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

• Myocardial infarction, unstable angina, or death for any reason [ Time Frame: In-hospital ] [ Designated as safety issue: No ]
• Postoperative complications (e.g., pneumonia, wound infection, thromboembolism, stroke) [ Time Frame: In hospital ] [ Designated as safety issue: No ]
• Survival [ Time Frame: 30-daym, 60- day and long term up to 5 years ] [ Designated as safety issue: No ]
• Disposition status (i.e., nursing home placement) [ Time Frame: 60 days ] [ Designated as safety issue: No ]
• Function (e.g., lower extremity activities of daily living, instrumental activities of daily living, fatigue/energy) [ Time Frame: 30 and 60 days ] [ Designated as safety issue: No ]
• Length of stay in hospital [ Time Frame: In-hospital ] [ Designated as safety issue: No ]
• Myocardial infarction [ Time Frame: In-hospital ] [ Designated as safety issue: No ]
• Composite outcomes (a) death, myocardial infarction, and pneumonia and b) death, myocardial infarction, pneumonia, thromboembolism and stroke) [ Time Frame: In-hospital ] [ Designated as safety issue: No ]

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.

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.

• Anemia
• Hematologic Diseases
• Blood Transfusion
• Cardiovascular Diseases
• Heart Diseases
• Myocardial Infarction
• Thromboembolism
• Pneumonia
• Cerebrovascular Accident

• 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.
• 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.

• Experimental: Liberal (10 g/dL) Transfusion Strategy
  Participants will undergo a transfusion strategy that maintains postoperative Hgb levels above 10 g/dL.
  Intervention: Biological: Liberal (10 g/dL) Transfusion Strategy
• Active Comparator: 2
  Participants will undergo a symptomatic transfusion strategy, a more conservative strategy, in which blood transfusion is withheld until the patient develops symptoms of anemia.
  Intervention: Biological: Restrictive (Symptomatic) Transfusion Strategy

• 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. Epub 2011 Dec 14.
• 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. Review. No abstract available.

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