When Should I Transfuse My Adult Hospitalized Patient Who Has Anemia?

Update to the 2017 article When should I transfuse a patient who has anemia? 

Case

An 82-year-old woman with chronic lymphocytic leukemia complicated by anemia of chronic disease (baseline hemoglobin [Hgb] 9-10 g/dL) and a history of non-ST elevation myocardial infarction two months prior, presents to the emergency department (ED) after a mechanical fall resulting in right femoral neck fracture. She reports significant hip pain but has no chest pain, shortness of breath, or dizziness. Her pulse is 95 beats per minute, her blood pressure is 140/80 mmHg, and her respiratory rate is 14 breaths per minute. A complete blood count reveals a hemoglobin level of 7.4 g/dL. She has normal troponins and an electrocardiogram without ischemic changes. The orthopedic surgeon is planning to perform open reduction and internal fixation for her femoral neck fracture. You are consulted for preoperative evaluation. Should you recommend a transfusion of packed red blood cells (pRBCs)?

Overview

Hospitalists frequently are asked whether their hospitalized patients would benefit from a transfusion of packed red blood cells. In patients who are hemodynamically unstable or symptomatic, transfusion should be guided by these clinical criteria. However, in patients who are stable and asymptomatic, the decision to recommend transfusion requires understanding the best available evidence and updated guidelines, while incorporating patient preferences.

In 2017, we wrote in The Hospitalist about the decision on when to transfuse an inpatient with anemia based on the clinical practice guidelines from the American Association of Blood Banks (AABB). The 2016 guidelines supported restrictive transfusion strategies over liberal ones, with a hemoglobin threshold of 7 g/dL for hemodynamically stable hospitalized adult patients, including critically ill patients, and a threshold of 8 g/dL for patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease (strong recommendation, moderate quality evidence). Patients with acute coronary syndrome, severe thrombocytopenia, and chronic transfusion-dependent anemia were excluded from the 2016 recommendations due to insufficient data.

In 2023, a panel of international experts published updated AABB international guidelines on transfusion thresholds for hospitalized adults. The authors performed a meta-analysis of 45 randomized controlled trials (RCTs) of adults, enrolling 20,599 participants, each comparing restrictive transfusion thresholds (Hgb 7-8 g/dL) to liberal transfusion thresholds (Hgb 9-10 g/dL). Among the 30 trials that evaluated mortality as an outcome, the pooled relative risk was 1.00 (95% CI, 0.86 to 1.16), suggesting no difference in mortality outcomes between restrictive and liberal transfusion strategies (also noting that patients in restrictive strategy groups were 32.4% less likely to receive a transfusion). Pooled analyses also found no apparent differences in morbidity outcomes between the two strategies.

Given the potential risks of blood transfusions and the fact that blood is a limited resource, the authors began with the premise that restrictive transfusion strategies should be favored if they do not adversely impact patient outcomes. Therefore, the 2023 guidelines again favor restrictive transfusion strategies, a recommendation supported by moderate quality evidence.

The panel recommends different transfusion thresholds for different patient populations as follows:

• Hgb <7 g/dL for hemodynamically stable hospitalized adult patients (strong recommendation, moderate certainty evidence)
• Hgb <7 g/dL for patients with hematologic and oncologic disorders (conditional recommendation, low certainty evidence)
• Hgb <7.5 g/dL for patients undergoing cardiac surgery
• Hgb <8 g/dL for patients undergoing orthopedic surgery
• Hgb <8 g/dL for patients with pre-existing cardiovascular disease

In this article, we review the data supporting the new recommendation for patients with hematologic and oncologic disorders and the data to support the higher transfusion thresholds for patients undergoing orthopedic surgery. We also review the mixed data around transfusion thresholds for patients with acute coronary syndrome and acute myocardial infarction, leading the panel again to not recommend for or against a liberal or restrictive transfusion threshold for patients with acute myocardial infarction.

Application to the case

Patients with hematologic and oncologic disorders

One of the most notable updates to the 2023 AABB guidelines is a new recommendation supporting a transfusion threshold of Hg <7 for patients with hematologic and oncologic disorders, though this is a conditional recommendation based on low certainty evidence. The prior 2016 AABB guidelines excluded this group from the recommendations due to limited evidence.

Small feasibility studies demonstrated that studying transfusion in patients with acute leukemia or stem cell transplantation was feasible and that restrictive transfusion strategies did not increase bleeding events in patients with acute leukemia. In 2020, investigators published a randomized, open-label, phase III noninferiority trial that randomized 300 patients with hematologic malignancies undergoing hematopoietic stem cell transplantation to restrictive (Hgb <7 g/dL) or liberal (Hgb <9 g/dL) RBC transfusion strategy. Patients randomized to the restrictive strategy scored higher on health-related quality of life assessment (difference of 1.6 points; 95% CI, -2.5 to 5.6 points), with no significant differences in clinical outcomes such as transplant-related mortality, length of stay, ICU admissions, or acute graft-versus-host disease. The investigators concluded that the restrictive transfusion strategy was non-inferior to the liberal one while requiring fewer RBC units transfused (mean 2.73 units [standard deviation, 4.81 units] versus 5.02 units [standard deviation, 6.13 units]; P=.0004).

Despite the strength of the above study, it did not include overall mortality as an outcome and therefore could not be included in the pooled mortality estimates. Only two trials reported mortality outcomes from transfusion studies of patients with hematologic malignancies, with 149 total participants. These smaller sample sizes led to wider confidence intervals, with the upper limit of the confidence interval for 30-day mortality at 6.2%, raising concern about the possibility of increased death in the restrictive transfusion group. Among the three RCTs that enrolled 448 participants with any hematologic or oncologic condition (not only patients with hematologic malignancy), bleeding risk also appeared to be similar in the two groups regardless of transfusion strategy.

Considering the above data, the AABB panel newly recommends a transfusion threshold of Hg <7 g/dL for inpatients with hematologic and oncologic conditions, a conditional recommendation based on low certainty evidence that there appeared to be neither harm nor increased bleeding when using a restrictive transfusion strategy,

The authors note that there is insufficient evidence to recommend a transfusion threshold in transfusion-dependent patients, such as those with myelodysplastic syndromes.

Patients with ACS

The AABB 2023 guidelines do not recommend a specific transfusion threshold or strategy for patients with acute coronary syndrome (ACS) or acute myocardial infarction (AMI) due to limited data in this population. This recommendation is unchanged from the 2016 guidelines.

Historically, anemia is an independent predictor of major adverse cardiovascular events in patients with ACS. Retrospective studies had conflicting conclusions on transfusion in patients with ACS as to whether anemia improved or worsened outcomes. Newer data remains mixed, as a 2013 meta-analysis concluded that in patients with ACS, a restrictive transfusion is associated with lower all-cause mortality overall. However, a 2014 retrospective study found that in patients with ACS undergoing blood transfusions who were matched with patients with similar clinical profiles, blood transfusion was associated with lower in-hospital mortality, though authors noted that the matching process was challenging, and most patients could not be adequately matched. Given the above conflicting retrospective data with a lack of randomized data, the previous 2016 AABB guidelines did not recommend for or against a liberal or restrictive transfusion strategy for patients with ACS.

More recently, a larger, randomized trial attempted to contribute higher-quality data to the literature. The 2021 Randomized Trial of Transfusion Strategies in Patients with Myocardial Infarction and Anemia, or REALITY, trial randomized 668 adults with AMI and anemia (Hgb 7 to 10 g/dL) to either a restrictive (Hgb <8 g/dL) or liberal (Hgb <10 g/dL) transfusion goal. The investigators found no significant differences between the groups in major adverse cardiac events (all-cause death, stroke, recurrent MI, or emergency revascularization) at 30 days. However, in a one-year follow-up analysis, patients randomized to the restrictive transfusion group were found to have higher rates of major adverse cardiovascular events (relative risk, 1.13), no longer meeting the pre-specified non-inferiority margin. This analysis raised concern about the safety of a restrictive transfusion strategy in patients with anemia and AMI.

Based on the mixed results from the above data, in 2023 the AABB panel again chose not to recommend for or against a specific transfusion threshold or strategy for patients with ACS or AMI.

In November 2023, the month after the AABB guidelines were released, investigators published the Myocardial Ischemia and Transfusion (MINT) trial. MINT enrolled 3,504 adults with AMI and anemia to a restrictive (Hgb 7 or 8 g/dL, per clinician discretion) or liberal (Hgb <10 g/dL) transfusion strategy. The investigators found no statistically significant difference in recurrent MI or death at 30 days between the two groups. However, there was a trend towards worse outcomes in the restrictive transfusion arm that was not statistically significant.

It remains unclear how data from MINT will be incorporated into future meta-analyses and guidelines. However, the totality of the data suggests that the restrictive strategy favored for almost any other indication may not be as applicable to patients with ACS.

Stable CAD and CHF

The AABB guidelines recommend a hemoglobin threshold of 8 g/dL for patients with preexisting cardiovascular disease. Patients with stable coronary artery disease and congestive heart failure have never been studied in dedicated randomized controlled trials examining liberal versus restrictive transfusion goals.

In the Transfusion Requirements in Critical Care, or TRICC, trial, which studied patients with critical illness and anemia, 26% of patients had a primary or secondary diagnosis of cardiac disease (definition unclear). Subgroup analysis found no significant differences in 30-day mortality between treatment groups, similar to that of the entire study population. A 2016 meta-analysis suggested that restrictive transfusion strategies for patients with cardiovascular disease may increase the risk of acute coronary syndrome, though not 30-day mortality. However, this meta-analysis pooled data from patients with both acute coronary syndrome and stable cardiovascular disease and was not sufficiently powered to draw independent conclusions about patients with stable coronary artery disease. For patients with heart failure, observational studies have suggested that anemia may be a marker for poor prognosis, but the impact of transfusions is unclear.

The AABB guidelines again recommend as they did in 2016, a hemoglobin transfusion threshold of <8 g/dL for patients with preexisting cardiovascular disease. However, the panelists do not specify the definition of preexisting cardiovascular disease. Many of the cited studies reference patients with stable coronary disease and congestive heart failure, but it is unclear whether this category should also include patients with arrhythmias, valvular disease, pericardial disease, peripheral artery disease, or other cardiovascular conditions.

Patients undergoing orthopedic surgery

Based on a review of 11 RCTs of patients undergoing orthopedic surgery randomized to different transfusion thresholds and strategies, the AABB panel recommends a transfusion threshold of Hgb <8 g/dL in patients undergoing orthopedic surgery. The panelists note that this number was based on the thresholds studied in the included trials and not because of any belief that a transfusion threshold of <8 g/dL would be superior to a threshold of <7 g/dL.

The landmark study that established the safety of a restrictive transfusion study in patients with hip fractures was the 2011 Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair, or FOCUS, trial. The investigators randomized 2018 patients 50 years of age or older who had a history of or risk factors for cardiovascular disease and anemia (Hgb <10 g/dL) after hip fracture surgery to a liberal (Hgb <10 g/dL) or restrictive (Hgb <8 g/dL at physician discretion, or symptoms of anemia), and found no difference in death or functional outcomes (inability to walk across a room without human assistance) in 60-day follow-up between the groups. A subsequent RCT enrolled 200 patients with proximal femoral fractures and anemia at a single center and randomized them to conservative (symptoms of anemia or Hgb <8 g/dL) or liberal transfusion strategy and again found no statistically significant difference in the outcomes of mortality, hospital stay, regain of mobility or complications between the two groups.

The 2015 Transfusion Requirements in Frail Elderly, or TRIFE, trial enrolled frail elderly (age ≥65 years, nursing home residents) patients with hip fractures and randomly assigned them to a restrictive (Hb <9.7 g/dL) or liberal (Hb <11.3 g/dL) RBC transfusion strategy; this trial also found no differences in measures of daily living activities or 90-day mortality. However, on per-protocol analysis, they found higher 30-day mortality in the restrictive strategy group. Therefore, unlike the other trials above, the authors conclude that specifically in nursing home residents, a more liberal RBC transfusion strategy may have the potential to increase survival.

Most recently, in 2021 investigators published the Restrictive vs Liberal Transfusion Strategy on Cardiac Patients Undergoing Surgery for Fractured NOF, or RESULT-NOF, trial, a small feasibility study of patients undergoing surgery for femoral neck fracture, which suggested a trend towards higher rates of myocardial injury in a liberal transfusion threshold, but because of the small sample size this difference was not statistically significant.

Despite the mixed data from TRIFE and the small feasibility RESULT-NOF trial, the strength and power of the FOCUS trial allowed the panelists to recommend a restrictive transfusion strategy with a hemoglobin threshold <8 g/dL for patients undergoing orthopedic surgery.

Risks and costs of blood transfusion

Transfusion of RBCs should be performed only when necessary due to its inherent risks and costs. The most common risks of blood transfusion are transfusion-associated circulatory overload, febrile reaction, and allergic reaction, occurring in approximately one in 125, 161, and 345 transfusions, respectively. Other risks, such as transfusion-related acute lung injury, anaphylactic reactions, and transmission of bloodborne pathogens, such as hepatitis B and C and Human Immunodeficiency Virus, are much rarer. Recent literature suggests there has been a narrowing between blood supply and demand, especially exacerbated by the COVID-19 pandemic, so blood should be preserved for individuals who need it most. Therefore, when demonstrated to be safe without negatively impacting individual patient outcomes, restrictive transfusion strategies should be favored. In fact, the AABB panel proposes research into even lower transfusion thresholds, such as hemoglobin 5-6 g/dL, to further protect our blood supply.

Back to the case

An 82-year-old woman with chronic lymphocytic leukemia, recent AMI, and impending orthopedic surgery for a femoral neck fracture with a hemoglobin of 7.4 g/dL should be offered an RBC transfusion.

Bottom line

The 2023 AABB guidelines overall favor a restrictive transfusion strategy, recommending RBC transfusion for hemoglobin <7 g/dL for the general hospitalized population, and newly extending this recommendation to patients with hematologic and oncologic disorders. However, in certain patient populations, such as patients with known cardiovascular disease and those undergoing orthopedic surgery, guidelines recommend a higher hemoglobin threshold of <8 g/dL based on available data. 

Dr. Berger

Dr. Sampat

Dr. Manian

Dr. Berger is a hospitalist at New York-Presbyterian/Weill Cornell in New York. Dr. Sampat is a hospitalist at Massachusetts General Hospital in Boston. Dr. Manian is a hospitalist and chair of the department of medicine at Mercy Hospital in St. Louis.