We performed a randomized clinical trial involving 2016 patients undergoing surgery for hip fracture and found no evidence that maintaining the hemoglobin level above 10 g per deciliter was superior to transfusion for symptoms or maintaining a hemoglobin level of less than 8 g per deciliter with respect to the primary outcome (a composite of death or an inability to walk across the room without human assistance) and to several clinically relevant secondary outcomes, including cardiovascular event rates and other functional measures. We enrolled a high-risk group of patients with a mean age of more than 81 years for whom untreated anemia would probably be more harmful than in a healthier or younger population undergoing most surgical procedures.
An ability to walk across the room at 60 days was selected as a main component of the primary outcome because such a measure is recognized to be an important functional outcome after hip fracture and is likely to be affected by factors that transfusion might influence (e.g., aerobic capacity and muscle strength). We hypothesized, in particular, that a higher hemoglobin level might facilitate more active participation in rehabilitation, leading to more successful recovery of ambulation.
We achieved a clinically important difference in the use of packed red cells and a good separation in hemoglobin levels in the two transfusion groups (). Patients in the restrictive-strategy group received 65% fewer units of blood than those in the liberal-strategy group; more than half the patients in the restrictive-strategy group did not receive any blood transfusion. Widespread implementation of this restrictive approach to transfusion in similar patients would greatly reduce blood use.
We found an interaction between the transfusion strategy and sex in the liberal-strategy group, suggesting a higher rate of death or an inability to walk without human assistance at 60-day follow-up in men but not in women. This difference was not anticipated and could have been due to chance.
We obtained primary-outcome information (including data regarding deaths) for more than 99% of patients and validated vital status. However, we did not perform follow-up examinations, and our telephone ascertainment of functional outcomes was subject to possible miscommunication, poorly informed proxy respondents, and recording errors. Although we did not validate patients’ ability to walk, in cases in which both patients and their proxies answered the question about walking ability, we found strong agreement between the two reports. Scores for physical activities of daily living, instrumental activities of daily living, and fatigue were not validated and were not useful for analysis for 45 to 60% of patients. We revised eligibility criteria in the course of the trial to include lower-risk patients who had cardiovascular risk factors but no history of cardiovascular disease, and there was no important treatment interaction with cardiovascular-disease status.
Our study had excellent statistical power for determining the primary outcome of death or inability to walk. On the basis of the 95% confidence interval, the restrictive transfusion policy plausibly resulted in at most a 3.7% increase in the risk of death or inability to walk without human assistance, a composite outcome that occurred in about 35% of patients. We had less statistical power for in-hospital outcomes; our data are compatible with an absolute change in the composite outcome of in-hospital acute myocardial infarction, unstable angina, or death, ranging from an increase of 3.3 percentage points to a decrease of 1.6 percentage points for the restrictive transfusion strategy.
Our results are consistent with most of the findings of the Transfusion Requirements in Critical Care (TRICC) trial, in which outcomes did not differ significantly between a transfusion threshold of 7 g per deciliter and a threshold of 10 g per deciliter among patients in intensive care units.5,13
However, in contrast to that report, we did not find increased rates of myocardial infarction or congestive heart failure in the liberal-strategy group. Furthermore, we did not confirm findings from observational studies of markedly higher mortality in patients who received transfusion than in patients who did not.14
A randomized clinical trial allows us to evaluate transfusion while avoiding selection bias.15
In summary, we found that a liberal transfusion strategy, as compared with a restrictive strategy, did not result in reduced rates of death or an inability to walk on 60-day follow-up or in significant reductions in rates of in-hospital complications in this population at increased cardiovascular risk. Our findings suggest that it is reasonable to withhold transfusion in patients who have undergone surgery in the absence of symptoms of anemia or a decline in the hemoglobin level below 8 g per deciliter, even in elderly patients with underlying cardiovascular disease or risk factors.