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Marie E. Steiner, MD, MS University of Minnesota for

The Re d Ce ll S torage Age S tudy: RECESS Trial Update for Society of Advancement in Blood Management. Marie E. Steiner, MD, MS University of Minnesota for

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Marie E. Steiner, MD, MS University of Minnesota for

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  1. The Red Cell Storage Age Study: RECESSTrial Update for Society of Advancement in Blood Management Marie E. Steiner, MD, MS University of Minnesota for Chris Stowell, Steven Sloan, Darrell Triulzi, Susan Assmann, Jerrold Levy, Shelley Pulkrabek, Megan Delaney, Pam D’Andrea, Suzanne Granger, Julie Miller (Protocol Leadership Committee) and NHLBI Transfusion Medicine & Hemostasis Clinical Trials Network

  2. Conflict of Interest DisclosureMarie E. Steiner, MD, MS Has no real or apparent conflicts of interest to report.

  3. Objectives • Explain RECESS design • Equipoise re: clinical impact of red cell age • Choice of patient population and inclusion / exclusion criteria • Randomization strategy and inventory management issues • Primary and secondary outcome measures • Describe the potential pitfalls in clinical research experienced during RECESS • Accrual shortfall remediation strategies • Impact of practice change during study

  4. Does controlled aging alter quality?

  5. Interrelationships of RBC Storage Lesion

  6. Does Storage Age Affect “Outcome” ? Zimrin AB & Hess JR. Vox Sang 2009; 96:93; Lelubre C. Transfusion 2009; 49:1994. Triulzi DJ. Transfusion and Apheresis Sci 2010; 43:95 22+ major studies show mixed results

  7. Design Appraisal of Clinical RBC Storage Studies Primarily retrospective/observational studies Studies are likely confounded Patient groups may not be not well matched # of RBC transfused a surrogate for severity of illness # of RBC transfused correlated with older units Cannot accommodate additional known/unknown factors No standard definition of storage “duration” Mean vs. Median RBC age? Oldest single RBC unit? # of oldest RBC units? RBC units > or < 7, 10, 14, 21, 28, 35 days? End point analyses may not be defined a priori

  8. Possible Impact of RBC Transfusion • Incompatible or erroneously administered • TACO • TRALI • Infection risk • From the product • Immune modulation (TRIM) increased susceptibility • Wound infection • Pneumonia • Sepsis • (? Malignancy relapse) • Multiple organ failure development • Renal • Respiratory • Cardiac • Length of stay • ICU • Hospital • Mortality

  9. Effect of RBC Storage Age Equipoise • No large, prospective human RCT has evaluated the effect of transfusion of RBC units stored for different periods on: • Clinical outcome • Standard hemodynamic variables and end-organ function measures • Immediate O2 delivery enhancement • Microvascular circulatory changes • ? REAL question: Do transfused RBC optimize oxygen delivery & consumption, thereby improving outcome

  10. RBC Storage Age RCT in Pediatrics ARIPI (Age of Red Blood Cells in Premature Infants) Prematures < 1250 g randomized to RBC stored for < 7 days vs. “Standard Practice” Multiple aliquots from single RBC unit until expires 1° outcome measure: composite of mortality, NEC, ROP, BPD and IVH up to 90 days No Δ in 1° outcome in arms; “std” too fresh? ABC-PICU (Age of Red Blood Cells in Children in PICU) PICU patients randomized to RBC stored for < 7 days vs. “Standard Practice” 1° outcome measure: new or worsening MOF

  11. Randomized Controlled Trials (RCT) Studying RBC Storage in Adults

  12. Transfusion Medicine & Hemostasis Clinical Trials Network • Multi-center clinical trials network: Blood Center of Wisc Case Western Children’s, BIDMC, BWH Boston Cornell Duke Emory Johns Hopkins Mass General Puget Sound/Swedish Tulane U of Iowa U of Maryland, Baltimore U of MN UNC, Chapel Hill U of OK HSC U of Penn U of Pitt • Funded by NHLBI (Transfusion Medicine & Cellular Therapeutics branch) in 2002; renewed in 2007 • DCC is New England Research Institutes (NERI)

  13. RECESS Primary Hypothesis • There is a clinically important difference between the effect of shorter storage age RBC vs. longer storage age RBC on clinical outcome and mortality risk in cardiac surgery patients

  14. Primary Endpoint • Clinical outcome, assessed using the change in Multiple Organ Dysfunction Score ( MODS) from pre-op to highest composite MODS through Day 7 (or death/ discharge)

  15. Study Design • Patient Population: • Patients ≥ 12 yo and 40 kg • Undergoing complex cardiac surgery • Likely to be transfused intra-op and/or within 96 hrs post-op • TRUST score >3 • Transfusion Randomization: • ≤ 10 day RBC vs. ≥ 21 day old RBC • Leukoreduced AS RBC of assigned age for all intra- & post-op transfusions through Day 28

  16. RECESS Schema Shorter storage age red cells CV Surgery Day 7 Day 28 Pre-op consent 1° Endpt 2° Endpt score score Longer storage age red cells (Study End) CV Surgery Day 7 Day 28 1° Endpt 2° Endpt score score (Study End)

  17. Inclusion Criteria • Inclusion Criteria: • Patients ≥ 12 years old or older • Patients ≥ 40 kg • Combined or complex primary procedure (i.e.- CABG and/or valve replacement or repair) or re-do cardiovascular surgery • On-pump or off-pump operations • TRUST probability score ≥ 3 • Patients < 18 years, regardless of TRUST score, are eligible if planned procedure is a complex operation and/or a re-do operation

  18. Exclusion Criteria • Refusing blood products • Known transfusion reaction history • Requirement for washed products • Expected residual cyanosis with O2 sat < 90 • Significant end-organ dysfunction • Renal dysfunction requiring renal replacement therapies (HD, CVVH) • Expected LVAD, IABP or ECMO support post-op • Planned use of deep hypothermic circulatory arrest during surgery • Appropriate ages of red cells not available

  19. Why Study Cardiac Surgery Patients? • Commonly require multiple RBC transfusions, so should reflect effects ascribed to allogeneic RBCs • Very large group with significant usage • Conflicting data from several retrospective studies that evaluated association of RBC storage time and cardiac surgery clinical outcomes • Undergo invasive cardiorespiratory monitoring, so physiologic parameters readily available • Complements ABLE study in ICU patients

  20. Transfusion Risk Understanding Scoring Tool (TRUST) Alghamdi A, et al. Transfusion 2006

  21. Include TRUST score ≥ 3 instead of ≥ 4 • 52% f subjects ≥ 3 with 80% transfused instead of 28% ≥ 4 with 87% transfused Predicted Probability RBC Transfusion: Observed at Total ScoreProbability4 TMH Centers 0 < 20% 1 20 – 39% 2 40 – 59% ≥3 (50% of pts) 60 – 79% 80% ≥4 (28% of pts) 80 – 100% 89% Transfusion Risk Understanding Scoring Tool (TRUST)

  22. RECESS Randomization Protocol • Transfusion Randomization: • ≤ 10 day RBC vs. ≥ 21 day old RBC • Leukoreduced AS RBC of assigned age for all transfusions received after randomization • including pre-, intra- & post-op transfusions • through discharge, death or Day 28 (whichever occurs first) • Stratification by: • age (+/-18 yo) • whether patient was in ICU prior to surgery • Partial blinding • clinical staff & research nurse not told of study arm • expiration on RBC label not obscured

  23. Why Choose ≤ 10 Day vs.≥ 21 Day RBCs? • Maximize storage age difference • Minimize overlap between arms • ≤ 10 Day • Ability to meet demand for study • Comparable to other studies (Hebert P. Anesth Analg 2005) • ≥ 21 Day • Comparable to current practice at TMH centers • 32% of CV surgery pts received RBC exclusively 21- 42 d old • 11% of CV surgery pts received RBC exclusively < 11 d old • Comparable to other studies (Hebert P. Anesth Analg 2005, van de Watering L. Trf 2006, Basran S. Anesth Analg 2006, Koch CG. NEJM 2008) • Average age at usage in US 19.5 d old

  24. Inventory Management: • Randomization will only occur when BOTH of the following criteria are met: • The transfusion service has enough suitable units stored ≤ 10 days to meet the crossmatch request • The general inventory of the transfusion service has enough suitable units stored ≥ 21 days to meet the crossmatch request • In other words, the crossmatch request would be filled with RBC units stored ≥ 21 days if issued according to standard inventory management (oldest product released first) • The transfusion service is not allowed to maintain a special study inventory of units stored ≥ 21 days, or to specifically order units stored ≥ 21 days.

  25. RECESS Primary Endpoint • Clinical outcome, assessed using the change in Multiple Organ Dysfunction Score ( MODS) from pre-op to highest composite MODS through Day 7 (or death/discharge)

  26. RECESS Secondary Endpoints • Δ MODS through discharge, death or post-operative Day 28 (end of study) • 28 day mortality • Measures of end-organ function & oxygenation • Global: lactate levels • Individual end-organ: troponin, creatinine • Cardiac composite • Pulmonary composite • Ventilator days (continuous variable)

  27. Primary Endpoint: Why Not Mortality? Estimates of mortality in this complex cardiac surgery population: 7-8% 25% reduction 7-8% to 5-6%: 3000 / arm Equivalence trial 7-8%: 11,500 / arm Enrollment concerns and cost of study precluded mortality as primary endpoint

  28. PAR= Pressure Adjusted Heart Rate Marshall JC, et al. Crit Care Med 1995 What is the MODS Scoring System? GoodBad

  29. Why Use MODS / ΔMODS? • Easily calculated from readily available data • Correlates well with mortality • 1 point  4%  mortality • Incorporates mortality (max score assigned) • Is NOT based on management or interventions • Widely used and well validated • Previously used in transfusion studies • TRICC (Hebert P. NEJM 1999) • TRICC CV subgroup (Hebert P. CCM 2001)

  30. Statistical Considerations 1696 subjects enrolled to have 1526 randomized of whom 1170 evaluable (surgery and transfused) Powered to have precision of 2-sided 95% CI for the treatment group difference in  MODS of ± 0.85 points or narrower  MODS difference of <1.0 not likely to be of clinical relevance (Hebert) Analysis is modified intention to treat Only transfused patients will be analyzed Transfused patients will be analyzed according to their randomization group

  31. Analysis Modeled After TRICC CV Subset RECESS powered to detect 0.85 difference CI, confidence interval; ICU, intensive care unit; MODS, multiple organ dysfunction score; ΔMODS, change in muyltiple organ score from baseline values. a Nonsurvivors are considered to have all organs failing on date of death. Crit Care Med 2001; Vol. 29, No. 2

  32. Primary Analyses • Primary outcome: • 7-day ∆MODS of ≤10d vs. ≥21d rbc trf arms • Secondary analyses of primary outcome: • ABO group • Race/ethnicity • On-pump vs. off-pump operation • ICU pt vs. non-ICU pt pre-op • Protocol arm transfusion compliance • Units transfused & treatment group interaction • Pediatric vs. adult status

  33. Primary Analyses • Secondary outcomes (pre-specified) • 28-day ∆MODS of ≤10d vs. ≥21d rbc trf arms • Time to all-cause mortality • ? Baseline characteristics confer risk • Time to first discontinuation of ventilation • Total time on ventilator • Days alive and ventilator free • Time to first bowel movement • Time to first solid food • Differences in complication rates • Composite major complication (death, stroke, MI, renal fx, sepsis) • Composite major cardiac events (death, MI, poor fx, arrthymia) • Composite major pulmonary events (vent > 48 hours, PE) • Adverse event description

  34. RECESS Site - Specific Planning • Blood Bank Strategy • ≤ 10 day RBC inventory may be actively altered/sequestered but… • ≥ 21 day RBC availability must be via routine inventory management • Patient Screening • Surgery scheduler, pre-op conferences • Patient Consenting • Pre-operative clinic visit (surgery, anesthesia) • Surgeon introduction and endorsement crucial • Patient Randomizing • Within 1 day of surgery IF both ages available

  35. RECESS Issues • Screening / Accrual “Misses” • Emergencies • Weekends • Blood of both storage ages not available • Washing non-negotiable • Surgeon declined phlebotomy for study labs • Remediation • Letters before pre-op appt to pts • Reminders to surgeons / work-up staff • Email monthly status updates • Monthly team status meetings (with food) • Grand Rounds / Research Conference • Hospital / academic center newsletter • Collaborative relationships with schedulers • Presence in pre-op clinic

  36. RECESS Accrual Update • Final target: 1526 enrolled for 1170 evaluable • 8/31/2013 target: 1448 subjects randomized • As of 8/31/2013: 1277 subjects randomized

  37. Participating Center Updates • 32 sites currently open for enrollment • 31 sites have randomized at least one subject • Top 3 enrolling sites: • Johns Hopkins • University of Pittsburgh • Indiana / Ohio Heart

  38. Froedtert St. Luke's (Wisc) Children's Boston Beth Israel Deaconess Brigham & Women’s Weill Cornell Duke Emory Johns Hopkins MGH Swedish Med Center Mayo Clinic (Rochester) UT Southwestern Vanderbilt Newark Beth Israel Columbia U Iowa U Maryland U Minnesota, Fairview UNC – Chapel Hill U Oklahoma U Pittsburgh UPMC Mercy Robert Wood Johnson Texas Heart Institute/St. Luke’s Baystate Med Center Indiana/Ohio Heart Indiana/Ohio Heart St. Joseph’s St. Elizabeth’s Med Center Aspirus Heart & Vasc Institute U of Florida Sanford Heart Center 32 RECESS Active Sites

  39. Patients Eligible and Randomized • As of 8/28/2013: • 1462 consented • 75 NOT eligible for randomization • 98 eligible but NOT randomized • 16 blood bank unable to provide enough units ≤10 days • 66 blood bank unable to provide enough units ≥21 days • 16 unable to provide enough units of both storage durations • 13 eligibility not yet known

  40. “All great achievements require time”- M. Angelou“It takes a village…”- H. Clinton, quotingAfrican proverb “I amnot your Cindawewwa”- C. Pyles, age 3

  41. Update on Coordinated Research Red Cell Storage Age Study (RECESS) NHLBI (TMH Network) Impact of Blood Storage Duration on Physiologic Parameters: RECESS Ancillary Study Protocol (RECAP) NHLBI 1R01 HL101382-01 E Bennett-Guerrero & C Stowell RECESS Mechanism & Repository Study (MARS) DoD/USAMRMC/NHLBI, 3 U01 HL0772268-09S1 P Spinella & P Norris

  42. Impact of Blood Storage Duration on Physiologic Parameters: (RECAP) Transfusion of longer vs. shorter storage-age RBC results in: Reduced peripheral tissue oxygenation measured by near-infrared spectroscopy (NIRS) Reduced cerebral oxygenation by NIRS Reduced microcirculatory perfusion by Orthogonal Polarization Spectroscopy (OPS)

  43. RECAP Measures Peripheral tissue and cerebral oxygenation with Near InfraRed Spectroscopy (NIRS) Microcirculatory perfusion with Sidestream Darkfield Spectroscopy (SDF) Serial comparisons: Pre-op before any RBC Post-op just before 1 unit RBC I hr after RBC Next day after RBC

  44. RECAP Participation • Duke • Mass General Hospital • Pittsburgh • Johns Hopkins • 62 patients enrolled to date

  45. RECAPAcknowledgments Protocol Committee Susan Assmann, PhD NERI Elliott Bennett-Guerrero, MD, PI Duke U Richard Kaufman, MD BWH Kerri Hayes, BS NERI Nathan Shapiro, MD BIDMC Marie Steiner, MD, MS U MN Christopher Stowell, MD, PhD, PI MGH Supported by NHLBI 1R01 HL101382-01

  46. RECESS Mechanism and Repository Study (MARS) Transfusion of RBCs of longer vs. shorter storage age will: Disable coupling between O2 gradients and NO metabolism in flowing blood Generate pro-inflammatory and pro-thrombotic states Associated with RBC membrane changes and microparticles released during storage Contribute to immunosuppressive profile

  47. RECESS Mechanism and Repository Study (MARS) • Laboratory measures addressing: • Inflammation and Coagulation • Microparticles, Immune Function • Nitric Oxide Parameters • Serial characterization of RECESS transfused patients • Days 0, 2, 6, 28, • Day 180 (optional) • Create large repository • Transfused RECESS patients (characterized & not) • Non-transfused RECESS patients • Healthy subjects

  48. MARS Participation Open for Enrollment: Aspirus Iowa Sanford Columbia Pending Activation: St. Luke’s • Indiana/Ohio Heart • St. Joseph’s (I/O Heart affiliate) • Emory • Texas Heart Institute • Baystate Medical Center • UT Southwestern • St. Elizabeth’s Hospital • U of Minnesota • Froedtert • Vanderbilt • Robert Wood Johnson

  49. MARS Accrual • Transfused RECESS subjects: • Target: 200 • To Date: 42 • Non-transfused RECESS subjects: • Target: 50 • To Date: 15 • Healthy volunteers: • Target: 50 • To Date: 50

  50. Incentives to Increase MARS Accrual Simplified protocol Longer window for plasma processing from 1 to 4 hrs Made TEG measurements optional (but encouraged) Simplified patient participation Made Day 180 sample optional (encouraged, help available to coordinate) Combined consent forms with MARS opt-out page to reduce coordinator & patient burden Enhanced reimbursement Personal appeal to RECESS PIs

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