVIIa 40 Day of Mean mL Mean mL Mean mL NR No difference NR Time from μg/kg surgery: 13 (range) (range) (range) in treatment heparin reversal (n=40, Day of Day of Day of emergent to chest closure treated case 48 to 72 surgery: 77 surgery: 65 surgery: adverse Mean time analysis) hours: 30 (25 to 250) (30 to 200) 82 (30 to events minutes (SE) 150) between [95%CI] 48 to 72 h: 48 to 72 h: 48 to 72 h: groups. 98.8 (27.3) [44.5 116 (20 to 51 (30 to 78 (30 to to 153.2] 490) 90) 200) SAE: NR
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Table A2: Results of Cardiac Surgery RCTs Study Treatment N patients RBCs Platelets FFP Length of Serious Deaths Other outcomes arms (n) transfused transfused transfused transfuse stay adverse (n) measured (RBC) d events, TAE Placebo Day of Day of Day of Day of NR No TAE in NR Time from (n=36) surgery: surgery: surgery: 43 surgery: either group heparin reversal 15, p=NS 127 (12 to (20 to 60)† 50 (50 to to chest closure: 400), p=NS 50)† 55.3 (29.2) [-2.8 48 to 72 48 to 72 h: to 113.4], n=35, hours: 29, 48 to 72 h: 57 (50 to 48 to 72 h: p=0.026 p=NS 100 (6 to 60)† 75 (40 to 320), p=NS 125)† Ma 200645 rFVIIa 40 NR Mean units Mean units Mean units Mean days No cerebral 0 Mean units of μg/kg (SD): 3.5 (SD): 3.4 (SD): 5.5 in ICU infarction, cryoprecipitate (n=11) (2.2) (2.2) (3.4) (SD): 2.7 MI, DVT or (SD): 0.9 (1.0) (0.5) PE events in Placebo NR 6.3 (3.1), 7.5 (3.2), 4.8 (4.7), 3.3 (0.7), either group 0 1.1 (1.7), p=NS (n=11) p<0.01 p<0.01 p=NS p<0.05 * Number of patients who received RBC, platelets, FFP or PCC; † Sample too small for statistical testing CI=confidence interval; DVT= deep vein thrombosis; FFP=fresh frozen plasma; ICU=intensive care unit; IQR=interquartile range; MI=myocardial infarct; NS=not statistically significant; PE=pulmonary embolus; rFVIIa=recombinant activated factor VII; RBC=red blood cells; SD=standard deviation; SE=standard error; TAE=thromboembolic adverse events
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Table A3: Results of Liver Transplantation RCTs Study Treatment N patients RBCs Platelets FFP Length of Serious Death Other arms (n) transfused transfused transfused transfused stay (days) adverse s (n) outcome (RBC) events, TAE measures Lodge 200546 rFVIIa 60 First 24 Median Median mL Median units ICU: 3.5† Number of 1/63 ‡ No μg/kg hours: units (range) (range) (range) within Total:19.0 patients with significant (n=63 56/62 (post within 24 h: within 24 24 h: 9.4 (0 to SAE: 17/63 difference treated case hoc 7.0 (0 to h: 81.8 (0 62.4) TAE: 12/63 between analysis) analysis) 76.5) [n=62] to 2640) groups in rFVIIa 120 52/56 6.3 (0 to 170.6 (0 to 11.9 (0 to ICU: 3.0 SAE: 16/58 2/58 ‡ operative μg/kg 76.4) [n=56] 886) 52.8) Total: 22.0 TAE: 7/58 time, (n=58) volume of Placebo 61/61 8.2 (1.5 to 141.7 (0 to 11.0 (0 to ICU: 3.0, SAE: 12/62, 1/62, plasma (n=61) (p=0.03) 100) [n=61], 1953) 87.2), p=NS p=NS p=NS p=NS volume p=NS p=NS Total: 17.0, TAE: 6/62, ‡ expanders p=NS p=NS administere d, or number of patients receiving cryoprecipi tate. Pugliese rFVIIa 40 NR Average mL NR Mean mL ICU No TAE in 0 Mean (SD) 200747 μg/kg (SD): 300 (SD): 600 Mean (SD) either group operative (n=10) (133) (154) 4.8 (1.3) time, minutes: 408 (56) Placebo 570 (111), 1400 (187), 5.2 (1.2), 0 432 (48), (n=10) p<0.017 p<0.001 p=NS p=NS
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Table A3: Results of Liver Transplantation RCTs Study Treatment N patients RBCs Platelets FFP Length of Serious Death Other arms (n) transfused transfused transfused transfused stay (days) adverse s (n) outcome (RBC) events, TAE measures Planinsic rFVIIa 20 NR Median Median Median units ICU length of Number of 1** No 200548 μg/kg units RBC units (IQR) (IQR) stay similar patients (%) significant (n=18) (IQR) in 5.5 (0 to 8.5 (0 to 41) between SAE: 5 (28%) differences first 24 11) groups Arterial between hours TAE:2 (11%) groups in 8.5 (3 to 18) operative rFVIIa 40 13.0 (6 to 9.0 (0 to 15.5 (8.8 to SAE:10 2** time or μg/kg 22) 19) 24) (42%) volume of (n=24)* Arterial crystalloid TAE:1 (4%) or colloid rFVIIa 80 7.0 (2 to 17) 1.5 (0 to 8) 6.0 (2 to 23) SAE:8 (36%) 1** administere μg/kg Arterial d (n=22) TAE:2 (9%) Placebo 8 (0 to 15), 4.0 (1 to 11 (2 to 23), SAE:6 (32%) 1** (n=19) p=NS 10), p=NS p=NS Arterial TAE:2 (11%) Zimmerer rFVIIa 1.2 NR 4.5† NR 3.7 † NR NR NR Operative 200549 mg (n=15) time, minutes 352† Usual care 14.6, 17.6, p=0.001 415, (n=8) p=0.002 p=0.02 * One patient had OLT cancelled so was only included in safety analysis; † not reported if value represents mean or median- variance not reported; ‡ Total of 6 deaths in the study period. Treatment group for 2 deaths not reported; **Total of 7 deaths in the study period. Treatment group for 2 deaths and results of statistical testing not reported. FFP=fresh frozen plasma; ICU=intensive care unit; IQR=interquartile range; NR=not reported: NS=not statistically significant; rFVIIa=recombinant activated factor VII; RBC=red blood cells; SD=standard deviation; SAE: serious adverse event; TAE=thromboembolic adverse events
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Table A4: Results of Prostatectomy RCTs Study Treatment N patients RBCs transfused Length of stay Serious Deaths Operative arms (n) transfused adverse (n) time (RBC) events, TAE (minutes) Friederich rFVIIa 20 3/8, p=0.65 Mean (SD) units: Mean (SD) days: 13 (1.3), No adverse 0 Mean (SD): 200350* μg/kg (n=8) vs placebo 0.6 (0.3), p=0.047 p=0.66 vs placebo events in any 126 (21), vs placebo group at 10 p=0.035 vs days placebo rFVIIa 40 0/16, 0 (0), p=0.0003 vs 11 (0.7), p=0.35 vs placebo 0 120 (15), μg/kg p=0.001 vs placebo 1 acute MI p=0.014 vs (n=16) placebo (at 14 days) placebo Placebo 7/12 1.5 (0.4) 12 (1.7) 0 180 (16) (n=12) MI=myocardial infarction; NS=not significant; RBC=red blood cells; rFVIIa=recombinant activated factor VII; SD=standard deviation; TAE=thromboembolic adverse events; * No patients received transfusion with blood products other than RBCs such as plasma or platelets.
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Table A5: Validity assessment of RCTs Study Jadad Allocation Risk of bias Comments score concealment assessment Diprose 200543 5 adequate low Small sample size, some imbalances between treatment groups Ekert 200644 3 unclear unclear Small sample size, high attrition rate for 6 week follow up, incomplete reporting of study methods and results (mainly adverse event data). Ma 200645 2 unclear unclear Small sample size, incomplete reporting of study methods and results. Length of follow up not clear. Lodge 200546 3 unclear unclear Reporting of methods and results incomplete. Adverse event data in text and tables do not agree. Pugliese 2 unclear unclear Reporting of study methods and results not 200747 complete. Length of follow up not clear. Small sample size. Planinsic 3 unclear unclear Reporting of methods and results 200548 incomplete. Adverse event data in text and tables do not agree. Small sample size. Zimmerer 1 unclear unclear Abstract therefore unable to adequately 200549 assess study quality. Does not appear to be blinded. Small sample size. Two patients excluded from analysis with no reason for exclusion provided. Friederich 5 adequate low Small sample size 200350
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APPENDIX 8: DATA EXTRACTION FORM FOR ECONOMIC STUDIES
Reference ID Author, title, journal, publication date Study characteristics 1. Study question/objective 2. Study indication 3. study population selection criteria 4. Study population characteristics 5. disease risk of included study population 6. Study intervention 7. Study comparator 8. Type of economic analytic techniques 9. Analysis type 10. Currency and its year 11. Care setting or study geographic location 12. Study perspective 13. discounting rate and justification 14. Analysis time horizon Source of data 15. source of effectiveness data 16. source of cost data Method for estimation of benefits/costs 17. health outcomes 18. If CBA study, status of outcomes or benefits 19. valuation for clinical effectiveness of intervention 20. approach for health state assessment 21. the content of cost considered in the study 22. cost estimation approach 23. modeling (if model used) 24. sensitivity analysis type 25. key parameters on which sensitivity analysis was done on 26. statistical analysis 27. sub-group analysis (if applicable) 28. regression analysis (if applicable) Results and analysis 29. clinical outcome/benefits 30. costs 31. synthesis of costs and benefits 32. health related quality of life benefits 33. statistical analysis results 34. sensitivity analysis results 35. sub-group analysis results 36. regression analysis results Conclusion 37. conclusion 38. limitation 39. funding source (if applicable)
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APPENDIX 9: EXCLUDED ECONOMIC STUDIES
Study Reason for exclusion Diprose P, Herbertson MJ, O’Shaughnessy D, Gill RS. Activated Not an economic evaluation. recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anesth 2005; 95:596-602. Ganguly S, Spengel K, Tilzer LL, O’Neal B, Simpson SQ. Cannot assess if rFVIIa given for Recombinant factor VIIa: unregulated continuous use in patients with prevention in indications of bleeding and coagulopathy does not alter mortality and outcome. Clin interest. Lab Haem 2006; 28:309-312. Magnetti S, Oinonen M, Matuszewski KA. An evaluation of off-label Preventive use unclear. use of recombinant activated human factor VII (NovoSeven): patient characteristics, utilization trends, and outcomes from an electronic database of US academic health centres. P&T 2007; 32(4):218-230. Reiter Pd, Valuck RJ, Taylor RS. Evaluation of off-label recombinant Cannot assess use in prevention. activated factor VII for multiple indications in children. Clin Appl Thromb Hemost 2007; 13:233-240. Owen PS, Golightly LK, MacLaren R, Ferretti KA, Badesch DB. Appears to be treatment of Formulary management of recombinant factor VIIa at an academic bleeding. Cannot assess if used medical centre. Ann Pharmacother 2008; 42:771-6. in prevention.
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APPENDIX 10: QUALITY ASSESSMENT USING BMJ 35-ITEM CHECKLIST60 FOR ECONOMIC EVALUATIONS
Criteria Studies
Odeyemi Ma Schoenhaus Study Design (2004)65 (2006)45 (2008)62-64 1 Research question stated 1 1 1 Economic importance of research question 2 stated 1 0 1 Viewpoint(s) of analysis clearly stated and 3 justified 1 0 0 Rationale for alternative interventions 4 stated 1 0 1 5 Alternatives clearly described 1 1 0.5 6 Form of economic evaluation used is stated 0.5 0 0 Choice of economic evaluation justified in 7 relation to question addressed 0 0 0
Data Collection 8 Source(s) of effectiveness estimates stated 1 1 1 Details of design and results of effectiveness study given (if based on 9 single study) 0.5 1 1 Details of method of synthesis or meta- analysis of estimates (if based on a number 10 of effectiveness studies) na na na Primary outcome measures for economic 11 evaluation clearly stated 1 0 1 Methods to value health states & other 12 benefits stated 0 0 0 Details on subjects from whom valuations 13 obtained stated 0 1 1 Productivity changes (if included) reported 14 separately na na na Relevance of productivity change to study 15 relevance discussed 0 0 0 Resource quantities reported separately 16 from unit costs 0.5 0.5 0 Methods for estimating resources and unit 17 costs described 1 0 0.5 18 Currency and price date recorded 1 0.5 0.5 19 Details of currency price adjustment for na na 0
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inflation or currency conversion given 20 Details of any model used given 1 0 0 Choice of model & key parameters on 21 which based justified 0 0 0
Analysis and Interpretation of Results 22 Time horizon of costs and benefits stated 1 0 0 23 Discount rate(s) stated na na na 24 Choice of rate(s) justified na na na Explanation given if costs/benefits not 25 discounted na na na Details of statistical tests and confidence 26 intervals given for stochastic data 0 1 1 27 Approach to sensitivity analysis given 0 0 0 Choice of variables for sensitivity 28 analysis justified 1 0 0 Ranges over which variables are varied 29 are stated 0 0 0 30 Relevant alternatives compared 0.5 0.5 1 31 Incremental analysis reported 0 0 0 Major outcomes presented disaggregated 32 & aggregated 1 0 0.5 33 Answer to study question given 1 1 1 34 Conclusions follow from data reported 1 1 1 Conclusions accompanied by 35 appropriate caveats 1 0 0
Total Criteria Reported 18 9.5 13 Total Criteria Applicable 29 29 30 Percent Criteria Reported 62% 33% 43%
1: information reported; 0.5: information partially reported or unclear; 0: information not reported; na: not applicable.
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APPENDIX 11: EXTERNAL VALIDITY OF ECONOMIC STUDIES
Odeyemi Ma Schoenhaus Criteria (2004)65 (2006)45 (2008)62-64 Does the research question reflect the issue presently yes yes yes concerned? Did the clinical data used in the analysis reflect what partial partial partial might be achieved in the routine clinical practice in Canada? Are resource use pattern and relative unit cost levels partial partial partial generalizable to Canada? Is uncertainty adequately reflected in the analysis? partial no no
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APPENDIX 12: SUMMARY OF STUDIES IN ECONOMIC REVIEW
Table A6: Methods Author and year of Indication Intervention Setting Type of economic Perspective publication evaluation Schoenhaus et al. Orthotopic liver rFVIIa (median dose of United States, Cost-consequences Not stated, however, (2008)62-64 transplant (OLT) 1.2 mg per patient, range: inpatient appears to be that of 0.6-8.4 mg) versus university hospital standard care centre Ma et al. (2006)45 Cardiac valve rFVIIa (40 μg/kg) versus China, inpatient Cost-consequences Not stated, however, replacement under placebo appears to be that of cardiopulmonary university hospital bypass centre Odeyemi et al. Abdominal rFVIIa (20μg/kg or Netherlands, Cost-consequences Stated perspective is (2004)65 prostatectomy 40μg/kg) versus placebo inpatient the Dutch National Health System, however the analysis was limited to inpatient outcomes and costs mg: milligrams; μg/kg: micrograms per kilogram; rFVIIa: recombinant activated factor VII
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Table A6: Methods (continued) Author and year of Clinical data sources Economic data Currency and Time horizon Sensitivity analysis publication sources year for cost evaluation Schoenhaus et al. Retrospectively Hospital billing US dollars, 2003 Duration of hospital Not done (2008)62-64 analyzed electronic databases to 2006 admission (median of health records of 119 12 days for rFVIIa patients (68 rFVIIa and patients and 10 days 51 control) from the for control patients) UCSD Medical Centre between January 2003 and November 2006 Ma et al. (2006)45 Single center double Not stated Chinese Yuan Duration of hospital Not done blind randomized (RMB), year not admission (LOS not control trial of 22 stated. reported) patients (11 rFVIIa and 11 placebo) from Shanghai Hospital Odeyemi et al. Single center double Resource data Euros (€), 2002- Duration of hospital One-way breakeven (2004)65 blind randomized obtained from 2003 admission (mean analysis conducted on control trial50 of 36 Friederich et al.50 and 11.3 days) the cost of a unit of patients (8 rFVIIa unit cost data packed blood cells, 20μg/kg, 16 rFVIIa obtained from the unit cost of rFVIIa 40μg/kg, and 12 published Dutch (1 μg), and the placebo) from Academic sources number of packed Medical Centre, cells transfused University of Amsterdam LOS: length of stay; μg: microgram; rFVIIa: recombinant activated factor VII; UCSD: University of California in San Diego.
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Table A7: Results
Author and year of Patient characteristics Clinical / health outcomes Cost outcomes publication Schoenhaus et al. rFVIIa / Control: rFVIIa / Control: rFVIIa / Control: (2008)62-64 Male, N (%): PRBC units, Blood costs, median (range): 43 (63) / 35 (69) median (range): 8 (0-120) / 8 (0-58) US$6,154 ($563-$55,742) / US$5,954 mean (SD): 13.8 (19.5) / 13.4 (14.3) ($517-$42,254) Age in years, median (range): mean log: 2.1 / 2.2 50.5 (25-68) / 51.0 (25-67) Surgical costs, median (range): FFP units, US$6,667 ($541-$27,509) / Weight in kg, median (range): median (range): 6 (0-59) / 7 (0-91) US$6,821 ($1,088-$19,756) 80 (49-145) / 83 (43-122) mean (SD): 11.3 (13.4) / 15.6 (20.5) mean log: 2.2 / 2.4 Total costs, median (range): Pre-op MELD, median (range): US$55,811 ($32,567-$479,735) / 16 (6-40) / 16.9 (6-35) Platelet units, US$57,279 ($33,096-$166,673) median (range): 3 (0-20) / 4 (0-50) Pre-op INR, median (range): mean (SD): 4 (3.5) / 6.6 (1.0) Total costs include accommodations, 1.4 (0.8-6.5) / 1.5 (0.9-2.6) mean log: 1.3 / 1.6 pharmacy, laboratory, blood, radiology, operating room, and transplant (organ) Pre-op SCr in mg/dL, median (range): LOS in days, median (range): costs 1.1 (0.6-4.9) / 1.0 (0.6-4.7) 12 (0-289) / 10 (1-55) Total costs of care do not include cost of Dialysis dependency, N (%): Thromboembolic events, N (%): rFVIIa. 2 (3) / 7 (14) 2 (3) / 1 (2) Between-group differences were not Between-group differences were statistically significant for any cost not statistically significant for any outcomes health outcomes
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Table A7: Results
Author and year of Patient characteristics Clinical / health outcomes Cost outcomes publication Ma et al. (2006)45 rFVIIa / Placebo: rFVIIa / Placebo: rFVIIa / Placebo:
Male, N (%): RBC units, mean (SD): Total cost of hospitalization, mean (SD): 6 (54.5) / 7 (63.6) 3.5 (2.2) / 6.3 (3.1), p<0.01 RMB 71,356 (11,438) / RMB 66,772 (19,272) Age in years, mean (SD): Plasma units, mean (SD): 50.3 (9.6) / 47.5 (10.9) 5.5 (3.4) / 4.8 (4.7), p=NS
Type of surgery, N (%): Platelet units, mean (SD): MVR/AVR: 8 (73) / 7 (64) 3.4 (2.2) / 7.5 (3.2), p<0.01 DVR: 3 (27) / 4 (36) TVP: 5 (45) / 4 (36) Cryoprecipitate units, mean (SD): 0.9 (1.0) / 1.1 (1.7), p=NS Pre-op INR, mean (SD): 1.11 (0.16) / 1.16 (0.12) ICU stay in days, mean (SD): 2.7 (0.5) / 3.3 (0.7), p<0.05
INR significantly lower in rFVIIa group up to two hours post- administration (p<0.01)
No cases of cerebral infarction, myocardial infarction, deep-vein thrombosis, pulmonary embolism, or death from any cause reported
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Table A7: Results
Author and year of Patient characteristics Clinical / health outcomes Cost outcomes publication Odeyemi et al. rFVIIa 20μg/kg / rFVIIa 40μg/kg / rFVIIa 20μg/kg / rFVIIa 40μg/kg / rFVIIa 20μg/kg / rFVIIa 40μg/kg / (2004)65 Placebo: Placebo: Placebo:
Age in years, mean (SD): Packed cell units transfused, rFVIIa: €997/ €1994/ €0 61(8.9) / 64(8.5) / 63(8.3) mean (median): Packed cells: €112 / €0 / €269 0.65 (0) / 0 (0) / 1.5 (2) Surgery: €1,823 / €1,808 / €2,525 Weight in kg., mean (SD): p=0.001 Hospitalization: €6,630 / € 5,324 / 76.8(9.2) / 82.0(13.1) / 82.1(11.8) €6,119 Operation duration in minutes, Medications: €113 / €113 / €406 Radical:Millin surgery, N (%) mean (median): Diagnostic tests: €283 / €283 / €283 4(50):4(50) / 7(44):9(56) / 126 (105) / 125 (105) / 180 (203) 5(42):7(58) p=0.014 Total average cost per patient: €9,958 / €9,522 / €9,602 Pre-op HGB (mmol/L), mean (SD): LOS in days, mean (median): 8.7(0.9) / 8.1(0.7) / 8.4(0.9) 13 (11) / 10 (9) / 12 (9.5) p=0.35
No adverse events reported AVR: aortic valve replacement; DVR: double valve replacement; €: Euros; FFP: fresh frozen plasma; HGB: haemoglobin; ICU: intensive care unit; INR: international normalized ratio; kg: kilogram; LOS: length of stay; MVR: mitral valve replacement; MELD: model for end-stage liver disease score; μg: microgram; mg/dL: milligrams per decilitre; NS: not significant; PRBC: packed red blood cell; rFVIIa: recombinant activated factor VII; RMB: Chinese Yuan; SCr: serum creatinine; SD: standard deviation; TVP: tricuspid valvuloplasty.
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Table A7: Results
Author and year of Sensitivity analysis Conclusion Limitations Funding publication results source Schoenhaus et al. NA rFVIIa use for reduction of blood Information for this reference Not stated (2008)62-64 product requirements in OLT has not obtained from abstract and poster been demonstrated to be cost- presentation and thus limited in effective and may be associated with detail; clinical and economic data risk of thromboembolic events. Based obtained retrospectively from single on this study, rFVIIa is no longer hospital centre and small sample recommended for preoperative use, size; duration of follow-up limited but is still used for rescue therapy. to hospital stay and so longer-term patient and cost outcomes could not be evaluated; patient health states not evaluated; inflation adjustment of four years of cost data not apparent; sensitivity analyses not conducted. Ma et al. (2006)45 NA rFVIIa effectively improved the Clinical and economic data Not stated coagulation function in the study obtained from single hospital centre population and reduced the need for study with small sample size; blood transfusion, without significant duration of follow-up limited to side effect; total hospital expenses hospital stay and so longer-term were not significantly increased when patient and cost outcomes could not compared to those without using be evaluated; patient health states rFVIIa. not evaluated; details of resources and costs included in total hospital cost calculation not provided (including cost of rFVIIa); sensitivity analyses not conducted.
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Table A7: Results
Author and year of Sensitivity analysis Conclusion Limitations Funding publication results source Odeyemi et al. Baseline / break-even: Compared with placebo, the use of Analysis based on one study from a Not stated (2004)65 rFVIIa at 40g/kg as a haemostatic single location, and of small sample however Cost of packed blood cell agent in abdominal prostatectomy size. Duration of follow-up was lead author unit: €179 / €126 lowers overall treatment costs and limited to hospital stay, and so was reduces surgery time by conferring longer-term outcomes, previously Unit cost of rFVIIa (1 μg): transfusion freedom. The potential for complications, and costs could not employed €0.712 / €0.741 such clinical and economic outcomes be evaluated. Patient health states by Novo in other surgical settings should be not evaluated. Inconsistent with Nordisk Number of packed cells for explored in more extensive studies. Friederich et al.50 in reporting of placebo group: outcomes. 2.25 / 1.60 €: Euros; μg: microgram; NA: Not applicable; rFVIIa: recombinant activated factor VII.
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