We found that almost half of patients who had normal hemoglobin at admission developed anemia by hospital discharge in this large, prospective, multi-center AMI cohort. Although inpatient bleeding was a strong independent predictor of HAA, most patients with HAA did not have a documented bleeding event during hospitalization, suggesting that HAA is not simply a surrogate for in-hospital bleeding events. Importantly, moderate-severe HAA was associated with increased long-term mortality independent of AMI severity, and regardless of presence and extent of bleeding, suggesting that HAA is prognostically important in its own right and may represent a target for prevention efforts. Supporting that there is opportunity to minimize the risk of developing HAA, we observed substantial variability in incidence of HAA across hospital sites.
Prior studies have established the short and long-term prognostic significance of chronic anemia,2–5
and more recent reports have examined the association between changes in Hgb during hospitalization and outcomes.7
Aronson and colleagues found that declines in Hgb during AMI hospitalization were independently associated with mortality, however, their analyses included both patients with baseline anemia and new-onset anemia during hospitalization.7
Since patients with chronic anemia presumably have poorer hematopoetic reserve or greater baseline co-morbidity, potentially predisposing them to large Hgb declines, it unclear from these data whether the relationship between inpatient Hgb decline and survival is present among those with normal baseline Hgb. Our work extends these insights by defining a population with acute anemia, a potentially preventable condition, and observing that moderate-severe HAA is associated with an increased risk of mortality of similar magnitude to those with chronic anemia, even after adjustment for the presence and severity of bleeding. Our findings also extend prior observations by Sattur and colleagues who reported, in a single-center study, that incident anemia in PCI patients was independently associated with long-term mortality.15
The anemia threshold used in that study (Hgb <10 g/dl) was relatively low, potentially leading to over-estimation of the association between anemia and outcomes. Our study provides new insights by examining a large, contemporary, multi-center cohort, focusing on patients with AMI, and using standard definitions of anemia. Moreover, our analyses include a broad range of outcomes (including health status), and provide important new data about the variability of HAA across hospitals.
Our findings have important clinical implications. Several of the correlates of HAA are also associated with chronic anemia and bleeding in AMI patients (such as age, female gender, acute heart failure and chronic kidney disease),2, 7, 16, 17
and likely identify a high risk population with poor hematopoetic reserve. On the other hand, some independent correlates are hospital-based variables (use of glycoprotein IIb/IIIa inhibitors and bleeding) – and could be targets for prevention efforts. Several of these variables are associated with bleeding,16–18
and the use of bleeding avoidance measures, such as radial artery access for PCI, smaller sheaths, or alternative antithrombotic agents such as bivalirudin in place of heparin and a glycoprotein IIb/IIIa inhibtor, present potential opportunities for improvement.19–22
Additionally, the strong association between moderate-severe HAA and 12-month mortality, even after adjusting for the presence and severity of bleeding, indicates that HAA is distinct from bleeding and is clinically important in its own right. Although the major causes of HAA among those without documented bleeding remain unclear, it is possible that it is related to subclinical blood loss (such as frequent phlebotomy), undetected bleeding, minor periprocedural bleeding, inadequate hematopoietic response or a combination of processes. Our findings indicate that additional emphasis on prevention of HAA, a process distinct from overt bleeding in many cases, could be just as important as prevention of bleeding. Further studies are needed to define specific causes of HAA and determine whether HAA prevention is feasible and improves patient outcomes.
Our findings should be interpreted in the context of their potential limitations. We used discharge hemoglobin values to define HAA as nadir hemoglobin values were not available. This approach may underestimate the prevalence of HAA; however, given the relatively short duration of hospitalization (median 3.0 days, (IQR) 2.0 – 4.0) it is unlikely that a substantial proportion of HAA cases were missed. More importantly, our goal was to examine prognosis after discharge, and discharge Hgb is the most accurate assessment of patients' anemia status at that time. It is also possible that undetected, mild bleeding episodes were not detected despite careful prospective collection of bleeding data. Even if this were the case, however, the association between bleeding and adverse outcomes has only been demonstrated for more severe categories of bleeding. Accordingly, our data could be viewed s providing novel insights that indicate further investigation of the outcomes associated with mild bleeding are need. Another possible limitation is that some misclassification of anemia severity occurred in patients with in HAA who received blood transfusions before discharge hemoglobin assessment. However, we adjusted the discharge hemoglobin values for in-hospital blood transfusion to minimize this issue and performed sensitivity analyses excluding patients who received a blood transfusion. Our definition of chronic anemia was any anemia present at admission, which could have captured sub-acute cases in addition to those with long term anemia. Finally, these observational data do not allow us to draw conclusions about causal relationships between HAA and mortality and it remains unclear whether HAA is a marker for, or a mediator of, poor outcomes.
In conclusion, we found that HAA is common in patients hospitalized with AMI and varies substantially across hospitals. Development of moderate-severe HAA is associated with higher mortality and worse health status in the first year after AMI, independent of documented in-hospital bleeding. Better understanding of whether prevention of HAA is feasible and can improve patient outcomes is needed.