Canadian Coordinating Office for Health Technology Assessment

LEUKOREDUCTION: the techniques used, their effectiveness and costs

CCOHTA Report 1998: 6E Cite as:

Canadian Coordinating Office for Health Technology Assessment. Leukoreduction: the techniques used, their effectiveness and costs. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1998.

Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA.

Legal Deposit - 1998 National Library of Canada ISBN 1-895561-60-4 Canadian Coordinating Office for Health Technology Assessment

LEUKOREDUCTION: the techniques used, their effectiveness and costs

Bernhard Gibis, MD, CCOHTA Research Fellow Jean-François Baladi, MBA

February 1998

This report was commissioned by the Canadian Blood Agency. The opinions and conclusions reached, however, are those of CCOHTA. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization, funded by the federal, provincial and territorial governments. It was established to encourage the appropriate use of health technology by influencing decision-makers through the scientific evaluation of medical procedures, devices and drugs. The effectiveness and cost of technology and its impact on health are examined.

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CCOHTA Publications 110-955 Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4 Telephone (613) 226-2553 Facsimile (613) 226-5392 E-mail [email protected]

or download full text from http://www.ccohta.ca REVIEWERS

Dr. Walter Dzik, MD Dr. Bernie O’Brien Director, Transfusion Medicine CCOHTA Scientific Advisory Panel Harvard Medical School subcommittee member Boston, USA Associate Professor, McMaster University Centre for Evaluation of Medicines, Dr. Sherill Slichter, MD St. Joseph’s Hospital Director, Division of Research and Hamilton, Ontario Education Puget Sound Blood Centre Dr. Murray Krahn Seattle, USA CCOHTA Scientific Advisory Panel subcommittee member Dr. Georges Andreu, MD Toronto Hospital Établissement de transfusion sanguine de Toronto, Ontario l’Assistance publique, Hôpitaux de Paris Paris, France This report was reviewed by external Dr. Andreas Laupacis reviewers and by members of a Chair, CCOHTA Scientific Advisory Panel subcommittee of CCOHTA’s Scientific Director, Clinical Epidemiology Unit Advisory Panel. These individuals Ottawa Civic Hospital kindly provided comments on drafts of Ottawa, Ontario this report. This final document incorporates most of the reviewers’ comments; however CCOHTA takes sole responsibility for its form and content.

ACKNOWLEDGEMENTS

CCOHTA would like to thank the Scientific Advisory Committee and staff members of the Canadian Blood Agency for their valuable input.

i EXECUTIVE SUMMARY

Leukocytes, as part of transfusions, can cause a variety of side-effects such as febrile reactions, platelet refractoriness, and transmission of viruses like the cytomegalovirus. In addition, transfused leukocytes may suppress the recipient’s immune response thereby increasing the risk of infection or malignancy. Therefore, reduction of leukocytes in blood and platelet transfusions may potentially reduce the frequency of these adverse events and save costs.

Currently, third generation adhesion filters exist which can achieve a three log reduction of the original leukocyte load. This study examines the efficacy of various filtration techniques and compares their costs and their potential savings. More specifically, it compares the efficacy of various filtration techniques in reducing the leukocyte load of transfused blood components (apheresis platelets, pooled platelets and red blood cells), their cost, as well as the savings associated with a reduction in treating the adverse events related to transfused leukocytes.

Adverse events examined include febrile reactions, platelet refractoriness following alloimmunization and immunomodulation. The efficacy of leukoreduction in reducing these adverse events was obtained from an extensive literature search of published literature complemented with a number of interviews with Canadian stakeholders. Level of evidence was assessed and is indicated throughout the report. Canadian resource use and cost estimates were obtained from a number of Canadian sources. A retrospective analysis of patient charts was conducted for estimating the cost of treating febrile reaction. The cost of platelet-refractoriness due to allo-immunization was estimated by a panel of experts. The cost of immunomodulation was estimated by assuming that immunomodulation increases the likelihood of surgical site infections. The use of blood products was based on the annual Red Cross statistical report and data obtained from the CBA. The analysis is conducted from the perspective of the Canadian health care and blood transfusion systems.

The efficacy of leukofiltrating three blood components (apheresis platelets, pooled platelets and red blood cells) was examined at three possible stages: in a regional blood centre before storage of the blood component, in a hospital blood bank following storage and prior to delivering it to the requesting ward, and at a patient’s bedside just before the transfusion. Thus, nine filtration techniques are assessed, each one having its own clinical efficacy and its cost.

Clinical Efficacy

Non Hemolytic Febrile Transfusion Reactions: non Hemolytic Febrile Transfusion Reactions (NHFTR) are the most common leukocyte-related adverse effects of blood transfusions. Pre- or post-storage filtered transfusions prevent most febrile reactions to red blood cell transfusions and in this respect, the advantage of pre-storage filtration has not been proven in a randomized controlled trial. However, platelet transfusions are associated with a higher rate of adverse events, and post-storage filtration of platelets is not as effective as post-storage filtration of red blood cells. In the case of platelets, pre-storage filtration offers the advantage of preventing the production of some leukocyte mediated cytokines during the storage period.

ii Infections: the risk of transmission of leukocyte born viruses such as the cytomegalovirus (CMV) via transfusion of red blood cells and platelets is markedly decreased by leukofiltration. Consequently, leukofiltration is increasingly accepted as an alternative to CMV screening of blood components. However, for other viral or bacterial/protozoal infections, we found no evidence that leukofiltration is an alternative to existing screening programs. Thus, apart from CMV, the impact of leukofiltration on the prevention of transfusion-related infections remains unknown.

Platelet-refractoriness: To prevent thrombocytopenic bleeding due to high dose chemotherapy, prophylactic platelet transfusions are usually given. The ability of these transfusions to increase the platelet count can be inhibited if the recipient has an immune response due to prior HLA- alloimmunization to donor blood components, mainly leukocytes. Leukofiltration reduces the incidence of alloimmunization and therefore platelet refractoriness particularly in desensitized patients. However, despite several experimental and retrospective studies, no randomized controlled trial exists that has demonstrated an advantage of pre- over post-storage filtration.

Immunomodulation: an immunomodulatory effect of blood transfusions in humans is still controversial. A recent meta-analysis of unconfounded randomized controlled trials concluded that any possible effect would be smaller than 25% (relative risk reduction of postoperative infection, cancer recurrence after surgery). At present, there is no evidence from clinical trials that the timing of filtration influences immunomodulation.

Cost Comparison

The cost of each of the nine filtration techniques was assessed in both single and multi- transfused patients. This cost included the cost of filters, the cost of related activities such as inventory management and overhead costs and the cost of treating adverse reactions. The cost of treating adverse events is itself dependent on the number of transfusions, the efficacy of the leukoreduction technique and the cost of treating the particular adverse reaction. We then calculated the cost impact for three main strategies, the first being filtering all blood components in a blood centre, the second, filtering all components in a hospital blood bank, and the third, filtering all blood components at the patient bedside.

This analysis focused on the costs associated with filtration and does not take into account the cost of producing different blood components. Thus the cost of one apheresis platelet cannot be compared directly with the cost of one pooled platelet. In addition, health-related-quality-of-life under different techniques were not examined. Costs are presented in 1997 Canadian dollars and have been estimated from the perspective of the health care system.

For the purpose of the cost comparison, the benefit of the doubt was given to pre-storage filtration. A higher efficacy for pre-storage was used than for post-storage filtration in reducing adverse events although this has not been proven in randomized controlled trials. It was assumed that leukofiltration can prevent alloimmunization and thus platelet refractoriness in a certain percentage of patients at risk. Febrile reactions were assumed to occur more frequently in multi- transfused patients than single-episode transfused patients.

iii This analysis revealed that the implementation of a 100% filtration strategy in a blood centre would cost $46.37 million and takes into account the savings resulting from a decrease in adverse events. Filtration at a hospital blood bank would cost $25.95 million, and at a hospital bedside, this cost would total $20.19 million. The much higher cost of pre-storage leukofiltration is mainly due to two factors that are specific to pre-storage filtration. Firstly, with pooled platelets, five filters have to be used instead of a single one for the production of one platelet concentrate. Also, since more blood components are produced than actually transfused to patients, 30% more pooled platelet concentrates have to be filtered in a blood centre level compared to hospital filtration.

An examination of the cost of each filtration technique reveals that the impact of red blood cell filtration drives the overall cost of strategies. When looking at apheresis platelets in isolation, leukofiltration is cost saving regardless of the timing of leukofiltration. For pooled platelets, the case is different. Post-storage blood bank or bedside techniques are cost saving compared to pre-storage filtration. The fact that savings can be achieved with platelet transfusions is not surprising since around 70% of all platelet components are directed at multi-transfused patients. This is the patient group who benefit most from leukofiltration. On the other hand, 90% of all red blood cells are directed at single-transfused patients such as surgical or obstetric patients. This patient group does not benefit as much from leukofiltration, and as a result the savings achieved by filtration do not outweigh its costs. Since the impact of an immunomodulatory effect of transfused leukocytes is now not known the results could change if this effect is better understood.

An extensive sensitivity analysis was performed and it showed that these results were robust.

It can be concluded that a 100% filtration strategy is not cost-saving, whatever the timing of leukofiltration. However, for certain patient groups, notably those who require either frequent red blood cell or platelet transfusions, leukofiltration can be cost saving.

iv TABLE OF CONTENTS

Reviewers ...... i

Acknowledgements ...... i

Executive summary ...... ii

List of tables ...... vii

List of figures ...... viii

1. Introduction ...... 1 1.1 Brief history of leukodepletion, the purpose of leukodepletion and the methods used ...... 1 1.2 Literature search ...... 1

2. The current situation ...... 3 2.1 Blood distribution ...... 3 2.2 Present users ...... 3 2.3 Current filtration activities in Canada ...... 4 2.4 International filter use ...... 4

3. Clinical issues associated with filtration and level of evidence for the efficacy of leukodepletion ...... 6 3.1 Non-hemolytic febrile transfusion reactions ...... 6 3.2 Leukocyte-transmitted infections ...... 9 3.3 Platelet-refractoriness ...... 11 3.4 Immunomodulation ...... 14

4. Filtration techniques ...... 16 4.1 Description of filtration techniques, stages of processing ...... 16 4.2 Filtration standards ...... 22

5. Cost-comparison analysis ...... 25 5.1 Methods ...... 25 5.2 Probabilities, unit costs and epidemiological assumptions ...... 28 5.2.1 Probabilities of adverse events ...... 28 5.2.2 Unit costs ...... 31 5.2.3 Epidemiological and transfusion assumptions ...... 34 5.3 Results ...... 37 5.3.1 Base case results ...... 37 5.3.2 Sensitivity analysis ...... 42 5.3.3 Threshold analysis ...... 43 5.4 Quality of life issues ...... 43 5.5 Financing considerations ...... 44

v 6. Discussion ...... 45

7. Conclusion ...... 50

References ...... 51

Additional references ...... 61

Appendices Appendix I Level of evidence scale ...... 65 Appendix II Glossary ...... 66 Appendix III Costing study on NHFTR ...... 67 Appendix IV Sensitivity analysis ...... 69 Appendix V Framework for categorizing economic study results Adopted from O’Brien et al ...... 79

vi LIST OF TABLES

Table 1 Expected blood components use for 1997/1998 ...... 3 Table 2 Distribution of platelet concentrates among patient groups ...... 4 Table 3 Incidence of non-hemolytic febrile transfusion reactions (per transfusions, excluding allergic and other reactions) ...... 9 Table 4 Platelet refractoriness in multi-transfused patients ...... 14 Table 5 Leukocyte content of blood and blood components per transfused unit .....16 Table 6 Considerations in the selection of timing of leukodepletion (adapted from Dzik) ...... 22 Table 7 FDA recommendations and licensure requirements ...... 23 Table 8 Council of Europe recommendation No. R(95)15 on the preparation, use and quality assurance of blood components ...... 24 Table 9 Probabilities associated with developing NHFTR ...... 29 Table 10 Probability of developing surgical site infection after surgery ...... 30 Table 11 Probabilities associated with the development of platelet refractoriness .....30 Table 12 Platelet filter unit prices ...... 31 Table 13 Red blood cell filter unit prices ...... 31 Table 14 Unit cost of related activities ...... 32 Table 15 Cost of treating NHFTR ...... 33 Table 16 Cost of treating refractoriness associated with allo-immunization ...... 33 Table 17 Cost of treating surgical site infection ...... 34 Table 18 Total number of blood units filtered and transfused per year ...... 35 Table 19 Distribution of red blood cells among patient categories ...... 35 Table 20 Distribution of blood components among patient categories ...... 35 Table 21 Distribution of red blood cells among patient categories ...... 35 Table 22 Number of transfusions per patient category ...... 36 Table 23 Range for sensitivity analysis ...... 36 Table 24 Filter and related costs of each strategy, in $000 ...... 37 Table 25 Filter and related costs of each technique, in $000 ...... 38 Table 26 Total cost of each strategy, in $000 ...... 38 Table 27 Total cost of each technique, in $000 ...... 39 Table 28 Number of adverse events avoided with each technique in Canada ...... 39 Table 29 Cost per transfusion in dollars ...... 40 Table 30 Budgetary impact of strategies with immunomodulation factor, in $000 .....41 Table 31 Sensitivity analysis results ...... 42 Table 32 Threshold analysis for filter prices ...... 43 Table 33 Level of evidence scale ...... 65 Table 34 Transfusions for leukemia and non-leukemia patients, 1996-1997, Ottawa General Hospital ...... 67 Table 35 Costs of febrile reactions ...... 68 Table 36 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration equals 0% (all febrile reactions are avoided by pre-storage filtration) ...... 69 Table 37 Costs per strategy in $000 ...... 69

vii Table 38 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration is equal to that of blood bank filtration (no advantage of pre- over post-storage filtration) ...... 70 Table 39 Costs per strategy in $000 ...... 70 Table 40 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 20 (this translates into that 3810 patients are at risk for suffering platelet refractoriness per year) ...... 71 Table 41 Costs per strategy in $000 ...... 71 Table 42 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 50 (this translates into that 1524 patients are at risk for suffering platelet refractoriness per year) ...... 72 Table 43 Costs per strategy in $000 ...... 72 Table 44 Sensitivity analysis: Costs per technique in $000 where the cost of treating one episode of NHFTR is $500 ...... 73 Table 45 Costs per strategy in $000 ...... 73 Table 46 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $5,000 ...... 74 Table 47 Costs per strategy in $000 ...... 74 Table 48 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $15,000 ...... 75 Table 49 Costs per strategy in $000 ...... 75 Table 50 Sensitivity analysis: Costs per technique in $000 where the number of filters used for pre-storage filtration is equal to the actual number of transfused blood components ...... 76 Table 51 Costs per strategy in $000 ...... 76 Table 52 Sensitivity analysis: Costs per technique in $000 where one single filter is used for pre-storage pooled platelet production instead of five ...... 77 Table 53 Costs per strategy in $000 ...... 77 Table 54 Sensitivity analysis: Costs per technique in $000 where the utilization rate of pre-storage filtered platelet units is 70% ...... 78 Table 55 Costs per strategy in $000 ...... 78

LIST OF FIGURES

Figure 1 Stages (used in the cost-comparison analysis), where leukofiltration of blood components is possible ...... 17 Figure 2 Strategies used for cost comparison analysis ...... 25

viii 1. INTRODUCTION

1.1 Brief history of leukodepletion, the purpose of leukodepletion and the methods used

The introduction of transfusions as a medical technology has been associated with both beneficial effects and adverse reactions. Some of these adverse reactions are caused by donor leukocytes, which are residual blood cells in platelet or red blood cell transfusions. Leukocytes with their specific allogeneic structure (exposing the HLA Antigens class I and II on their surface) are main targets of the recipient’s immune system. During or shortly after transfusion, some patients become febrile in response to leukocytes in the blood component. Repeated exposure to donor leukocytes can create an immune response which inactivates donor platelets. The state of refractoriness diminishes the effect of platelet transfusions - in spite of transfusing platelets, no therapeutic platelet increment is achieved. In addition, some viruses or bacteria are transmitted inside leukocytes. The cytomegalovirus (CMV), for example, survives in the leukocyte and is transmitted via blood transfusions. Another not so well established effect of transfused leukocytes is a modulating influence on the recipient’s immune system. Leukocytes are believed to diminish the ability of the recipient’s immune system to fight infection or cancer recurrence.

In an attempt to prevent these problems, methods have been developed to remove transfused leukocytes (‘unwanted passengers’). Filters were designed which are able to filter out 99.9% of all leukocytes, and as a result, leukocyte mediated adverse reactions can be prevented or delayed.

However, this technology is not without cost and it is competing with other technologies which reduce the use of allogeneic blood components (for example erythropoetin or autologous blood donations)1. The cost and clinical benefit of leukocyte filtration must be weighed against the costs saved by the avoidance of adverse events. Ideally, the costs saved by using the technology will be more than the cost of the technology itself. The aim of this report is to help identify the costs involved with and without filtration, to explore whether it is costly or cost saving to the Canadian health care system to introduce leukodepletion of blood components, and to compare these costs with the benefits involved.

1.2 Literature search

The literature search was divided into three main topics:

leucocyte depletion of blood transfusion and associated adverse events leucocyte depletion of platelet transfusion and associated adverse events costs associated with leukocyte depletion

Canadian Coordinating Office for Health Technology Assessment 1 Leukoreduction: the techniques, their effectiveness and costs

Each search was run on the following databases:

MEDLINE HealthSTAR Cancerlit Toxline Dissertation Abstracts Pascal Embase SciSearch BIOSIS PREVIEWS

The basic search terms used were:

leu?ocyte? (? = various spellings and truncation) or blood in proximity with filt? or reduc? or deplet?; or leukotrap or buffy coat deplet? or leu?ofilt? blood transfusion? or blood component transfusion or blood component removal or erythrocyte transfusion? or blood storage or apheresis platelet transfusion or blood platelets or plateletpheresis

These terms were combined with the following keywords for adverse events and costs:

immunomodulat? or CMV or cytomegalovirus or contaminat? or infection? or alloimmun? or bacterial infection? or immunization or immunisation or immunity or adverse event? or FNH or non hemolytic febrile reaction? or safety or reaction or cytokine? cost? or economic?

All searches were limited to references of studies with human subjects published from 1990-1997 (searches were run April 30, 1997).

Additional searches for new publications were run on Current Contents: Clinical Medicine, at monthly intervals during the project. Searches were also run on the Cochrane Library. Other references were obtained through contact with representatives of the Canadian Blood Agency and the Canadian Red Cross, through hand scanning of new journals received at the CCOHTA library, through searches of publications from agencies such as the American Association of Blood Banks, and from the reference lists of publications obtained in the course of this research.

2 Canadian Coordinating Office for Health Technology Assessment 2. THE CURRENT SITUATION

2.1 Blood distribution

There is little epidemiological data about the use of blood components in Canada. Using statistics provided by the Canadian Blood Agency (CBA), we are using the expected production and utilization data2 of platelets and red blood cells for 1997/1998 shown in Table 1.

Table 1 Expected blood components use for 1997/19982,3

Product Expected Blood components prepared by the Red Cross utilization

Apheresis platelets 14330 16127 Red Cross utilization rate of 88% (1993/1994)

Pooled platelets 83066 121068 Red Cross utilization rate of 68% (1993/1994)

Red blood cells 829298 945399 Red Cross utilization rate of 87% (1993/1994)

The utilization rate refers to the Blood Services Statistical Report2 for the years 1993/1994. Platelet units are prepared from individual units of whole blood by centrifugation. Five platelet units are then pooled into one platelet concentrate. In this report we will refer to this as ‘pooled platelets’. Apheresis platelets are prepared by cytapheresis; we use the term ‘apheresis platelets’ for this blood component.

2.2 Present users

We estimated the distribution of red blood cell (RBC) concentrates to different patient groups from data from a cross-sectional survey done by Chiavetta in 1991/1992 surveying 45 Ontario teaching and non-teaching hospitals4. In this study, information was collected from 439,373 patients discharged between September 1991 and August 1992, of whom 26,611 (6.1%) received at least one unit of red cells. Out of 101,116 red cell units, approximately 70% were given to surgical patients. In this study 50% of all RBC units were for ‘clean’ and 20% for ‘clean- contaminated’ operations. Transfused patients undergoing ‘clean’ surgery (ie. heart surgery, hip replacement, etc.) received an average of 2.9 RBC units. Patients undergoing ‘clean- contaminated’ surgery (ie. colon surgery, etc.) received an average of 4.7 RBC-units. Only 4.9 % of all RBC units were used for patients with diseases of blood and blood-forming organs.

The study has several limitations. It was undertaken in 45 hospitals in central Ontario. Thus, it may not be representative of the Canada-wide use of blood-components. Since the data were collected in 1991/1992, changing medical procedures and practices, such as the increased

Canadian Coordinating Office for Health Technology Assessment 3 Leukoreduction: the techniques, their effectiveness and costs

use of blood components for high dose chemotherapy, could alter the blood distribution among recipients. In addition, it is likely that practice has changed in surgery and emergency medicine, so that clinicians are now less likely to transfuse for a given indication than they were in the past5,6,7,8.

With respect to platelets, no similar study with distributional data was found. Following conversations in Winnipeg (Dr. Blajchman and Dr. Growe at the Canadian Blood Agency meeting, May 12, 1997), we assume the percentages given in Table 2.

Table 2 Distribution of platelet concentrates among patient groups

Patient group Pooled platelets Apheresis platelets

Leukemia patients 72% 100%

Other patients (surgery/emergency etc.) 28% 0%

2.3 Current filtration activities in Canada

In 1996, Medsep, a subsidiary of the Pall Corporation, one of the biggest manufacturers of leukocyte filters, surveyed the use of filters for platelet transfusions4. Filters were used mostly to avoid febrile reactions, to prevent or delay alloimmunization (refractoriness), or in the case of transplantation, to provide cytomegalovirus (CMV)-safe platelets. The strategy of filtering is an ‘on- demand’ one. Five out of 63 hospitals surveyed were using a 100% filtration strategy for oncology and long-term transfusion patients. The survey reported a 43% filtration rate of pooled platelets (post-storage) and a lower rate of filtration for apheresis platelets.

In a current chart review done in the Ottawa General Hospital (Appendix III), a 439-bed university-affiliated tertiary care centre, 73% of all RBC units for leukemia patients were filtered versus 6.4% of RBC units for all other patients (surgery, emergency, etc.).

2.4 International filter use

United States

The American Red Cross is currently offering both pre-storage filtered RBC and platelets10. We did not find actual information about the rate of either pre-storage or post-storage filtered blood components in the United States. However, the FDA released regulatory advice for the manufacturing of leukoreduced blood components11.

4 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Great Britain

We found two documents regarding the filtration situation in Great Britain. During the annual scientific meeting of the British Society for Haematology in association with the British Blood Transfusion Society in Bournemouth on April 21, 1993, specific indications were stated for which leukofiltrated blood components should be used. A 100% filtration strategy was not promoted12.

In a technology assessment about pre-storage filtration of blood components prepared in 1996 by the NHS Executive South and West Research and Development Directorate, the authors outline the current service of the National Blood Service in Bristol13. Most hospitals in this region already filter blood components at the bedside and for red blood cells ‘the blood service currently leukofilters pre-storage a small number of units for a few hospitals’. For platelets 80-90% are actually leukoreduced without need for leukofiltration and 20-30% of the pooled platelets are leukoreduced using the buffy coat technology. The authors do not state which level of leukoreduction is maintained. However, they regard a level of 1-5 x 108 leukocytes per unit as ‘leukopoor’.

Denmark

The Society of Clinical Immunology released in 1994 (published in 1996) indications for leukofiltered blood components that were established during a consensus conference14. They did not recommend a 100% filtration strategy.

Canadian Coordinating Office for Health Technology Assessment 5 3. CLINICAL ISSUES ASSOCIATED WITH FILTRATION AND LEVEL OF EVIDENCE FOR THE EFFICACY OF LEUKODEPLETION

We have reviewed the literature about the efficacy of leukofiltration to prevent febrile reactions, leukocyte transmitted infections, platelet-refractoriness and immunomodulation. We have not addressed TRALI (Transfusion related lung injury) since it is due to preformed anti- granulocyte antibodies in the donor plasma and thus is not preventable by leukofiltration15. Also we do not refer to graft versus host disease since the standard preventive procedure remains irradiation of the blood component12. Reperfusion injury in heart transplant surgery is related to donor leukocytes, but postoperative hemodynamics studies could not demonstrate a better clinical outcome in the leukoreduced-group16.

There are relatively small patient groups like thalassemia patients who seem to benefit more from leukofiltration than the majority of blood component recipients17. In addition, patients after organ transplant or patients on a waiting list for organ transplant also benefit from leukofiltration. For these patients it is important to preserve the individual HLA-antibody status. Newly produced HLA-antibodies (for example, caused by receiving an allogeneic blood component) could induce a rejection of the donor-organ. Leukofiltration of blood components is more likely to prevent alloimmunization and thus the production of HLA-antibodies if such a patient should receive a blood transfusion. Although data about possible savings due to leukofiltration for this small group of patients groups is scarce, we would like to mention the importance of leukofiltration for these patients.

We assessed the methodological quality of the retrieved studies using the level of evidence scale of Jovell18. In the Jovell scale, randomized controlled trials (RCT) and meta- analyses of RCTs receive a score from I-III, while non-controlled clinical series receive a score of VIII.

3.1 Non-hemolytic febrile transfusion reactions (NHFTR)

Non-hemolytic febrile reactions are the most common adverse effects of blood transfusions. These, along with allergic reactions, are clinical manifestations of alloimmunization19. Symptoms following transfusions can be chills, a cold feeling, or discomfort. Discomfort often includes pain at the transfusion site, headache, nausea, and tightness of the chest19. Allergic reactions, which occur at a higher rate after platelet transfusions than after RBC transfusions, are thought to be caused by soluble plasma proteins independent of leukocytes. Consequently, a reduction of allergic reactions could not be demonstrated in studies of leukofiltration20, 21.

In this summary, we will focus mainly on clinical data and not on experimental studies. Alloimmunization can occur after transfusion of leukocytes with their specific antigenic structure, during pregnancy, or after organ transplantation. More women than men are primarily sensitized

6 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

due to the transplacental transmission of fetal leukocytes during pregnancy and they react more frequently with febrile events20,22. In particular, leukocytes induce the development of HLA- antibodies by the recipient which leads to alloimmunization.

The minimum number and type of white blood cells needed to generate a post-transfusion febrile reaction in an alloimmunized recipient of blood components remains unclear. It is also not known which role fragmented leukocytes play (i.e. whether they have an allogeneic structure which can induce alloimmunization or not)23,15. Studies show that leukocytes are only one of the possible causes for febrile reactions24.

NHFTRs occurred in 32% of patients with antibodies and 37% of the patients without measurable antibodies in a study of 123 hematologic patients25. The prevention of febrile reactions associated with platelet transfusions is more problematic than with RBC transfusions. The plasma remaining in the platelet transfusion after production from platelet rich plasma seem to cause more reactions than the leukocytes themselves26. Another study in recipients who were already alloimmunized showed that 14% of patients who received bedside filtered pooled platelets still had febrile reactions, versus 20.3% who received unfiltered pooled platelets27. There are fewer febrile reactions with leukofiltrated blood components, but a total prevention does not seem to be possible20,24,28.

As mentioned above, post-transfusion fever can be caused by a variety of underlying conditions, for example: the disease itself, infection, a hemolytic transfusion reaction or bacterial contamination of the applied blood component. Therefore, it is important to differentiate between fever caused by transfusions with that caused by other factors. Several diagnostic steps (depending on the severity, for example: blood sample, blood culture, chest x-ray, etc.) must be undertaken before a conclusion can be made that the fever is due to remaining leukocytes in the blood component. The estimated costs for the work up of a febrile reaction range from $300- $1000 in leukemia patients29,30. We found no study related to costs for surgical patients. In a chart review undertaken in July 1997, we calculated the average cost of a febrile reaction to be $81 (Appendix III).

While some studies found no valuable advantages in the leukofiltration of blood components27,28, others point out that the timing of filtration is important for reducing rates of NHFTRs. The age of the blood component is an accepted risk factor. The older the component is, the more adverse reactions are observed. This is in particular the case for platelet concentrates which are stored at higher temperatures than RBC-units. Several studies found this to be a more obvious cause for a transfusion reaction than the number of remaining leukocytes19,24,31. Since older blood components have higher rates of cytokines, the accumulation of soluble cytokines set free from leukocytes during storage may be the explanation for this result24,26,30,32. Therefore, it seems reasonable that pre-storage filtration of blood components prevents cytokine accumulation during storage. Some clinical trials (not prospective, randomized controlled trials), were able to demonstrate positive effects of pre-storage filtration for RBC24 even in previously sensitized patients30.

Canadian Coordinating Office for Health Technology Assessment 7 Leukoreduction: the techniques, their effectiveness and costs

Despite the fact that transfusion reactions are more common in platelet than RBC transfusions19 due to a higher storage temperature and higher cytokine levels33, no conclusive studies in humans have shown the clear benefit of pre- over post-storage leukofiltration. In an experimental study, Hashemi et al demonstrated that with pre-storage leukoreduction of platelet concentrates, some cytokines (PAI-I, PAF, tPA) still accumulated similar to in unfiltered platelets34. In contrast, Muir et al showed, in an abstract of a retrospective study, a 5.8-fold greater chance of a febrile reaction with post-storage filtered platelets than with pre-storage filtered ones in sensitized patients30. The theory of preventing cytokine mediated NHFTR reactions with pre- storage filtration of leukocytes is convincing. However, unfortunately, no randomized controlled trials exist to prove these advantages in a patient population.

We found six studies in humans published after 1990 addressing the incidence of febrile reactions in the context of leukocyte filtration, with the results reported separately for platelets and RBC (Table 3). All studies achieved a level of leukoreduction of < 5 x 106 leukocytes in the applied blood component. In all studies, the real effect of leukoreduction is masked by the prophylactic use of antipyretics. Additionally, the definition of a febrile reaction is not always the same, resulting in different levels of occurrence. At minimum all studies showed a reduction of febrile events while using leukocyte filtration.

Conclusion

Leukofiltration prevents most febrile reactions to RBC-transfusions. This result can be achieved with post-storage filtered transfusions. The advantage of pre-storage filtration has not been proven in a randomized controlled trial. Platelet transfusions are associated with a higher rate of adverse events, and filtration is not as effective as in RBC.

8 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Table 3 Incidence of non-hemolytic febrile transfusion reactions (per transfusions, excluding allergic and other reactions)

Pre-storage filtration Post-storage filtration No filtration Level of Study evidence Platelets RBC Platelets RBC Platelets RBC

24 1.73% 1.1% 2.15% V 59/3405 60/5412 139/6447

20+ 1.58% 2.15% VIII 82/5197 152/7080

19++ 28% 37.5 6.8% VIII 7/25 12/32 8/117

30+++ 0.9% 5% 0.8% VIII 2/223 14/280 4/467

19.4% 27.2% PP 40/206 55/202 [630] 7.8% 14% VIII AP 14/179 26/207

[582]++++ 0.2% VIII 7/4238

+= apheresis platelets, FNHTR only; ++= pooled platelets, all reactions; +++= sensitized hematologic patients, apheresis platelets; ++++= pooled platelets; PP= pooled platelets; AP= apheresis platelets

3.2 Leukocyte-transmitted infections

Viruses

The transmission of leukocyte-born viruses such as CMV, HTLV I or Epstein-Barr Virus (EBV) can be reduced by filtration36,37. CMV pneumonia is a widely feared complication in immunosuppressed patients undergoing transplantation38,39 or during high-dose chemotherapy. To avoid this complication, CMV-negative patients suitable for bone marrow transplant should receive only CMV-safe blood components12,37. With a prevalence of 50-80% in the North American population16,37, it is not always possible to obtain an appropriate CMV-seronegative donor. At the same time, the demand for CMV-seronegative blood components is rising because of the increase of transplants and physicians’ attempts to maintain the seronegative status of potential transplant candidates36.

Canadian Coordinating Office for Health Technology Assessment 9 Leukoreduction: the techniques, their effectiveness and costs

Two prospective, randomized controlled trials showed that reduction of the leukocyte fraction of blood components (RBC and platelets), similar to the use of CMV-negative (laboratory antibody-screened) blood components, almost prevented CMV-infection in bone marrow transplant patients. One trial used platelets leukoreduced by centrifugation39, the other by bedside 3log- leukofiltration36. In the latter trial, six of 250 patients who received leukofiltered blood developed CMV-disease and five of these six died of CMV pneumonia. In the group of 252 patients receiving CMV-seronegative blood, four developed CMV infection and none died of CMV pneumonia. The authors remarked in a response to a letter40 that in the later follow-up, two more recipients of CMV seronegative blood became infected and both developed disease indicating that CMV- seronegative blood also is not 100% safe. Although in a recent association bulletin37 the American Association of Blood Banks felt that leukofiltration to a level < 5 x 106 was as safe as CMV- seronegative components, others do not believe that leukofiltration should be a substitute for the already established practice of CMV-screening of blood components for patients who need CMV- safe blood components40,41.

For other viruses such as EBV and HTLV I and II, no conclusive studies exist that demonstrate a similar efficacy of virus removal due to leukofiltration as for CMV. Some experimental studies indicate a significant reduction of HTLV I in a blood component but the prevention of HTLV I infections with leukofiltration in humans has not been proven42. Thus, leukofiltration cannot currently be used as a substitute for HTLV I testing for this rare disease (the rate of infection in the United States blood donor population has been estimated to be between 0.009% and 0.0043%43.) However, leukofiltration could add more safety to transfusions of blood components since not all HTLV-I infected donors necessarily express HTLV I antibodies44.

Bacterial/protozoal infection

Bacterial contamination of blood components can be a severe complication of blood transfusions. The risk of contaminated pooled platelet-transfusion is estimated to be up to 2% (asymptomatic cases) since platelet concentrates are stored at room temperature to preserve their viability and function6,45.

Asymptomatic infection of a donor, and the ability of Yersinia enterocolitica to grow at low temperatures in an iron-rich environment such as in blood components, makes Y. enterocolitica the most commonly encountered serious bacterial contaminant in red cell concentrates22,46. Transfusion-associated Y. enterocolitica fatal sepsis cases related to red blood cell47 and platelet transfusions48 have been reported in the U.S. Several studies demonstrated that the bacterial overgrowth of blood components by Y. enterocolitica inoculated in blood components in experimental conditions is diminished or prevented by pre-storage leukofiltration after a room- temperature holding period46,47,49. However, these studies have been criticized because these experimental results might not be achieved with blood components of an infected donor50. Taking this into consideration, and due to the unknown actual number of cases of Y. enterocolitica sepsis cases related to transfusion, it is speculative to estimate how many cases of Y. enterocolitica sepsis could be prevented by pre-storage filtration43.

10 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

The transmission of Trypanosomaniasis, which is caused by Trypanosoma cruzi, is more common in South America but a rare disease in North America. Transmission was decreased by leukofiltration in an experimental study51, but no observational studies in humans exist.

Conclusion

The risk of CMV transmission via transfusion of RBC and platelets is markedly decreased by leukofiltration. However, whether leukofiltration is an alternative to CMV-seronegative blood components remains controversial. For other viral or for bacterial/protozoal infections we found no evidence that leukofiltration is an alternative to existing screening programs. The impact of leukofiltration on the prevention of transfusion-transmitted infections beside CMV remains unknown.

3.3 Platelet-refractoriness

During chemotherapy for leukemic or other patients who receive high dose chemotherapy, thrombocytopenic bleeding can be a severe clinical complication. Because of the thrombocytopenic side effect of drugs used in chemotherapy, in particular when applied in high doses, platelet counts can fall below the level necessary to prevent spontaneous bleeding. A common treatment to prevent thrombocytopenic bleeding, once the platelet count is below a certain value, is prophylactic transfusion of either pooled platelets or apheresis platelets. However, the efficacy of this approach has never been demonstrated in a randomized trial.

The ability of these transfusions to increase the platelet count can be inhibited if the recipient has an immune response due to prior HLA-alloimmunization to donor blood components, mainly leukocytes. In such cases patients’ antibodies inactivate the donor platelets. In other words, the patient platelet count continues to be very low despite platelet transfusions, a potentially life- threatening situation.

Morbidity and mortality caused by bleeding is relatively rare, occurring in 2.3% of patients receiving induction chemotherapy for acute leukemia52. Therefore, published studies use ‘platelet refractoriness’ instead of bleeding as an outcome. However, the term ‘refractoriness’ is not clearly defined. An “inadequate platelet increment on two consecutive platelet transfusions in the absence of clinical factors known to the affect platelet response”52 is the usual definition of platelet refractoriness. Numerous clinical factors influence platelet response, and only in rare cases are they absent. They include: hereditary or disease-associated variations in immune responsiveness; the extent of therapy-induced immuno-suppression (due to chemotherapeuticals, cortisone, etc.)15; non-immunologic factors such as fever; specific drug treatment (for example, antibiotics like

Canadian Coordinating Office for Health Technology Assessment 11 Leukoreduction: the techniques, their effectiveness and costs

Amphotericin B); splenomegaly, and bleeding53. Doughty et al found in a small prospective study of 26 hematology patients who received 116 unsuccessful platelet transfusions (inadequate platelet increment after transfusions) that immune factors were present in only 25% of those transfusions. The most common non-immune factors were fever, infection, antibiotic treatment or a combination of these54. In addition, patients suffering refractoriness can change their refractory state during different treatments52. The authors conclude that leukofiltration “may have thus a limited impact in reducing the incidence of refractoriness to platelet transfusions”29.

Since donor leukocytes are not responsible for all cases of platelet refractoriness, leukocyte reduction can prevent some cases of refractoriness: those which have leukocyte-related immunologic causes54. It has been hypothesized that pre-storage filtration may also prevent cases of refractoriness which are due to soluble antigens and white cell fragments set free from leukocytes during storage55.

The therapeutic strategies to overcome platelet refractoriness are costly and often not effective16. Thus it is better to prevent alloimmunization rather to treat it56.

The extent to which refractoriness is avoided by leukofiltration differs among the clinical studies. Heddle et al performed a meta-analysis of five randomized controlled trials on this topic. The five studies were undertaken with patients with hematological malignancies in the years 1983- 1991. Compared with patients receiving unfiltered blood components, the common odds ratio was 0.27 (95% CI, 0.13-0.55) for alloimmunizationa, and for refractoriness 0.28 (95% CI, 0.13-0.54)52. The authors conclude that “(1) leukodepletion of red blood cell and platelet concentrates to levels below 5x106 leukocytes per product will delay and in some patients possibly prevent alloimmunization; and (2) prevention of alloimmunization seems to improve the post-transfusion platelet increment in selected transfusions when concomitant clinical factors known to affect platelet response are absent”52. They also conclude that 63 patients would have to be administered leukodepleted blood products to prevent one clinically significant bleeding event.

The largest randomized controlled trial regarding alloimmunization in leukemia patients is the TRAP study (Level II study). The study is currently not published and we rely on information kindly given by Dr. Slichter during the CBA ad hoc meeting in Winnipeg57. The primary endpoint of the study was platelet refractoriness in AML patients and its prevention by leukofiltration and ultraviolet technology. Only non-alloimmunized patients (ie. those who tested negative in a lymphocytotoxicity assay) were considered eligible for inclusion in the study. All patients were randomly assigned either to a control arm in which patients received regular pooled platelets or to one of the three treatment arms in which patients received ultraviolet B radiated pooled platelets (not discussed in this report), WBC-reduced pooled platelets, or WBC-reduced apheresis platelets58. The overall conclusions were that leukofiltration can prevent or delay alloimmunization in some patients, since not all patients benefited from leukofiltration. In particular, those with prior

aThe outcome measure of alloimmunization is the development of HLA-Antibodies. These are measured in the laboratory with a lymphocytotoxicity assay52.

12 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

pregnancies or prior transfusions were at a higher risk for platelet-refractoriness. Some patients, about 40% of the study group, were non-reactive and remain non-immunized regardless of the amount and the type (filtered or unfiltered) of the received blood component. In contrast, 20% of all recipients became alloimmunized regardless of the use of leukofiltrated blood products. Similar to the meta-analysis of Heddle, the key threshold to prevent alloimmunization was 5x106 leukocytes per unit. Interestingly there was no difference in development of platelet-refractoriness due to HLA alloimmunization between those patients receiving post-storage filtered low-leukocytes apheresis platelets or post-storage filtered pooled platelets59.

Table 4 shows the rate of platelet refractoriness after the transfusion of blood components. We compared studies regarding this topic published after 1990, achieving a level of 5x106 leukocytes in the administered blood component by leukocyte filtration. Two of the studies21,60 were part of the meta-analysis done by Heddle. The studies vary considerably in study design (prospective and retrospective; randomized and non-randomized etc.), their definition of refractoriness, and the study population. Furthermore, some leukocyte-reduced blood components were produced using the buffy coat technologyb, and others were not. In all studies clinically important outcomes were not measured (eg. serious bleeding).

The results show a reduction, but with the exception of two studies, not a total prevention of platelet refractoriness. Patients who were previously exposed (prior unfiltered transfusion, prior pregnancy), benefited less from receiving leukocyte-reduced components (filtered either pre- or post-storage) than unexposed patients. The extent to which the reduction in platelet refractoriness translates into reduced morbidity or mortality from bleeding is not established52,59.

Conclusion

Leukofiltration of platelet and red blood cell components reduces the incidence of alloimmunization and thus platelet refractoriness, particularly in unsensitized patients. Despite several experimental and retrospective studies, no RCT exists to demonstrate the advantage of pre - over post-storage filtration.

bBuffy coat technology: red cells and plasma are expressed from the primary collection pack leaving a platelet-rich, greyish-white ‘buffy coat layer’ in the primary pack (Optipress-instrument). Approximately one log of leukocyte reduction in the red blood cells can be produced with the buffy coat technology with the residual buffy-coat subsequently processed to produce a platelet unit.64

Canadian Coordinating Office for Health Technology Assessment 13 Leukoreduction: the techniques, their effectiveness and costs

Table 4 Platelet refractoriness in multi-transfused patients

Pre- Post-storage No filtration p-value comments Level of Study storage filtration evidence filtration

25 26% (6/23) 30% (8/27) n/a pregnancy included, II bedside, AP/PP

35 40.7% n/a PP VIII (79/194)

60 11% (3/27) 46%(12/26) p < 5x108 leukocytes, II <.005 centrifugation. pre- storage RBC, post- storage PP

61 29% (8/28) 41% (14/34) p<.52 AP, using RBC- II Filter

21 0%(16) 6.6% (1/15) n/a Prior pregnant w. III included.

53 3% (2/67) 21% (14/68) VII

62 0% (50) 10% (1/10) n/a children V

63 2.2% (2/90) n/a PP, only non VIII sensitized patients

PP: pooled platelets, AP: apheresis platelets

3.4 Immunomodulation

Several studies in various fields of medicine have demonstrated an immunosuppressive effect of allogeneic blood transfusions. In the pre-cyclosporine era of transplantation it was observed that kidney transplant patients with allogeneic blood transfusion before or during operation had a lower risk of allograft rejection than non-transfused patients65. However, the impact of the immunosupressive effect remains unclear66. Allogeneic white blood cell (WBC) immunotherapy for recurrent spontaneous abortion has shown a small treatment effect due to its immuno-modulating effect69. Some studies indicate that surgical patients receiving allogeneic blood components tend to have more infections than those without transfusions68,69,70,71. However, it remains unclear whether blood transfusions are a sign of more complicated cases, or whether this effect is due to immunomodulation. Some studies indicate that transfusions of leukocyte- containing blood components accelerate HIV-I dissemination and disease progression59,66,72. As yet, there are no specific, reproducible mechanisms that show the immuno-modulating effect on

14 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs the cellular level, to prove the theory of immunomodulation73.

Despite clear results of experiments with animals showing a higher rate of tumor growth and recurrence with allogeneic transfusions and lower rates with leukodepleted ones74, the randomized controlled trials (RCTs) in humans are still inconclusive75. This may be due to the lack of homogeneity among the studies. Among other factors, the differences in blood component preparation (buffy coat method versus platelet rich plasma), multi-centre versus single centre trials and heterogeneity in the postoperative infection analysis66,75,76 are examples of the differences in study designs. Randomized controlled trials, carefully controlled for confounders in the comparison of leukodepleted or even autologous blood versus unfiltered allogeneic blood components showed different, or opposing results which do not allow us to make a definite conclusion on the immune suppressing effect of blood transfusions68,69,70,75,77,78,79,80. While one multi-centre trial68 could not demonstrate an effect of leukofiltration on the prevention of wound-infections, a single-centre trial showed a total prevention of all wound-infections in the leukofiltration group70.

In a recent meta-analysis, McAlister et al rigorously chose only RCTs and controlled cohort studies in colon cancer patients which compared autologous and leukofiltrated blood versus allogeneic blood components. The authors could not find a statistically significant difference in the overall mortality, cancer recurrence and postoperative infection. While this meta-analysis was underpowered for detecting small differences (in the order of 10%-20%), the authors concluded that the magnitude of any relative effect on mortality, cancer recurrence or postoperative infection from allogeneic transfusion must be less than 25%.

In a large randomized controlled trial with 944 patients in cardiac surgery, van der Watering et al found a statistically significant reduction in postoperative non-cardiac death for patients receiving filtered red blood cell transfusions. Interestingly, the timing of filtration (post- versus pre- storage) did not influence the protective effect of filtered blood components in this study81. The study is currently only available in abstract form.

Conclusion

There is still no convincing proof for an immunomodulatory effect of blood transfusions in humans. A recent meta-analysis of unconfounded randomized controlled trials concluded that any possible effect would be smaller than 25% (relative risk reduction). At present, there is no evidence from clinical trials that the timing of filtration (pre- vs. post-storage) influences the outcome in respect to immunomodulation.

Canadian Coordinating Office for Health Technology Assessment 15 4. FILTRATION TECHNIQUES

4.1 Description of filtration techniques, stages of processing

Several strategies have been used to reduce the amount of leukocytes in cellular blood components. Saline washing of blood, frozen-deglycerolized blood, the use of double-spun, buffy- coat poor units, and the centrifugation of red blood cells followed by microaggregate filtration have been used. For the purpose of leukoreduction, these methods are not used due to lack of efficacy or excessive cost15. In our report we refer only to the available third-generation filters (adhesion filter), which achieve a 3log reduction of leukocytes, i.e. 99.9%. The leukocyte content differs between the various blood components82 (Table 5).

Table 5 Leukocyte content of blood and blood components per transfused unit

Component Number of leukocytes per unit

Whole blood 109

Red blood cell (RBC) 108-109

Apheresis platelets 106-108

Pooled platelets (6-10) 108

Since there are many different ways to produce blood components and different storage conditions, we have focused on those currently used in Canadian manufacturing techniques (fresh, variably stored for different lengths of time, warm, cold, soft spin, hard spin, buffy-coat present, high and low hematocrit).

The following criteria should be considered when evaluating a filter83:

safe passage and low loss of the cellular component and the soluble constituent, while achieving the specified level of leukocyte depletion (low filtration failure); good flow rate and good capacity compatible with the normal requirements for the transfusion of fresh or stored blood and its cellular components, while remaining compact for ease of handling and minimizing product wastage; highly effective in reducing the incidence of complications and adverse reactions; low cost per filter.

There is an inevitable loss of platelets58,84 and red blood cells85 during filtration. This loss varies between 5-20 %, and the mean loss of even one filter (Pall RC 100) used in different studies can vary about 5% (23% ±4, 18%±5)84,85 . However, two studies21,57 did not find an

16 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs increased use in blood components in the filtration group for non-refractory patients, which might be expected as a consequence of platelet loss. Oksanen found a higher platelet increment in multiple transfused hematologic patients after administering unfiltered components, but in later stages of the treatment course these patient required more transfusions than in the filtered group due to higher rate of alloimmunization53,86. We therefore did not include an increased use of blood components due to leukofiltration in our model.

Figure 1 shows nine different filter options. In fact, we are concentrating on the most common filtration options since option one alone can be split up in three sub-options.

Figure 1 Stages (used in the cost-comparison analysis), where leukofiltration of blood components is possible

Canadian Coordinating Office for Health Technology Assessment 17 Leukoreduction: the techniques, their effectiveness and costs

Pre-storage filtration

All pre-storage filtration systems have certain requirements. The system has to be a ‘closed’ one to meet the standards of Health Canada87. There are no consistent recommendations about the timing of leukodepletion. Early leukocyte depletion might permit enhanced bacterial proliferation during storage. Under experimental conditions it appears that leaving the leukocytes for a certain time after donation offers some advantages, but the length of time is not clear: 24 hours was optimal in some studies, shorter time in others83,88.

In addition, early filtration (< 2 hours) diminished the filter performance compared to filtration after 2 hours [759]. At a Canadian Blood Agency (CBA) meeting, held in May 1997 in Winnipeg, Manitoba, Dr. Blajchman recommended waiting at least 6-8 hours after collection of whole blood units before filtration.

In Canada, pre-storage filtration is performed at Red Cross Blood Centres and the procedure is done by well-trained laboratory-technologists in an environment that allows quality control. Other available standards for quality control are those recommended by the U.S. Food and Drug Administration11.

During storage, leukocytes undergo morphologic degeneration, and the number of intact cells decreases23. As previously discussed, fragmented leukocytes release cytokines which are linked to NHFTR90. In animal experiments, pre-storage filtration was shown to reduce the incidence of NHFTR more effectively than post-storage filtration55. Laboratory comparisons also showed a lower cytokine level in pre-storage filtered platelets31,90,91 than in post-storage filtered ones. However, no randomized controlled trials in humans have demonstrated a reduction in adverse reactions of pre-storage versus post-storage filtered blood components. Retrospective and prospective studies and reviews related to this topic report different conclusions about the timing of RBC- and platelet filtration24,30,32,35,63,90. It is now well established that increasing the time of storage of platelet concentrates is associated with a rise in the rate of adverse reactions31. Since platelets are stored at 22C (lower temperatures activate the thrombocytes), prevention of cytokine- mediated febrile non hemolytic reactions provides a rational for pre-storage leukodepletion59,92.

Several studies showed that pre-storage filtration has no disadvantages in terms of storage93. However, results of animal studies which indicated a better platelet survival after pre- storage filtration55 could not be reproduced in human studies94.

Pre-storage apheresis platelet filtration (Technique 1)

Platelets may be obtained from a donor by a process known as apheresis or plateletpheresis. In this process, blood is drawn from the donor into an apheresis instrument, which, using centrifugation, separates the blood into its components, retains the platelets, and returns the remainder of the blood to the donor. The resulting component contains about six times

18 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs as many platelets as a unit of platelets obtained from whole blood95. There are two available ways to leukoreduce apheresis platelets. The Cobe Spectra, Cobe Spectra LRS or Baxter CS 3000+ are able to produce platelet concentrates which meet FDA11,96,97 regulations regarding white cell content. In a study evaluating the white cell reduction in platelet concentrates, apheresis platelets produced with the Cobe Spectra failed to reach FDA standards in 7% of the produced units, despite sophisticated working conditions during the study58. The authors explained that high prefiltration WBC counts limit the ability of leukoreduction by apheresis devices. Technical improvements now include several devices such as the LRS (leuko-reduction-system) to reduce the leukocyte content in a higher percentage of platelet concentrates98,99.

A second method is to filter ‘inline’ the apheresis platelets within the apheresis device. For example, such systems are available for the Haemonetics MCS/MCS+ and Fresenius AS 104. Both techniques are closed systems and therefore allow the storage of units for up to 5 days11,59,87. A third process would be to filter the apheresis product in a closed system after delivering it to the Red Cross Blood Centre.

Pre-storage pooled platelet filtration (Technique 4)

While the buffy-coat technology is not used, units of platelets are produced in Canada by using a centrifuge to separate the platelet-rich plasma from the donated unit of whole blood87. The platelet-rich plasma is then centrifuged again to concentrate the platelets further. In this preparation step it is possible to filter the platelet unit for leukocytes ‘inline’. Since the system is a closed one, it is possible to store this platelet-unit, after separation of the plasma, for 5 days11,59,87,95. Several studies conclude that pre-storage filtration has no disadvantages, and that there is no improvement of leukodepleted platelet units in terms of storage23,92,93,94. Oksanen demonstrated that pre-storage filtration of platelets caused a loss of 14% of the platelets versus 24% in post-storage filtration24. This was seen as a consequence of a loss of platelet viability after storage. Less viable platelets seem to stick in the filter, while more flexible, viable ones can pass through the filter more easily. Therefore, the greater loss of platelets in post-storage leukodepletion appears to be more a matter of platelet viability due to storage time, than of leukocyte filtration itself. We therefore do not include the platelet loss due to leukocyte filtration as an additional cost in our model.

Since five units of platelets are combined for a therapeutic dose before administration to the patient, the preparation of one concentrate requires five filters. The pooling of five concentrates before storage is done with an open system that requires delivery of the product within six hours87. It is therefore not suitable for storage.

Canadian Coordinating Office for Health Technology Assessment 19 Leukoreduction: the techniques, their effectiveness and costs

Pre-storage red cell concentrate filtration (Technique 7)

This technology is not currently available for use in Canada, and until now, there has been no inquiry for licensing57. Many manufacturers, including Pall, Asahi/Baxter and Hemasure, are marketing inline filters in the U.S. These operate in a closed system. The American Red Cross is currently promoting the use of pre-storage filtered RBC-concentrates10. The filtration is done after the viral testing is finished to avoid filter costs for unusable RBC concentrates. The filtration is usually done in ‘walk in refrigerators’ at 4o C, which enhances the filter performance23. Sprogoe- Jacobson compared the filter performance of blood bank pre-storage filters with the Pall RC100. Their results showed much lower rates of filtration failure for blood bank systems (13% bedside vs. 0% blood bank), most likely due to violation of the filtration protocol100.

Post-storage laboratory filtration

Post-storage filtration has several advantages and disadvantages. One of the advantages is that filtration is available on demand. When filtration is done to fulfill specific orders by the physician it is not necessary to run costly double inventories for filtered and unfiltered products. All blood bank delivered products can be filtered in the hospital laboratory before being sent to the requesting ward. This filtration would be done in an open system and the filtered product must be delivered to the patient within six hours for platelets and 24 hours for RBC-concentrates87. The filtration is done by skilled laboratory staff and is dependent on factors such as the size of the laboratory and the amount of blood components processed. As previously mentioned, especially for platelet concentrates, those filtered post-storage contain a higher level of cytokines. However, studies are not conclusive in this respect. In a prospective study about postoperative mortality in cardiac surgery De Watering found a lower mortality and infection rate in those patients who received leukofiltrated blood products. However, a comparison of pre- and post-storage filtration showed no difference in clinical outcomes81. In a retrospective study, Federowicz found a reduction of NHFTRs in RBC-concentrates filtered pre-storage vs. post-storage (1.1% vs 2.15%, p=0.0045), but found no significant difference in avoidance of allergic reactions24. Another retrospective study in oncology patients demonstrated a statistically significant benefit in prevention of NHFTR with pre-storage versus post-storage filtered blood30. Since no RCT directly compared pre- and post- storage filtration in respect to avoided cases of NHFTR and platelet refractoriness it remains unclear which is superior.

Post-storage laboratory apheresis platelet filtration (Technique 2)

After storage of the apheresis platelet concentrate, the unfiltered product can be filtered in the hospital laboratory on demand. It is also possible in this environment to control the quality of the filtered products. This type of filtration uses an open system. Therefore, the filtered product must be administered to the patient within six hours87.

20 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Post-storage laboratory pooled platelets filtration (Technique 5)

Usually five platelet units are combined for one pooled platelet concentrate. After combination of the five units into one, filtration can take place with one filter. This type of filtration uses an open system. Therefore the filtered product must be administered to the patient within six hours. It is possible to filter on demand.

Post-storage laboratory (blood bank) RBC-concentrate filtration (Technique 8)

After storage of the RBC-concentrate, the unfiltered product can be filtered in the hospital laboratory on demand. It is also possible in this environment to maintain quality control of the filtered products. Since this type of filtration uses an open system, the filtered product must be administered to the patient within 24 hours87.

Bedside filtration of apheresis-platelets, pooled platelets and RBC concentrate (Techniques 3,6,9)

The bedside filtration of blood components is done during the transfusion of the blood component to the patient. Usually the filter is mounted at the bedside and placed between the blood bag and the transfusion tube. Quality control in this environment is difficult to maintain. The conditions of the filtration process are altered by higher temperatures during filtration, and by the speed of the filtration process101,102,103. Severely ill patients often have to be transfused at a slow speed and this diminishes the efficiency of the filter103. With respect to training costs, Dr. Dzik estimated that one blood centre serving 100 hospitals will need to develop protocols and training for perhaps 10 individuals to prepare leukoreduced components. In contrast, bedside filtration may require each hospital to train 100 nurses23 (Table 6).

The value of bedside filtration remains controversial. Jensen reported the reduction of post- surgical infections using a bedside filter69. In CMV prevention for bone marrow transplant patients, Bowden at al found bedside filtration useful in a prospective, randomized trial36. C3a, a vasodilating cytokine which plays a role in NHFTR, appears to be absorbed by newer filters, but this effect appears to be achievable only with filtration immediately prior to transfusion, i.e. at the bedside34. However, Williamson could find no benefit in bedside filtration of blood products versus no filtration for 172 hematological patients in a prospective randomized trial. And, as she points out, it was not possible to control the quantity of leukocytes finally transfused25. Sirchia et al showed that bedside filtration of red blood cells can be equal in quality to post-storage filtration performed in a laboratory104. But, this result was not found by most other authors101,102,103 and in a later study, Sirchia pointed out that “continued, controlled nurse education and full understanding of the WEB-reduction process are of paramount importance”105, conditions which are more likely achieved in a laboratory than on the ward.

Canadian Coordinating Office for Health Technology Assessment 21 Leukoreduction: the techniques, their effectiveness and costs

Table 6 Considerations in the selection of timing of leukodepletion (adapted from Dzik59,102)

Strategy Pre-storage In-laboratory Bedside Issue 1+4+7 2+5+8 3+6+9

Process control Excellent Excellent Poor (temperature, flow rate, appropriate use of filter etc)

Quality control Excellent (Excellent) Poor

Number of persons Few Moderate number Many needing training

Filter performance Excellent Excellent Good but more difficult to control

Cost versus availability In case of indication Filtration tailored to Filtration tailored to based use inventory demand. Delays in demand. must be maintained. A release of blood degree of over-filtration could occur in is inevitable smaller facilities.

Filter system type ‘closed’ ‘open’ ‘open’

4.2 Filtration standards

Health Canada addressed some aspects of leukofiltration in the Drugs Directorate Guidelines as described below87.

Quality control

A quality control program must be in place to ensure that reagents, equipment, and methods are performing properly without demanding specific steps of quality controls. Products manufactured with an open system must be delivered to the patient within 24 hours for RBC- concentrates (stored between 2-6C), and six hours for platelets (stored between 20- 24C).Therefore, only closed systems can be used for pre-storage filtration of blood components.

22 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Red blood cells

Some leukocyte-filtration specific regulations are issued for red blood cells. The method chosen to reduce the leukocyte content should be known to produce a unit containing fewer than 1x108 leukocytes and at least 75% of the red blood cells in the original whole blood. There are no regulations about labeling.

Platelets

No specific regulations regarding leukofiltration for platelets are mentioned.

United States

In 1996 the FDA issued Recommendations and Licensure Requirements for Leukocyte- Reduced Blood Products11 (Table 7). Following the FDA-regulations, the Standard Operating Procedures (SOPs) should specify the time period when leukocyte reduction should be performed (during the initial 8-hour room temperature hold or after refrigeration consistent with manufacturers’ instructions), and for pre-storage filtration no bedside filters should be used. After using an ‘open system’ the products must be delivered within four hours for platelets and 24 hours for RBC concentrates.

Table 7 FDA recommendations and licensure requirements11

Blood product RBC-concentrate Pooled platelets Apheresis platelets Issue

Remaining original 85% 85% 85% product

Leukocyte content (per < 5x106 < 8.3x105 * < 5x106 unit)

Labelling Red Blood Cells, Platelets, leucocyte Platelets, Pheresis, Leukocyte reduced reduced leukocytes reduced

Quality control 1% of monthly 1% of monthly 1% of monthly production, at least 4 production, at least 4 production, at least 4 controls per month+ controls per month+ controls per month+

+ All units tested (100%) should meet the standards. Quality control can be performed with manual (Nageotte Chamber) or automated methods. * Six platelet units are combined to one platelet concentrate; the final platelet concentrate has thus < 5x106 leukocytes

Canadian Coordinating Office for Health Technology Assessment 23 Leukoreduction: the techniques, their effectiveness and costs

Council of Europe

The Council of Europe issued in 1995 a “guide to the use, preparation and quality control of blood components”106 (Table 8). For red blood cells, a level of 1x106 leukocytes per unit was regarded as sufficient and pre-storage filtration is recommended. For pooled platelets, the residual leukocyte count after leukofiltration should be less than 0.2 x 106 per single unit, for apheresis platelets 1x106 per standard unit. Blood components leukoreduced according to the mentioned standards are seen as an ‘acceptable alternative to CMV negative blood for prevention of CMV transmission’.

Table 8 Council of Europe Recommendation No. R (95) 15 on the preparation, use and quality assurance of blood components106

Blood product RBC-Concentrate Whole blood platelets Apheresis platelets Issue

Remaining original min 40g/unit >60x109/single unit > 300x109/unit product equivalent

Leukocyte-content (per < 1x106 < 0.2x106* < 1x106 per standard unit) unit

Labelling depending on country depending on country depending on country standards standards standards

Quality control 4 units per month or 5% of units 1% of all units with a 1%, whichever is 10/month+ minimum of 4 higher+ units/month+

Recommendation pre-storage filtratrion pre-storage filtration pre-storage filtration regarding timing (within 48 h after (within 6 hours after collection) recovery)

+These requirements shall be deemed to have been met if 90% of the units sampled fall within the values indicated.

24 Canadian Coordinating Office for Health Technology Assessment 5. COST-COMPARISON ANALYSIS

5.1 Methods

Filtration techniques and strategies

This analysis examines and compares the cost of three platelet and red blood cell filtration strategies. These are: 100% pre-storage filtration, 100% post-storage filtration in a blood bank and 100% post-storage filtration at bedside. These strategies were given to us for investigation by the Canadian Blood Agency (CBA), as these represent possible strategies that could be followed for the delivery of blood products in Canada. Each of these strategies consists of different techniques which were outlined in Section 4 above.

Figure 2 Strategies used for cost comparison analysis

Strategy 1 Strategy 2 Strategy 3 Techniques 1+4+7 Techniques 2+5+8 Techniques 3+6+9 (prestorage) (hospital blood bank) (hospital bed side)

multi-transfused patients single transfused patients - febrile reactions - febrile reactions - platelet refractoriness -surgical site infections in ‘clean’ surgery in ‘clean-contaminated’ surgery

The pre-storage strategy consists of the pre-storage filtration of apheresis platelets, pooled platelets and of red blood cells. The post-storage blood bank filtration strategy consists of filtration at the blood bank of apheresis platelets, pooled platelets and red blood cells. The post-storage bedside filtration strategy consists of the filtration at the bedside of apheresis platelets, pooled platelets and red blood cells. As shown in Figure 2, for all three strategies we focus on two patient groups who could potentially benefit from leukofiltration: patients who repeatedly receive either platelet or red blood cell transfusions; and patients who are transfused for one specific event (eg. emergency, surgery, etc.). The clinical endpoints in our analysis for both patient groups are non- hemolytic febrile reactions. For the group of multi-transfused patients we also calculated cases of platelet refractoriness avoided, since these occur only with these patients. For the group of surgical patients (single transfused) we calculated the possible savings of avoided surgical site infections due to leukofiltration.

Canadian Coordinating Office for Health Technology Assessment 25 Leukoreduction: the techniques, their effectiveness and costs

Undoubtedly, a combination of the different techniques could be considered, such as the pre-storage filtration of platelets for leukemia patients, the post-storage blood bank filtration of pooled platelets and the bed-side filtration of red blood cells. We chose not to formally identify more than the three strategies outlined above. However, the results are presented in a way which makes it possible to identify and evaluate other strategies.

Analytic technique and comparator

The model we built compares the direct and consequential costs of different filtration techniques (Techniques 1 to 9) in comparison to no filtration. The cost of these filtration techniques are then aggregated in order to obtain the cost of each filtration strategy. The analysis is therefore a cost comparison analysis.

The analysis also compared the total number of adverse reactions avoided with each filtration technique. This is undertaken by taking into account epidemiological information concerning the distribution of blood products among patient categories.

Viewpoint

The cost of the different filtration techniques were calculated from a health care system perspective irrespective of which institution (the Canadian Blood Agency, the Canadian Red Cross or individual hospitals) pays for the different activities. Financing issues are discussed in subsequent sections.

End point of the analysis

The clinical outcome examined is the adverse events that are avoided per year as a result of the use of filtered versus unfiltered blood components. The analysis was carried out over a one- year time horizon. These adverse events include: non hemolytic febrile transfusion reactions (NHFTR), refractoriness following allo-immunization, and immunomodulation (see also Table 9). Cytomegalovirus was discussed previously in qualitative terms.

As discussed in Section 3, the strength of the evidence related to these adverse events varies. Whereas there is strong evidence in favor of the efficacy of leukodepletion in reducing NHFTR and platelet-refractoriness, the evidence is still lacking for immunomodulation. Therefore, results pertaining to transfusion reaction and to allo-immunization are presented first. A module which incorporates the possible impact of immunomodulation is added later.

26 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Patient population

The cost of each filtration technique is calculated separately for several patient groups. The patient population has been subdivided because there is evidence to believe that the probability of occurrence of adverse events and/or the cost of treating these adverse events differ among patient groups. Therefore, patient groups are identified according to the specific effect being examined. Thus, to study the impact of filtration on NHFTR, patients are grouped as multi- transfused versus single transfused patients. For allo-immunization, only multi-transfused (leukemia) patients are examined since platelet refractoriness is a clinical problem in this patient group. Regarding immunomodulation we chose surgical site infections as a possible clinical outcome of immunomodulation. Thus we evaluated surgical patients (as part of the single- transfused patient group) and grouped them as ‘clean surgery’ (eg. hip replacement, heart surgery) and ‘clean-contaminated” surgery (eg. colon surgery) since the incidence of SSI is different in both groups.

Source of clinical information

The probabilities of adverse events following each technique are derived as much as possible from controlled studies. When no controlled studies were available, we estimated the possible effect of filtration from animal or uncontrolled studies. For example, this source was used to estimate adverse events for pre-storage filtration techniques (Techniques 1, 4 and 7). Although not proven in randomized controlled trials (RCTs), we use a higher effectiveness for pre-storage filtration than post-storage filtration to avoid adverse events. Therefore, the analysis gives the benefit of the doubt to pre-storage filtration.

Resource items and cost estimates

Filtration costs encompass the cost of filters, the cost of related activities and the cost of treating adverse events. The cost of filters was provided to us by the CBA. Related costs comprise handling and human resource costs, as well as overhead and quality control costs whenever appropriate. These costs have been estimated following conversations with different stakeholders and from available literature. Adverse events include non-hemolytic febrile transfusion reactions (NHFTR), platelet refractoriness, and immunomodulation.

The costs involved in treating these adverse events were estimated from the literature29,30,66 as well as from discussions with content experts57. Since we found neither published nor unpublished information on costs related to transfusion reactions we commissioned a chart review of 400 charts at one Ontario teaching hospital [Appendix III]. Full cost allocation of the resources consumed by these events was performed.

Canadian Coordinating Office for Health Technology Assessment 27 Leukoreduction: the techniques, their effectiveness and costs

The cost generated by refractoriness following allo-immunization is more complex to determine. It entails, among other clinical requirements such as a higher use of blood components, finding single matched donors for some patients who suffer platelet refractoriness. This search usually requires the establishment and regular update of a database of donors, in addition to the costs of reaching appropriate donors and performing multiple testing and additional transfusion of blood components. We estimated the cost of refractoriness following discussions with transfusion medicine experts and hematologists.

The cost of immunomodulation was taken from an internal non-published study conducted at one Ontario teaching hospital. This study had reviewed the probability of developing surgical infections following various procedures, and estimated the cost associated with treating these events using fully allocated costing methods.

Sensitivity analysis

Sensitivity analysis was performed in order to test the robustness of our results, and to determine how sensitive our conclusions are to specific estimates. Sensitivity analysis was performed on cost and probability estimates as well as on epidemiological assumptions.

A threshold analysis was also performed in order to determine the price for filters that would make the particular filtration technique cost neutral.

5.2 Probabilities, unit costs and epidemiological assumptions

5.2.1 Probabilities of adverse events

Section 3.1 dealt in detail with the extent and level of evidence associated with each of the adverse events (i.e. NHFTR, refractoriness associated with allo-immunization, and immunomodulation). This section highlights the probabilities which are associated with the different adverse events under each filtration technique and which are used in the model.

Non-hemolitic febrile transfusion reaction

Table 9 indicates the probabilities associated with NHFTR. These probabilities were derived from various literature sources, and complemented and/or verified during verbal communications with various clinical experts. When probabilities were not available, they were estimated.

28 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Table 9 Probabilities associated with developing NHFTR

Technique Multi-transfused Single transfused patients patients (% of transfusions) (% of transfusions) Platelets Unfiltered apheresis platelets 14%* n.a. 1 pre-storage apheresis platelet filtration 5% n.a. 2 post-storage platelet filtration 12% n.a. 3 bedside platelet filtration 12% n.a.

Unfiltered pooled platelets 30%** 19% 4 pre-storage platelet filtration 15% 9% 5 post-storage platelet filtration 26% 15% 6 bed-side platelet filtration 26%** 15%

Red blood cells No red blood cell filtration 6.8%¶ 2% 7 pre-storage red blood cell filtration 1.1%‡ 0.5% 8 post-storage red blood cell filtration 2.15%‡ 1% 9 bed-side red blood cell filtration 3% 1%

Sources:* 630 (VIII), ** 589 (II), ¶ 638 (VIII) , ‡ 474 (V); in parenthesis level of evidence (Jovell-scale)18

Immunomodulation

Table 10 indicates the probabilities of surgical site infection (SSI) following surgery associated with immunomodulation that were used in our model. The probabilities associated with no filtration were derived from the work of Cruse107 and are used as benchmarks for the audit of postoperative surgical site infections. In his analysis based on 100,000 operations, Cruse reported an infection rate of 1.4% in clean wound and 6.3% in clean-contaminated operations. However, new operative technologies (minimally invasive, laparoscopy), shorter length of stay and other factors make it likely that the average infection rate is changing.

Canadian Coordinating Office for Health Technology Assessment 29 Leukoreduction: the techniques, their effectiveness and costs

Table 10 Probability of developing surgical site infection after surgery

Type of operation Infection rate (% of patients)

No filtration Filtration

Clean surgery 1.4% 1.05%

Clean-contaminated surgery 6.3% 4.73%

Allo-immunization

Table 11 indicates the probabilities associated with the development of platelet refractoriness. This situation is relevant only for multi-transfused, mostly leukemia, patients. These probabilities are derived from various literature sources25,27,52,108, as well as from discussions with clinical experts during the expert meeting on leukodepletion organized by the CBA57. Since the TRAP-Trial was not published yet (August 1997), we were not able to include the results of this large RCT in this table.

Table 11 Probabilities associated with the development of platelet refractoriness

Techniques Multi-transfused Single transfused patients patients Platelets Unfiltered apheresis platelets 30%* n.a. 1 5% n.a. 2 15% n.a. 3 15% n.a. Unfiltered pooled platelets 50%** n.a 4 14% n.a 5 26%* n.a 6 26* ¶ n.a

Sources:* 27, ** 188, ¶ 19 n.a.: Not applicable

A number of points are worth noting. First, the definition of ‘refractoriness’ is not the same in all studies. Second, failure to achieve an appropriate platelet increment does not necessarily

30 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs lead to (costly) HLA-matched single-donor transfusions. Third, the definition of pre-storage and post-storage filtration is different among studies. In the TRAP trial for example, any platelet component filtered after 16 hours was regarded as a post-storage one, while other studies do not mention the maximum time allowed before filtration was performed that is considered to be pre- storage35,57. Fourth, no RCT exists that compares pre- versus post-storage filtration in respect to platelet refractoriness. Consequently, we used evidence from retrospective, uncontrolled or animal studies to assign a lower rate of refractoriness to techniques 1 and 4 than to techniques 2,3,5 and 6.

5.2.2 Unit costs

Filter costs

The following unit costs for platelets and red blood cell filters were used in the calculations (Tables 12 and 13). These unit costs were provided to us by the CBA as the manufacturers’ discounted prices. We used prices that included manufacturers’ discounts in order to make the report directly applicable to the CBA. If other filter prices prevail, the cost of the different techniques would change accordingly.

Table 12 Platelet filter unit prices

Technique Description Unit price 1 pre-storage apheresis platelet filtration $25.00 2 Laboratory apheresis platelet filtration $31.74 3 bedside apheresis platelet filtration $34.10 4 pre-storage pooled platelet filtration $28.59 * 5 laboratory pooled platelet filtration $6.35 6 bedside pooled platelet filtration $6.51

* Five of these filters are used for one platelet concentrate. See Figure 6.

Table 13 Red blood cell filter unit prices

Technique Description Unit price 7 pre-storage red blood cell filtration $30.50 8 laboratory red blood cell filtration $24.45 9 bedside red blood cell filtration $20.16

Canadian Coordinating Office for Health Technology Assessment 31 Leukoreduction: the techniques, their effectiveness and costs

Cost of related activities

Related activities include overhead cost such as inventory management, quality control and the human resources necessary for filtration; as well as costs related to additional filter use for pre- storage filtration techniques since not all produced blood components are finally transfused (Table 14). The cost of these activities was estimated from published literature1,23,29,30,66,83,100,109,110,111,112,113,114 and from conversations with experts during a special scientific meeting in Winnipeg in April-May 199757. We did not implement any ‘wastage’ effect. It can be assumed that in particular with bedside filtration, due to false application of the filter or non- optimal conditions (temperature, flow-speed), on average more filters are used than blood components being transfused. However, we were not able to quantify this effect.

Table 14 Unit cost of related activities

Activity Cost per transfusion Overhead cost In blood centre (pre-storage) $3.00 In hospital blood bank (post-storage) $4.50 At bed-side (post-storage) $3.00 Human Resources In blood centre (pre-storage) $8.00 In hospital blood bank (post-storage) $6.00 At bed-side (pre-storage) $6.00 Quality Control In blood centre (pre-storage) $0.20 In hospital blood bank (post-storage) $1.00 At bed-side (pre-storage) $0.00

Cost of treating adverse events

Since we were unaware of any Canadian study which investigated the cost of treating febrile reactions, we commissioned a chart review at the Ottawa General Hospital, a university- affiliated tertiary care centre. The costs obtained from this study were used in the analysis. These costs appear in Table 15, and Appendix III gives more detail about this chart review.

32 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Table 15 Cost of treating NHFTR

Type of patient Cost per febrile reaction Multi-transfused patient $81 Single-transfused patient $81

The estimated cost of treating refractoriness associated with allo-immunization has been obtained from discussion with transfusion medicine and hematology experts (Table 16). The estimate is based on the assumption that not every patient who suffers refractoriness needs HLA- matched platelets, and that different patients may need different treatments depending on their grade of refractoriness.

Table 16 Cost of treating refractoriness associated with allo-immunization

Type of patient Cost per patient Multi-transfused (leukemia) patient $10,000 Single-transfused patient Not applicable

To calculate the immunomodulatory side effects of transfusions, we chose surgical site infections as one possible clinical outcome of immunomodulation. Most of the controlled trials studying immunomodulation used patients undergoing colorectal surgery (usually bacteria- contaminated) because of their risk of developing a SSI. Since health care costs differ markedly among countries115,116,117, we estimated the cost of surgical site infections from Canadian studies only. To do this, we used the costs derived from an unpublished case control study undertaken in the Ottawa General Hospital investigating surgical wound infections occurring after ‘clean’ surgery. This study showed that in 1995, 3607 “clean” in-patient surgical procedures were performed and 47 (1.3%) nosocomial SSI were identified. The hospital’s case costing system was used to determine the variable direct cost for infected patients. These costs included those associated with personnel (nursing, laboratory, imaging, social work, etc.), medical and surgical supplies including drugs and referred-out-services (lab fees for referred out test, referred out laundry, etc.). The controls were matched to key factors: case mix group, principal procedure, most responsible diagnosis, number of co-morbidities, age/gender and temporal period. The total cost difference between infected patients and uninfected control patients was then calculated. This study revealed that the difference in costs between a patient with an SSI compared to a patient without infection was on average $6,994 and the associated additional length of stay was 16.7 days. These results are similar to a study undertaken in Alberta in 1995118 but somewhat different from a Finnish study (additional length of stay of 33.2 days due to SSI) and a US study (higher costs for SSI in cancer patients, US$ 12542116) but these costs are difficult to compare since they arose in different health care systems, and there is a ‘no-fault’ compensation program for surgical infections in Finland115.

Canadian Coordinating Office for Health Technology Assessment 33 Leukoreduction: the techniques, their effectiveness and costs

The cost associated with a SSI that we used in this model appears in Table 17. We however assume that this cost will be the same in patients with “clean” or “contaminated” surgery.

Table 17 Cost of treating surgical site infection

Type of patient Cost per patient Surgical patients $7,000

Savings due to discontinuing the CMV-screening program

We calculated possible savings due to the abolition of the existing CMV screening program. Following the Red Cross blood services statistical report 1993/19942 we assumed a screening rate of 40% of all transfused red blood cell and platelet concentrates. The cost per test of $4.50 (including handling and human resources) were provided to us by the CBA.

5.2.3 Epidemiological and transfusion assumptions

In order to calculate the aggregate budgetary impact, and the total number of adverse events avoided with each possible filtration technique, epidemiological information as well as assumptions regarding the number of transfusions per patient are necessary. These estimates were obtained from the literature2,4 as well as from discussions with clinical and Red Cross experts.

The total number of transfusions and utilization rates per year in Canada for the year 1993/1994 is indicated in Table 18. Utilization rates are taken into account in the model for techniques 1, 4 and 7, since Red Cross utilization rates indicate that more units are produced than are actually transfused to patients. In order to remain conservative, we assumed that 10% more blood products are produced and filtered with Techniques 1 and 7 than actually transfused, and 30% more for Technique 4. Our aggregate analysis is based on 15,000 apheresis platelet concentrates per year, 85,000 pooled platelet units per year, and 830,000 red blood cell units per year.

34 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Table 18 Total number of blood units filtered and transfused per year

If filtration is done on If filtration is done Utilization Rate* demand pre-storage Apheresis platelets 15000 16666 90% Pooled platelets 85000 110390 77% Red blood cells 830000 922222 90% Source: CBA data. * Derived from Red Cross Statistical Report, 1993-19942.

The distribution of blood products among patient categories is indicated in Tables 19 to 21.

Table 19 Distribution of red blood cells among patient categories

Patient category Platelets* Red blood cells4 Multi-transfused patients 72% 10% Single transfused patients 28% 90% All patients 100% 100% *Source: Verbal communication during CBA expert meeting on Leukodepletion, 1997, Winnipeg57

Table 20 Distribution of blood components among patient categories

Patient category Platelets* Red blood cells4 Surgical patients 20% 72% Non-surgical patients 80%` 28% All patients 100% 100% *Source: Verbal communication during CBA expert meeting on Leukodepletion, 1997, Winnipeg57

Table 21 Distribution of red blood cells among patient categories

Patient category Share of all red blood RBC per procedure* cells4 Surgical patients/’clean surgery’ 52% 2.9 RBC per procedure Surgical patients/’clean-contaminated 20% 4.7 RBC per procedure surgery’ Surgical patients 72% * per transfused patient

Canadian Coordinating Office for Health Technology Assessment 35 Leukoreduction: the techniques, their effectiveness and costs

The average number of transfusions per patient category is displayed in Table 22.

Table 22 Number of transfusions per patient category

Patient category Platelets Red blood cells Multi-transfused (leukemia) patients 35* per year 25* per year Surgical patients/clean surgery n.a. 2.9** per case Surgical patients/clean-contaminated n.a. 4.7** per case surgery Non-surgical patients 3* n.a. * Source: Investigators ** Source: 4 n.a.: Not applicable

Sensitivity analysis values

The variables tested in sensitivity analysis and the range of values used appear in Table 23.

Table 23 Range for sensitivity analysis

Variable Sensitivity analysis values or range of values NHFTR following pre-storage filtration 0 % NHFTR following pre-storage filtration Equal to that of blood bank filtration (no advantage of pre- over post-storage) Number of platelet transfusions per multi- 20-50 transfused patient per year Cost of treating one episode of NHFTR $500 Cost of treatment for platelet refractoriness $5,000 - $15,000 Number of filters used for pre-storage filtration Equal to the actual number of transfused blood components Utilization rate for pooled platelets 70% Number of filters for pre-storage pooled platelet 1 filtration Abandoning CMV-screening+ Savings of $1.674 M + Under the assumption that only blood centre and blood bank filtration can achieve CMV-safe products37.

36 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

5.3 Results

5.3.1 Base case results

Results of the base case analysis are displayed in Tables 24 to 30 below. First, we present the cost of the filtration activity only, i.e. the cost of filters and related activities for each technique and strategy; second, we present the total cost of each technique and activity, i.e. the cost of filters and related activity plus the cost of treating adverse events. Third, we present the total number of adverse events avoided with each technique, and fourth, we present the detailed cost of a single transfusion with each filtration technique. At the end, we present the results of an analysis which includes immunomodulatory effects.

Filter and related costs

Table 24 indicates the cost of filters and related activities with each strategy. Bedside filtration appears the least expensive strategy whereas pre-storage is the most expensive one. Table 25 indicates these costs (filter and related costs) for each technique separately. For apheresis platelets, post-storage filtration is cheaper than pre-storage. For pooled platelets, again bedside filtration is the cheapest and pre-storage filtration is approximately 13 times more expensive. For red blood cells, again bedside filtration is the cheapest alternative.

Table 24 Filter and related costs of each strategy, in $000

Strategy No Pre-storage Blood bank Bedside filtration filtration filtration filtration

All transfusions 0 56077 32004 26168

Canadian Coordinating Office for Health Technology Assessment 37 Leukoreduction: the techniques, their effectiveness and costs

Table 25 Filter and related costs of each technique, in $000

Technique Cost for all transfusions 1 603.33

2 648.6

3 646.5

4 17016.56

5 1517.25

6 1318.35

7 38456.67

8 29838.5

9 24202.8 Techniques are the same as shown in Figure 1.

Total cost

The total cost and budgetary impact of each strategy encompasses the cost of treating adverse events in addition to the cost of filters and related activities (Table 26). Again, the strategy of bedside filtration is, overall, the least expensive. Its incremental cost over no filtration is estimated at $20 million. Similarly, the incremental cost of a 100% pre-storage strategy is estimated at $46 million and that of a 100% blood bank post-storage filtration at $26 million.

Table 26 Total cost of each strategy, in $000

Strategy No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 60093 39667 33887 Incremental Cost 46374 25948 20168

When costs are presented by filtration technique, additional conclusions appear (Table 27). Filtration of apheresis platelets with any technique is cost saving. For pooled platelets, post- storage filtration results in net savings to the health care system principally because of its impact in multi-transfused patients. However, no filtration technique of red blood cells would result in savings in both multi-transfused and single transfused patients.

38 Canadian Coordinating Office for Health Technology Assessment Table 27 Total cost of each technique, in $000

Apheresis platelets Pooled platelets Red blood cells Technique No 1 2 3 No 4 5 6 No 7 8 9 filtration filtration filtration Multi-transfused patients 1,456 878 1437 1435 10230 15444 6928 6784 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4938 714 658 1210 34914 27,460 22388 All patients 1,456 878 1,437 1435 10596 20392 7642 7443 1667 38833 30588 25010 Incremental cost of a -577 (19) -21 9785 -2955 -3154 37166 28921 23342 filtration technique over no filtration

Table 28 Number of adverse events avoided with each technique in Canada

Apheresis platelets Pooled platelets Red blood cells Technique 1 2 3 4 5 6 7 8 9 Muti-transfused patients Number of NHFTR avoided 1350 300 300 9180 2448 2448 4731 3860 3,154 Percentage of all cases 64% 14% 14% 50% 13% 13% 84% 68% 56% Number of refractory patients 107 64 64 629 420 420 n.a. n.a. n.a. avoided Percentage of all cases 83% 50% 50% 72% 48% 48% Single transfused patients Number of NHFTR avoided n.a. n.a. n.a. 2,380 952 952 11,205 7,470 7470 Percentage 53% 21% 21% 75% 50% 50% Table 29 Cost per transfusion in dollars

Apheresis platelets Pooled platelets Red blood cells Technique No No No 1 2 3 4 5 6 7 8 9 filtration filtration filtration Multi-transfused patients Cost of filters 0 27.78 31.74 34.1 0 185.65 6.35 6.51 0 33.89 24.45 20.16 Related costs 0 12.44 11.50 9 0.00 14.55 11.50 9 0 12.44 11.50 9 Cost of treatment of 11.34 4.05 9.72 9.72 24.3 12.15 21.06 21.06 5.51 0.89 1.74 2.43 NHFTR Cost of treatment 85.71 14.29 42.86 42.86 142.86 40 74.29 74.29 aaf aaf aaf aaf refractoriness Total cost for multi- 97.05 58.56 95.82 95.68 167.16 252.34 113.2 110.86 5.51 47.22 37.69 31.59 transfused patients Incremental cost of a -38.5 -1.24 -1.38 -85.19 -53.96 -56.3 41.72 32.18 26.08 filtration technique over no filtration Single transfused patients Cost of filters n.a. n.a. n.a. n.a. 0.00 185.84 6.35 6.51 0 33.89 24.45 20.16 Related costs n.a. n.a. n.a. n.a. 0 11.20 11.50 9 0 12.44 11.5 9 Cost of treatment of n.a. n.a. n.a. n.a. 15.39 7.29 12.15 12.15 1.62 0.41 0.81 0.81 NHFTR Total cost for single n.a. n.a. n.a. n.a. 15.39 204.33 30.00 27.66 1.62 46.74 36.76 29.97 transfused patients Incremental cost of a 188.94 14.61 12.27 45.12 35.14 28.35 filtration technique over no filtration aaf: already accounted for Leukoreduction: the techniques, their effectiveness and costs

It should be noted that although it is possible to achieve cost savings with leukofiltrated apheresis platelets, the production of apheresis platelets is itself much more expensive than the production of pooled platelets. This fact is not included in our calculation since we only evaluated filtration-related costs. It is therefore not possible to directly compare the total costs of filtered apheresis and pooled platelets.

Adverse events

Table 28 indicates the total number of adverse events avoided with each technique. For apheresis platelets, pre-storage filtration results in the avoidance of the largest number of adverse events. The same is true with pre-storage filtration of pooled platelets and red blood cells.

Cost per unit transfused

Table 29 gives the cost of each filtration technique broken down by type of cost: filter costs, related activity costs and costs of adverse events for each of multi-transfused and single transfused patients. Here again, the cost of filtration techniques are comparable, but it is not possible to directly compare the costs of filtered apheresis platelets with that of pooled platelets because the cost of production of platelets is not included in our calculation. The cost of production of apheresis platelets is much more expensive than the production of pooled platelets. In this study, we only evaluated filtration-related costs.

Immunomodulation

When the impact of immunomodulation simply on surgical site infection is taken into account, this alone could add $7.38 M in savings. However, according to this model, no strategy would be cost-saving (Table 30).

Table 30 Budgetary impact of strategies with immunomodulation factor, in $000

Strategy No filtration Pre-storage Blood bank Bed side filtration filtration filtration Total cost 43245 82237 61811 56031 Incremental cost 38992 18566 12787 Number of cases 1,054 1,054 1054 avoided

Canadian Coordinating Office for Health Technology Assessment 41 Leukoreduction: the techniques, their effectiveness and costs

January 23, 19985.3.2 Sensitivity analysis

One-way sensitivity analysis

Table 31 indicates the results obtained by running our model with the cost and probability estimates outlined in Table 22. For simplicity of presentation, only the cost of the strategies are shown (pre-storage strategy consisting of techniques 1+4+7, post-storage filtration in blood bank consisting of techniques 2+5+8, and post-storage filtration at bed-side consisting of techniques 3+6+9). The cost of each strategy takes into account the cost of filters and related activities as well as the cost of treating adverse events for a total pre-storage filtration strategy, a total post- storage filtration strategy in a blood bank, and total post-storage filtration at bed-side. The costs of each technique are displayed in Appendix IV.

Table 31 Sensitivity analysis results

Case Budget impact result summaries Comments Incremental cost over no filtration in $000

Pre-storage Blood bank Bedside filtration filtration filtration

Baseline $46,374 $25,948 $20,168 All costly

p(NHFTR) pre-storage = 0 $45,019 $25,948 $20,168 All costly

p(NHFTR) pre storage = $47,493 $25,948 $20,168 All costly p(NHFTR) post storage

No. of platelet transfusion = 20 $40,849 $22,318 $16,538 All costly

No. of platelet transfusion = 50 $48,584 $27,399 $21,620 All costly

Cost of NHFTR = $500 $34,287 $19,650 $14,166 All costly

Cost of Refractoriness = $5,000 $50,057 $28,367 $22,588 All costly

Cost of refractoriness = $15,000 $42,691 $23,528 $17,748 All costly

Same amount of filters for all $38,554 $25,948 $20,168 All costly strategies

Abandoning CMV -Screening* 44,700 $ 24,274 $ 18,494 $ All costly

Utilization rate = 70% 48,075 $ 25,948 $ 20,168 $ All costly

1 single filter for pre-storage whole 33,750 $ 25,948 $ 20,168 $ All costly blood platelet

*Under the assumption that only blood centre and blood bank filtration can achieve CMV-safe products37.

42 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

Under no assumption would a filtration strategy result in net savings to the health care system. However, under specific conditions, specific filtration techniques could result in cost savings.

5.3.3 Threshold analysis

In this section, we determine the price of a pre-storage pooled platelet filter that would make this particular filtration technique cost neutral, i.e. we determine the filter price at which the savings resulting from the decrease in adverse events be equal to the costs associated with filtration for all patients together. We also calculated the an upper and lower bound for the threshold price based on the values used in sensitivity analysis in order to indicate a possible range for the calculated threshold price (Table 32).

Table 32 Threshold analysis for filter prices

Technique Filter Threshold Range Baseline price price

4 Filter for pre-storage $12 $5.70 - $20 28.59 $ filtration of pooled platelets

We did not calculate the threshold values for red blood cell transfusions. For single- transfused patients (who receive 90% of all red blood cell concentrates) the handling cost alone are higher than the possible savings due to avoided febrile reactions. Multi-transfused patients (who receive 10% of all red blood cell concentrates) require both filtered platelets and red blood cells to avoid or delay alloimmunization. Since filter prices cannot differ for different patient groups, the model has not been built to calculate separate threshold values for particular patient groups. Therefore, we did not perform a threshold-analysis of RBC-filter prices for multi-transfused patients.

5.4 Quality of life issues

This analysis has not considered health-related quality of life. Anxiety could be a factor in both patients’ and practitioners’ quality of life if there is a perception (founded or not) that there is a risk which is involved in the transfusion of non-leukoreduced blood products.

Canadian Coordinating Office for Health Technology Assessment 43 Leukoreduction: the techniques, their effectiveness and costs

5.5 Financing considerations

The present analysis is undertaken from a health care system perspective. It has calculated the costs and savings associated with different techniques and strategies irrespective of which group or institution actually pays for each service. In the case of blood filtration, at least three separate institutions are involved; the Canadian Blood Agency, the manufacturer of blood components and individual hospitals. Filter and related cost would be incurred by a blood distribution authority (such as the CBA or the Red Cross) or the hospital, whereas the cost of treating adverse events would usually be incurred by individual hospitals.

44 Canadian Coordinating Office for Health Technology Assessment 6. DISCUSSION

Results

Focusing on the three filtration strategies (pre-storage, blood bank and bedside), and including the costs potentially avoided due to platelet refractoriness and non-hemolytic febrile reaction in various patient groups, we obtained the following results from our model:

Filtering all Canadian platelet and red blood cell transfusions is costly in all strategies, both in a hospital or in a blood centre setting. Additional costs of $46.37 M for Strategy 1 (pre- storage filtration), $25.95 M for Strategy 2 (hospital blood bank) and $20.2 M for Strategy 3 (hospital bed side) versus no filtration will arise with the introduction of a 100% filtration scheme. For multi-transfused patients post-storage leukofiltration is cost-saving. Pre-storage filtration of red blood cells has the greatest budgetary impact compared to other RBC filtration techniques. In addition, pre-storage filtration of pooled platelets is costly even in the group of multi-transfused patients.

The results indicate that the filtration of red blood cell transfusions is not cost-saving. The handling costs alone as more costly than the cases of febrile reactions possibly avoided. Even the assumption that virtually all febrile reactions would be avoided by pre-storage filtration does not translate into a cost saving result. The case of platelet transfusions is different. Leukofiltration for single donor platelets actually saves costs, regardless of pre- or post-storage techniques. Post- storage filtration techniques are cost saving for pooled platelets. However, pre-storage filtration of pooled platelets is still not cost-saving even for multi-transfused patients.

We also performed a threshold analysis to calculate the filter price which allows a 100% filtration strategy to be cost-neutral. For the baseline case, which was robust in sensitivity analysis, a filter cost of $12 for pre-storage filtered pooled platelets would be necessary to achieve a cost neutrality for Technique 4 (pre-storage filtered pooled platelets). For red blood cell filtration, no filter price would bring about a savings since the handling costs alone are more costly than the possible savings of febrile reactions avoided. This is also the case even when all febrile reactions could be prevented by leukofiltration.

We did not consider CMV in the baseline-case in our model, since CMV-screening of blood components is an established procedure to avoid infections in CMV seronegative immuno- suppressed patients. Therefore, it is necessary that the FDA or Health Canada regard leukofiltration as a surrogate for the already existing screening program. It is also possible that both procedures, CMV screening and leukofiltration, could be performed. Nonetheless we calculated a sensitivity analysis about the impact of possible savings due the abolition of the CMV-screening program. Savings of $1.7 M can be achieved if CMV-screening of blood components is obsolete, a sum which did not drive the overall result. There could be potential benefits of leukofiltration in those CMV and also HTLV I positive blood components which are not detected by the current laboratory screening methodology. Unfortunately, there is only scarce information on this subject in the scientific literature and we are thus not able to quantify this effect17,36,44.

Canadian Coordinating Office for Health Technology Assessment 45 Leukoreduction: the techniques, their effectiveness and costs

The immunomodulatory effect of blood transfusions is still controversial. Despite the lack of scientific evidence for such an effect we calculated the savings of avoided cases of surgical site infections due to leukofiltration. We have chosen SSIs as a clinical endpoint since most of the published randomized controlled trials were done in the field of colon surgery. The specific clinical endpoint of immunomodulation showed that savings of $7.38 M could be achieved with leukofiltration. The consideration of other clinical outcomes, such as avoided cases of pneumonia and cancer recurrence, would favour the analysis towards leukofiltration. As long as the question of immunomodulation is not resolved, all calculations about possible savings remain hypothetical.

Strength of this analysis

In this study, we relied as much as possible on evidence-based methods and findings and indicated the strength of the evidence at each stage of the investigation. Throughout the study, five reviewers monitored the process and revised the document. Methods included a review of all available published data on leukofiltration for the years 1990-1997 and regular updates of Current Contents on diskette. We were thus able to include studies up to July 1997. We also attempted to cover the ‘grey’, unpublished, literature in order to locate and use Canadian studies particularly in relation to costing issues. The literature reviewed has included studies on the efficacy of the different techniques of leukodepletion as well as studies dealing with their cost. With these studies we used current Canadian costs for the immunomodulation module. For cost data on febrile reactions, we commissioned a chart review since no published or ‘grey’ data was found. To test the robustness of our results, we conducted a sensitivity analysis with a number of variables. Within the range of values used in sensitivity analysis, the results were stable.

Since the risk of adverse events is different among different patient groups, we carried out separate analyses for multi-transfused and single transfused patients. To study immunomodulation, patients were divided between surgical clean and surgical clean-contaminated patients to reflect clinical practice.

Limitations of this analysis

The results are valid with certain limitations. Epidemiological data on the use of blood is rare and we thus had to rely mainly on one Ontario study4 and expert advice. As far as possible, we verified the plausibility of our findings regarding the distribution of blood products by making comparisons with international studies. We also had to calculate the number of patients frequently transfused with platelets in Canada, who are mainly leukemic patients, since we found no data about the number of treated leukemia patients per year. This imprecision in the underlying epidemiological data could be translated into less accurate results. However, we altered the epidemiological data within sensitivity analysis and found the base case results to be robust.

The published studies are mainly efficacy analyses and we thus had to rely on results which were achieved under specific, well-controlled, clinical settings. To which extent these results are

46 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs reproducible in average clinical practice is not known. In other words, the clinical effectiveness of leukofiltration and its ability to prevent adverse reactions in daily practice could be lower than indicated in published studies.

Another limitation derives from the low level of evidence present in many studies which are not RCTs. The efficacy of pre- over post-storage filtration has not been tested in randomized controlled trials. The same situation exists for febrile reactions and alloimmunization. In our base case model, we used probabilities which give an advantage to pre-storage filtration, but which are not proven by direct comparison in clinical trials. However, altering efficacy probabilities did not change the essential result that pre-storage filtration is costly.

The results should be considered preliminary as long as the immunomodulatory impact of allogenic blood transfusions is not known. As mentioned above, savings of $7.38 million in avoided cases of SSI alone indicate the magnitude of an immunomodulatory effect. If the immunomodulatory effect of transfusions is proven and better understood, other savings could balance the results more favorably towards filtration.

It should be mentioned that we could not use an appropriate outcome measure for calculating the costs of alloimmunization. For reasons mentioned above, studies use alloimmunization (as a laboratory result) or platelet refractoriness as clinical endpoints instead of bleeding. The number of cases of bleeding which are actually avoided by leukofiltration remains unclear since the real effect of platelet refractoriness on bleeding is not established. Thus it was only possible to calculate the cost impact of leukofiltration on platelet refractoriness rather than on the real clinical endpoint which is bleeding. In other words: the real value of leukofiltration on avoiding cases of clinically significant bleeding is unknown and thus not calculable.

Policy implications

O’Brien et al introduced a framework for categorizing economic study results when data on incremental costs and effects have been determined119. This 3x3 matrix has 9 cells to categorize studies depending on whether the new treatment or technology is more, the same, or less costly than the control and whether it has more, the same, or less effectiveness (see also Appendix V). An incremental effectiveness of treatment compared with no filtration is given for pre-storage leukofiltration. The incremental effectiveness of pre-storage filtration compared with post-storage filtration can be assumed although there are no RCTs which directly compared both techniques. Considering these two alternatives, pre-storage filtration offers both additional effectiveness and an increased cost (category 7). The authors call this a case of ‘non-dominance’; it is a matter of judgement whether the added benefit is worth the extra cost and other factors would have to be considered.

Since not all patients benefit equally from leukofiltration, many expert groups and developers of guidelines conclude that leukofiltration should be made available only to those patient-groups who benefit most from leukofiltration12,13,14,120. This requires strategies to deliver the right product at the right time. Such a strategy is filtration on demand which is possible with post-

Canadian Coordinating Office for Health Technology Assessment 47 Leukoreduction: the techniques, their effectiveness and costs storage filtration. In other words, the filter is only mounted when a filtered product is requested. With this strategy, it is not necessary to use a costly ‘closed’ system where the blood product will be delivered to the ward shortly after filtering it. In contrast, filtration on demand is not feasible with a pre-storage strategy. In the case of pre-storage filtration, ‘closed’ systems are required to allow a longer storage time than for those produced with a open system. These filtered blood components must then to be stored in the hospital blood bank. In order to have filtered products always in stock, more filtered products than are actually demanded have to be maintained. This means that if, for example, 80% of all blood products transfused have to be filtered, a safety margin of 10% additional filtered blood components would require a 90% filtration rate.

Offering filtered and unfiltered products at the same time could result in a higher demand for the filtered, better product. The filter cost for blood bank filtration will likely be covered by the hospital which has an interest in controlling the appropriate use of filters and using them according to guidelines or recommendations given to physicians. In a pre-storage filtration strategy, neither the hospital nor the physician has to pay for the requested product49, and this will likely lead to an increase in requests for filtered products. An indication-based usage of filtered products in this situation might be difficult to control, and could subsequently lead to a 100% filtration scheme.

Although these issues favour the use of hospital-based filtration techniques, some disadvantages arise as well. Quality control for bedside filtration is difficult to maintain. The major characteristics of the administered blood product, such as hemoglobin content or leukocyte content are therefore not known. Also, clinical circumstances often do not allow filtering at an appropriate speed. The mounting of the filter will be done by a nurse who has to find the time in an already tight workload. This does not lead to an appropriate environment for leukofiltration. Therefore, it is possible that bedside leukofiltration will be viewed with some scepticism by already overworked health professionals.

The hospital blood bank environment seems to be more suited as the site for leukofiltration. Here quality control is feasible and it is possible to maintain higher standards for leukofiltration because it is performed by trained laboratory technologists. On the other hand, in a hospital blood bank leukofiltration has to be done in addition to various other workloads presumably without an increase in personnel. Hospitals, where leukofiltration is already performed, are more likely to favor the possibility of relying on already filtered blood components. This strategy would save them filter costs as well as human resource costs since all expenses will arise at the Red Cross Blood Centre. This might influence the demand for pre-storage filtered blood components.

As described above, the report is valid within certain limits. Some of these limits arise due to the lack of clinical and epidemiological data. More accurate calculations of the cost and cost- savings of leukofiltration would be possible if accurate databases about the frequency and quantity of blood transfusion for different types of patients were available.

The lack of randomized controlled trials was most evident in the field of pre- versus post- storage filtration. Despite multiple experimental studies with animals there is still no clinical trial proving the advantages of pre-storage filtration for the prevention of febrile reactions or alloimmunization. Since pre-storage filtration is far more expensive than post-storage scenarios,

48 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs further research is needed to provide more knowledge about the value of different filtration techniques. The case is similar for immunomodulation. Conducting a meta-analysis of patient data can be a step towards quantifying the real effect size of immunomodulation. Further large controlled multi-centre trials may be necessary to provide the final answer to this question

Canadian Coordinating Office for Health Technology Assessment 49 7. CONCLUSION

A 100% filtration strategy is not cost-saving regardless of the timing of leukofiltration. For certain patient groups (i.e. patients who require frequent transfusions of either red blood cells or platelets) leukofiltration can be cost-saving. To which extent pre-storage filtration in opposite to post-storage filtration achieves benefits for the patient is not known.

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58 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

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115. Hyrylä ML, Sintonen H. The use of health services in the management of wound infection. Journal of Hospital Infection 1994;26:1-14.

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60 Canadian Coordinating Office for Health Technology Assessment ADDITIONAL REFERENCES

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AuBuchon JP. Blood transfusion options: Improving outcomes and reducing costs. Archives of Pathology and Laboratory Medicine 1997; 121 (1) : 40-47.

Aubuchon J, Blumberg N, Sniecinski I. Cost-effectiveness of leukocyte depletion of blood components. AABB (American Association of Blood Banks) Meeting, Miami Beach, Florida 1993.

Blumberg N, Heal JM. Immunomodulation by blood transfusion: An evolving scientific and clinical challenge. American Journal of Medicine 1996;101(3):299-308.

Blundell EL, Pamphilon DH, Fraser ID, Menitove JE, Greenwalt TJ, Snyder EL, et al. A prospective, randomized study of the use of platelet concentrates irradiated with ultraviolet-B light in patients with hematologic malignancy. Transfusion 1996;36(4):296-302.

Böck VM, Heim MU. Leukozytendepletion von blutprodukten: Indikationen und technische durchführung [Leukocyte depletion of blood products. Indications and technical execution] Fortschritte der Medizin 1995;113(8):46, 49-50.

Bordin JO, Bardossy L, Blajchman MA. Experimental animal model of refractoriness to donor platelets: The effect of plasma removal and the extent of white cell reduction on allogeneic alloimmunization. Transfusion 1993;33(10):798-801.

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Copplestone JA, Williamson P, Norfolk DR, Morgenstern GR, Wimperis JZ, Williamson LM. Wider benefits of leukodepletion of blood products [letter]. Blood 1995;86(1):409-410.

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Dumont LJ, Dzik WH, Rebulla P, Brandwein H. Practical guidelines for process validation and process control of white cell-reduced blood components: report of the Biomedical Excellence for Safer Transfusion (BEST) Working Party of the International Society of Blood Transfusion (ISBT). Transfusion 1996;36:11-20.

Canadian Coordinating Office for Health Technology Assessment 61 Leukoreduction: the techniques, their effectiveness and costs

Dzik WH, Cusack WF, Sherburne B, Kickler T. The effect of pre-storage white cell reduction on the function and viability of stored platelet concentrates. Transfusion 1992; 32(4):334-339.

Farrugia A, Tan Y, Romeo A, Martin L, Rolland JR, Kellner S, et al. Relative efficiency of leucocyte removal procedures for the production of leucocyte-poor red cell concentrates assessed by flow cytometry. Vox Sanguinis 1994;66(3):153-160.

Friedberg RC, Donnelly SF, Boyd JC, Gray LS, Mintz PD. Clinical and blood bank factors in the management of platelet refractoriness and alloimmunization. Blood 1993; 81(12) 3428-3434.

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Kurz M, Greinix H, Höcker P, Kalhs P, Knöbl P, Mayr WR, et al. Specificities of anti-platelet antibodies in multitransfused patients with haemato-oncological disorders. British Journal of Haematology 1996;95(3):564-569.

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62 Canadian Coordinating Office for Health Technology Assessment Leukoreduction: the techniques, their effectiveness and costs

28(5):328-331.

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64 Canadian Coordinating Office for Health Technology Assessment APPENDIX I

Table 33 Level of evidence scale

Level Strength Type of study design Conditions of scientific rigour* (highest -l - of to lowest- evidence IX)

I* Good Meta-analysis of randomized Analysis of patient individual data controlled trials Meta-regression Different techniques of analysis Absence of heterogeneity Quality of the study

II* Large sample randomized Assessment of statistical power controlled trials Multicentre Quality of the study

III* Good Small sample randomized Assessment of statistical power to controlled trials Quality of the study

IV* Fair Non-randomized controlled Assessment of statistical power prospective trials Concurrent controls Multicentre Quality of the study

V* Fair Non-randomized controlled Assessment of statistical power prospective trials Historical controls Quality of study

VI* Fair** Cohort studies Matching Multicentre VII* Case-control studies Quality of study

VIII Poor Non-controlled clinical series Multicentre Descriptive studies: surveillance of disease, surveys, registers, data bases, prevalence studies IX Expert committees, consensus conferences Anecdotes or case reports

* Quality of the study assessed by specific protocols and conditions of scientific rigour. ** If the clinical condition being studied has a low prevalence in the population, they could be the only type of study to be designed.

Source: Adapted from Jovell AJ, et al18.

Canadian Coordinating Office for Health Technology Assessment 65 APPENDIX II

Glossary

AP Apheresis Platelets AML Acute Myelogenous Leukemia CBA Canadian Blood Agency CCOHTA Canadian Coordinating Office for Health Technology Assessment CMV Cytomegalovirus EBV Ebstein Barr Virus FDA Federal Drug Administration HIV I Human Immunodeficiency Virus HLA Human Major Histocompatibility Complex HTLV I Human T-cell Leukemia (retro-)Virus I ICD International Classification of Diseases LRS Leukocyte Reduction System NHFTR Non-Hemolytic Febrile Transfusion Reaction PC Platelet Concentrate PP Pooled Platelets TRAP Trial to Reduce Alloimmunization to Platelets RBC Red Blood Cell RCT Randomized Controlled Trial SDP Single Donor Platelets SSI Surgical Site Infection TRALI Transfusion Related Lung Injury WBC White Blood Cells WBP Whole Blood Platelets

66 Canadian Coordinating Office for Health Technology Assessment APPENDIX III

Costing study on NHFTR

Purpose

In order to calculate the treatment costs of a febrile reaction we commissioned a chart review to the Utilization Unit of the Ottawa General Hospital in July 1997. The Ottawa General Hospital is a 439-bed university-affiliated tertiary care centre. The purpose of the study was to retrieve the actual costs related to febrile non-hemolytic reactions after transfusion of red blood cells or platelets.

Method

The following methodology was used to identify and randomly select charts for this study:

The Case Costing System was used to identify in-patients who received either red blood cells or platelets for the fiscal year 1996/1997.

All in-patient encounters were identified and downloaded into a spreadsheet. All leukemia cases were included as part of the study using the ICD9-CM diagnosis code (204 - 208). All other cases were randomly selected using a random number generation program (315 cases). Nine out of the 400 total cases received fresh frozen plasma or autologous blood component transfusions and were excluded from further evaluation.

The febrile reaction cases were evaluated by two independent reviewers for leukemia patients and all other patients (surgery, emergency, solid tumor, etc.) separately.

We compared the average treatment cost per febrile reaction for leukemia patients and non-leukemia patients using the unpaired t-test (Statistica for windows, Ver.5).

Table 34 Transfusions for leukemia and non-leukemia patients, 1996-1997, Ottawa General Hospital

Absolute Average RBC Apheresis platelets Pooled platelets numbers Discharges number of Reactions transfusions Discharges unfiltered filtered unfiltered filtered unfiltered filtered

Leukemia 85 22.24 240 663 66 430 244 247 20 patients

Non-leukemia 306 4.59 1082 74 20 16 190 2 10 patients

Total 391 8.37 1322 737 86 446 434 249 30

Canadian Coordinating Office for Health Technology Assessment 67 Leukoreduction: the techniques, their effectiveness and costs

Results

All febrile reactions occurred with platelet transfusions; no febrile reactions were documented for RBC transfusions. Out of the 30 patients with febrile reactions, 18 patients had had transfusions and febrile reactions before; four were transfused with (unfiltered) platelets for the first time and experienced febrile reactions. Eight had prior transfusions without reactions. The overall reaction rate was 0.9% per transfusion. Seventy-one percent of all platelet and red blood cell transfusions for leukemia patients were filtered in laboratory or bedside versus 7 % for non- leukemia patients. In addition, 50% of all platelet transfusions for leukemia patients were filtered apheresis platelets versus 16% for non-leukemia patients (which were mostly not filtered). Thus febrile reactions were documented in 2.03% of all platelet transfusions for leukemia patients and in 4.39 % of all platelet transfusions for non-leukemia patients. The incidence of febrile reactions in this chart review is far below the rates reported in other studies19,20,24,26,28. Although it is generally felt that febrile reactions are under-reported, only those cases that attract the attention of nurses or physicians are associated with costs.

The cost per febrile reaction include the following resources:

Laboratory work up: Bacterial cultures, immunological tests (ABO, Rhesus), laboratory technologists wages Nursing costs: We estimated nursing time for a mild febrile reaction to be 30 min and 60 min for a severe reaction ($40 per hour) Medication: Antipyretics, cortisone, antihistaminic drugs Diagnostic procedures: X-ray, EKG, blood samples, blood cultures

Table 35 Costs of febrile reactions

Number of Total Cost per Number of Cost per unit reactions costs ($) febrile transfusions (all blood Patients reaction components)

Leukemia 20 $1557 $77.85 1890 $0.82

Non-leukemia 10 $884 $88.40 1384 $0.61

Total 30 $2441 $81.37 3274 $0.75

The average cost related to a febrile reaction in these 30 cases was $81.37.

There was a statistically not significant difference (p=0.43) between the costs in leukemia patients and non-leukemia patients, $77.85 and $88.40. The lower costs for leukemia patients was due to a higher rate of documented mild cases. For leukemia patients no antibiotic treatment was initiated after the documented febrile reaction since all patients were on antibiotic treatment before the febrile event.

68 Canadian Coordinating Office for Health Technology Assessment APPENDIX IV

Sensitivity analysis

Table 36 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration equals 0% (all febrile reactions are avoided by pre-storage filtration)

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,456 818 1437 1435 10230 14700 6928 6784 457 3846 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4765 714 658 1,210 34611 27,460 22388 ALL PATIENTS 1,456 818 1,437 1435 10596 19465 7642 7443 1,667 38457 30,588 25010 Incremental cost of a filtration -638 (19) -21 8868 -2955 -3154 36789 28,921 23342 technique over no filtration

Table 37 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 58739 39667 33887 Incremental cost 45019 25948 20168 Table 38 Sensitivity analysis: Costs per technique in $000, where NHFTR following pre-storage filtration is equal to that of blood bank filtration (no advantage of pre- over post-storage filtration)

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,456 993 1,437 1435 10230 15989 6928 6784 457 3990 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 5054 714 714 1,210 35216 27,460 22388 ALL PATIENTS 1,456 963 1,437 1435 10596 21043 7642 7642 1,667 39206 30,588 25010 Incremental cost of a filtration -492 (19) -21 10446 -2955 -2955 37539 28921 23342 technique over no filtration

Table 39 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 61212 39667 33887 Incremental cost 47493 25948 20168 Table 40 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 20 (this translates into that 3810 patients are at risk for suffering platelet refractoriness per year)

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 2,420 1039 1,919 1917 16787 17280 10337 10194 457 3920 3128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4938 714 658 1,210 34914 27460 22388 ALL PATIENTS 2,420 1039 1,919 1917 17153 22218 11051 10852 1,667 38833 30,588 25010 Incremental cost of a filtration -1381 (501) -503 5064 -6102 -6301 37166 28,921 23342 technique over no filtration

Table 41 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 21241 62090 43559 37779 Incremental cost 40849 22318 16538 Table 42 Sensitivity analysis: Costs per technique in $000, where the number of platelet transfusions per multi-transfused patient equals 50 (this translates into that 1524 patients are at risk for suffering platelet refractoriness per year)

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,070 814 1,244 1242 7607 14709 5564 5420 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4938 714 658 1,210 34914 27,460 22388 ALL PATIENTS 1,070 814 1244 1242 7973 19647 6278 6079 1,667 38833 30,588 25010 Incremental cost of a filtration -256 174 172 11674 -1696 -1895 37166 28921 23342 technique over no filtration

Table 43 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside Filtration filtration filtration filtration Total cost 10711 59294 38110 32331 Incremental Cost 48584 27399 21620 Table 44 Sensitivity analysis: Costs per technique in $000 where the cost of treating one episode of NHFTR is $500

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 2,336 1193 2,191 2189 17923 19290 13595 13451 2,822 4302 3,876 3665 Single transfused patients n.a. n.a. n.a. n.a. 2,261 5836 2,210 2154 7,470 36479 30,590 25518 ALL PATIENTS 2,336 1193 2,191 2189 20184 25126 15805 15606 10,292 40781 34,466 29183 Incremental cost of a filtration -1143 (144) -146 4942 -4379 -4578 30489 24174 18891 technique over no filtration

Table 45 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total Cost 32812 67099 52462 46978 Incremental Cost 34287 19650 14166 Table 46 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $5,000

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 813 771 1,116 1114 5859 14220 4654 4511 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4938 714 658 1,210 34914 27,460 22388 ALL PATIENTS 813 771 1,116 1114 6225 19158 5368 5170 1,667 38833 30,588 25010 Incremental cost of a filtration -42 303 301 12933 -856 -1055 37166 28921 23342 technique over no filtration

Table 47 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 8705 58762 37072 31293 Incremental cost 50057 28367 22588 Table 48 Sensitivity analysis: Costs per technique in $000 where the cost of treating platelet refractoriness is $15,000

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 2,099 986 1,759 1757 14601 16668 9201 9058 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 4983 714 658 1,210 34914 27,460 22388 ALL PATIENTS 2,099 986 1,759 1757 14968 21606 9915 9716 1,667 38833 30,588 25010 Incremental cost of a filtration -1113 (340) -342 6638 -5053 -5252 37166 28,921 23342 technique over no filtration

Table 49 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 18734 61424 42262 36482 Incremental cost 42691 23528 17748 Table 50 Sensitivity analysis: Costs per technique in $000 where the number of filters used for pre-storage filtration is equal to the actual number of transfused blood components

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,456 818 1,437 1435 10230 12626 6928 6784 457 3,535 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 3,842 714 658 1,210 31,452 27,460 22388 ALL PATIENTS 1,456 818 1,437 1435 10596 16468 7642 7443 1,667 34,987 30,588 25010 Incremental cost of a filtration (638) (19) -21 5872 -2955 -3154 33320 28921 23342 strategy over no filtration

Table 51 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 52273 39667 33887 Incremental cost 38554 25948 20168

Table 52 Sensitivity analysis: Costs per technique in $000 where one single filter is used for pre-storage pooled platelet production instead of five

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,456 878 1,437 1435 10230 6354 6928 6784 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 1402 714 658 1,210 34914 27,460 22388 ALL PATIENTS 1,456 878 1,437 1435 10596 7757 7642 7443 1,667 38833 30,588 25010 Incremental cost of a filtration -577 (19) -21 -2839 -2955 -3154 37166 28921 23342 strategy over no filtration

Table 53 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 47469 39667 33887 Incremental cost 33750 25948 20168

Table 54 Sensitivity analysis: Costs per technique in $000 where the utilization rate of pre-storage filtered platelet units is 70%

Apheresis platelets Pooled platelets Red blood cells TECHNIQUE No filter 1 2 3 No filter 4 5 6 No filter 7 8 9 Multi-transfused patients 1,456 878 1,437 1435 10230 16669 6928 6784 457 3920 3,128 2622 Single transfused patients n.a. n.a. n.a. n.a. 366 5415 714 658 1,210 34914 27,460 22388 ALL PATIENTS 1,456 878 1,437 1435 10596 22083 7642 7443 1,667 38833 30,588 25010 Incremental cost of a filtration -577 (19) -21 11487 -2955 -3154 37166 28921 23342 strategy over no filtration

Table 55 Costs per strategy in $000

STRATEGY No Pre-storage Blood bank Bedside filtration filtration filtration filtration Total cost 13719 61795 39667 33887 Incremental cost 48075 25948 20168

Appendix V

Framework for categorizing economic study results Adopted from O’Brien et al119

Incremental effectiveness of treatment compared with control

More Same Less

More 7 4 2

Incremental cost Same 3 9 5 of treatment compared with Less control 1 6 8

Strong dominance for decision 1=accept treatment 2=reject treatment

Weak dominance for decision 3=accept treatment 4=reject treatment 5=reject treatment 6=accept treatment

79