Safety and Effectiveness of Two Blood Transfusion Strategies in Surgical Patients With Cardiovascular Disease (FOCUS)

Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS)

The purpose of this study is to compare liberal red blood cell transfusion therapy with restrictive red blood cell transfusion therapy in surgical patients with cardiovascular disease or risk factors.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Heart Diseases; Cardiovascular Diseases; Pneumonia; Hematologic Diseases; Anemia; Thromboembolism; Cerebrovascular Accident
• Intervention / Treatment: Biological: Liberal (10 g/dL) Transfusion Strategy; Biological: Restrictive (Symptomatic) Transfusion Strategy

Detailed Description

BACKGROUND:

Red blood cell transfusions are an extremely common medical intervention in both the United States and worldwide; over 14 million units of blood are transfused in the United States. Between 60 and 70 percent of all blood is transfused in the surgical setting. Despite the common use of red blood cell transfusions, the threshold for transfusion has not been adequately evaluated and is very controversial. A decade ago, the standard of care was to administer a peri-operative transfusion whenever the hemoglobin (Hgb) level fell below 10 g/dl (the "10/30 rule"). Concerns about the safety of blood, especially with respect to HIV and hepatitis, and the absence of data to support a 10 g/dl threshold led to the current standard of care, which is to administer blood transfusions based on the presence of symptoms, and not a specific Hgb/hematocrit level. However, there have not been any randomized clinical trials done with surgical patients that have tested the efficacy and safety of withholding blood until the patient develops symptoms, or the "10/30" approach to transfusion. Patients with underlying cardiovascular disease are at greatest risk of adverse effects from reduced Hgb levels.

DESIGN NARRATIVE:

This is a multi-center randomized trial to test the effectiveness of a transfusion strategy that maintains postoperative Hgb levels above 10 g/dl (liberal transfusion) in improving patient outcome. This will be compared to the restrictive (symptomatic) transfusion strategy in which blood transfusion is withheld until the patient develops symptoms of anemia or Hgb less than 8 g/dL. Participants will be randomly assigned to one of the two transfusion strategies. The liberal (10 g/dl) threshold strategy will use enough red blood cell units to maintain Hgb levels at or above 10 g/dl through hospital discharge. Restrictive (Symptomatic) transfusion strategy patients will receive red blood cell transfusions for symptoms of anemia, although transfusion is also permitted, but not required, if the Hgb level falls below 8 g/dl. Outcomes will include functional recovery (primary outcome: ability to walk 10 feet across a room without human assistance or death 60 days post-randomization), lower extremity activities of daily living and instrumental activities of daily living, survival up to 60-days and long-term, disposition (i.e., nursing home placement), and postoperative complications (e.g., myocardial infarction, unstable angina, or death in hospital, pneumonia, wound infection, thromboembolism, stroke).

Ambulation at 60 days is known to be highly predictive of ultimate functional outcome as well as of mortality at one year. Because inability to walk has such important implications for quality of life, and because it is a common problem, it far outweighs the small risk of viral infection or other complications from transfusion in elderly patients.

The trial will also evaluate the effect of transfusion threshold on postoperative risk of acute cardiac ischemia. The strategy will be to enhance surveillance for ischemic events by increasing the number of EKG and serum troponin measurements beyond those already called for in the original FOCUS protocol.

There is an ancillary study to the trial (R01 HL085706) to examine delirium as an outcome in a subsample of 139 patients. We will assess short-term (in hospital) and longer-term (after 30 days) severity of delirium.

• Study Type: Interventional
• Enrollment (Actual): 2016
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • University Medicine & Dentistry of NJ

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has undergone surgical repair for a hip fracture
• Has a postoperative Hgb level below 10 g/dL within three days of surgery
• Diagnosis of cardiovascular disease (e.g., coronary artery disease, congestive heart failure, stroke or transient ischemic attack, or peripheral vascular disease) or cardiovascular risk factors (e.g., diabetes mellitus, hypertension, hypercholesterolemia, tobacco use, or creatinine levels greater than 2.0 mg/dL)

Exclusion Criteria:

• Unable to walk prior to hip fracture
• Declines blood transfusions
• Suffered multiple traumas
• Pathologic fracture of the hip due to malignancy
• Clinically recognized acute myocardial infarction within the 30 days prior to study entry
• Previously participated in the trial and fractured the other hip
• Symptoms associated with anemia (e.g., ischemic chest pain) or actively bleeding at the time of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liberal (10 g/dL) Transfusion Strategy; Transfusion strategy that maintains postoperative Hgb levels above 10 g/dL.	Biological: Liberal (10 g/dL) Transfusion Strategy; This transfusion strategy will maintains postoperative Hgb levels above 10 g/dL. This threshold strategy will use enough red blood cell units to maintain Hgb levels at or above 10 g/dL through hospital discharge or up to 30 days after randomization.
Active Comparator: 2; Symptomatic transfusion strategy, a more conservative strategy, in which blood transfusion is withheld until the patient develops symptoms of anemia.	Biological: Restrictive (Symptomatic) Transfusion Strategy; Transfusion is withheld until the patient develops symptoms from anemia (i.e., chest pain or ECG changes thought to be ischemic, congestive heart failure, unexplained tachycardia or hypotension unresponsive to fluids) or until the hemoglobin level falls below 8 g/dL. Transfusion is permitted, but is not mandatory, if the hemoglobin level falls below 8 g/dL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inability to Walk 10 Feet or Across a Room Without Human Assistance or Death	ascertained via telephone follow-up	60 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial Infarction, Unstable Angina, or Death for Any Reason		In-hospital
Mortality at 30 Days		30 days
Mortality at 60 Days		60 Days
Composite Outcomes (a) Death, Myocardial Infarction, or Pneumonia and b) Death, Myocardial Infarction, Pneumonia, Thromboembolism, or Stroke		In-hospital
Myocardial Infarction		In-hospital
Postoperative Complications (e.g., Wound Infection, Thromboembolism, Stroke)		In hospital
Disposition Status (i.e., Nursing Home Placement)	Nursing Home Residence	60 days
Function - Lower Extremity Activities of Daily Living,at 30 Days	Using the Functional Status Index, score range 0 to 11, higher scores indicate greater dependency	30 days
Function - Instrumental Activities of Daily Living, at 30 Days	Using the Older Americans Resources and Services Functional Assessment Questionnaire, score range from 0 to 4, higher scores indicating greater dependency	30 days
Function - Fatigue/Energy, at 30 Days	Using the Functional Assessment of Chronic Illnesses Therapy-Fatigue, score range from 0 to 52, higher scores indicating greater level of energy	30 days
Function - Lower Extremity Activities of Daily Living. at 60 Days	Scale range 0 to 11, higher scores indicate greater dependency	60 Days
Function - Instrumental Activities of Daily Living, at 60 Days	Scale range 0 to 11, higher scores indicate greater dependency	60 Days
Function - Fatigue/Energy, at 60 Days	Scale ranging from 0 to 52, higher scores indicating greater level of energy	60 Days
Length of Stay in Hospital for United States Participants		Days from randomization to discharge
Length of Stay in Hospital for Canadian Participants		Days from randomization to discharge

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Chair: Jeffrey L. Carson, MD, University Medicine & Dentistry of NJ; Principal Investigator: Michael Terrin, University of Maryland, College Park

Publications and helpful links

General Publications

• Carson JL, Stanworth SJ, Dennis JA, Trivella M, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD002042. doi: 10.1002/14651858.CD002042.pub5.
• Carson JL, Terrin ML, Magaziner J, Chaitman BR, Apple FS, Heck DA, Sanders D; FOCUS Investigators. Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS). Transfusion. 2006 Dec;46(12):2192-206. doi: 10.1111/j.1537-2995.2006.01056.x. No abstract available.
• Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, Nemo G, Dragert K, Beaupre L, Hildebrand K, Macaulay W, Lewis C, Cook DR, Dobbin G, Zakriya KJ, Apple FS, Horney RA, Magaziner J; FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011 Dec 29;365(26):2453-62. doi: 10.1056/NEJMoa1012452. Epub 2011 Dec 14.
• Carson JL, Sieber F, Cook DR, Hoover DR, Noveck H, Chaitman BR, Fleisher L, Beaupre L, Macaulay W, Rhoads GG, Paris B, Zagorin A, Sanders DW, Zakriya KJ, Magaziner J. Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial. Lancet. 2015 Mar 28;385(9974):1183-9. doi: 10.1016/S0140-6736(14)62286-8. Epub 2014 Dec 9.

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: October 9, 2003
• First Submitted That Met QC Criteria: October 10, 2003
• First Posted (Estimate): October 13, 2003

Study Record Updates

• Last Update Posted (Actual): November 16, 2020
• Last Update Submitted That Met QC Criteria: October 28, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: blood transfusion; Blood Disease
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Embolism and Thrombosis; Myocardial Infarction; Infarction; Heart Diseases; Stroke; Cardiovascular Diseases; Hematologic Diseases; Thromboembolism
• Other Study ID Numbers: 159; U01HL073958-06 (U.S. NIH Grant/Contract); U01HL073958 (U.S. NIH Grant/Contract); U01HL074815 (U.S. NIH Grant/Contract)