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Among patients undergoing percutaneous coronary intervention (PCI), baseline anemia substantially increases the risk of major bleeding despite use of bivalirudin, according to a study published online February 13, 2014, ahead of print in the American Journal of Cardiology. In turn, in-hospital bleeding predicts higher long-term mortality primarily in anemic patients, especially those who receive blood transfusions.

Researchers led by Ziad A. Ali, MD, DPhil, of Columbia University Medical Center (New York, NY), analyzed data from 11,991 patients who underwent PCI with bivalirudin as the primary antithrombotic agent between July 2002 and May 2010. Forty percent (n = 4,815) of the cohort had baseline anemia (hemoglobin level < 13 g/dL in men and < 12 g/dL in women).

Major Bleeding Far More Common in Anemic Patients

There were 322 (2.7%) in-hospital bleeding complications after PCI. Of these, 210 (1.8%) were major according to HORIZONS-AMI trial criteria, including 88 vascular access site bleeds, 5 GI bleeds, and 4 retroperitoneal bleeds. In addition, 156 patients (1.3%) received blood transfusions. Rates of major bleeding and transfusion were higher in anemic vs nonanemic patients (HR 3.25; 95% CI 2.3-4.6; P < 0.001) and anemic patients were more likely to receive a transfusion (P < 0.001; table 1). The interaction between anemia and major bleeding approached significance (P for interaction = 0.066).

Table 1. Major Bleeding According to Baseline Anemia Status

There were lower drops in hemoglobin after PCI among all anemic patients and those with major bleeding compared with nonanemic patients (both P < 0.001). Moreover, among patients who received a transfusion, the hemoglobin drop was lower in the anemic group than the nonanemic group (1.0 ± 1.9 g/dL vs 3.0 ± 1.5 g/dL; P = 0.003).

At a median follow-up of 2.6 years, 1,157 patients had died (9.6%). Survival was lower in those who experienced major bleeding, which was an independent predictor of mortality (HR 1.4; 95% CI 1.1-1.8; P = 0.027.) The same survival pattern held true for anemic patients, with major bleeding remaining an independent predictor of mortality (HR 1.5; 95% CI 1.1-2.0; P = 0.008). However, in patients without baseline anemia, survival was similar for those with or without major bleeding (P = 0.62).

On multivariable analysis, anemia strongly predicted major bleeding (OR 3.3; 95% CI 2.3-4.6; P < 0.001) independently of other covariables including female gender, ACS, age, GFR, and use of a vascular closure device. In addition, anemia independently predicted long-term mortality (OR 1.8; 95% CI 1.6-2.0; P < 0.001).

How Anemia May Increase Risk

As expected with PCI patients receiving bivalirudin, the authors observe, the overall incidence of bleeding was low. However, the risk of both major bleeding and mortality was increased in anemic compared with nonanemic patients, and they suggest several possible explanations:

• Anemia stimulates release of erythropoietin, which activates platelets and plasminogen activator inhibitor-1, potentially leading to a prothrombotic state
• Anemic patients are more likely to stop antithrombotic therapy after suffering a major bleed due to the perceived risk of acutely low hemoglobin levels, and chronic subclinical blood loss may become overt if patients receive potent antiplatelet and anticoagulant drugs during PCI
• Anemic patients often have chronic kidney disease, which is associated with platelet dysfunction and coagulopathy—conditions that are compounded during periprocedural antiplatelet and anticoagulant administration

Transfusion’s Downside

Interestingly, Dr. Ali and colleagues say, major bleeding events were driven predominantly by transfusion unsupported by a substantial drop in hemoglobin, ischemia, or hemodynamic instability. And although a causal connection has not been proven, transfusion has been linked to increased mortality following PCI. They say this may be attributed to the fact that during storage, red blood cells undergo changes that can lead to microvascular obstruction after transfusion. In addition, a decrease in the bioavailability of nitric oxide may alter local vasodilation and platelet function.

“Overall these findings suggest that refinements in the use of blood transfusion could have major clinical impact,” the authors say. Guidelines have been proposed to limit transfusion use to cases of severe anemia causing symptoms or ischemia, they report, noting that a strategy of pre-emptively treating anemic patients with aggressive use of iron repletion, erythropoietin, or other disease-specific measures outside the periprocedural period has proven effective at their institution. The authors add that they have abandoned use of arbitrary cut-offs of specific hemoglobin levels as the trigger for transfusion and instead base the therapy on clinical need. 

Study Details 

Almost two-thirds (64%) of patients without anemia (n = 176) were treated for stable angina or silent ischemia, while more than half (57%) of patients with anemia (n = 4,815) had stable angina or silent ischemia at baseline. All patients were loaded with aspirin (325 mg), clopidogrel (300-600 mg), or prasugrel (60 mg) prior to PCI. Administration of glycoprotein IIb/IIIa inhibitors was at the discretion of the operator. Unless contraindicated, femoral vascular closure devices were used. Post PCI, aspirin was prescribed indefinitely and clopidogrel or prasugrel for at least 1 month after BMS implantation and at least 1 year after DES implantation.

Note: Dr. Ali and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD. 

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