Antithrombin Therapy for Elective Percutaneous Coronary InterventionWhich Agent to Use? Does It Matter?*
Sorin J. Brener, MD*
New York Methodist Hospital, Division of Cardiology, Brooklyn, New York
Key Words: anticoagulation • antithrombin • percutaneous coronary intervention
The notion that antithrombin therapy is needed in patients undergoing percutaneous coronary intervention (PCI) evolved empirically from the understanding of the pathophysiology of atherosclerosis (1,2) and the mechanisms involved in PCI, particularly with respect to arterial wall dissection and the thrombus formation that can follow (3). Unfractionated heparin (UFH) has been the traditional antithrombin agent during PCI, despite little evidence to support the need and the intensity of anticoagulation desired for optimal results (4). In fact, in an analysis of 4 recent studies of PCI, there was no relationship between the intensity (measured with the activated clotting time [ACT]) of anticoagulation with UFH and the incidence of ischemic complications (5). As expected, higher ACT was associated with a small increase in, predominantly, minor bleeding up to 365 s, and higher total doses of UFH were also associated with more bleeding. Among more than 8,000 patients with a high rate of treatment with thienopyridines and glycoprotein IIb/IIIa inhibitors (GPIs) and almost universal stenting, there was no evidence of a lower threshold for anticoagulation below which ischemic events were increased. Moreover, the median ACT did not differ among patients with or without ischemic or hemorrhagic events in 7 PCI trials. Some even suggested that only a minimal dose of UFH is needed when adequate antiplatelet therapy is provided (6).
In this issue of JACC: Cardiovascular Interventions, Montalescot et al. (7) provide the 1-year outcome of the STEEPLE (Safety and Efficacy of Enoxaparin in PCI Patients, an International Randomized Evaluation) trial, initially published in 2006 (8). Elective PCI patients, nearly all pre-treated with clopidogrel and not previously treated with an antithrombin agent, were randomized to receive a single IV dose of enoxaparin 0.50 or 0.75 mg/kg (without weight restriction) or UFH with ACT adjustment to 300 to 350 s in the absence of GPI and 200 to 300 s in the presence of GPI (40% of patients). The primary end point, assessed for noninferiority, was noncoronary artery bypass graft surgery major or minor bleeding within 48 h of PCI (Table 1). Compared with UFH, bleeding was reduced by enoxaparin from 8.5% to 6.5% (0.75 mg/kg dose, p = 0.05) and 5.9% (0.50 mg/kg dose, p = 0.01), respectively. Major bleeding occurred in 2.8%, 1.2% (p = 0.007), and 1.2% (p = 0.004), respectively. The main category in which a reduction was noted was the >3 g/dl decrease in hemoglobin. There was no significant difference in the incidence of minor bleeding or ischemic events among the groups. Of note is that using other scales of bleeding, such as the Thrombolysis In Myocardial Infarction (TIMI) flow grade (9) and the GUSTO (Global Utilization of Streptokinase and TPA for Occluded Arteries) (10), did not reveal any significant differences in the primary end point among the groups. There were <5 events of TIMI major bleeding in each of the groups. Only one-fifth of UFH patients were in the pre-specified range of 0.5 to 1.8 IU/ml of anti-Xa activity, compared with 79% and 92% of the enoxaparin groups, respectively. Notwithstanding the acknowledged limitations of insufficient power for the mortality end point, the need to re-consent patients for unplanned 1-year follow-up, and the substantial loss of patients for follow-up, at 1 year the cumulative rates of all-cause mortality were 1.9%, 2.2%, and 2.3%, for enoxaparin 0.50 mg/kg, enoxaparin 0.75 mg/kg, and UFH, respectively (p = NS). Echoing many recent publications on the predictors of 1-year mortality (11–13), the authors found that having periprocedural bleeding or an ischemic event increases the odds of subsequent death by a factor of 3.0 and 1.7, respectively.
The STEEPLE trial also provided a lesson in trial conduct. Early termination of the 0.5-mg/kg dose allocation because of a higher number of deaths resulted in only a small discrepancy in the overall enrollment, because the trial was completed anyhow 1 month after the decision to stop enrollment in the 0.50-mg/kg arm. Furthermore, the preliminary analysis was not confirmed at 1 year, when the rate of death was numerically the lowest in the group terminated early.
The American College of Cardiology recommends the use of UFH during PCI, with the dose adjusted for ACT (Class I, Level of Evidence: C), or enoxaparin (Class IIa, Level of Evidence: B) (14). The former is unpredictable with respect to its anticoagulant effect, is more likely to be bound by circulating proteins, and incites a vascular response that promotes platelet adhesion and aggregation by liberating von Willebrand factor from the endothelium. Yet, it can be easily reversed and offers to many practitioners the comfort of familiarity and measurement of effect. Enoxaparin is extremely predictable in its effect (15), does not require monitoring or adjustments (particularly for single dose), and is less conducive to platelet adhesion and aggregation. Its main disadvantage is the inability to reverse it quickly and completely. Higher costs have also limited its penetration for this indication in the U.S.
Does the follow-up information from the STEEPLE trial modify this balance? Is it a reason to adjust the recommendation for PCI anticoagulation? Probably not! The population studied was very low-risk, and the majority of major bleeding events in each group were related to an asymptomatic decrease in hemoglobin. The more important contribution of the study lies in the confirmation of the significance of periprocedural bleeding as an important predictor of 1-year mortality. In that respect, this report joins others in urging all of us to make every effort to lower the rate of periprocedural significant bleeding by using anticoagulation judiciously and, potentially, altering the access site in patients at high risk for bleeding. Other alternatives to UFH and enoxaparin, such as the direct thrombin inhibitor bivalirudin (16) (Class IIa, Level of Evidence: B) and the synthetic factor Xa inhibitor fondaparinux (17), should also be considered as valuable tools for reducing PCI-related bleeding. The former has been shown to reduce major bleeding regardless of the scale used for its assessment and has no stimulatory effect on platelets.
From this and other reports, we can conclude that elective PCI can be conducted with very few serious ischemic and hemorrhagic complications, regardless of the antithrombin agent used. Enoxaparin is, certainly, an acceptable alternative to UFH or bivalirudin, and physicians should acquire the same level of familiarity with its use as they have with the time-honored, insufficiently researched, and unpredictable precursor, unfractionated heparin.
It is not how we thin the blood that counts; it is how much of it we lose that predicts outcome.
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Footnotes
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* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. Sorin J. Brener, New York Methodist Hospital, Cardiology, 506 6th Street, Brooklyn, New York 11215 (Email: sjb9005{at}nyp.org).
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