Health Technology Appraisal Cancer treatment induced anaemia: Epoetin (alpha & beta) and Darbepoetin alpha

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1 Health Technology Appraisal Cancer treatment induced anaemia: Epoetin (alpha & beta) and Darbepoetin alpha Joint Submission by National Blood Service Gwasanaeth Gwaed Cymru Welsh Blood Service 1) Background a. Action of erythropoietin and relevance to Blood Services ) Blood Transfusion Process a) Introduction b) Resource issues, supply and demand... 2 Figure 1 Blood issued in Wales... 3 Figure 2 Percentage of donors bled... 3 Figure 3 Age of donors... 3 Figure 4 Change in donor base in Wales... 3 Figure 5 Change in donor base in England... 4 Figure 6 Red cell demand in England 4 2c) Cost of blood d) Complexity of the transfusion process e) Quality and safety of supply... 5 Figure 7 Complications of transfusion... 6 Figure 8 Distribution of IBCT errors 6 2f) Quality of patient care ) Blood Use in Anaemia Attributable to Cancer Treatment a)Haematological Malignancy b)Non-haematological Malignancy ) Effect of erythropoietin on blood use ).Tools for auditing the effect of erythropoietin on blood use in malignancy ) Summary ) References ) Background 1a) Action of erythropoietin and relevance to Blood Services The primary action of erythropoietin, whether physiological or pharmacological, is to increase red cell production in the presence of a functioning bone marrow, hence its therapeutic use in the support of anaemia. (1) The Blood Services (NBS in England and WBS in Wales) are the professional bodies responsible for the provision of all blood components suitable for transfusion, the most significant of which, in relation to this submission, is red blood cells for the support of anaemia. The Blood Services and erythropoietin therefore have the potential to fulfil similar roles in those patients able to respond to erythropoietin therapy. However, current practice in the UK does not usually consider these as either/or options in the management of cancer treatment associated anaemia, blood transfusion being used for those with severe symptoms, and those with milder symptoms managing with no specific therapy for their anaemia. Transfusion is the only option for support of the 1

2 anaemia arising from bone marrow failure or acute blood loss, and as such is a precious resource that must be protected. The Blood Services are not therefore in competition with erythropoietin therapy and the use of erythropoietin in any group of responding patients is in line with all current advice (on transfusion alternatives) from the NBS, National Blood Transfusion Committee (NBTC) and WBS. As many aspects of the collection and provision of blood for transfusion are similar within the NBS and WBS, as are the issues relevant to an appraisal of erythropoietin, we are presenting a joint submission. However, the services are independent and where regional variations exist and are relevant to the issue of erythropoietin, these will be highlighted. 2) Blood Transfusion Process 2a) Introduction Refinements to the donor recruitment process and the introduction of appropriate technologies over the years have allowed the continued supply of a high quality, safe, reliable product from volunteer donors in the UK. However, blood transfusion safety can only ever be measured against current known potential threats, and the possibility of transmission of as yet unknown pathogens via the blood supply remains likely. The Blood Service has traditionally been the provider, working on a demand led basis. Supply has been matched to the needs of increasing productivity and throughput within hospitals, on the assumption that all transfusions are necessary. Maintaining this position of demand driven supply remains the major challenge for the Blood Services. Increasing public and media concerns about the safety of blood, the increasing costs of production and testing, and falling donor numbers led to the DH Better Blood Transfusion initiative in 1998 (HSC 1998/224) (2). More recently, in 2002, Better Blood Transfusion 2 (HSC 2002/09, WHC 2002/137) (3,4) encouraged all hospitals and Trusts to explore alternatives to blood transfusion where appropriate. Hospitals have been instructed to raise the profile of blood transfusion, address issues of safety in blood administration, deliver adequate transfusion training and ensure appropriate patient information regarding blood transfusion is available. The aim must be to offer patients the best quality of care, with transfusion only being used when benefits outweigh the risks. As part of this it is essential that the feasibility of alternatives to transfusion be properly evaluated. The use of erythropoietin is one constituent of a raft of measures that can be taken in some anaemic patients to improve haemoglobin levels without the use of allogeneic blood. It is therefore important to understand the issues around the use of allogeneic blood in order to make informed decisions regarding the use of erythropoietin. 2b) Resource issues, supply and demand There is a fine balance between supply and demand in the Blood Services, with the average stock holding being 8 10 days supply of blood for the NBS and days for the WBS. For both services, a shortage is declared when stocks fall below 3 days. Approximately 10,000 units of blood are collected from donors every day in the UK and over 3 million components are transfused every year. Over the past two decades increasingly stringent donor selection criteria have been introduced by the UK Blood Transfusion Services. The net effect of these changes has been to reduce the potential blood donor pool, as illustrated in Figures 2 to 5. The impact of the latest change deferral of previously (including possibly) 2

3 transfused donors to reduce the risk of transmission of vcjd is yet to be fully realised. However, these measures have already resulted in the loss of approximately 5% of NBS donors, many of whom were regular attenders. Figures are similar in England and Wales, although the WBS has experienced a disproportionate loss of group O NEG donors. Welsh statistics also demonstrate an ageing donor base, and a fall in the percentage of attendees at donor sessions who are actually bled, which is around 80-90% for England and Wales. Blood use has decreased in England (Figure 6). This may be due to changing clinical practice. There was no corresponding decrease in demand in Wales over the same period, with WBS red cell issues rising from 85,548 in 1991/92 to 108,171 in 2003/04 an increase of over 20,000, or 26%, in 12 years (Figure 1). In Wales, although demand is flattening off (Figure 1), there has not as yet been a similar down turn as evident in England (Figure 6). This may in part be due to the financing of blood transfusion, which in Wales is centrally funded through the Welsh Assembly Government (WAG), whereas in England it is paid for at the point of use, either at Trust level, or more usually on an individual departmental basis. Money saved by reducing blood use can therefore be used to offset related alternative initiatives or technologies, or to support other unrelated projects within the department. In Wales, the WBS, in conjunction with the WAG, has been primarily responsible for funding initiatives related to alternatives to transfusion. Figure 1 Blood issued in Wales Figure 2 Percentage of donors bled RBC concentrates issued by the WBS: 1991/ /04 Donors bled as a percentage of attendees: 1990/ /04 120, ,000 80,000 60,000 40,000 20,000 0 RBC Issues Welsh Blood Service Erythropoietin Technology Appraisal October / / / / / / / / / / / / / Donors Bled Welsh Blood Service Erythropoietin Technology Appraisal October / / / / / / / / / / / / / /04 Figure 3 Age of WBS donors Figure 4 Change in WBS donor base 100% 80% 60% 40% 20% 0% 1990/91 Age Demographics 1992/ / / / / /03 Welsh Blood Service Erythropoietin Technology Appraisal October Net change in WBS donors Net Change in Donorbase Welsh Blood Service Erythropoietin Technology Appraisal October / / / / / / / / / / / / / / /04 3

4 Figure 5 Change in donor base-england Annual decline in donor numbers Active Donors 1,850,000 1,800,000 1,750,000 Donors 1,700,000 1,650,000 1,600,000 1,550,000 Oct-00 Apr-01 Nov-01 May-02 Dec-02 Jun-03 Jan-04 Aug-04 Feb-05 Month At present, despite the above negative trends, the English and Welsh Blood Services continue to fully meet the demand of their customer hospitals. However, both blood services consider that there is a real risk that demand might outstrip supply, and also that acute shortages of blood may occur as a result of the new deferral criteria, disasters or terrorism, influenza epidemics, holiday periods, or bad weather. The Welsh Blood Service has calculated that if the donor-base contracted by 3,000 donors per year (a rate lower than at present) even if the mean donation frequency remained constant at 0.8 (1.5 in England), annual red cell collections would fall below 110,000 during the financial year 2006/07. For all these reasons, the Department of Health and the Welsh Assembly Government have asked the Blood Services to work with Trusts to develop contingency plans for the management of such shortage, to ensure support for life saving blood transfusion can be maintained under such circumstances (5). This, in conjunction with BBT2, is increasing awareness of blood transfusion issues. It would appear to be having an impact on blood use, according to the figures for red cell issues, at least across England. The additional impact of increasing costs of red cells may also be partly responsible for the down turn. Figure 6 Red Cell Demand in England Red Cell Demand to 2005/06 2,300,000 2,200,000 2,100,000 2,000,000 1,900,000 1,800, These trends in blood use are occurring despite increasing activity across the health service, with more and increasingly complicated surgery being performed on an ageing population. Developments in cancer diagnosis and management mean greater potential for treatments, including surgery, radiotherapy and chemotherapy, as individual modalities or in combination, all with anaemia as a possible consequence. There is some data to suggest that outcome may be improved by 4

5 maintaining the haemoglobin in the normal range during treatment (6). If this were to prove true for even a proportion of current cancer therapies it would be difficult for the blood services to increase supply to match the required transfusion demand. This group of patients would constitute a new cohort of transfusion recipients as current clinical practice only tends to offer transfusion to those with marked symptoms and haemoglobins falling below 9, or possibly even 8g/dl. If blood use in nonhaematological malignancy now accounts for 9.2% of blood use (200,000 units per year in England), as described on page 8 of this document, maintaining normal Hb levels of >12g/dl would place significant new demands on the transfusion services if it were to be met solely through blood transfusion. In summary, both the NBS and the WBS are managing to keep pace with demand at present, but this position may be threatened by changes in clinical practice, and the predicted reduction in the donor database. 2c) Cost of blood The provision of blood for transfusion is an increasingly costly process. Huge resources are required to attract and keep donors, and to incorporate the technology necessary for testing to ensure microbiological safety. One example is the introduction of discretionary testing for West Nile Virus. As can be seen from the figures for donor demographics, at least within Wales, we are paying more for diminishing returns. Donors who are deferred are lost from that donation event, and potentially lost indefinitely through disappointment, misunderstanding, or fear of future failure. Although the work of the blood services is essential to the transfusion process, the costs of blood collection and supply represent only a fraction of the overall resources needed to support the administration of blood components. 2d) Complexity of the transfusion process The section on supply and demand gave an indication of some of the logistical difficulties faced by the blood services in relation to maintaining a supply of a product with a limited shelf life, dependent on repeated attendance of donors, and driven by a variable and uncontrolled demand. To fully understand the complete resource requirement for the transfusion process, it is important to also consider the involvement required by the patients themselves and many hospital-based personnel and processes. A minimum of 8 different people (patient, doctor, phlebotomist, porter, laboratory clerical and technical staff, nurse, ancillary worker) and 11 separate steps may be involved in the hospital side of the transfusion chain, making it a hugely complex procedure and creating the potential for compounded errors if performed by the inexperienced or untrained (7). These multiple factors have a significant impact on the safety of blood transfusion, as will be addressed under quality and safety. 2e) Quality and safety of supply The UK Blood Services are licensed pharmaceutical manufacturers, operating under licence from the Medicines and Healthcare products Regulatory Authority (MHRA). The blood components produced are also quality assured under the regulations that govern good manufacturing practice (ISO9000). All aspects of collection, processing, storage and distribution comply with these standards. These standards guarantee consistency and quality, both of which contribute to the safety of the product supplied. However, the UK haemovigilance scheme, SHOT (Serious Hazards of Transfusion) has consistently identified the greatest risk relating to blood transfusion as the receipt of the wrong component (IBCT) at the time of the transfusion episode (Figure 7) and that errors leading to IBCT most commonly occur at the hospital end of the transfusion chain (Figure 8) (8). 5

6 This is perhaps not surprising given the complex nature of the process, with multiple sites for potential error, reinforcing the message from BBT2 and SHOT regarding the imperative that blood is used only when necessary and appropriate. Many detailed protocols, policies and guidelines have been written in relation to safe transfusion practice. However, fundamental aspects such as correct patient identification and appropriate monitoring of patients during the infusion of blood, are still performed poorly. This has been shown by the results of the recent National Comparative Audit of Blood Transfusion (9). Education, awareness and support to address these issues are all major components of the Better Blood Transfusion initiative, which aims to promote the appropriate and safe use of blood. Despite this the public perception of risk of blood transfusion is that of transmitted infection (TTI), which comprises only 2% of reported adverse incidents in the UK (Figure 7). Infection risk is minimised by 1. Stringent donor selection criteria (impacts on donor numbers and hence supply) 2. Screening tests on donated units (cost implications) 3. Processing eg leucodepletion (further cost implications) 4. Pathogen reduction techniques including the use of Methylene Blue or Solvent Detergent treatment for fresh frozen plasma 5. Appropriate use (transfusion only where no alternative) Figure 7 Complications of transfusion Complications of Transfusion SHOT Report (n = 482) Figure 8 Distribution of IBCT errors Incorrect Blood Component Transfused DISTRIBUTION OF ERRORS (n = 552) % IBCT ATR DTR TRALI PTP TTI Blood Centre Prescription/Sampling Blood Bank Collection/Admin 4 Other Levels of residual risk of infection quoted in the current patient information leaflets are 1 in 900,000 for hepatitis B (more likely to be struck by lightning) and less than 1 in 30 million for hepatitis C (10). The chance of HIV infection is less than 1 in several million, but the level of risk from vcjd is as yet unknown. Recent donor deferral measures have been put in place to try to limit any potential risk, but there is as yet no definite evidence that vcjd is transmitted by blood transfusion, and no test available to detect the prion agent in human blood. These are the agents we know of. There is no way of quantifying risk for pathogens as yet unknown. Bacterial contamination is another potential hazard, and can cause acute morbidity and mortality. It is minimised by strict adherence to the policy for arm cleansing and draw process at the time of blood collection, storage of red cells strictly at 4 o C, and inspection of all units by laboratory staff prior to issue, and nursing staff prior to 6

7 administration. However, 3 cases of bacterial contamination were reported to SHOT in 2003, one of which resulted in death (8). These were all related to platelet concentrates rather than red cells, however this form of TTI remains an important risk factor in the transfusion process. A further source of risk associated with transfusion relates to the potential immune reactions that may arise, many of which are unpredictable, but some of which arise as a consequence of laboratory testing error or failed patient identification. All may be serious and cause significant morbidity and mortality. TRALI (Transfusion Related Acute Lung Injury) has been reported to be as common as 1 in 5000 transfusions and has a significant mortality rate (1 definite and 7 possible deaths in 2003 SHOT report) (8). The number of cases reported per annum in the UK has been increasing. TRALI is believed to be associated with the presence of anti-hla and/or anti-granulocyte antibodies in the donor, which are present following previous transfusion or pregnancy. The exclusion of transfused donors, and the exclusive use of male donors for preparation of FFP should reduce the incidence of this complication. GvHD (Graft versus Host Disease) occurs when there is engraftment of viable donor lymphocytes in an immuno-compromised (or immuno-competent near HLA-identical) recipient. The condition is prevented by irradiation of cellular blood components, and the sporadic incidence appears to have been reduced by leucodepletion. (8) 2f) Quality of patient care There are very real risks associated with the transfusion of red cells. However, it is the only potentially lifesaving therapy for massive acute blood loss, and its use to support patients with bone marrow failure, acute or chronic, has enabled us to increase the intensity and treatment potential of many cancers. Like all medical treatments, it should only be used when really necessary. 3) Blood Use in Anaemia Attributable to Cancer Treatment 3a) Haematological Malignancy The most recent study of blood use in the Northern region, involving 4703 units over a 14 day period, showed that 811 units (17.2% of all red cells, 95% Confidence Interval (CI) %) were transfused into haematology patients. (11) This correlates with other findings. (12,13) The overall use of blood in specialities other than surgery or obstetrics and gynaecology was 61.3%. A recent study of blood use in the North west of England showed that 25% of medical blood usage was for patients with a haematological malignancy. (14) Assuming that a similar proportion of blood use in this region is medical, then 15% of blood is transfused for haematological malignancy a similar figure to that above. The Northern regional study showed that patients with lymphoproliferative disorders, including Hodgkin s Disease, Non-Hodgkin s Lymphoma and Chronic Lymphocytic Leukaemia, received 161 units (3.4% of all units). Myeloma patients received 93 units (2%). The other haematological categories for transfusion identified patients who were unlikely to have been receiving chemotherapy (e.g. myelodysplasia), or conditions in which erythropoietin is not considered a suitable therapy e.g. acute leukaemias. It has been assumed that all transfusion in haematological malignancy was clinically justified. 7

8 Therefore, the percentage of transfused blood that is used by patients with haematological malignancy, who might benefit from erythropoietin in accordance with the scope of this study, is 5.42% (95% CI: %), a total of 117,180 units per annum, based on a total blood usage of 2,162,000 units in England and Wales in b) Non-haematological Malignancy The study of blood use in the Northern Region showed that 432 units (9.2% of all transfused blood) (95% CI: %) were transfused to patients with nonhaematological malignancy (11). It is likely that all were receiving treatment for their cancer, and it is assumed that all transfusions were clinically justified. The North- West Region study showed that 14% of units were transfused to patients with nonhaematological malignancy (14) and assuming that medical blood use accounted for 61.3% of the total, this would imply a similar figure of 8.6% of all red cells were transfused into patients with non-haematological malignancy. If all patients within this category were receiving transfusions for anaemia related to their cancer treatment, approximately 9.2% of all transfused blood is used by patients with non-haematological malignancy who might benefit from erythropoietin within the scope of this appraisal (200,000 units). From these figures, it can be estimated that 14.6% of blood (95% CI: %) is transfused to patients receiving treatment for haematological or non-haematological malignancy who might benefit from erythropoietin within the scope of this NICE appraisal (approximately 315,650 units). 4) Effect of erythropoietin on blood use It is difficult to provide accurate figures. An analysis of studies using erythropoietin suggests a definite reduction in transfusion need, in both non-haematological and haematological malignancy. (15) Most studies are small, and differing haemoglobin triggers are used. Many did not use an intention to treat analysis. Some studies quote a reduction in red cell use per patient, but it is not possible to give a definite figure for the anticipated reduction in blood use with erythropoietin treatment. Meta-analysis of these studies showed an absolute reduction of the risk of exposure to transfusion. The number needed to treat, to benefit one patient, was 5.2. (15) Although the amount cannot be quantified, the use of erythropoietin in anaemia associated with treatment of cancer or haematological malignancy would result in a significant reduction in blood use, as these categories account for 14.6% of all blood use (315,650 units). This figure has risen, both in percentage and absolute terms, according to the Northern Region study of 2002 (12.6%, 273,000 units) (16). The increase in Non-Hodgkin s Lymphoma, and increasing intensity of chemotherapy for other conditions, may lead to a further increase in patients who either require blood transfusion or erythropoietin therapy. 5) Tools for auditing the effect of erythropoietin on blood use in malignancy The British Committee for Standards in Haematology has developed guidelines for the clinical use of blood. (17) These have been used as the basis for a set of indication codes developed by the National Blood Transfusion Committee, which can be used as an audit tool for red cell transfusion. (18) The code R5 is used for red cell transfusion post-chemotherapy. There is no evidence base to guide practice, but most hospitals use a trigger haemoglobin of 8 or 8

9 9g/dl. R6 denotes transfusion post-radiotherapy, usually to maintain haemoglobin above 10g/dl. The audit of blood use in the Northern Region, organised by the Regional Transfusion Committee, has provided useful information about requirements in malignancy. (16) Regular repeats of this audit would show trends of blood use in haematological and non-haematological malignancy, which would be aided by further refinement of categories. 6) Summary Falling donor numbers, and increasingly stringent donor selection have led to concerns about the continued sufficiency and safety of the blood supply to clinical users. The UK blood services have addressed this by measures to increase the collection of blood nevertheless there is a fine line between supply and demand, and falling donor numbers and changes to clinical practice may lead to demand outstripping supply. Studies of the use of blood show that a significant proportion of blood is used in cancer and haematological malignancy (11,12,13,14). This figure is likely to grow, due to factors such as an ageing population, increase in incidence of Non-Hodgkin s Lymphoma, and increasing intensity of chemotherapy for certain tumours. The majority of higher-quality studies do show that erythropoietin treatment does reduce the incidence of blood transfusions, although no accurate percentage of reduction can be quoted. (15) Erythropoietin therapy differs from regular top up transfusions as a more stable haemoglobin level is achieved, which may be of clinical benefit. Although UK blood is produced to rigorous standards, there are concerns about the safety of the actual clinical process of administering a blood transfusion, which involves many complex steps and is prone to human error (8). Erythropoietin is therefore not comparable to blood transfusions. It may be an equivalent, or even better, therapeutic option for the type of anaemia seen in cancer and haematological malignancy, whilst transfused blood will still be needed for clinical situations such as acute blood loss, or blood replacement in conditions associated with bone marrow failure, such as acute leukaemia. The Blood Services (NBS and WBS), together with the National Blood Transfusion Committee, have encouraged hospitals to look at alternatives to blood transfusion, where clinically appropriate. (3,4) Indeed, both the NBS and WBS patient information leaflets on blood transfusion advise patients to discuss alternatives with their treating physicians (10). This advice is consistent with that contained in the Health Service Circulars of the Chief Medical Officers (England and Wales) on Better Blood Transfusion. Failure to sanction the use of erythropoietin to prevent or ameliorate cancer treatment induced anaemia would appear inconsistent with the CMOs advice, especially given the wider use of erythropoietin in Europe for this indication. The National Blood Service and the Welsh Blood Service would therefore welcome the approval of erythropoietin for the management of anaemia associated with treatment of cancer and haematological malignancy. 9

10 7) References 1 Littlewood TJ, Bajetta E, Nortier JWR et al: Effects of epoietin alfa on hematologic parameters and quality of life in cancer patients receiving non-platinum chemotherapy: Results of a randomised, double-blind, placebo-controlled trial. Journal of Clinical Oncology 2001; 19: HSC 1998/224 Better Blood Transfusion culars/healthservicecircularsarticle/fs/en?content_id= &chk=m%2bhvg w 3 HSC 2002/009 Better Blood Transfusion culars/healthservicecircularsarticle/fs/en?content_id= &chk=wrvsdf 4 WHC 2002/137 5 Chief Executive Bulletin Contingency Planning for Blood Shortage 6 Bohlius J, Langensiepen S, Schwarzer G et al. Erythropoietin for Patients with Malignant Disease (Cochrane review). In: The Cochrane Library, Issue 3, 2004, Chichester, UK:John Wiley & Sons, Ltd) 7 Ann Benton, Singleton Hospital, Swansea. Personal communication 8 Serious Hazards of Transfusion (SHOT) Annual Report A Precious Gift-Better Blood Transfusion 10 Receiving a Blood transfusion Wells AW. Where does blood go? 2004 (unpublished) 12 Stanworth SJ, Cockburn HAC, Boralessa H, Contreras M: Which groups of patients are transfused? A study of red cell usage in London and south-east England. Vox Sanguinis 2002; 83: Mathoulin-Pelissier S, Salmi LR, Verret C, Demoures B: Blood transfusion in a random sample of hospitals in France. Transfusion 2000; 40: Pendry K: Appropriate use of blood in medical patients. Presentation at NBS audit conference, Improving Quality Together, Sheffield Rizzo DJ, Lichtin AE, Woolf SH et al: Use of Epoetin in patients with cancer: evidence-based clinical practice guidelines of the American society of Clinical Oncology and the American society of Haematology. Journal of Clinical Oncology 2002; 20: Wells AW, Mounter P, Chapman CE, Stainsby D, Wallis JP: Where does blood go? Prospective observational study of blood use in north England. BMJ 2002; 3 10

11 17 The clinical use of red cell transfusion: British Committee for Standards in Haematology Blood transfusion Task Force. British Journal of Haematology 2001; 113: Indication codes for red cell transfusion-an audit tool: Murphy MF, Wallis JP 11