Clinical Trial Opportunities in Transfusion Medicine: Proceedings of a National Heart, Lung, and Blood Institute State-of-the-Science Symposium

TRANSFUSION MEDICINE REVIEWS Vol 24, No 4

October 2010

Clinical Trial Opportunities in Transfusion Medicine: Proceedings of a National Heart, Lung, and Blood Institute State-of-the-Science Symposium Morris A. Blajchman, Simone A. Glynn, Cassandra D. Josephson, and Steve H. Kleinman, for the State-of-the Science Symposium Transfusion Medicine Committee The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time. Relevantly, significant practice variation in the use of blood products exists among practitioners and institutions, largely because of the lack of robust clinical trial data, in many instances, which are critical for providing practitioners with evidence-based guidelines for appropriate blood product utilization. Recognizing this gap, the National Heart, Lung, and Blood Institute recently established a State-ofthe-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis. Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject

areas of endeavor. The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees. This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full randomized clinical trials. The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence-based clinical trial research in the field of Transfusion Medicine. © 2010 Elsevier Inc. All rights reserved.

VER THE PAST few decades, the use of blood products for transfusion has continued to increase. These products are used in the care of a large variety of patients. These include patients with hematologic and oncologic conditions, patients undergoing surgery, and trauma victims. In 2002, the National Heart, Lung, and Blood Institute (NHLBI) established the Transfusion Medicine and Hemostasis Clinical Trials Network (TMH CTN). This network comprised 17 Clinical Centers in various geographic locations in the US as well as a Data Coordinating Center. The goal of the TMH CTN was to design and perform multicenter clinical trials comparing treatment and transfusion management strategies of potential benefit to both children and adults with hemostatic disorders and

other conditions as well as to evaluate novel and existing blood component therapies for the treatment of specific hematologic disorders. The TMH CTN is currently in its eighth year of a 10-year

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From McMaster University, Hamilton, Ontario, Canada; the National Heart, Lung, and Blood Institute, Bethesda, MD; Emory University, Atlanta, GA; and University of British Columbia, Victoria, British Columbia, Canada. Address reprint requests to Morris A. Blajchman, MD, FRCP(C), Professor Emeritus, Departments of Pathology and Medicine, McMaster University, 1200 Main St W, HSC-4N67 Hamilton, Ontario, Canada L8N 3Z5. E-mail: [email protected] 0887-7963/$ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.tmrv.2010.05.002

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funding cycle, and this State-of-the-Science (SoS) Symposium was convened to define various areas of clinical trial research that would enhance the scientific agendas for the disciplines of Transfusion Medicine and Hemostasis/Thrombosis. This SoS Symposium was held in Bethesda, MD, on September 19 and 20, 2009, and was designed to assist the NHLBI to identify the most important clinical research issues in the fields of Transfusion Medicine and Hemostasis/Thrombosis that could be addressed through clinical trials. The specific aims of the Symposium were therefore to identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, would significantly impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. Two parallel streams of protocols were developed: one for Transfusion Medicine and another for Hemostasis/Thrombosis. For Transfusion Medicine, 7 general subject areas for potential trials were identified; and for the Hemostasis/Thrombosis stream, 6 general areas were identified. Each subject area was assigned to 1 of 13 subcommittees, each of which had a Chair and a Co-Chair. The 7 specific areas assigned to a subcommittee in the Transfusion Medicine stream were as follows: platelet products; neonatal and pediatrics; surgical; intensive care unit (ICU) and trauma; plasma, fresh frozen plasma (FFP), and therapeutic apheresis; red blood cell (RBC), blood conservation, and blood management; and medical and blood donor issues. The Hemostasis/Thrombosis Oversight Committee identified 6 specific areas for discussions: platelet disorders, bleeding; platelet disorders, thrombosis; thrombosis prevention; thrombosis therapy; hemophilia and von Willebrand disease; and neonatal and pediatric issues. Separate Oversight Committees were formed for the Transfusion Medicine and the Hemostasis/ Thrombosis streams. Each subcommittee was charged by their Oversight Committees to develop 3 to 4 high-priority clinical phase 2 or 3 trials. Each Oversight Committee also established an independent External Panel of experts to review the various proposals and to identify those having the highest priority. Appendix A summarizes the organizational structure for the Transfusion Medicine stream. In her introduction, Dr Susan B. Shurin, Acting Director for NHLBI, explained that the NHLBI specifically would like to invest its limited resources in addressing the most important and

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urgent scientific, clinical, and public health problems. She indicated that this SoS Symposium would help the Institute identify some of the questions and problems that need to be addressed in both the Transfusion Medicine and Hemostasis/ Thrombosis fields. She indicated that the research priority areas identified by the SoS Symposium would help determine the Institute's infrastructure investments over the long term. The Chair of the SoS Symposium, Morris A. Blajchman, pointed out that the main aims of this SoS Symposium were 5-fold: (1) to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, would have a significant impact in advancing transfusion therapies and the treatment of patients with hemostatic or thrombotic disorders; (2) to provide the opportunity to find priorities for future directions for randomized trials in the areas of both Transfusion Medicine and Hemostasis/Thrombosis; (3) to provide opportunities for investigators to exchange scientific ideas with their peers and NHLBI about new perspectives related to future clinical trial research; (4) to recommend priorities for future trials in Hemostasis/Thrombosis and Transfusion Medicine that could be undertaken over the next 5 to 10 years; and (5) to provide an opportunity to discuss clinical trial methodology and how the institution of effective relevant processes could have a positive impact on both the development and performance of randomized clinical trials (RCTs) in the Transfusion Medicine and Hemostasis/Thrombosis fields. Dr Blajchman noted that a second phase of this endeavor would take place and would involve the development of recommendations for NHLBI to consider regarding how to best structure subsequent programs to effectively support clinical trials in high-priority areas (such a meeting took place for the field of Transfusion Medicine at NHLBI on January 25, 2010). It was anticipated that at least 2 publications describing the proceedings of the SoS Symposium would be published: one dealing primarily with projects proposed in the areas of Transfusion Medicine (SoS:TM) and the second those that would deal primarily with Hemostasis/Thrombosis (SoS:HT) proposals. This present article reports on the discussions relating to the clinical trial concepts developed by the 7 Transfusion Medicine subcommittees whose full membership is documented in Appendix A. The meeting generated a rich

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assortment of ideas, with the expectation that these concepts (see below) would require further development before being considered for implementation. However, it is at this juncture of development that an idea meets with reality of whether or not a relevant and feasible trial can be designed. SUBCOMMITTEE 1: PLATELET PRODUCT ISSUES

Trial TM-101: RCT Comparing Prophylactic Platelet Transfusions Versus Therapeutic-Only Platelet Transfusions in Thrombocytopenic Patients Background and rationale. Patients with severe thrombocytopenia are at an increased risk of bleeding. In many countries, the standard approach to prevent excessive bleeding in patients with hypoproliferative thrombocytopenia is by transfusing prophylactic platelet transfusions. It is important to note, however, that no recent clinical trial has provided evidence that transfusing platelets prophylactically to such patients is superior to therapeutic transfusions to be used in the event of bleeding or vice versa.1 Recently, several trials have investigated lowering the threshold for prophylactic platelet transfusions from the previously used 20 × 109/L prophylactic platelet transfusion trigger to 10 × 109 /L. These studies have demonstrated no increase in bleeding risk with reduction in platelet use of 20% or greater.2 The recent Platelet Dose (PLADO) study involving more than 1300 subjects concluded that there was no increase in bleeding risk when transfusing lower doses of platelets compared with a standard dose or a higher dose of platelet products.3 Moreover, even the need for prophylactic platelet transfusions is currently being challenged in Europe (in both Germany and the United Kingdom), where 2 separate RCTs are being conducted comparing prophylactic vs therapeutic-only platelet transfusions. In these 2 studies, platelets are being administered only after the onset of World Health Organization grade 2 or greater bleeding. These 2 trials are still ongoing, but preliminary data from the study in Germany suggest that a therapeutic platelet transfusion strategy may be safe when compared with a prophylactic platelet transfusion strategy given at a patient platelet count of 10 × 109/L in some patient populations.1,4,5 Trial design and feasibility. This proposal addresses the following specific question: “Is a

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therapeutic-only platelet transfusion strategy in hematology patients undergoing intensive chemotherapy or hematopoietic stem cell transfusion not inferior to a prophylactic platelet transfusion strategy (transfusion trigger 10 × 10 9 /L), as measured by clinically significant bleeding during the patient's period of thrombocytopenia?” This proposed phase 3 RCT, comparing the 2 approaches to platelet transfusions, would have as its primary end point clinically significant bleeding. The sample size estimate for the proposed study is 1800 patients; and it is estimated that approximately 20 participating sites would be necessary, with each study site needing to recruit subjects over a 36-month period into a parallel-design, 2-arm RCT. The patient population would be subjects with a hematologic malignancy undergoing intensive chemotherapy as well as those undergoing hematopoietic cell transplantation who are expected to have severe thrombocytopenia for 5 days or more. The subjects would be randomly assigned to receive prophylactic or therapeutic-only platelet transfusions. Discussion. A number of questions were raised about how the trial would account for bleeding episodes that may occur in an outpatient setting. The investigators' response was that this trial would primarily include inpatients. Another question was whether the attending clinicians would be able to use platelet transfusions if they had concerns about significant bleeding risk in the patients randomized to either arm. The investigators indicated that, if the attending clinicians had such concerns, they would be free to use additional platelet transfusions as deemed clinically necessary and then return the patient to the previously allocated treatment assignment. Another question was whether the study would standardize platelet dose and the type of platelet preparation administered. The investigators responded that, to make it easy for subjects to participate, the trial would not specify a particular dose or platelet preparation, particularly as the recently published PLADO study clearly showed that the transfused platelet dose appeared not to influence bleeding risk.3 TM-102: Evaluation of Pathogen-Reduced Platelets Background and hypothesis. Bacterial transmission by platelet transfusions remains a major cause of morbidity and mortality in thrombocytopenic patients who receive platelet transfusions because

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such patients are often immunosuppressed and leukopenic. Although culture techniques are available to detect contaminating bacteria that might be present in platelet products before transfusion, such techniques are not used for all platelet products. Moreover, the current bacterial testing algorithms often underestimate the bacterial risk because sampling for bacterial testing occurs early after platelet preparation (within 1-2 days), such that the small numbers of bacteria that may be present have not yet proliferated to the point that the aliquot taken for bacteria testing contains sufficient bacteria to be detected.6 Another approach to preventing bacterial transmission by transfusion is to use pathogen reduction.7,8 These technologies have been demonstrated to inactivate 3 to 6 logs of both gram-positive and gram-negative bacteria. As a platelet transfusion trial based on the prevention of bacterial transmission is not feasible because the risk is so low that a very large patient sample size would be required to show benefit, this present trial proposes to look at pathogen-reduced platelets compared with standard platelet products to demonstrate adequate hemostasis and a good safety profile. Trial design and feasibility. The proposed trial design is a randomized, blinded, 2-arm, phase 3 RCT comparing pathogen-inactivated platelets using the Mirasol technology8 to conventional platelet transfusions in 300 patients (150 per arm) with hypoproliferative thrombocytopenia. The subjects would have platelet counts of 10 × 109/L or less during 5 or more hospital days and would be stratified for underlying disease and trial site. All subjects would be transfused with prophylactic low-dose platelets at 1.1 × 1011/m2 based on a morning platelet count of 10 × 109/L or less. Hemostatic assessments would be performed daily by research staff who would also record all transfusion-related adverse events. The primary end point of this trial would be the percentage of patients in each arm who develop World Health Organization grade 2 or greater bleeding. Discussion. One of the major discussion points relating to this presentation was the sample size proposed. The platelet subcommittee felt that, although the sample size might be large enough to show a difference in the proposed primary outcome, it might not be sufficiently large to justify Food and Drug Administration (FDA) licensure for such platelet products, particularly in the United States. It is clear that the final sample size for this study

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would require further discussions before implementation. Although the investigators had proposed that the trial evaluate only one preparation of pathogenreduced platelets, discussion took place about the need to evaluate other currently available pathogen reduction technologies other than the one proposed.9 It was agreed that this issue would need further discussion so that all available types of pathogen reduction technologies could be evaluated in a potential head-to-head study. A question was asked as to whether the proposed RCT would characterize the properties of the platelets used, such as the storage time. The response was that this trial would monitor storage duration of the platelets administered as well as other relevant parameters. The issue of acute lung injury (ALI), particularly in bone marrow transplant patients, was raised; and a suggestion was made that a blinded adjudication panel be used to evaluate the diagnosis of ALI. The investigators indicated that this is an issue that would need to be resolved if this particular proposal were to be further developed. SUBCOMMITTEE 2: TRANSFUSION MEDICINE: PEDIATRIC AND NEONATAL

Trial TM-103: RBC Transfusion Trigger Trial in Critically Ill Pediatric Patients Background and rationale. The optimal pretransfusion hemoglobin trigger at which to transfuse pediatric intensive care unit (PICU) patients has yet to be definitively established. A recent large multicenter RCT was limited to a highly selected group of patients who were in fairly good clinical condition and who were given relatively few transfusions.10 Patients actively bleeding at initial evaluation, those who were hemodynamically unstable, or those with cardiovascular problems were excluded. Furthermore, the assigned RBC trigger was suspended for 14% of patients. Trial design and feasibility. We propose a prospective RCT, enrolling a broad array of PICU patients to determine which RBC transfusion strategy is safe and efficacious for the majority of PICU patients. Patients would be randomized to receive RBC transfusions at either a 7- or a 10-g/dL hemoglobin concentration trigger. The proposed primary end point would be a composite outcome/ end point of death and/or cardiac arrest within 30 days of randomization, or a longer-than-expected stay in the PICU. Secondary outcomes would

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include 90-day mortality, number of RBC transfusions, number of transfusions of other blood components, and infections An estimated sample size of 3484 subjects would be needed to evaluate 3136 subjects. This sample size would have 80% power to detect a 3% difference in the composite outcome between the 2 groups. The Transfusion Requirements in the Pediatric Intensive Care Unit (TRIPICU) study data suggest that 19 sites could enroll this many subjects in approximately 4 years.10 The National Collaborative Pediatric Critical Care Research Network of the National Institute of Child Health and Human Development (NICHD) currently has 7 clinical sites plus a data coordinating center and would be a good infrastructure to start this study, but at least 12 additional sites would be needed. Discussion. The issue of a standard-of-care arm for this study was raised, which the investigators indicated should be feasible. This question was engendered by a relevant concern that if the outcomes were similar in the 2 groups, both might be considered worse than standard-of-care. Trial TM-104: Incidence of Moderate and Severe Bleeding in Thrombocytopenic Premature Neonates Treated With a Restrictive Versus Liberal Platelet Transfusion Approach: The Neonatal Platelet Transfusion Threshold Study Background and rationale. Thrombocytopenia affects 20% to 35% of patients admitted to neonatal intensive care units (NICUs).10-14 In at least 25% of premature infants, platelets are transfused in an attempt to decrease the risk of hemorrhage. The platelet count at which the benefit-risk ratio favors platelet transfusions in newborns is currently unknown. Recent publications revealed that there is great variability in the platelet transfusion thresholds chosen by neonatologists and that North American practices differ markedly from those in Europe.13,14 Trial design and feasibility. Patients would be eligible for this study if they have a birth weight of less than 1500 g and a gestational age between 22 and 33 completed weeks. Eligible patients would be randomized to a liberal or a restrictive platelet transfusion group. The specific triggers in the groups would depend on the patient age and risk status and would range from 50 to 100 × 109/L for the liberal group vs 20 to 60 × 109/L for the restrictive group. Every study subject would remain in the originally

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assigned study arm throughout his or her entire hospital stay (or until a postconceptional age of 44 weeks is reached). Babies would be stratified by birth weight. The primary end point would be the incidence of moderate and severe bleeding based on assessment of intraventricular, pulmonary, gastrointestinal, genitourinary, and other bleeding. Secondary end points would include survival from the NICU to discharge home, serious brain abnormality on ultrasound or magnetic resonance imaging, short gut syndrome subsequent to necrotizing enterocolitis (NEC), bronchopulmonary dysplasia, stage 3 or higher retinopathy of prematurity, number of platelet transfusions during the hospital stay, and neurodevelopmental impairment at 18 to 22 months of age. This trial would require 2252 patients to have 90% power to detect a 3% bleeding rate difference between the 2 trial arms. The study accrual is estimated to take approximately 2 years to complete if 25 centers are able to recruit approximately 50 thrombocytopenic infants per year. Discussion. Two issues were raised concerning this proposal: standardization of platelet products used and platelet dose. The investigators indicated that standardization of the platelet product might be difficult because different centers use different products. Regarding the issue of platelet dose, the investigators indicated that quantification of the number of platelets in administered products could be considered. Trial TM-105: Impact of a Liberal RBC Transfusion Strategy on Neurologically Intact Survival of Extremely Low Birth Weight Infants: The Transfusion and Brain Injury Trial Background and rationale. Decades of speculation as to the benefits and risks of RBC transfusions in preterm newborns have been enlightened only by sparse randomized data. Although there have now been 2 recent mediumsized RCTs, clear evidence-based guidelines on desirable threshold hemoglobin values are still uncertain. These 2 recent RCTs were the Premature Infants in Need of Transfusion (PINT) trial (and its follow-up, PINT-OS) and the Iowa trial.15-17 These trials differed in crucial areas of design, enrolled population, and hemoglobin thresholds (or triggers) for transfusion and came to differing conclusions regarding the outcomes by the time of NICU discharge. Both trials independently raise the

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hypothesis that using a higher hemoglobin transfusion threshold (more liberal transfusion strategy) might confer neuroprotection.16,17 The Iowa study found that the more restrictive hemoglobin transfusion threshold arm led to worse outcome of periventricular leukomalacia or grade IV intraventricular hemorrhage. The PINT/PINT-OS trial found that the cognitive subscale of the Bayley assessment at 18 to 24 months was significantly worse. These data, accrued from the only reported trials in preterms of RBC thresholds, call for a new, larger trial. The primary hypothesis would thus be that in infants weighing less than 1000 g at birth, a high hemoglobin threshold for RBC transfusion compared with a lower hemoglobin threshold would lead to a higher survival rate at time of discharge from the neonatal ICU and these survivors would have a better neurodevelopment outcome at 18 to 24 months, measured using a standardized Bayley III test assessment. Trial design and feasibility. The trial would be powered to address a composite outcome of survival free of neurodevelopmental impairment in a cohort of very high risk preterm infants randomized to be transfused with RBC at a low (hematocrit, 38.5%) or high (hematocrit, 45.5%) transfusion trigger. Neurodevelopmental impairment would be assessed by standardized Bayley III developmental tests. The trial would be powered to address important secondary outcomes: death by time of discharge from the hospital and the individual components of the Bayley examination at 18 to 24 months corrected age. This trial would enroll patients with a birth weight of less than 1000 g and with a gestational age of at least 22 weeks but less than 29 completed weeks who are less than 48 hours old. Based on results from the PINT trial, the trial would need to randomize 1793 subjects to evaluate 1614 subjects for 80% power to detect a 7-point difference on the Bayley III test score. Feasiblity would be enhanced if collaborations with the NICHD network of NICUs and the international team composing the PINT trial network could be developed. Discussion. A concern was raised about the availability of patients for follow-up at 18 to 24 months. The investigators indicated that previous studies both in Canada and in Australia had 95% follow-up rates and that all sites that would be included in this study would need to achieve a followup rate of at least 90% at 18 to 24 months. The issue

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of the mechanism of the neurodevelopmental impairment was raised. The investigators pointed out that this was unknown at this point in time and that they had not yet formulated a hypothesis but would do so when the study is actually proposed. SUBCOMMITTEE 3: SURGICAL ISSUES

Trial TM-106: The Use of FFP to Prevent Bleeding in Patients Undergoing Radiographic and Bedside Procedures Background and rationale. The primary hypothesis on which this proposal is based is to determine if the administration of FFP to patients with an international normalized ratio (INR) of 1.3 to 1.9 reduces the change in hemoglobin concentration after an invasive procedure compared with a placebo infusion. The transfusion of FFP to patients with mild and moderate abnormalities of their coagulation tests before invasive procedures is a common practice. In a recent survey of FFP transfusions, approximately 30% of requests for FFP were for patients who were about to undergo an invasive procedure.18 There are few RCTs that address the efficacy and safety of this practice. The rationale for FFP transfusion before an invasive procedure is to prevent bleeding complications in patients who are presumed to be at increased risk based on an abnormal coagulation screening test result. However, numerous studies in patients undergoing surgery or bedside invasive procedures have demonstrated that an elevated prothrombin INR (International Normalized Ratio) has a very low positive predictive value for bleeding, in the absence of a history of bleeding.19 In addition, the transfusion of the amount of FFP often used in this setting (≤4 units) produces very little change when the INR is only mildly elevated.18 These data suggest that mild abnormalities in coagulation screening tests do not effectively identify patients who are likely to have procedure-related bleeding and that transfusing small volumes of FFP produces minimal correction of these laboratory values.20 However, the interpretation of these data is limited by the retrospective design of most of the available studies and, for many of them, the small number of patients. There is a clear need to perform an RCT to evaluate the widespread practice of transfusing FFP to prevent bleeding associated with bedside invasive procedures in patients with mild abnormalities in their coagulation tests.

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Trial design and feasibility. The primary end point of this study would be the change in hemoglobin concentration at 48 hours after the invasive procedure. Secondary end points would include the number of RBC units transfused and the occurrence of congestive heart failure. The study would recruit all patients 18 years or older undergoing an invasive procedure and with an INR between 1.3 and 1.9. Invasive procedures would include any radiological invasive procedure (eg, lung biopsy, liver biopsy, angiogram) or any bedside procedure (eg, thoracentesis, paracentesis), except for peripheral intravenous access lines. Exclusions would include (1) patients with active bleeding; (2) patients with hemodynamic instability based on the judgment of the treating physician; (3) patients who decline blood transfusion; (4) any patient who, in the judgment of the research team, should not be enrolled in the trial (this would include, but not be limited to, factors such as alcohol or drug dependence, or psychiatric illness); or (5) patients unable to provide informed consent. This study would be a multicenter clinical trial. Patients would be randomly allocated to receive FFP (15 mL/kg) or placebo before their invasive procedure stratified by baseline INR (1.3-1.6 and 1.61-1.9). A baseline hemoglobin concentration and INR would be obtained before this procedure and at least every 12 hours after the procedure for 48 hours. The use of RBC transfusions would be at the attending physician's discretion. If the INR is greater than 2.0 after the procedure, FFP may be administered at the attending physician's discretion. Patients would be seen daily for 2 days, and clinical events including bleeding would be assessed. Total sample size required to have a 90% power to detect a difference in mean hemoglobin of 0.33 g/dL is 388 patients. Using very broad entry criteria with patients undergoing any invasive procedure should make the study feasible. Research nurses would be available for urgent daytime cases; emergent cases on nights and weekends would not be recruited. Using a placebo to blind the trial may be difficult to implement. It would be difficult to enroll enough patients to examine secondary outcomes of interest. Trial TM-107: The Use of FFP to Prevent Blooding in Patients Undergoing Surgical Procedures in the Operating Room This study proposal was similar to that proposed in Trial TM-106 except for the use of a different

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patient population. In proposed study TM-107, the study subjects would undergo their invasive procedure in the operating room, whereas in TM106, the procedure would be done at the bedside. This study would be performed after completion of the trial conducted in patients undergoing bedside procedures (TM-106) and if that trial found that FFP did not reduce bleeding. Discussion. It was pointed out that some interventional procedures have a higher risk of bleeding than others. The investigators responded that the intention of both studies (TM-106 and TM107) would be to stratify subjects both by INR and by procedure. Concern was expressed related to the potential wording in the informed consent. The investigators indicated that it is intended for study personnel to explain that the patient's physician wants to administer plasma that may not be necessary and that current data do not indicate the value of such transfusions in clinical situations like that of the patient. Another question was related to whether the study might find that most patients do not bleed at all and that a few bleed catastrophically. The investigators responded that there is no reason to think that FFP would make a difference in catastrophic bleeding, which would likely be due to laceration of blood vessels and likely require surgery. They also pointed out that if the study indeed showed that the risk of clinically significant bleeding was low, such evidence would support the concept that FFP is not necessary for patients similar to the study subjects proposed in these studies. Trial TM-108: Transfusion Trigger Trial in Cardiac Surgery Background and rationale. The primary hypothesis of this study is to determine if a liberal RBC transfusion strategy (transfusion trigger hemoglobin 10 g/dL) is associated with a lower composite outcome incidence of all-cause mortality at 30 days, recurrent myocardial infarction, infection, and other complications within 30 days of enrollment compared with a restrictive RBC transfusion strategy (transfusion trigger hemoglobin b7 g/dL) in elective cardiac surgery patients. Patients undergoing cardiac surgery and cardiopulmonary bypass frequently receive RBC transfusions in the postoperative period. It has been estimated that 11% of RBC resources in the United

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States are used for transfusion support of patients undergoing coronary artery bypass surgery and that nearly 20% of blood transfusions are associated with cardiac surgery. The optimal hemoglobin concentration to be used for RBC transfusions in patients having cardiac surgery is unknown. Blood transfusion has been associated with an increase in infection, as well as both short- and long-term mortality in observational studies. However, there has never been an adequately powered RCT evaluating RBC transfusion hemoglobin triggers in elective cardiac surgery patients. Trial design and feasibility. The primary end point for this study would be a composite outcome of all-cause mortality at 30 days and in-hospital complications including serious infection (pneumonia, mediastinitis/deep sternal infection, and sepsis), acute renal failure, stroke, prolonged ventilation greater than 48 hours, and myocardial infarction. The patient population would all be adult patients (18 years or older) scheduled to undergo elective cardiac surgery during the index hospitalization who are likely to receive blood transfusion (Transfusion Risk Understanding Scoring Tool score ≥3). Patients would be excluded if they had any bleeding requiring surgery or clinically important hemodynamic instability based on the judgment of the treating physician. Patients would be consented in the preoperative period and enrolled provided they had a hemoglobin concentration less than 10 g/dL at the time of randomization. Patients would be randomly allocated to either a liberal or a restrictive transfusion strategy group. Patients randomized to the liberal transfusion strategy would receive only one unit of packed RBCs following randomization and receive enough RBCs to raise the hemoglobin concentration to greater than 10 g/dL any time the hemoglobin concentration is detected to be less than 10 g/dL during the hospitalization for up to 30 days. Patients randomized to the restrictive transfusion strategy would be permitted to receive a transfusion if they developed symptoms related to the anemia or if the hemoglobin concentration fell to less than 7 g/dL. Symptoms of anemia that would be indications for transfusion in the symptomatic transfusion strategy would be as follows: (1) definite angina requiring treatment with sublingual nitroglycerin or equivalent therapy; (2) new or worsening congestive heart failure including dyspnea, orthopnea, or

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paroxysmal nocturnal dyspnea, S3 gallop, edema without other apparent cause, elevated jugular venous pressure without other apparent cause, new or worsening congestive heart failure on chest radiograph; and (3) new unexplained tachycardia or hypotension. Electrocardiogram (ECG) and troponin concentrations would be performed every 12 hours for 1 day and then daily for 2 days or until discharge from the hospital. Patients would be called at 30 days and 6 months after enrollment or at the end of the study to learn of their vital status and whether they were admitted to the hospital. It was estimated that the primary outcome would occur in 15% of patients. The sample size needed to detect a 25% effect was estimated to be 4190 patients. Discussion. A question was raised about the possible use of a noninferiority design for this study. It was pointed out that a noninferiority design was more likely to increase than decrease the sample size. Moreover, a superiority study design was indicated, as the goal would be to determine whether giving more blood produces a superior outcome. The investigators also indicated that for those who believed that the standard of care transfusion trigger is 10 g/dL, then the study approach proposed might show that using a lower trigger is as effective an intervention in such patients as the 10-g/dL trigger. The study would then show that using less blood is an effective intervention for such patients. Trial TM-109: Transfusion Trigger Trial in Coronary Artery Disease Background and rationale. Patients with acute coronary artery syndrome and coronary artery disease (CAD) frequently become anemic because they undergo invasive procedures and are treated with multiple antithrombotic agents.21 The primary hypothesis to be evaluated in this study is to determine if a liberal transfusion strategy in anemic CAD patients is associated with a lower incidence of composite outcome for all-cause mortality at 30 days, recurrent myocardial infarction, emergent percutaneous intervention (angioplasty or stent insertion), or coronary artery bypass graft (CABG) surgery within 30 days of enrollment compared with a restrictive transfusion strategy. Patients with acute coronary syndrome who develop bleeding have a very high risk of death (relative risk = 1.6-10.0) and recurrent myocardial infarction (relative risk = 4.4) compared

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with patients who do not develop bleeding, and frequently receive RBC transfusions.22 Cardiologists frequently transfuse patients to maintain a hemoglobin concentration greater than 10 g/dL—because oxygen delivery to the myocardium is flow dependent because the heart extracts nearly 100% of oxygen—and myocardial ischemia may be precipitated by low hemoglobin concentrations. Trial design and feasibility. This trial would recruit all patients 18 years or older with (1) STsegment elevated myocardial infarction, (2) non– ST-segment elevation myocardial infarction), (3) unstable angina, or (4) stable CAD who are undergoing cardiac catheterization during the index hospitalization. To be enrolled, the patient would need to have a hemoglobin concentration less than 10 g/dL at the time of allocation. Exclusion criteria would include (1) uncontrolled bleeding at the cardiac catheterization puncture site or need for surgical repair, (2) retroperitoneal bleeding requiring surgery, (3) clinically important hemodynamic instability based on the judgment of the treating physician, and (4) anticipated scheduled cardiac surgery within the next 30 days. Patients randomly allocated to the liberal transfusion strategy would receive 1 unit of RBCs following randomization and receive enough blood to raise the hemoglobin concentration to greater than 10 g/ dL any time the hemoglobin concentration is detected to be less than 10 g/dL during the hospitalization for up to 30 days. Patients randomized to the restrictive transfusion strategy would receive an RBC transfusion if they developed symptoms related to anemia. Transfusion would also be permitted, but not required, in the absence of symptoms only if the hemoglobin concentration falls to less than 8 g/dL. Red blood cells would be administered one unit at a time, and the presence of symptoms would be reassessed. Only enough RBCs would be given to relieve symptoms. If the transfusion was given because the hemoglobin concentration falls to less than 8 g/dL, then only enough blood would be given to increase the hemoglobin concentration to greater than 8 g/dL. Symptoms of anemia that would be indications for transfusion in the symptomatic transfusion strategy would be as follows: (1) definite angina requiring treatment with sublingual nitroglycerin or equivalent therapy and (2) new unexplained tachycardia or hypotension. All ECGs and troponin and creatine

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kinase results ordered for clinical purposes would be collected, and troponin concentrations would be obtained every 12 hours for 1 day and then daily for 2 days; ECGs would be obtained daily for 3 days. Patients would be called at 30 days and 6 months after enrollment to determine vital status and rehospitalization. The sample size needed to detect a 25% effect would be between 3000 and 5000 depending on the frequency of the outcome. Discussion. A question arose as to whether the Transfusion Therapy Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) study results could have ethical implications for the proposed study. The investigator responded by saying that if FOCUS shows that the lower arm does as well as the upper arm, this would not provide a reason not to randomize patients with acute coronary syndrome because the clinical settings for the 2 studies are different (FOCUS enrolled patients with cardiovascular risk factors or cardiovascular disease who underwent a hip fracture repair). Cardiologists are thus unlikely to believe that they can give less blood because they would want more data from relevant patients (ie, patients with acute coronary syndromes). If FOCUS showed that using more blood improves outcomes, randomizing patients to the lower threshold might be more difficult to justify. However, the currently available observational data in this setting show that whenever patients receive more blood, they have an increased mortality. Thus, there would be reason to randomize patients in the proposed study regardless of the FOCUS study results. Another question related to whether study participants in the restrictive transfusion arm would be able to receive RBC transfusions if they continued to have symptoms at a hemoglobin level of greater than 8 g/dL. The response was that if a patient had angina and did not respond to nitroglycerin, that patient would be transfused if the attending physician chose to do so. A second indication for giving a transfusion to such patients would be unexplained tachycardia or hypotension. The following comment was made: Transfusion practice is often faith based, and the prevailing bias has been that transfusions are good in patients with CAD. But accumulating evidence indicates that transfusion might not always be good in such patients. Without data from the proposed study, physicians would continue their current RBC

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transfusion practices. Hemoglobin level is probably not the best way to decide whether to transfuse a patient, but that is how such decisions are currently being made; so a study is clearly needed to ask whether hemoglobin levels do make a difference to the transfusion needs of CAD patients. SUBCOMMITTEE 4: ICU AND TRAUMA ISSUES

Trial TM-110: Transfusion Requirements in Critical Care Patients With Evidence of Coronary Syndromes Background and rationale. This trial proposes to ask the following question: Does the transfusion of RBCs to volume-replete patients with evidence of ischemic heart disease and a hemoglobin greater than 7g/dL improve outcome? This trial thus proposes to examine the risk or benefit of RBC transfusions in patients in the ICU with a history of cardiovascular disease such as the cardiovascular disease subgroup in the Transfusion Requirements in Critical Care Patients With Evidence of Coronary Syndromes (TRICC-PECS) trial (n = 357).23,24 Such a trial cannot be performed with a mortality end point with less than a sample size of 30 000 patients. However, by using a combined end point of the change in the multiple organ dysfunction syndrome (MODS) score and death counted as the highest MODS score (ΔMODS), a TRICC-PECS– like trial as proposed with 90% power would require approximately 628 patients per arm. Trial design and feasibility. The primary end point for this multicenter RCT would be 30-day allcause mortality. Patients with a history of CAD or CAD equivalent(s) would be randomly assigned to a restrictive arm (1 unit of packed RBCs when the hemoglobin is lower than 8 g/dL to maintain a hemoglobin level of 8 to 10 g/dL) or a liberal arm (1 unit of packed RBCs when the hemoglobin level is lower than 10 g/dL to maintain a hemoglobin level of 10 to 12 g/dL). Discussion. A question was asked about whether the storage age of the RBCs transfused would be considered. The investigators responded that they would record blood storage age. The investigators also indicated that a major challenge for this trial would be how to classify patients by storage age of the blood received because patients with multiple exposures might receive RBCs of different storage ages.

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Trial TM 111: Moderate Traumatic Brain Injury Coagulopathy Treatment Trial Background and rationale. The question posed by this trial is as follows: Does the transfusion of plasma or platelets improve outcome in patients using aspirin, clopidogril, warfarin, or heparins who sustain mild head injury but have a normal brain computed tomographic (CT) scan result? This trial thus would look at the effects of plasma and/or platelet transfusions in trauma patients with a history of mild head injury and who use anticoagulants. At the University of Maryland trauma center, 6400 trauma patients were admitted directly from the scene of injury in 2008; and more than 4000 of them had a head CT within 8 hours of their admission. A review of the literature suggested that 20% of patients with diffuse brain injury but without a mass lesion on CT will develop an intracerebral hemorrhagic mass lesion on follow-up (presumably higher in the elderly patients on anticoagulants and lower in those with less severe initial brain injury) and that 3% without a subarachnoid hemorrhage on initial CT would have evidence of one on follow-up. Data from 2 centers will be reviewed to try to ascertain more precise numbers, specifically as they relate to mild traumatic brain injury. Such baseline data would be needed before a randomized trial can be fully developed. Trial design and feasibility. The primary end point for this study would be the rate of new intracranial bleeding within 24 hours of a head injury. Patients aged 45 to 85 years on warfarin brought to a trauma center with a moderate traumatic brain injury and an initially normal head CT result would be randomly assigned to receive FFP or not to reverse their coagulopathy. Discussion. Would the study consider the riskbenefit ratio for patients not on anticoagulants? The investigators indicated that the study team would consider this issue if the study were to be further developed. Trial TM 112: Prospective, Randomized Optimal Platelet and Plasma Ratios Background and rationale. The question posed by this trial is the following: Does a high initial ratio of plasma to RBC units, for example, 1:1, as suggested by recent military practice compared

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with 1:3 as previously suggested save more lives during massive transfusion for trauma? 25 The Prospective Randomized Optimum Platelet and Plasma Ratios (PROPPR) Trial is a follow-up of the PRospective Observation Monitoring of Massive Transfusion for Trauma (PROMMTT) study currently underway. The PROPPR study is proposed as a prospective RCT comparing 2 different resuscitation strategies in massively injured patients judged at risk for massive transfusion.26 Such a trial would need to be done with community consultation, as many of the patients would be too sick and their conditions too urgent to obtain informed consent from either the patients or their legally authorized representatives. Twenty-seven academic trauma centers have expressed interest in participating in PROPPR. Best available estimates of the sample size are of the order of 400 to 800 massively transfused patients per arm, but these estimates may need to be adjusted on the basis of the findings of the currently ongoing PROMMTT study. Trial design and feasibility. The PROPPR trial would be a 2-arm randomized trial: The referent group would receive a 1:1:2 ratio of plateletsplasma-RBCs and the experimental arm would receive a 1:1:1 ratio. The primary end point for this study would be the difference in 24-hour mortality between the 2 groups, adjusted for center, injury severity score, and other prespecified confounders. Discussion. Considerable interest focused on the standard-of-care arm proposed for this study and what this currently might be. The investigators felt that a 1:1:4 ratio would be difficult to justify. Furthermore, the 1:1:2 ratio is the current standardof-care at 16 trauma centers across the United States. The final determination of the standard-ofcare arm would nonetheless eventually be based on input from the currently ongoing PROMMTT study as well as close collaboration with combat casualty study investigators. Questions were also asked related to when the various transfusions in a 1:1:1 ratio should stop and whether the order of the RBC and plasma transfusions mattered. The investigators responded that little is known concerning the relevance of the order of the RBC and plasma transfusions and that the 1:1:1 ratio transfusions would stop when a patient's bleeding ceased.

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SUBCOMMITTEE 5: PLASMA, FFP, CRYOPRECIPITATE, AND THERAPEUTIC APHERESIS ISSUES

Trial TM-113: Plasma in Critical Care: A Sequentially Stratified, Noninferiority Trial of Plasma Versus No Treatment for Critical Care Patients Undergoing Invasive Bedside Procedures Background and Rationale. Nationally, in the United States, the most common nonoperative reason for plasma transfusion is for prophylaxis before an invasive procedure. Evidence-based guidance for plasma transfusion is lacking because the pivotal RCT has not yet been done. Plasma is commonly given to patients with an abnormal INR with the expectation of reducing the chance of bleeding complications following invasive procedures.19,20 However, the predictive value of mild to moderate prolongation of the INR for bleeding risk following invasive procedures is low.20 Moreover, plasma does not cause mild to moderate prolongations of the INR to return to the reference range.19,20 The INR serves as a common guide to plasma infusion before bedside procedures. It is not known, however, at what level of INR the benefit of plasma infusions outweighs the risk. “No-treatment” may thus be inferior to plasma infusion if plasma infusion reduces bleeding complications to a greater degree than it causes adverse reactions. On the other hand, “no-treatment” may not be inferior to plasma infusion either if the infusion of plasma lacks efficacy or if the adverse reactions caused by plasma exceed its hemostatic benefit. The primary hypothesis on which this study is based suggests that among patients in medical or surgical critical care units undergoing an invasive procedure with an INR value between 1.5 and 3.0, “no treatment” is not clinically inferior to plasma transfusion for the prevention of bleeding complications during the 24 hours following the procedure. Trial design and feasibility. The primary end point of this study would be the proportion of patients transfused with allogeneic RBCs within 24 hours of the procedure. This measure represents a clinically meaningful outcome that correlates with bleeding and is easily quantifiable. Other factors beyond bleeding would affect the need for RBC transfusion including the pre-procedure hemoglobin level and other comorbidities, but these factors would be balanced by randomization. As such, the difference in the proportion of patients who receive RBC transfusions shortly

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after the procedure would reflect differences in clinically important bleeding between the 2 study groups. The following critical care patients would be eligible: adult or pediatric, with an INR of at least 1.5 and not exceeding 3.0 who require invasive bedside procedures including central venous and arterial line placement, gastrointestinal endoscopy, bronchoscopy, lumbar puncture, paracentesis, thoracentesis, pericardiocentesis, tracheostomy, insertion of percutaneous feeding tube, insertion of an intracranial pressure monitor, and placement of a dialysis catheter. This study would be a multicenter, noninferiority RCT. Attending physicians responsible for ICU patients would be asked to give permission to approach all patients admitted to their unit who meet eligibility criteria. Consent from individual patients would be obtained after admission to the ICU, before the index invasive procedure. Randomization would occur just before the procedure among previously consented patients. Initial enrollment would be patients with INR values of 1.5 to 1.9 who would be randomized to plasma vs no plasma. After enrolment of a specific number of patients, a check would be done to verify that the 2 arms do not statistically differ for the primary outcome. If no difference is observed, patients would continue to be enrolled at that INR range; but in addition, a second stratum of patients (with INR values of 2.0-2.4) would begin enrollment. The same data review process would be repeated; and if no difference is again observed, then the third stratum of patients with INR values of 2.5 to 3.0 would begin enrollment. Each enrolled patient would be randomized once, before an invasive procedure. The treatment arm would be a 1-time infusion of plasma at a target dose of 10 to 15 mL/kg. Clinicians would be free to adjust the actual dose within this range, depending on the clinical circumstances of the patient. Plasma transfusions would be unmasked and unblended. The no-treatment arm would not receive a plasma transfusion, nor would they receive a placebo infusion. For 48 hours from the time of randomization, patients would be observed for signs of bleeding and for adverse reactions to plasma among those given plasma. After 48 hours, observation would cease. Thirty-day mortality would also be recorded. Discussion. Concern about this study centered around the possibility of central nervous system

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bleeding in some patients. The investigators responded that FFP is often used out of fear that something would cause the patient to bleed. Global counting of RBC unit use in this context would thus be quite relevant. Several secondary end points would also be captured including central nervous system–related adverse events as well as those adverse events known to be related to the use of plasma infusions. Trial TM-114: A Prospective, Randomized, Controlled Clinical Trial of Cryoprecipitate Transfusion in Cardiac Surgery Patients Experiencing Major Hemorrhage After High-Risk Cardiac Surgery Background and rationale. This proposal addresses the practice of cryoprecipitate transfusion in patients undergoing cardiac surgery. There is a paucity of data as to the rationale and clinical benefit of such practice, yet a significant number of cardiac patients receive cryoprecipitate.27-30 Cryoprecipitate use in cardiac surgery has never been studied in an adequately powered RCT.30 Approximately half of all cryoprecipitate is nonetheless used in the setting of cardiac surgery. Only 15% of cardiac surgery patients are at risk of requiring large-volume RBC transfusions (defined as N5 units of RBCs). A very high risk cardiac surgery patient population has been identified with a rate of transfusion of 5 or more RBC units or with a need for reexploration of 75%.31 There is considerable interhospital variation in the percentage of patients transfused cryoprecipitate at the time of cardiac surgery (0.3%-10.1%). This product is most commonly used in the setting of postbypass hemorrhage without waiting for the fibrinogen level due to the slow turnaround time for this laboratory assay and the lack of data on the appropriate target fibrinogen level in a bleeding patient in this setting. Small cohort studies have evaluated the impact of cardiac surgery on the fibrinogen level. These studies show a transient decline in the level immediately postoperatively with a doubling of the level and then a gradual return to normal by 45 days postoperatively without the transfusion of cryoprecipitate. The fibrinogen level is not different when nonbleeders are compared with bleeders in some studies, but not others. A recent article suggested that fibrinogen levels (even within the reference range) may be a limiting factor in hemostasis, particularly in women.29 This latter

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study involved only 170 patients and has not been replicated. It is therefore not clear if a low normal fibrinogen level causes bleeding or is a consequence of bleeding. In particular, there are no data to suggest that the correction of the fibrinogen level to a supraphysiologic level would be associated with a reduction in perioperative hemorrhage and the need for reoperation for bleeding. Thus, the primary hypothesis of this study is that the addition of cryoprecipitate to standard blood component therapy (plasma and platelets) decreases the rate of large-volume RBC transfusion (5 or more units) or need for reexploration in cardiac surgery patients at high risk for bleeding. The primary end point of his study would be the proportion of patients transfused with 5 or more RBC units or needing reexploration in the first 48 hours. Trial design and feasibility. This would be a multicenter RCT testing whether the liberal use of cryoprecipitate with standard plasma and platelet therapy is superior to a restrictive cryoprecipitate strategy with only standard plasma and platelet therapy. • Liberal arm—immediate use of cryoprecipitate with plasma/platelet therapy irrespective of the fibrinogen level. • Restricted arm—permitting cryoprecipitate use with plasma/platelet therapy only when fibrinogen level falls to less than 1.0 g/L in the setting of ongoing bleeding. The dose of cryoprecipitate would be standardized to 10 units per infusion. Patients would be randomized when the clinical team orders the transfusion of plasma and/or platelets within the first 4 hours following protamine reversal for postoperative hemorrhage. Thereafter, component therapy of plasma, platelets, and cryoprecipitate would continue to be used as per the study transfusion protocol. Requirements for participation would include the use of standardized antifibrinolytic therapy, acceptance of the transfusion protocol, and standardization of the use of cell salvage and recombinant factor VIIa. Patients would be randomized by the blood bank to minimize time delays in preparation of the cryoprecipitate. Assuming the baseline rate of large-volume transfusion (5 or more RBC units within the first 48 hours postoperatively) or the need for reexploration is 75% in this high-risk

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population, 279 evaluable patients would be required in each group to detect a reduction of 65% in the cryoprecipitate liberal arm. Assuming 75 patients per center per year at a consenting rate of 60%, 6 centers would be participating in this trial that would require 25 months to complete plus the necessary training and pilot run-in at each center. Patients would be stratified by sex and participating center. The study is highly feasible, as previous studies have already identified the high-risk population for large-volume transfusion. The size of the study to detect a 10% difference in the rate of high-volume transfusion is not large (total 558 patients) and can be completed in a small number of centers. A diversity of cardiac centers would be sought to ensure that both academic and nonacademic institutions are included. The major limitations of this study include the lack of blinding, concern regarding protocol compliance in this unstable patient population, and concerns regarding adherence to a standardized transfusion protocol in the postoperative period. Discussion. Comments related primarily to the hypothesis that the hemostatic effect being tested is mainly that of fibrinogen replacement. The investigators acknowledged that other possibilities exist including von Willebrand factor, or factor XIII levels. A suggestion was made that the Food and Drug Administration has approved the use of intravenous fibrinogen concentrate, which could be the logical basis for a third arm. It was suggested that such an arm could help answer the question about the theoretical basis for the hemostatic effect of cryoprecipitate. Trial TM-115: Phase 2, Multicenter, Randomized Trial of Plasma Exchange in Severe Sepsis With Multiple Organ Failure Background and rationale. This study would be conducted in a cohort of patients with sepsis and therefore would include subjects with a very high mortality rate. In previous studies, early intervention with plasma exchange, though not fully explained pathophysiologically, appeared to have a significant impact on patients' mortality.32,33 Sepsis, a systemic inflammatory response to infection, is the most common cause of death in noncoronary ICUs and the 10th most common cause of death in the United States. Sepsis also accounts for 2% to 3% of all hospital admissions.

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The incidence of sepsis has increased over the last 2 decades and has a mortality rate of 28% to 50%. Signs and symptoms consist of fever or hypothermia, tachycardia, hyperventilation, and leukocytosis or leukopenia. Organ dysfunction, hypoperfusion, and hypotension can be seen. Risk factors include age extremes, chronic medical conditions, immune compromise, indwelling catheters and devices, and disruption of natural defense barriers. Sepsis is a complex process consisting of the activation of a variety of host defense systems. Production of a wide variety of inflammatory molecules and consumption of substances can lead to organ dysfunction or an anti-inflammatory response resulting in an immunocompromised state. Current management of sepsis includes antimicrobial agents and control of the source of the infection, hemodynamic support including pressors, oxygenation, and ventilatory support. Additional innovative treatments have included the administration of corticosteroids, monoclonal antibodies to tumor necrosis factor, the soluble tumor necrosis factor receptor, antithrombin, activated protein C, and tissue factor pathway inhibitor. These therapies have sought to interrupt the cascade of inflammation and anti-inflammatory response by interfering with discreet steps in the various relevant cascades. Attempts to block or remove single mediators of sepsis have been somewhat successful; but it may be that a broader, more nonselective approach that affects multiple mediators and replaces multiple factors consumed in sepsis may be more beneficial. Plasma exchange, because of its nonselective nature, has the potential to remove all of the toxic mediators of the syndrome and may therefore be more effective than blocking single components of the process. In addition, if plasma were used as the replacement solution in the plasma exchange, substances consumed during the systemic inflammatory process, such as ADAMTS 13 (A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, no. 13), would be replaced, which in turn could influence the pathophysiology of sepsis and patient outcomes. A number of reports of the use of plasma exchange in the treatment of sepsis have been published. These have included several small nonrandomized clinical trials (6 trials examining 197 patients), case series of 97 reports treating 182 patients, and single case reports (3 reports). The controlled trials have found survivals of 66% to 87% compared with

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either predicted survivals or survival of historical controls of 20% to 40%. Three RCTs of 106, 30, and 10 patients have been published.32-34 The largest randomized trial by Busund et al32 found 28-day mortality rates of 33% in the plasma exchange group compared with 53.8% in the control group (P b .05). When differences between the control and experimental groups were considered using multiple logistic regression, the significance of the treatment variable on mortality was P = .07. The trial by Reeves et al33 using continuous plasma filtration examined 22 adults and 8 children. No difference in mortality was seen between the control group and those treated with plasma filtration. Finally, in the trial by Nguyen et al,34 10 children were randomized to plasma exchange or standard treatment. A decrease in organ severity score and improved survival was seen in the plasma exchange group. This resulted in stoppage of the trial early due to the interim analysis showing significant improvement in the treatment group.34 Trial design and feasibility. The primary hypothesis of this proposal is that plasma exchange would result in improved mortality in patients with sepsis suffering from multiple organ failure. This study would be a multicenter RCT involving patients with severe sepsis. Patients would be randomized to either standard therapy or standard therapy plus plasma exchange. The plasma exchange protocol would consist of 1.5-vol plasma exchanges using plasma as the replacement fluid. Anticoagulant would be according to local practice at each site (citrate, heparin, or heparin citrate). Plasma exchange course would consist of 14 plasma exchanges over 14 days or until resolution of multiorgan failure (MOF) to one organ failure or resolution of thrombocytopenia to a platelet count greater than 100 × 109/L, whichever occurs first. The first plasma exchange would be performed as soon as possible after the diagnosis of MOF involving 3 or more organs but no later than 24 hours. The following laboratory values would be assayed: • Immediately before and daily for the 14 days following initiation on plasma exchange— lactate dehydrogenase, free plasma hemoglobin, ADAMTS 13 activity and inhibitor, ADAMTS 13 autoantibody, interleukin-6, plasminogen activator inhibitor–1, tissue factor, antithrombin, protein C, and quantity of schistocytes.

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• Immediately before initiation of plasma exchange and daily for 30 days after the initiation of plasma exchange—platelet count. Reported 30-day mortality rates in severe sepsis with MOF are 40% to 50%. A 2-sided log-rank test with an overall sample size of 100 subjects (50 in each arm) would provide 80% power at a .05 significance level to detect a change in 30-day survival rate from 40% in the standard therapy arm to 60% in the standard therapy plus plasma exchange arm (hazard ratio of 0.5575). Discussion. Concern was expressed about the feasibility of this study, particularly relating to the timing of entering patients into the study. The investigators responded that the intention of the study was to target critically ill patients and that they would discuss this proposal further with their critical care colleagues before its implementation. Trial TM-116: A Prospective RCT of Extracorporeal Photopheresis for Treatment of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplant Background and rationale. This study attempts to address a very important therapeutic issue of steroid-resistant graft-vs-host disease (GvHD) in a fairly large population of patients who develop chronic GvHD after hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been suggested to have a steroid sparing effect and, as such, could possibly improve the quality of life by decreasing the number of serious complications associated with prolonged steroid therapy.35,36 The primary hypothesis of this study is that the use of ECP along with standard therapy would increase the time to GvHD treatment failure compared with standard therapy alone. The primary end point would be a composite of total skin score and steroid tapering at the time of assessment.37,38 Trial design and feasibility. Patients who receive HSCT and develop chronic GvHD with cutaneous manifestations at 100 days or more after HSCT would be randomly assigned to receive standard therapy with or without ECP. Discussion. It was pointed out to the investigators that they would need to make sure that transplant physicians embrace the proposed concept. Another concern raised was the randomization to standard treatment when the nature of standard

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treatment is not at all clear. The investigators indicated that some centers do not provide ECP and not all clinicians are convinced that ECP was useful for the treatment of GvHD. The investigators pointed out that without data from an adequately powered RCT to demonstrate whether ECP has a role in this patient population, it would be difficult to move forward in the treatment of this serious complication of HSCT. SUBCOMMITTEE 6: RBCS, BLOOD CONSERVATION, AND BLOOD MANAGEMENT ISSUES

Trial TM-117: Blood Salvage and Cancer Surgery Background and rationale. Cancer surgery can result in profound blood loss. In many surgical procedures, blood salvage devices are used to reduce allogeneic blood exposure. However, in cancer surgery, blood salvage is considered by many to be contraindicated. This contraindication arises from the fear of causing disseminated metastasis from cancer cells being contained in the shed blood product and then reinfused. Little data are currently available to support this contraindication. In fact, 10 studies have been published encompassing 476 patients who have received blood salvage during resection of multiple different tumor types involving the liver, prostate, uterus, and urologic system. In all circumstances, the long-term outcome was equivalent or better in the blood salvage group when compared with the control groups.39-42 All these studies were retrospective, so the level of evidence is weak; nevertheless, these studies provide a compelling argument that diffuse metastases do not occur following the application of blood salvage. Currently, the standard therapy for managing anemia during cancer surgery is through the use of allogeneic RBC transfusions. The proposed study would compare allogeneic transfusion vs autologous RBC transfusions via blood salvage. The patient population chosen to perform this study is composed of patients undergoing laparotomy for the cytoreduction of gynecologic malignancies. Trial design and feasibility. The primary hypothesis of this study is that blood collection and reinfusion (blood salvage) during cancer surgery result in at least as good or better cancer outcomes when compared with leukocyte-reduced allogeneic transfusion. The primary end point would be time to recurrence; the expected frequency of cancer

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recurrence in this population is approximately 50%. Follow-up would occur at 3-month intervals or when a patient suspected that his or her cancer had recurred. The time to recurrence would be defined in months from the time of surgery and exposure to blood products during this surgery. Patients undergoing laparotomy for cytoreduction surgery of gynecologic malignancies would be included in the study. Patients would be randomized to receive either allogeneic RBCs or blood salvage. Allogeneic RBCs would be further subdivided into non– leukocyte-reduced and leukocyte-reduced products. It is anticipated that approximately 1200 patients (600 salvage, 300 non–leukocyte-reduced, and 300 leukocyte-reduced) would need to be enrolled. This figure is based upon the expected frequency of cancer recurrence at 3 years of 50%, and aims at a 75% power to detect a 2-sided 10% difference in outcome between the autologous (600 patients) and the allogeneic (600 patients) arms. Before cytoreduction surgery, noninvasive (CT and positron emission tomographic) scans would be obtained to assess the extent and potential respectability of the disease. In addition, laparoscopic evaluation would be made in patients where noninvasive evaluation is unsatisfactory. Upon identification of a patient who is a candidate for cytoreduction surgery, randomization to 1 of 3 study arms would follow: (1) perioperative blood salvage, (2) allogeneic transfusion with leukocyte-reduced RBCs, and (3) allogeneic transfusion with non–leukocyte-reduced RBCs. Surgery and postoperative chemotherapy would be performed in the customary way for this patient population. Patients would be followed at 3month intervals for evidence of disease progression. Computed tomographic and positron emission tomographic scans would be obtained for the delineation of disease progression and the distribution of disease. Patients would be enrolled in the study for a 3-year period. Trial TM-118: P2Y12 Inhibitors and Post-CABG Bleeding Background and rationale. Inhibitors of platelet P2Y12 adenosine diphosphate (ADP) receptors, for example, clopidogrel, are important agents in the medical management of CAD. Abundant evidence (mostly small, retrospective, nonrandomized studies) suggests that clopidogrel is associated with excessive perioperative bleeding.43 Off-pump procedures do not seem to lessen this risk.44 There is a

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highly variable response to clopidogrel based on laboratory measurement of ADP response. As many as 30% of treated patients show diminished or absent effect on ADP-mediated platelet aggregation that reflects bleeding risk. A recent reevaluation of the Acute Catheterization and Urgent Intervention Triage Strategy trial data found that dual-antiplatelet therapy (clopidogrel plus aspirin) administered before catheterization in patients with acute coronary syndromes who require CABG was associated with significantly fewer adverse ischemic events without significantly increased bleeding compared with withholding clopidogrel until after catheterization.45 This desirable outcome occurred with adherence to a policy of withholding clopidogrel for up to 5 days before operation whenever possible. There is a significantly increased cost of delaying operation for up to 5 days in patients with acute coronary syndromes because most of these patients would require hospitalization usually in an intensive care setting. A significant cost savings and, perhaps, improved outcome could result from earlier operation if the risk for bleeding could be accurately predicted. As many as 30% of patients who receive a loading dose of clopidogrel do not have satisfactory platelet inhibition. Preoperative tests of platelet inhibition are available, but their clinical usefulness is unproven. The intent of this study is to identify clopidogrel-treated patients who can safely undergo urgent operations as well as to identify the best clinical test for determining clopidogrel resistance. The primary hypothesis of this study is that bleeding risk is not increased in clopidogrel-resistant patients who require urgent CABG. The primary end point of this study would be a composite end point of bleeding including allogeneic transfusions, reoperation for bleeding, and excessive chest tube bleeding (N1500 mL in 24 hours). Trial design and feasibility. Patients with abnormal platelet function tests after a loading dose of clopidogrel who require urgent CABG would be candidates to be enrolled into this study. Resistant patients would be randomized to either proceeding with an urgent operation or delaying their surgery for 5 days. The estimated sample size is 713 subjects per arm for a total of 1426 subjects. Discussion. The ensuing discussion centered around what platelet function test would be used in

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this study. The investigators indicated that VerifyNow is a point-of-care test. The best test is the vasodilator-stimulated phosphoprotein (VASP) index. The latter, however, is a research tool that is highly specific for platelet inhibition; and some recent studies have used the VASP index to guide clopidogrel administration with good results. A translation of the VASP index to a point-of-care test would be very valuable. However, none of the currently available point-of-care tests is clearly superior to the others. This issue is one of the key ones that will need to be decided before this study goes forward. Trial TM-119: Study of Safety and Efficacy of Acute Normovolemic Hemodilution in Reducing Surgical Transfusion Rates Background and rationale. Of various available blood management strategies, acute normovolemic hemodilution (ANH) is among the oldest. This technique is based on the theory that replacing a portion of patient's blood with fluids before surgery to induce hemodilution and returning the drawn blood during or after surgery, if blood is needed, could result in a net savings of a patient's blood and reduce the need for allogeneic RBC transfusions. Controversy exists as to the efficacy of this method in reducing allogeneic blood transfusion requirements in surgery. Cited reasons include the lack of a standard approach (blood volume drawn, replacement fluid, etc), uncertainties over the target hemoglobin, a wide range of blood loss in patients, the issue of standard/objective transfusion triggers for various blood components, and design issues (randomization, blinding, sample size).46-49 The proposed study is a large RCT to compare safety and efficacy of performing ANH (with 1 of 3 predefined volumes) vs no ANH in reducing allogeneic transfusion in patients undergoing major orthopedic or gynecologic surgeries. The primary hypothesis of this study is that patients undergoing ANH have lower allogeneic blood transfusion requirements (rate and volume). Trial design and feasibility. Preliminary screening would be done during preoperative assessments, and eligible patients would be approached for consent. Consenting patients would have hemoglobin and weight measurement within 24 hours of scheduled surgery; and if within

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the inclusion criteria, they would be randomized to either of the 4 following arms based on their estimated blood volume (EBV): A—ANH with 5% of EBV B—ANH with 10% of EBV C—ANH with 15% of EBV D—no ANH (control) The EBV would be calculated using each patient's weight and sex (75 mL/kg for males and 54 mL/kg for females, with adjustment for obesity). The ANH volume would be calculated based on a percentage of EBV. In the operating room, a standardized approach would be used to withdraw blood and replace it with predefined fluids. Standard, objective RBC transfusion (eg, transfuse if hemoglobin reaches 7 g/dL or if there are signs of ischemia) criteria would be used throughout the surgery; and whenever blood is indicated, ANH blood (if available) would be given first, followed by regular, crossmatched allogeneic RBCs. Plasma/ platelet transfusions would also be governed by preestablished guidelines. Patients would be followed up during their hospital stay for complications. Assuming a baseline transfusion rate of 30% in the target patient population and a 50% reduction to 15% in the arm randomized to 1000 mL ANH, 120 cases per arm would be needed to achieve a power of 80% with α of 0.05 (total sample size will be 4 × 120, or 480 subjects). An adjusted sample size of 600 is also suggested to account for protocol deviations, failed consents, and other unforeseen issues. It is estimated that 8 to 12 centers with an estimated enrollment of 2 to 3 patients per month over a 2-year period would be required to complete this study. SUBCOMMITTEE 7: MEDICAL AND BLOOD DONOR ISSUES

Trial TM-120: Prevention of Alloimmunization via Pathogen Inactivation of Platelets Background and rationale. Observations from the Trial to Reduce Alloimmunization to Platelets (TRAP) study suggest that patients without evidence of prior exposure to human leukocyte antigen (HLA) antigens experience a significant decrease in platelet transfusion effectiveness with prolonged platelet suppor.50,51 One explanation is that nonimmune conditions in these patients might lead to

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damage of the vascular endothelium, increasing the fixed daily platelet requirement to stabilize vascular integrity.52 An alternative explanation is suggested by observations from trials of pathogen-inactivated (PI) platelets treated with UV irradiation and photosensitizers that showed that patients receiving these platelets did not experience the same degree of decay in platelet transfusion recoveries or intertransfusion intervals as seen with control untreated platelets or in TRAP study patients.53,54 The possibility is raised that the decrease in transfusion effectiveness with subsequent transfusions is due to undetected alloimmunization that is prevented by the treatment of the products by the PI procedure. The ability of UV light treatment to inactivate APCs and lymphocytes in platelet concentrates lends support to this hypothesis.53,54 A second potential advantage of using PI-treated platelets in support of patients requiring prolonged platelet transfusion relates to the possibility that the risk of serious transfusion reactions, in particular, ALI, may be reduced. Acute lung injury is a significant cause of morbidity and mortality, occurring in 25% to 50% of allogeneic HSCT patients and may account for 50% of mortality. Blood transfusion is a risk factor for ALI, but the impact of blood transfusion on the incidence and mortality of HSCT recipients is unknown. Furthermore, the true prevalence of ALI may be underestimated in this population. Recent analysis of a large, randomized, controlled, clinical trial to evaluate the therapeutic efficacy and safety of PI platelets demonstrated a trend for reduced mortality among all patients supported with the PI platelet components and specifically for patients with AL 50. There may be several potential explanations for these differences in mortality between patients supported with PI platelets vs conventional components that relate to residual white blood cell in the platelet products including reduction of cytokine synthesis and/or antigen presentation.55-57 Trial design and feasibility. The hypothesis on which this proposal is based is that the declining responsiveness to successive platelet transfusions seen in heavily transfused patients is due to previously undetected HLA (or other antigen) alloimmunization related to residual leukocytes in the transfusion products and can be decreased by treatment of platelet products with UV-based PI

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procedures. A multicenter, randomized, controlled trial is thus proposed involving patients who are undergoing high-dose chemotherapy and/or HSCT for hematologic/oncologic disease who require prolonged platelet transfusion support. The primary end point of the study would be the mean sequential 1-hour post–platelet transfusion increments for the first 20 platelet transfusions received for patients transfused with PI platelets vs standard leukoreduced platelets. Secondary end points would include the following: comparisons of HLA or platelet antigen sensitization using sensitive serologic techniques, rates of transfusion reactions, including ALI, 18- to 24-hour platelet increments, intertransfusion intervals, 1- and 18- to 24-hour corrected count increments (CCIs), number of platelet transfusions required, bleeding episodes, and all-cause mortality. The study population would include adult and pediatric patients requiring large numbers of platelet transfusions for support in myeloablative chemo/ HSCT therapy for hematologic/oncologic disease. This study would be a multicenter RCT with 2 arms comparing patients receiving PI-treated vs standard leukoreduced apheresis single-donor platelets. Patients would be randomized before their first platelet transfusion and followed for the first 20 to 25 transfusions or for 8 weeks. Baseline demographic and laboratory data would include age, sex, ethnic origin, race, height, weight, diagnosis, procedure/chemotherapy (type and date of transplant), history of prior pregnancy or transfusion, ABO type, coagulation studies (prothrombin time, activated partial thromboplastin time, PTT, fibrinogen) complete blood count, platelet count, and HLA/platelet-specific antibody screen. Concerning feasibility, (1) multicenter large-scale platelet transfusion trials have been successfully conducted (eg, TRAP, PI Trials, PLADO), suggesting that it would be possible to recruit sufficient patients for such a study; (2) more sensitive methods of HLA and platelet antibody detection are widely available; and (3) the developers of both the Mirasol and INTERCEPT treatment for PI of platelets are supportive of the concept of this study. Discussion. Discussants urged that this trial be designed as a 3-arm RCT study to include both currently available platelet pathogen inactivation methodologies, if possible. The investigators agreed

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that this was a logical course of action for this proposal, but were concerned about the potential sample size required for such a 3-arm study. Trial TM-121: Effect of the Use of Erythropoietic Stimulating Agents, With or Without Parenteral Iron, on the Transfusion Requirements in Anemic Cancer Patients Receiving Platinum-Based Chemotherapy Background and rationale. Cancer patients receiving chemotherapy, especially platinum based, frequently become anemic and require RBC transfusions. Previously, the use of erythropoietic stimulating agents (ESAs) had substantially reduced the need for transfusions in cancer patients; and this has had a salutary effect on the nation's blood supply. However, because of safety concerns around the use of ESAs, particularly at doses designed to raise the hemoglobin to near normal, restrictions on ESA use and reimbursement have sharply lowered the use of this class of drug and have led to early reports of increased RBC utilization in large oncology practices. The increased risk associated with the use of ESAs in cancer patients has been a topic of considerable debate. 58,59 There is a statistically significant increased risk of cardiovascular and thrombotic events in anemic cancer patients receiving an ESA. However, the risk of tumor progression or early death is not so clear for patients receiving chemotherapy who are also being treated with an ESA; and the results are a matter of controversy. Although the excessive use of ESAs should be avoided, current restrictions placed on such drugs may be unnecessarily stringent. Currently, the package inserts state that an ESA should be started when the patient‘s hemoglobin falls to less than 10 g/dL. But reimbursement restrictions threaten to increase the use of RBC transfusions to support patients. Red blood cell transfusions themselves may not be entirely safe in this clinical setting and may, in fact, independently contribute to adverse outcomes in cancer patients. At the same time that substantial retrenchment was taking place in the use of ESAs for the anemia of cancer chemotherapy in the United States, several European (as well as American) randomized studies demonstrated a reduction in the ESA dose needed to achieve a target hemoglobin level if the drug were given with parenteral iron.60,61 If, by giving iron and an

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ESA together, a lower dose of ESA would be needed to achieve a desired hemoglobin level, the adverse events associated with earlier trials might be avoided. Thus, it is timely to try to resolve some of the outstanding issues. The basic question of this study is this: Are there outcome differences in survival or tumor progression if chemotherapyinduced anemia is managed with an ESA, iron, ESA plus iron, or RBC transfusions alone? The hypothesis for this study is as follows: Using ESA plus parenteral iron would reduce the dose of ESA needed to achieve a hemoglobin target and would also result in reduction of need for RBC transfusion in cancer patients receiving platinumbased chemotherapy. Trial design and feasibility. This study would be a randomized, blinded trial with 4 arms: (1) ESA alone, (2) ESA plus intravenous iron, (3) intravenous iron alone, and (4) RBC transfusions alone. There would need to be several hundred patients per arm. The primary outcomes would be survival and tumor progression. Secondary outcome would be the number of RBC transfusions required over the course of the study. The clinical trial would involve patients with any nonhematologic malignancy who would receive platinumbased chemotherapy. As the patients became anemic, they would be randomized into the 4 arms. Randomization and intervention would begin as the patients' hemoglobin levels fell to 10.0 g/dL. Goals of the study would be to achieve and maintain a hemoglobin level of 11.5 to 12.5 g/dL. Outcomes would be tumor progression, “on study” survival, and overall survival at 6 months. Comparisons would be the percentage of patients achieving the target hemoglobin, numbers of RBC transfusions per patient in each arm, and dose of ESA required. This would be a multicenter trial involving no less than 200 patients per arm. Randomization would be 1:1:1:1. Laboratory monitoring would be no less than every 2 weeks, and the trigger to transfuse would either be symptomatic anemia or a hemoglobin level less than 9.0 g/dL. Discussion. Concern was expressed about the availability of data to indicate that the maintenance of a hemoglobin concentration of greater than 10 g/dL was clinically necessary. The investigators acknowledged that no such evidence exists.

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Trial TM-122: Trial of Reduced-Volume Whole-Blood Collections to Mitigate the Risk of Vasovagal Reactions in Young Donors Background and rationale. Most blood donations are uneventful. However, 3% to 5% of donors suffer adverse events that threaten their well-being, reduce the likelihood of their returning to donate, and may influence their friends and associates against giving blood. Young donors of high-school and college-going age are especially likely to suffer such adverse events.62,63 Various interventions are being considered in an attempt to reduce the incidence of adverse events, especially in young donors. 64,65 Current American Association of Blood Banks standards allow as much as 525 mL of blood (10.5 mL/kg) to be removed in a single collection from even the smallest eligible donors (≥50 kg), representing greater than 17% of the donor's EBV in female donors less than 5 ft tall. This study would test whether collecting a smaller volume of blood (maximum blood loss of 460 mL vs current maximum of 525 mL) from young college donors would significantly reduce the incidence of prefaint and systemic vasovagal reactions, presumably through a reduction in the proportion of the donors' EBV removed during each blood collection. The benefit of an overall reduction in the volume of blood collected is not known and cannot easily be predicted from current hemovigilance data. There is considerable variation in reporting among blood centers that prevents direct comparisons of reaction rates. Therefore, the primary assessment of outcomes of intervention to reduce adverse events should be compared within a given blood center and a demonstration of an effect should be confirmed in multiple blood centers to establish the generalizability of conclusions. However, the introduction of low-volume collections into a blood center operation is a major undertaking. Changes need to be made to the blood collection sets, the calibration and validation of collections scales, the training of collection staff, and the component manufacturing process due to a change in the expected yield of random donor platelets and plasma from each collection. The primary hypothesis of this study is that reduced-volume whole-blood collection (460-mL volume) from young donors would reduce the incidence of prefaint reactions relative to conventional volume blood donation (b525 mL total volume) by greater

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than 20%. The primary end point would be the rate of self-reported donor adverse experiences within 7 days postdonation. Secondary hypotheses would be that young donors donating lower volumes are more likely to donate again within 12 months, are less likely to require outside medical care after donation, and have fewer systemic vasovagal reactions compared with regular-volume donors, and that the rate of self-reported adverse reactions over 7 days would correlate with but exceed the rates reported by blood center staff at the time of donation. Trial design and feasibility. This trial would be carried out in 6 regional blood centers that each collects more than 20 000 blood donors at college blood drives annually. The trial would be a prospective crossover study of 1-year duration. Donors would not be randomized, as logistics of randomization are not feasible in the routine blood donation environment. Instead, blood centers would collect all high school and college drives for 6 months with either test or control protocol and then crossover to the alternative protocol arm for the second 6 months. The order would be determined by the flip of a coin. Because blood center staff cannot be blinded to the volume of blood collected, efforts would be made to prevent the donors from knowing the arm of the study in which they are participating. Discussion. A question was asked about whether adverse donor events fluctuate seasonally. The investigators responded by indicating that the prevalence is highest in the fall and the spring. Another questioner asked about the point during the donation that these reactions occurred. The answer was that 10% occur during the donation, 25% within 15 minutes of the donation, and the rest within 2 hours of the donation. Trial TM-123: Enhancing Recruitment and Retention of Novice High School Blood Donors Background and rationale. At the same time that a growing list of restrictions has dramatically reduced the pool of eligible blood donors, a progressively aging society has steadily increased the annual demand for blood for use in surgeries and cancer treatments. Currently, individuals aged at least 69 years represent 10% of the US population, but account for 50% of all transfusions received; by 2029, individuals 69 years and older will represent

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15% of the population. A crucial component of the effort to meet the growing demand for blood is the recruitment and retention of young donors. Ideally, new recruits would become lifelong donors, contributing up to 6 times per year and hundreds of units of blood in a lifetime. In reality, most young donors do not provide a second donation; and only 2% donate on a regular basis. Syncopal and presyncopal reactions (eg, fainting, dizziness, and nausea), which are most common in younger and novice donors, are primary deterrents to both recruitment and retention.65-67 Over the last decade, strategies have been developed (eg, distraction, applied muscle tension, water loading) to prevent adverse reactions to blood donation.68 Most recently, a donor recruitment brochure was developed that addresses common donor concerns about fear, pain, and syncopal reactions and suggests strategies that can be used to cope with these potential barriers to donation.69 In 2 separate samples, this new approach to predonation education was demonstrated to significantly enhance donation attitudes, reduce donation-related anxiety, and increase confidence and intention to give blood. Furthermore, individuals exposed to the new brochure were more likely to volunteer to give blood, an effect that is mediated by enhanced confidence in their ability to avoid syncopal reactions.

those who receive the enhanced predonation education would experience fewer reactions during donation and would be more likely to provide a repeat donation during a 2-year follow-up period. The proposed study is novel and innovative because it (a) develops an entirely new approach to preparing donors for blood donation, (b) extends the current predonation education program to include Web-based audiovisual materials to enhance treatment effects, (c) provides the first empirical assessment of predonation education on subsequent donor reactions and retention, and (d) focuses intervention efforts on the young men and women who represent the future of blood donation. The results of this study would make an important contribution by developing an effective intervention that is inexpensive, easily disseminated, and readily implemented by blood collection agencies to bring about long-term enhancement of the nation's blood supply.

Trial design and feasibility. The goal of the current study would be to evaluate an enhanced predonation education program that teaches empirically validated strategies to prevent adverse reactions to blood donation. Using a multicenter RCT conducted at high schools and colleges in Ohio, 1576 young, prospective first-time blood donors would be recruited and randomly assigned to either a control condition (standard predonation materials) or an enhanced predonation education condition (standard predonation materials + printed brochure and Web-based audiovisual materials that address common barriers to donation and teach strategies to prevent adverse reactions). The primary hypothesis is that, relative to the control condition, prospective donors who receive enhanced predonation education would have more positive attitudes toward donation, less donationrelated anxiety, and greater confidence in their ability to avert reactions. Most importantly, they would be more likely to donate. In addition, it is predicted that, among those who go on to donate,

Trial TM-124: Use of Thrombopoiesis-Stimulating Agents to Decrease Blood Product Transfusions in Patients With Liver Disease

Discussion. A suggestion was made that this trial should consider randomizing at the school level, as students interact with each other and thus the different study groups could become contaminated. This would be particularly relevant, as the unit of randomization for this study would be the donor.

Background and rationale. Patients with endstage liver disease often experience bleeding as part of a procedure, spontaneously, or during liver transplantation. In part, this bleeding is usually due to hemostatic abnormalities related to the underlying disease but is also due to these patients being thrombocytopenic because of a lack of production of thrombopoietin. Newly licensed platelet-stimulating agents (PSAs) have been shown to increase the number of platelets in patients with advanced liver disease and thrombocytopenia.70,71 However, these studies have not yet established whether the use of PSAs in these patients reduces the severity or frequency of bleeding. Platelet-stimulating agents not only increase the number of platelets but also increase the percentage of young platelets that are thought to be more hemostatically active. Therefore, this study proposes to evaluate the effect of PSAs on: (1)

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increasing the platelet count in thrombocytopenic patients with end-stage liver disease, (2) the production of younger platelets, and (3) clinical hemostasis. The effect on hemostasis in vitro would be studied using the thromboelastograph, PFA1000 in vitro platelet analyzer, and platelet aggregometer. There is a long history of the use of the thromboelastograph for monitoring hemostasis during operative procedures including the treatment of patients with liver failure and patients undergoing liver transplantation. However, there are no studies to determine whether the use of these functional assays after PSA therapy reduces either the actual amount of bleeding or the utilization of blood components. The primary hypothesis of this study is that the use of PSAs would increase the number of circulating platelets and the percentage of young reticulated platelets in patients with liver disease and thrombocytopenia, thereby favorably altering their hemostatic profile compared with the hemostatic profile of patients receiving standard allogeneic platelet transfusions. The primary end point would be a comparison of the in vitro hemostatic profile in patients receiving PSA vs those receiving only standard transfusion therapy. Secondary end points would include the number of blood products including coagulation factor products transfused in patients receiving PSA vs those receiving standard transfusion therapy. Trial design and feasibility. This study would be carried out in patients with end-stage liver disease due to chronic viral hepatitis, nonalcoholic hepatitis, or alcoholic liver disease; coagulopathy (INR N 1.5); and thrombocytopenia. Subjects scheduled to undergo an elective invasive procedure would be recruited from 4 to 7 liver transplant centers carrying out 40 or more transplants per year. This study is novel in that it attempts to identify a new clinical use of PSAs and has the potential to reduce blood utilization in this group of complex patients. Discussion. The role of platelet function tests in this study was questioned, as some hematologists feel that the role of platelet dysfunction in patients with liver disease is vastly overrated and that thrombocytopenia is the real issue in the bleeding associated with liver disease. The investigators responded that platelet function should be monitored in addition to simply examining platelet counts during this study.

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SPECIAL SESSION ON ISSUES IN CLINICAL TRIAL METHODOLOGY

Critical Issues in the Logistics of Clinical Research Presented by David Dilts, PhD, MBA, Oregon Health and Science University. As an example of the difficulty of accruing sufficient numbers of patients to clinical trials, Dr Dilts reported that 29% of all the oncology trials conducted by 6 major comprehensive cancer centers accrued no patients and only 38% of trials accrued the target number of patients. According to a review by Kathryn Hassell, MD, of data on 64 completed thrombosis trials listed on ClinicalTrials.gov, approximately 30% of sites accrued no patients. The cost of opening a trial at a single site typically ranges from $25 000 to $30 000, but the sites incur no penalty for not accruing patients. The median time to start a phase 3 clinical trial is 920 days. When researchers report on a hot new drug at a major meeting, everyone wants to put their patients on this drug. Delaying the trial by 1 year decreases the likelihood of accruing patients by approximately 60%. In selecting a trial to conduct, whether the trial addresses an important scientific question is not the only issue to consider. The trial's feasibility and whether the trial will produce a meaningful result are also important. If a trial has a high level of scientific merit and high levels of strategic merit and operational ease, it should be funded. Given limited resources, trials that have high scientific merit but low strategic merit or low operational ease should not be funded. Another concern is that nearly every institution or organization creates its own standard templates. Institutions rarely share these templates; and as a result, no universal set of “building blocks” for clinical trials exists. To maximize efficiency, clinical trials need standard contracts, informed consent forms, protocol components, end points, and language. Dr Dilts mapped out the steps involved in opening a phase 3 clinical trial through the National Cancer Institute's Cancer Therapy Evaluation Program. He found that the process involves at least 810 process steps, including at least 652 working steps and 158 decision points. Approximately 38 groups were involved in the process, which took a median time of 920 days or 2.5 years. On average, trials take another 2.5 years to complete. Because phase 3 trials take so long to start, many investigators conduct phase 1 or 2

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trials instead simply because they are quicker to complete. Unfortunately, this approach usually does not translate into patient benefit. Moreover, trials that take longer to launch are less likely to accrue the desired number of patients. Specific Needs for Thrombosis/Hemostasis Clinical Trials Presented by Gary Raskob, PhD, University of Oklahoma Health Sciences Center. The 3 key elements of successful clinical trials that will have an impact on patient care, change practice, and improve health outcomes are the following: • Clearly defined, specific, and important research question. • Scientifically rigorous methodology (including study design, statistics, and analysis). • Strong project management. Research questions should have a clear impact on population health, health care resource use, and costs. The questions posed by a proposed study should address an unmet clinical need and continue to be relevant in 3 to 5 years. Finally, research questions should be focused and specific and should identify specific public and private sector responsibilities. Issues to consider in choosing appropriate methodology include whether the design is appropriate for the research question, eligibility and exclusion criteria, outcome measure definition, avoidance of bias at all steps, and sample size. Project management issues include protocol development, feasibility, regulatory affairs expertise and support, human research subjects protection expertise and assistance, data management, and budget. Dr Raskob offered the following recommendations for the development of future NHLBI thrombosis/hemostasis clinical trials: • Strengthen “marrying” clinical expertise with clinical trial methodological expertise. • Strengthen infrastructure for the project management of clinical trials. • Establish a limited number of data coordinating centers as core infrastructure. • Establish a mechanism to link principal investigators and steering committees with data coordinating centers for protocol development and feasibility assessment.

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• Establish a process to move selected protocols to full implementation and conduct with continued partnership between principal investigators, steering committees, and data coordinating centers. Specific Needs for Transfusion Medicine Clinical Trials Presented by Nancy Heddle, MSc, McMaster University. Mrs Heddle listed the following needs for transfusion medicine trials in the following order: 1. Outcomes: Investigators often use surrogate outcomes because they are easier to measure and make the study feasible. Surrogate measures must have a demonstrated association with the clinical outcome of interest. Some studies use composite outcomes, also selected for statistical efficiency. These composite outcomes must be associated with the primary objective, biologically plausible, meaningful to patients and clinicians, translated into clinically important long-term outcomes, and (ideally) of equal value. Problems with composite outcomes include the difficulty of calculating sample sizes, lack of relevance to patients, and interpretation difficulty.72,73 2. Knowledge translation: The reasons why study results do not change practice include the difficulty for providers of staying up-to-date, provider concerns that their patients are different from those involved in the research, internal validity concerns (such as outcomes that are not considered clinically relevant, or perceived flaws in the design due to omissions in reporting), and the poor reporting of studies.74 3. Timelines: Failure to recruit subjects is the top reason why most studies do not meet their deadlines. Only 10% of the general public is involved in clinical research, and 50% of sites enroll only one or no patients into each study they initiate. Only 6% of clinical trials are completed on time, and 72% of trials run over schedule by more than 1 month. It is important to note that 30% of all research sites provide 70% of all valuable subjects in most studies. 4. Understand the concept and implications of noninferiority: Noninferiority studies are becoming more common, but their sample size

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determination is more complicated than that of superiority studies. Noninferiority studies require appropriate analysis and interpretation and often involve certain ethical considerations (such as whether it is appropriate to expose patients to an intervention when investigators have no reason to believe that it is better and only want to prove that it is not worse). Investigators need to remember that when a superiority study does not show superiority, this does not mean that the study has shown noninferiority.75 5. Clearly formulate the research question and hypothesis: The main elements of a good research question are the patient population, the intervention used, the control group, the outcome, and the timing of the outcome measurement. Three possible study hypotheses are superiority (A is better than B), noninferiority (A is not worse than B), and equivalence (A is neither worse nor better than B). Investigators need to consider the hypothesis a priori because hypotheses affect sample size calculations and the interpretation of results. When the hypothesis and research question are clearly articulated, the research design generally falls clearly into place.76 CONCLUSIONS

This SoS Transfusion Medicine section of the SoS Symposium framed 24 potential proposals in transfusion medicine that would advance the field if conducted over the next 5 to 10 years. The breadth and importance of the science proposed identified many opportunities and underscore the need for well-designed evidence-based clinical research in the field of transfusion medicine. It is important to note that some investigators have already pursued ideas presented at the SoS symposium. For example, the Myocardial Ischemia and Transfusion study, which was recently funded by NHLBI through the American Recovery and Reinvestment Act of 2009, is a pilot study based on SoS Proposal TM-109. The Myocardial Ischemia and Transfusion study is aimed at evaluating the feasibility of conducting a phase 3 clinical trial designed to evaluate the treatment effectiveness of 2 RBC transfusion trigger strategies in patients with CAD. The 24 proposals presented were vetted by the External Panel (Appendix A) who reviewed the

proposals and, following in camera discussions, made recommendations about the 24 proposals that were divided into 3 priority tiers. Of the 24 trials proposed, 10 protocols were rated in the highest tier. The 10 protocols rated in the highest tier were the following: TM-101: Randomized controlled trial comparing prophylactic platelet transfusions (given at a platelet count trigger of 10 × 10 9 /L) vs ‘“therapeutic-only” platelet transfusions in thrombocytopenic patients with hematologic malignancies. TM-102: Evaluation of pathogen-reduced platelets. TM-103: RBC transfusion trigger trial in critically ill pediatric patients. TM-104: Incidence of moderate and severe bleeding in thrombocytopenic premature neonates treated with a restrictive vs liberal platelet transfusion approach: the Neonatal Platelet Transfusion Threshold study. TM-105: Impact of a liberal RBC transfusion strategy on neurologically intact survival of extremely low birth weight infants: the Transfusion and Brain Injury trial. TM-108: Transfusion trigger trial in cardiac surgery. TM-109: Transfusion Trigger Trial in Coronary Artery Disease. TM-110: Transfusion Requirements in Critical Care Patients With Evidence of Coronary Syndromes. TM-112: Prospective, Randomized Optimal Platelet and Plasma Ratios. TM-120: Prevention of alloimmunization via pathogen inactivation of platelets. APPENDIX A. SOS SYMPOSIUM ORGANIZATIONAL STRUCTURE FOR TRANSFUSION MEDICINE ISSUES

Morris A. Blajchman, Chair, SoS Symposium Keith Hoots, NHLBI, Director of Division of Blood Diseases and Resources Simone A. Glynn, NHLBI Branch Chief (Transfusion Medicine and Cellular Therapies) Cassandra Josephson, Chair, SoS:TM Oversight Committee Steven H. Kleinman, Co-chair, SoS:TM Oversight Committee

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Traci Heath Mondoro, NHLBI Deputy Branch Chief (Transfusion Medicine and Cellular Therapies) George Nemo, NHLBI Program Director (Transfusion Medicine and Cellular Therapies) There were 7 Transfusion Medicine subcommittees, as follows: Subcommittee 1: Platelet Product Issues Sherrill Slichter (Chair) Nancy Heddle (Co-Chair) Terry Gersheimer Richard Kaufman Evelyn Lockhart Mike Murphy Marty Tallman Dan Weisdorf

Subcommittee 2: Neonatal and Pediatric Issues Cassandra Josephson (Chair) Steve Sloan (Co-Chair) Christof Dome Haresh Kirpalani Martha Sola-Visner Ron Strauss Jack Widness

Subcommittee 3: Surgical Issues Jeffrey L. Carson (Chair) Darryl Triulzi (Co-Chair) John Marshall Lena M. Napolitano Chris Stowell Richard Weiskopf

Subcommittee 4: ICU and Trauma Issues John Hess (Chair) John Holcomb (Co-Chair) Susan Assman Howard Corwin Ognjen Gajic David Hoyt Giora Natzer Michael Terrin

Subcommittee 5: Plasma, FFP, and Therapeutic Apheresis Issues Ziggy Szczepiorkowski (Chair) Lynne Uhl (Co-Chair) Jeannie Callum Larry Dumont Sunny Dzik Alan Tinmouth Sarah Vesely Jeffrey Winters Subcommittee 6: RBC, Blood Conservation, and Blood Management Issues Jonathan Waters (Chair) Victor Ferraris (Co-Chair) Elliott Bennett-Gurrero Art Bracey Aryeh Shander Maria Steiner Stephen Vamvakas

Subcommittee 7: Medical and Blood Donor Issues Jeffrey McCullough (Chair) John Adamson (Co-Chair) Richard Benjamin Chris France Jan McFarland Ed Snyder

External Panel for Transfusion Medicine Harvey Klein (Chair) Chris Hillyer Naomi Luban Paul Ness Pearl Toy

REFERENCES 1. Blajchman MA, Slichter SJ, Heddle NM, et al: New strategies for the optimal use of platelet transfusions. Hematology. Am Soc Hematol Educ Program 198-204, 2008 2. Stanworth SJ, Hyde C, Brunskill S, et al: Platelet transfusion prophylaxis for patients with haematological malignancies. Where to now? Br J Haematol 131:588-595, 2005 3. Slichter SJ, Kaufman RM, Assman SF, et al: Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Eng J Med 362:600-613, 2010 4. Stanworth SJ, Dyer C, Choo L, et al: Do all patients with hematologic malignancies and severe thrombocytopenia need prophylactic platelet transfusions? Background, rationale, and design of a clinical trial (Trial of Platelet Prophylaxis) to assess the effectiveness of prophylactic platelet transfusions. Transfus Med Rev 24:163-171, 2010 5. Wandt H, Schaefer-Eckart K, Pilz B, et al: Experience with a therapeutic platelet transfusion strategy in acute myeloid leukemia: Preliminary results of a randomized multicenter study after enrollment of 175 patients. Blood 113(Supplement):289a-290a, 2009(abstract) 6. Kleinman S, Dumont LJ, Tomasulo P, et al: The impact of discontinuation of 7-day storage of apheresis platelets (PASSPORT) on recipient safety: An illustration of the need for proper risk assessment. Transfusion 49:903-912, 2009

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