Anemia Common in ACS Patients, Linked with Higher Mortality

In a large cohort of adult patients with acute coronary syndrome, more than one in four individuals are anemic, a condition that is associated with a significantly increased risk of death at 30 days and 1 year, a new observational study shows.

In an analysis of 422,855 ACS patients in the Myocardial Ischemia National Audit Project (MINAP) registry in England and Wales, individuals with anemia, which included 27.7% of the cohort, had a 28% and 31% increased risk of death at 30 days and 1 year, respectively, when compared with non-anemic ACS patients.

Lead investigator Mamas Mamas, BMBCh (Keele University, Stoke-on-Trent, UK), said anemia is a “really big” and common burden for practicing physicians. “Once you identify a patient as anemic and being at high risk, there aren’t really any good guidelines or good data for how we should treat these patients,” said Mamas. “It’s quite extraordinary—more than one quarter of all patients we encounter are anemic and yet we don’t know how to treat them.”

For example, despite the increased risk for death at 30 days and 1 year, there is a “lack of clarity” in the guideline recommendations about whether or not these patients should receive a blood transfusion and the optimal transfusion strategy, said Mamas. The American Association of Blood Banks has “no recommendation for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with acute coronary syndrome,” the researchers point out.   

“It’s quite extraordinary—more than one quarter of all patients we encounter are anemic and yet we don’t know how to treat them.” Mamas Mamas

For Serdar Farhan, MD, Usman Baber, MD, and Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who wrote an accompanying editorial, the study confirms earlier observations documenting a high prevalence of anemia in ACS, a finding that has also been observed in heart failure patients.

“In any observational datasets we’ve seen, the presence of anemia is not uncommon in patients with not just ACS, but with coronary artery disease, such as all-comers undergoing PCI,” Baber told TCTMD. “This certainly extends to ACS patients as well. The observation is not all that novel, but confirmatory, and highlights that this risk factor is highly prevalent and has prognostic implications that we all should be aware of, particularly interventionalists who are taking care of these patients.”

The study and editorial is published November 19, 2016 in the Journal of the American Heart Association.

Anemia Increases Risk in Multiple Conditions

Speaking with TCTMD, Mamas said that in a number of cardiovascular conditions, including heart failure, stroke, and ACS, anemia is a risk factor known to be associated with adverse clinical outcomes. However, it is difficult to tease out whether the anemia contributes to the increased risk or whether it is mainly a marker of comorbidity.      

In the analysis, for example, patients with anemia were significantly older, were more likely to smoke, and were more likely to have prior hypertension, angina, MI, heart failure, stroke, peripheral vascular disease, diabetes, and renal failure. Mamas noted that one of the most common causes of anemia is chronic renal failure, and renal failure alone is an independent predictor of adverse outcomes across a spectrum of cardiovascular conditions.

“We were very careful to try to reduce the impact of cofounders so we adjusted for all the variables we know are predictors of anemia and that portend to worse outcomes,” said Mamas. “Second, in a sensitivity analysis, we removed patients who had bleeding complications and patients with renal disease. And yet, we still saw the association between poor outcomes and anemia even after we removed the potential confounders.” 

Mamas noted that anemic patients in the registry were also less likely to receive aggressive therapy than their non-anemic counterparts. For example, patients with anemia were more likely to arrive at the hospital taking aspirin and clopidogrel compared with those without anemia (7% vs 5%; P<0.001), but less likely to receive dual antiplatelet therapy upon discharge (75% vs 79%; P<0.001). In addition, patients with anemia were less likely to receive angiography (26% vs 38%; P<0.001).

The reasons for the increased mortality rate among anemic patients is likely multifactorial, said Mamas. Anemic patients are older, have more comorbidities, and more severe disease, and while these variables were adjusted for in the analysis, there might be residual and unmeasured confounding variables that contribute to the increased risk of death. Additionally, anemia is a strong predictor of future bleeding events, which might explain the less aggressive treatment, he said.

To TCTMD, Baber said the “million-dollar question” is whether anemia is the cause of the increased mortality risk or if it’s a marker for something else.  

“We have a lot of data, which Dr. Mehran and others have published, showing a nice associative relationship between the presence of anemia and subsequent risk, which could be cardiac-specific risk or even non-cardiac risk,” he said. “That’s been shown in several datasets, both from randomized studies and this large observational dataset. The difficulty when these observations are made—either from randomized cohorts or nonrandomized cohorts—is deducing any causal inference.”

In their editorial, Baber and colleagues said there is biological plausibility for the increased risk in anemic patients—imbalance between myocardial oxygen supply and demand, an hypothesized impairment of vascular healing in ACS patients with anemia, and inflammatory flux related to hemoglobin levels—but this would only explain the short-term, rather than long-term, mortality risks observed.

“What we do know is that anemia is very common, that there’s a risk that is substantial in its magnitude and durable over time, and that it’s consistent,” said Baber.

Management of Anemia

There have been some small pilot studies testing different transfusion strategies in ACS patients with anemia/low hematocrit levels, but the results are mixed. A meta-analysis of 10 studies, most of which were registry studies, a liberal transfusion strategy increased the risk of mortality three-fold in acute MI patients, a risk that remained independent of anemia status.

In their editorial, Farhan, Baber, and Mehran suggest physicians treating ACS patients with anemia should take measures to minimize the risks of bleeding, such as performing PCI via the radial artery and using vascular closure devices. Dosing an antithrombotic agent by weight and renal function can also further reduce the risk of bleeding. “When you add additional bleeding in someone who has anemia, you’re only going to exacerbate the underlying problem,” noted Baber.  

The editorialists point out that blood transfusions have well documented side effects and randomized studies comparing different transfusion thresholds have failed to show any advantage with a more liberal cutoff for hemoglobin levels.

“My recommendation, which I think is in accordance with routine practice, is to be conservative with the administration of blood products,” Baber told TCTMD. “We have certainly learned that the [transfusion of] blood and blood products is not a benign process. For a long time, there was a thought that with [hemoglobin] around 10 g/dL, you should give blood, but we’ve certainly changed our practice. We’re more conservative around this now. We’re using more stringent thresholds, around 7 or 8 g/dL, before transfusion.”