Temporal Trends in Bleeding among Acute Coronary Syndrome Patients: Is It Going Up or Down? Does It Matter?

Abstract

In this issue of Cardiology, Sabbag and colleagues [1] utilize a large Israeli registry of patients presenting with acute coronary syndrome (ACS) from 2004–2010 to describe temporal trends of major bleeding and associated outcomes. Among the 11,538 patients enrolled in the study, 142 (1.2%) had a major bleeding event (MBE), defined as one of the following: a decrease in hemoglobin of 5mg/dL or a hematocrit drop of >15%, intracranial hemorrhage, or retroperitoneal bleeding. Bleeding events were then further divided into access site and non-access site bleeding. Despite a modest decrease in bleeding events from 2000–2004, rates of bleeding increased markedly over the study period, with the highest rates of reported bleeding in 2010, the last year of collected data. This is in the setting of increasing use of primary PCI and decreasing use for fibrinolytic therapy in patients presenting with ST-segment elevation MI (STEMI). Although rates of major adverse and cerebrovascular events (MACCE) were lower in all patients during this time period, patients experiencing a MBE had worse short- and long-term outcomes compared with patients who did not have a bleeding episode. Although the overall rate of bleeding is low and likely reflects the specific bleeding definition utilized, the increasing rate of major bleeding over time described in this analysis is concerning and stands in stark contrast to prior studies in large registries, none of which have shown significant increase in bleeding rates over time despite the use of more robust antithrombotic strategies. Utilizing data from more than 1.7 million patients in the National Cardiovascular Data Registry’s CathPCI Registry, Subherwal and colleagues described a 20% reduction in major bleeding events following PCI from 2005–2009. In that analysis, rates of bleeding reduction were similar among patients presenting with unstable angina/NSTEMI (2.3% to 1.8%) compared with STEMI (4.9% to 4.5%) [2]. Additionally, rates of access-site and non-access site bleeding were similar in the UA/NSTEMI population but significantly higher rates of non-access site bleeding were observed in the STEMI population, presumably due to differences in procedural antithrombotic therapy. Fox and colleagues reported a similar reduction in major bleeding events (defined as life-threatening bleeding occurring in-hospital resulting in a hematocrit decrease of ≥ 10%, transfusion of ≥ 2 units PRBCs, and/or resulting in death due to subdural hematoma or hemorrhagic stroke) among 50,947 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) Registry from 2.6% to 1.8% from 2000–2007 [3]. Similar increases in the rate of primary PCI and reduction in the rate of fibrinolytic therapy were observed in that population as well. In another analysis that combined NSTE-ACS patients across four prospective multicenter registries, Elbarouni and colleagues describe no significant increase in the rate of major bleeding (defined as in the study by Fox et. al.) over time despite increasing use of dual antiplatelet therapy and cardiac catheterization with PCI [4]. So what accounts for the disparity between the study by Sabbag and the others that have been published? One challenge in the study by Sabbag is the heterogeneity of the study population. Although the spectrum of ACS often shares a common pathophysiology, treatment pathways differ markedly based on initial patient presentation, and the balance of benefit from early and rapid revascularization versus risk of adverse events may shift in unstable angina patients where immediate PCI is not the standard practice. In STEMI patients, timely and rapid reperfusion is the preferred treatment strategy despite the potential increase in bleeding risk. Therefore, combining patients with non-ST-segment elevation ACS with STEMI may lead to results that are not necessarily reflective of actual rates of bleeding in different categories of ACS. Indeed, the authors describe a significant reduction in the use of fibrinolytic therapy, from under 50% in 2004 to less than 5% by 2010. A significant change in practice over a 6 year period can certainly influence the rate of bleeding; however, one would expect that a conversion from fibrinolysis to primary PCI would reduce bleeding, not increase it. Another reason for the increase could be greater vigilance and reporting of bleeding complications. Recognition of the prognostic impact of bleeding in patients with ischemic heart disease was increasing between 2004 and 2010, and this may have influenced the reporting of major bleeding in the registry. So is the incidence of bleeding in ACS patients increasing or decreasing? And does it really matter? The answer to the first question is probably “both” – while the preponderance of evidence suggests that bleeding is likely decreasing, this may not apply to all ACS patients. Regional differences in antithrombotic therapy, dosing, genetic response to antiplatelet drugs, and use of “bleeding avoidance strategies” all influence the risk of bleeding complications. Ultimately the second question may be more important. The results of Sabbag’s analysis underscore the need for a focused effort to reduce the likelihood of major bleeding events in all patients using risk reduction strategies (Table). Appropriate dosing and administration of antithrombotic therapies is essential, particularly with respect to more potent antiplatelet agents such as prasugrel which have demonstrated net harm in certain, high-risk patients. Prior studies have noted incorrect dosing of anticoagulant therapies, particularly in high-risk populations [5]. The authors note that among patients with bleeding events, one third of patients developed either access site bleed (25%) or retroperitoneal hematoma (8%), both of which could be significantly reduced with radial artery access, which was almost never used among patients in this study. Multiple prior studies have demonstrated the benefit of transradial access with respect to access site complications and bleeding reduction. Among patients presenting with STEMI, the RIFLE-STEACS Trial showed reduced rates of the primary outcome of death/MI/stroke/target vessel revascularization among patients undergoing transradial PCI (13.6% vs. 21.0%) along with significant mortality (5.2% vs. 9.2%, p=0.02) and bleeding (7.8% vs. 12.2%, p=0.026) reductions. More recently, the MATRIX Trial highlighted the superiority of radial approach in patients presenting with ACS with reductions in BARC bleeding and all-cause mortality among patients undergoing transradial access [6]. Previous trials, including the ACUITY [7], HORIZONS-AMI [8], and EUROMAX [9] trials have demonstrated reduced rates of major bleeding with bivalirudin among patients presenting with ACS undergoing PCI, and bivalirudin use has been implemented as a bleeding avoidance strategy. However, more recent data from the HEAT-PPCI [10] have suggested that a periprocedural regimen of heparin only in the setting of increased transradial use and more potent antiplatelet therapies may have similar efficacy and bleeding. Although this is currently a topic of major debate, bivalirudin may play a role in bleeding reduction in high-risk patients, particularly those undergoing transfemoral PCI like those in the study by Sabbag. Finally, it should be noted that the data for bleeding reduction with vascular closure devices is mixed and may not support a significant role as part of a comprehensive bleeding reduction strategy. Table Strategies to Reduce Bleeding Among Acute Coronary Syndrome Patients The authors are to be commended for drawing attention to this concerning trend among patients in this registry. The most recent results demonstrating continued increase in major bleeding events in Israel should serve as a focal point to develop a comprehensive strategy for bleeding reduction incorporating procedural innovations as well as appropriate administration and dosing of anticoagulant and antiplatelet agents among ACS patients. Encouraging is the fact that major bleeding has decreased markedly worldwide from the earlier era of ACS management, suggesting that increasing focus and attention to bleeding and the implementation of evidence-based bleeding avoidance strategies should reverse the trend of increased bleeding and worse short-and long-term outcomes observed in this study.