Fwd: An Ethically Dubious Blood Experiment: RECESS

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ALLIANCE FOR HUMAN RESEARCH PROTECTIONA Catalyst for Public Debate: Promoting Openness, Full Disclosure, andAccountability http://www.ahrp.org Dear Dr. Menikoff:The Alliance for Human Research Protection is concerned about the ethics andsafety of human subjects in a blood storage experiment ( RECESS) sponsoredby the National Heart Lung and Blood Institute.The study description, posted on ClinicalTrials.gov(http://clinicaltrials.gov/ct2/show/NCT00991341) states:"Longer RBC storage is associated with structural, biochemical, and cytokinelevel alterations. A number of observational studies in cardiac surgery,ICU, and trauma patients have demonstrated an association between longer RBCstorage time and worse outcomes. A recent large retrospective study showedan increased risk of post-operative complications, including reduced shortand long-term survival, in patients undergoing cardiac surgery who receivedRBCs stored < 14 days vs. > 14 days, but the groups were imbalanced in termsof prior disease characteristics, in the proportion receiving leukoreducedRBC, and in ABO blood group. In contrast, a small study (22 patients) didnot find deleterious effects with transfusion of 2 units of RBCs < 5 daysold vs. ? 20 days old. A pilot randomized controlled trial in 65 ICUpatients of < 8 day old blood vs. 15 day old blood actually reported worseoutcomes in recipients of the < 8 day old units. A much larger retrospectivesingle center study showed no difference in 30 day mortality between 942CABG patients who received only RBCs < 18 days old vs. 941 patients who hadreceived only RBCs > 18 days old. There are also complications oftransfusions, such as immunomodulation, microchimerism, and graft-vs.-hostdisease which are associated with transfusion of RBCs stored for only shorttime periods.Cardiac surgery patients often require RBC transfusion, and account for asignificant proportion of RBC use. In addition, following bypass they are ina pro-inflammatory state and may be particularly vulnerable to any adverseconsequences of RBC transfusion. They generally undergo invasivecardiopulmonary monitoring, allowing measurement of oxygen consumption anddelivery and other parameters which may be affected by RBC transfusion.The RECESS study will compare the effects of transfusing RBC units stores <=10 days vs. RBC units stored >= 21 days, in patients who are undergoingcomplex cardiac surgery and are likely to need a red blood cell transfusion.The primary hypothesis is that there is a clinically important differencebetween the effects of shorter-storage red cell units and longer-storage redcell units on clinical outcomes and mortality risk." Previous blood storage study results in cardiac patients are described onthe clinicaltrials.gov website:1. A large retrospective study demonstrated association between longer RBCstorage time and worse outcomes--but groups were imbalanced.2. A small study (22 patients) found no deleterious effects in either <5 dayold blood and >20 day old blood 3. A pilot randomized controlled trial in 65ICU patients of <8 day old blood vs 15 day old blood showed worse outcomesin patients who received <8 day old blood.4. A large retrospective single center study showed no difference in 30 daymortality between 942 CABG patients who received <18 day old blood vs. 941patients who received >18 day old blood..Our concern is that the trial design is unethical because it fails tocompare the best current clinical practice--which uses available blood inhospital blood banks--some of which may be new, some old. The protocolrandomizes patients to receive either old or new blood--depending upon whichgroup they are randomized to--for however many transfusions they need.However, the informed consent document fails to clearly inform the humansubjects of the experiment's end point, which is potential death.In the protocol the investigators are informed that the major risk is death:"The primary hypothesis is that there is a clinically important differencebetween the effects of shorter-storage red cell units and longer-storage redcell units on clinical outcomes and mortality risk."However in the informed consent documents given to patients, such languageas "death" or "mortality risk" is nowhere to be found.The informed consent document given to patients is vague and misleading. Under the heading "possible risks, side effects, and discomforts," thepatient informed consent states: "Blood cells change during storage, butwhether these changes have an effect on the human body after they aretransfused is unknown. Some data has shown that patients undergoing cardiacsurgery do better using shorter storage time red blood cells; some data hasshown no disadvantage to using longer storage age red blood cells; and somestudies have not shown any difference. It is possible that there are risksassociated with giving blood stored for either of these periods that are notknown at this time."However, a large retrospective study published in The New England Journal ofMedicine paper, Duration of Red-Cell Storage and Complications after CardiacSurgery by Colleen Gorman Koch, et al (2008) reported a significantassociation between longer red blood storage time and worse mortality: "Inpatients undergoing cardiac surgery, transfusion of red cells that had beenstored for more than 2 weeks was associated with a significantly increasedrisk of postoperative complications as well as reduced short-term andlong-term survival."Thus, a large retrospective study in cardiac surgery patients--the types ofpatients being enrolled in this clinical trial (RECESS)-- show that olderstored banked blood when transfused significantly increases mortality.Neither AHRP nor our network of medical consultants know of any comparabledata in cardiac surgery patients suggesting fresher stored banked blood whentransfused increases mortality. Moreover there is extensive data showingthat as banked blood ages it looses functionality. Neither do we know of anycomparable data to suggest that as banked blood ages it gains functionality.So, it does not appear that equipoise--a requirement for ethical humanexperimentation--exists between the two arms of the study.Also, blood is a valuable scarce resource and if banked blood is aged tomeet protocol requirement of having 21 day old blood, then this would beunethical because it would effectively decrease the avail be blood supplyfor patients.A further cause for concern is the uncooperative response AHRP received(below) to our request to the principle investigator, to provide thecitations of the four studies described on the clinicaltrials.gov website.Why would the investigator withhold citations to published information??? The Alliance for Human Research Protection requests that the Office of HumanResearch Protections examine the ethics of this protocol which putspatients' lives at unjustifiable risk; and examine the deficient informedconsent document which fails to disclose to patients that the experimentseeks to document the increased risk of death using longer stored bloodcompared to shorter stored blood without a comparative usual practice arm.Vera Hassner SharavPresidentAHRPveracare212-595-8974VERACARE [veracare]Wednesday, January 13, 2010 2:34 PM'sassmann'RECESS studyALLIANCE FOR HUMAN RESEARCH PROTECTIONA Catalyst for Public Debate: Promoting Openness, Full Disclosure, andAccountability http://www.ahrp.org Dear Dr. AssmannBelow is the description posted on ClinicalTrials.gov of previous bloodstorage study results in cardiac patients.1. A large retrospective study demonstrated association between longer RBCstorage time and worse outcomes--but groups were imbalanced.2. A small study (22 patients) found no deleterious effects in either <5 dayold blood and >20 day old blood 3. A pilot randomized controlled trial in 65ICU patients of <8 day old blood vs 15 day old blood showed worse outcomesin patients who received <8 day old blood.4. A large retrospective single center study showed no difference in 30 daymortality between 942 CABG patients who received <18 day old blood vs. 941patients who received >18 day old blood.Can you please provide the studies (or at least the references) for thosecited studies?Thank you for in advance for the information.Vera Hassner Sharavveracare212-595-8974Julie (Nannicelli) Miller [JMiller]Wednesday, January 13, 2010 5:19 PMveracare; Suzanne GrangerCc: Susan AssmannRE: RECESS studyHello,Please forward your request to the NHLBI Freedom of Information Office.Thank you,Julie _____________Infomail1 mailing listto send a message to Infomail1-leave =====In accordance with Title 17 U.S.C. 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