There have been important advances in recent years in the management of patients with acute coronary syndrome (ACS), leading to a significant reduction in mortality.1 However, ACS remains one of the main causes of morbidity and mortality in developed countries. Traditionally ACS covers a wide spectrum of clinical entities, which includes unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI) and sudden cardiac death.2

ACS is frequently complicated by the presence of comorbidities, including anemia, renal failure and diabetes mellitus. Anemia is common in ACS patients at admission, being found in over 15% of patients with myocardial infarction (MI), and in up to 43% of older patients.3

Anemia can exacerbate myocardial ischemia in ACS patients, adversely affecting their prognosis. The harmful effect of anemia is due to various mechanisms: it decreases the blood oxygen saturation required to meet myocardial demand and raises oxygen demand by increasing cardiac ejection volume to maintain an adequate oxygen supply to all systemic tissues. The combination of these two processes may be the pathophysiological basis for the worse outcomes observed in ACS patients with lower baseline hemoglobin (Hb) concentrations.4,5

Although the cardiovascular repercussions of anemia are relatively well known, other questions remain to be clarified, such as the prevalence of anemia in ACS patients at the time of hospital admission, the Hb concentration associated with worse prognosis, and the actual effect of low Hb in the short and long term.5

While the general effect of anemia is decreased myocardial oxygenation, the ideal Hb level has yet to be established. At the other extreme, polycythemia can result in hyperviscosity, which increases coronary vascular resistance and promotes thrombus formation, thus also reducing oxygen supply to ischemic myocardium. Sabatine et al. demonstrated that patients with very high baseline Hb (>16–17g/dl) also presented higher cardiovascular risk.4

The adverse effect of anemia on prognosis in coronary disease has been comprehensively studied. In animal models, higher Hb levels have been shown to prevent myocardial ischemia in the presence of significant coronary disease.4 However, the data available on the real predictive value of anemia in ACS patients are limited and at times inconsistent. Few studies have specifically examined its value as an independent predictor of short- and long-term mortality.

The purpose of this study was to assess the impact of different baseline Hb levels on short- and long-term prognosis in patients with ACS.

Our population was similar in terms of age and gender distribution, prevalence of diabetes mellitus and cardiovascular history to those in international multicenter studies on ACS.1,8

The present study confirmed that anemia is a common comorbidity in ACS patients, and is associated with greater morbidity and cardiovascular mortality. In this unselected real-world population, the prevalence of anemia at admission for ACS (65.6%) was above the highest values in published series. In most studies in this area the incidence of anemia ranges between 23% and 42%, lower rates being reported in clinical trials with selective patient recruitment.3,9–12 One possible explanation for the higher incidence in our population may be the fact that it was a single-center study in a tertiary hospital, which thus frequently receives more severe cases referred from other hospitals.

In our study, anemia was associated with more elevated troponin I, higher Killip class at admission and a greater tendency for ST-segment depression on ECG, which when taken together suggest that patients with ACS and anemia may suffer more severe ischemia, and hence have worse short- and long-term prognosis.

Low Hb was frequently associated with other comorbidities in our analysis. The greater incidence of anemia in diabetic patients may be explained by the high prevalence of renal dysfunction in diabetes, associated with reduced erythropoietin production and an impaired hemopoietic response to this hormone. The prevalence of diabetes increases with advancing age, which may also help explain the association between anemia and diabetes, both of which are more common in the elderly,10 as are hemopoietic disorders and other conditions such as cancer and bleeding diathesis.

We also found that systemic inflammation, as reflected in C-reactive protein levels, was more marked among anemic patients. Elevated inflammatory parameters may have some pathophysiological significance in this instance, since pro-inflammatory cytokines inhibit erythropoietin production, leading to reduced red blood cell production. At the same time, inflammation by itself carries a higher risk of atherothrombosis and thus worse long-term cardiovascular prognosis.5

Chronic use of certain drugs may also have contributed to low Hb concentrations in our population. Use of ACE inhibitors was significantly more common in patients with low Hb, and the link between these agents and anemia is well established, which is probably related to increased metabolism of erythropoietin mediated by ACE inhibitors.13 Prior to admission 45% of patients were also taking aspirin, an important factor in these patients’ higher risk of bleeding complications. The literature also describes the possible suppression of bone marrow activity and decreased red blood cell production as a rare secondary effect of certain antiplatelet agents such as clopidogrel.5,14

In recent years, several studies have investigated the possible association between low Hb levels and worse short- and long-term cardiovascular prognosis. As found in our study, various analyses have reported higher rates of ischemic events with lower Hb levels.5,14 Our results regarding long-term mortality are generally in agreement with most studies to date.

In contrast to our analysis, Nikolsky et al. and Meneveau et al. concluded that anemia was an independent predictor of in-hospital mortality, with odds ratios (OR) of 1.43, 3.26 and 2.27, respectively.12,15 Archbold et al. demonstrated that anemia was an independent predictor of left ventricular dysfunction and thus of worse prognosis, but as in our study, no independent association was found between low Hb levels and in-hospital mortality.9

Few studies have specifically analyzed the link between anemia and long-term mortality. In agreement with our results, Nikolsky et al. demonstrated that the presence of anemia in ACS patients undergoing percutaneous coronary intervention was an independent predictor of one-year mortality, with an OR of 2.38.15

Our study found that anemia was associated with increased risk of in-hospital and long-term mortalities, longer hospital stays and a higher rate of rehospitalizations. It should be noted that although anemia was associated with classic factors of poor prognosis such as diabetes mellitus, advanced age and renal dysfunction, multivariate analysis showed Hb <10.8g/dl to be one of the strongest independent predictors of mortality throughout 12-month follow-up (OR=2.3), but it was not a predictor of in-hospital mortality.

The physiological effect on the heart of anemia is due to the cardiovascular system's hemodynamic response to oxygen deprivation, by reducing afterload, increasing preload and activating the sympathetic nervous system, which in turn increases heart rate. These changes are intended to increase cardiac ejection volume in order to meet the oxygen demands of all systemic tissues, but in chronic situations they can lead to left ventricular dilatation and eccentric hypertrophy. Continuous increases in blood flow can also predispose to adaptive arterial remodeling and hypertrophy, resulting in arterial wall thickening and systolic hypertension. All these changes may be directly linked to increased risk for chronic arterial disease and thus worsen prognosis in patients with ACS and anemia.10,16

Diabetes mellitus was also identified as a predictor of one-year mortality, which highlights the importance of changes in glucose metabolism and their control for prognosis in these patients. Other independent predictors of one-year mortality were ST-segment depression, probably due to more severe ischemia, age ≥69.5 years (after which the presence of several comorbidities is common), and Killip class >1 at admission. The latter was also the only predictor of in-hospital mortality in our study.

Despite advances in management of ACS patients in recent years, most studies report mortality of between 2.0% and 13.6%.4,8–11

In-hospital mortality in our population was 5.9%, while at 12-month follow-up it was 12.1%. The higher in-hospital mortality in our study compared to the 4.4% reported in the last Euro Heart Survey on ACS (ACS-II, 2004) may be explained by the high incidence of anemia in our population, the fact that all forms of ACS presentation (STEMI, NSTEMI and UA) were included, and that it was performed in a tertiary hospital that would tend to receive more severe cases.18

There was greater use of most drugs recommended for ACS in our population than in international multicenter studies.4,8 However, as in other reference studies, antiplatelets (aspirin and clopidogrel) and beta-blockers were prescribed less in patients with low Hb levels, prescription rates of antiplatelets still being lower in these patients at discharge. Antiplatelet therapy has been recommended for some years in the guidelines, but although it reduces ischemic events, it is also associated with a greater risk of bleeding complications, which may mean that patients with anemia receive suboptimal treatment.12,17

Our study confirmed that anemia is common in ACS patients and identified it as a potentially modifiable risk factor. However, the question remains as to whether correcting anemia during the acute phase of ACS improves cardiovascular outcomes. Blood transfusions can in fact have an immunomodulatory effect that results in increased risk of infection, hemolytic reactions, volume overload, and infusion of procoagulant and proinflammatory cell products, promoting arterial thrombosis.14,16

While uncertainties remain as to the ideal Hb level in patients with ACS, anemia does appear to be associated with adverse short- and long-term cardiovascular outcomes, and so its inclusion in risk scores could be advantageous.

We believe that assessing Hb concentration, an accessible laboratory parameter that is usually measured in all patients at admission, could enable therapeutic strategies to be tailored to the individual, and improve the poor prognosis of ACS patients with anemia.

This was a single-center study based on data collected retrospectively of patients admitted to a teaching hospital, who probably represented more severe and complex cases of ischemic heart disease, and so may not accurately reflect the majority of ACS patients.

Furthermore, the etiology of anemia in our study population was not specified, and it was therefore not possible to establish a causal relationship between different underlying pathophysiological entities and different types of anemia (microcytic, normochromic and macrocytic), and worse prognosis.

Notwithstanding these limitations, we consider that the study makes an important contribution, since similar studies are few and their results are inconsistent.

Despite advances in the management of ACS patients, anemia is common and associated morbidity and mortality remain high. The present study identified anemia as an independent predictor of long-term mortality, highlighting the importance of identifying individuals with low Hb levels during initial assessment of patients with ACS.

The authors have no conflicts of interest to declare.