Do transfusions get to the heart of the matter?

OVER THE LAST HALF-CENTURY, IT HAS BECOME WELL recognized that patients with cardiovascular diseases and, more specifically, ischemic heart disease may be adversely affected by anemia. This is because the myocardium consumes or extracts 60% to 75% of all oxygen delivered to the coronary circulation. Such an elevated extraction of oxygen, termed extraction ratio, is unique to the coronary circulation. As a result, oxygen delivery to the myocardium can be augmented only by increasing blood flow or oxygen content. Animal and human studies have investigated the effects of normovolemic anemia on coronary circulation. There appear to be minimal consequences from moderate levels of anemia with hemoglobin levels in the range of 7.0 g/dL if coronary circulation is normal. However, at comparable hemoglobin concentrations, myocardial dysfunction and ischemia occur earlier and are more pronounced in anemic animal models with moderateto high-grade coronary stenoses. In humans, a retrospective study involving 1958 patients who declined a blood transfusion documented an increase in the risk of death with decreasing preoperative hemoglobin concentrations in patients with underlying cardiovascular disease compared with other patients. Despite consistent findings from physiological and observational studies regarding the risks of anemia in patients with ischemic heart disease, there remains limited clinical evidence that blood transfusions increase survival in this population following moderate levels of anemia. In this issue of JAMA, Rao and colleagues report the results of their observational study examining the relationship among anemia, blood transfusion, and survival based on combined data from 3 large randomized trials involving 24111 patients who had an acute myocardial infarction. The authors present a survival analysis using proportional hazards modeling demonstrating that the risk of death was estimated to be 3.94 times higher in patients who underwent transfusion compared with those who did not, adjusting for the influence of time, risk of bleeding, type of myocardial infarction, and procedures. Prior to this study, conflicting results were reported in 2 other studies attempting to discern whether blood transfusions improve outcomes in patients with ischemic heart disease. One of the few large randomized trials evaluating transfusion practice, undertaken in 838 critically ill patients, concluded that a restrictive transfusion strategy was at least as good and possibly superior to a liberal transfusion strategy, given a trend toward improved 30-day mortality (23.3% vs 18.7%; P=.11) and improved secondary outcomes. In a subgroup analysis of 327 patients with cardiac disease, there were no significant differences in primary or secondary outcomes in this high-risk subgroup. The authors acknowledged many of the limitations of this subgroup analysis, including the inability to detect clinically meaningful difference given the small sample size. Rao and colleagues based their evaluation on the second publication, which made use of 78974 Medicare records. Wu et al retrospectively studied patients older than 65 years who were hospitalized with a primary diagnosis of acute myocardial infarction, and categorized patients according to their admission hematocrit level. Although anemia, defined in the study as a hematocrit level less than 39%, was present in nearly half the patients, only 3680 patients (4.7%) received a red blood cell transfusion. The authors observed a reduction in 30-day mortality for patients who received at least 1 red blood cell transfusion if their admission hematocrit level was less than 33%, whereas red blood cell transfusion was associated with increased 30-day mortality for patients whose admitting hematocrit values were 36.1% or higher. This study was among the first to demonstrate that red blood cell transfusion may be beneficial in patients with acute myocardial infarction. However, a number of potential biases limited any inferences made from this study. Specific concerns include a low rate of exposure to red blood cells, limited statistical adjustments made in the multivariable analysis, an analysis based on the admission hematocrit value rather than the value associated with the transfusion, no consideration for the time-dependent use of red blood cells, and