AHRP letter to the Office of Human Research Protection

Dear Dr. Menikoff:

The Alliance for Human Research Protection is concerned about the ethics and safety of human subjects in a blood storage experiment ( RECESS ) sponsored by the National Heart Lung and Blood Institute.

The study description, posted on ClinicalTrials.gov states:

“Longer RBC storage is associated with structural, biochemical, and cytokine level alterations. A number of observational studies in cardiac surgery, ICU, and trauma patients have demonstrated an association between longer RBC storage time and worse outcomes. ” “A recent large retrospective study showed an increased risk of post-operative complications, including reduced shortand long-term survival, in patients undergoing cardiac surgery who received RBCs stored < 14 days vs. > 14 days, but the groups were imbalanced in terms of prior disease characteristics, in the proportion receiving leukoreduced RBC, and in ABO blood group. In contrast, a small study (22 patients) did not find deleterious effects with transfusion of 2 units of RBCs 5 daysold vs. > 20 days old. A pilot randomized controlled trial in 65 ICU patients of < 8 day old blood vs. 15 day old blood actually reported worse outcomes 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 of transfusions, such as immunomodulation, microchimerism, and graft-vs.-host disease which are associated with transfusion of RBCs stored for only shorttime periods. Cardiac surgery patients often require RBC transfusion, and account for a significant proportion of RBC use. In addition, following bypass they are ina pro-inflammatory state and may be particularly vulnerable to any adverse consequences of RBC transfusion. They generally undergo invasive cardiopulmonary monitoring, allowing measurement of oxygen consumption and delivery and other parameters which may be affected by RBC transfusion.

The RECESS study will compare the effects of transfusing RBC units stored <10 days vs. RBC units stored > 21 days, in patients who are undergoing complex 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 on the clinical trials.gov website:

A large retrospective study demonstrated an increased risk of post-operative complications, including an association between longer RBC storage time and worse outcomes–but groups were imbalanced in terms of prior disease characteristics, the proportion receiving leukoreduced RBD, and in ABO blood group. A small study (22 patients) found no deleterious effects in either <5 day old blood and >20 day old blood A pilot randomized controlled trial in 65 ICU patients of <8 day old blood vs 15 day old blood showed worse outcomes

in patients who received <8 day old blood. A large retrospective single center study showed no difference in 30 day mortality between 942 CABG patients who received <18 day old blood vs. 941 patients who received >18 day old blood..

Our concern is that the trial design is unethical because it fails to compare the best current clinical practice–which uses available blood in hospital blood banks–some of which may be new, some old. The protocol randomizes patients to receive either old or new blood–depending upon which group they are randomized to–for however many transfusions they need.

However, the informed consent document fails to clearly inform the human subjects 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 difference between 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 language as “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,” the patient informed consent states:

“Blood cells change during storage, but whether these changes have an effect on the human body after they are transfused is unknown. Some data has shown that patients undergoing cardiac surgery do better using shorter storage time red blood cells; some data has shown no disadvantage to using longer storage age red blood cells; and some studies have not shown any difference. It is possible that there are risks associated 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 of Medicine paper, Duration of Red-Cell Storage and Complications after Cardiac Surgery by Colleen Gorman Koch, et al (2008) reported a significant association between longer red blood storage time and worse mortality:

“In patients undergoing cardiac surgery, transfusion of red cells that had been stored for more than 2 weeks was associated with a significantly increased risk of postoperative complications as well as reduced short-term andlong-term survival.”

Thus, a large retrospective study in cardiac surgery patients–the types of patients being enrolled in this clinical trial (RECESS)– show that older stored banked blood when transfused significantly increases mortality.

Neither AHRP nor our network of medical consultants know of any comparable data in cardiac surgery patients suggesting fresher stored banked blood when transfused increases mortality. Moreover there is extensive data showing that as banked blood ages it looses functionality. Neither do we know of any comparable data to suggest that as banked blood ages it gains functionality.

So, it does not appear that equipoise–a requirement for ethical human experimentation–exists between the two arms of the study.

Also, blood is a valuable scarce resource and if banked blood is aged to meet protocol requirement of having 21 day old blood, then this would be unethical because it would effectively decrease the avail be blood supply or patients.

A further cause for concern is the uncooperative response AHRP received (below) to our request to the principle investigator, to provide the citations 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 Human Research Protections examine the ethics of this protocol which puts patients’ lives at unjustifiable risk; and examine the deficient informed consent document which fails to disclose to patients that the experiment seeks to document the increased risk of death using longer stored blood

compared to shorter stored blood without a comparative usual practice arm.

Vera Hassner Sharav

President

AHRP

veracare@ahrp.org

212-595-8974

cc: To: Jerry Menikoff MD (jmenikof@kumc.edu); Michael Carome MD

Cc: Francis.Collins@nih.hhs.gov; Margaret Hamburg (MargaretAHamburg@aol.com); Joshua Sharfstein MD (joshua.sharfstein@fda.hhs.gov); Kathleen.Sebelius@hhs.gov

—–Original Message—–

From: VERACARE [mailto:veracare@ahrp.org]

Sent: Wednesday, January 13, 2010 2:34 PM

To: ‘sassmann@neriscience.com’

Subject: RECESS study

ALLIANCE FOR HUMAN RESEARCH PROTECTION

A Catalyst for Public Debate: Promoting Openness, Full Disclosure, and Accountability https://www.ahrp.org

Dear Dr. Assmann

Below is the description posted on ClinicalTrials.gov of previous blood storage study results in cardiac patients.

A large retrospective study demonstrated association between longer RBC storage time and worse outcomes–but groups were imbalanced. A small study (22 patients) found no deleterious effects in either <5 day old blood and >20 day old blood 3. A pilot randomized controlled trial in 65 ICU patients of <8 day old blood vs 15 day old blood showed worse outcomes in patients who received <8 day old blood. A large retrospective single center study showed no difference in 30 day mortality between 942 CABG patients who received <18 day old blood vs. 941 patients who received >18 day old blood.

Can you please provide the studies (or at least the references) for those cited studies?

Thank you for in advance for the information.

Vera Hassner Sharav

veracare@ahrp.org

212-595-8974

—–Original Message—–

From: Julie (Nannicelli) Miller [mailto:JMiller@neriscience.com]

Sent: Wednesday, January 13, 2010 5:19 PM

To: veracare@ahrp.org; Suzanne Granger

Cc: Susan Assmann

Subject: RE: RECESS study

Hello,

Please forward your request to the NHLBI Freedom of Information Office.

Thank you,

Julie