The Relationship Between Bleeding and Adverse Outcomes in ACS and PCI: Pharmacologic and Nonpharmacologic Modification of Risk

ABSTRACT: Antithrombotic therapy, including antiplatelet and antithrombin agents, effectively reduces the risk of ischemic events in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Unfortunately, these agents intrinsically increase the risk of bleeding complications, which in turn are associated with adverse outcomes, particularly mortality. Accordingly, there is great value in improving the understanding of bleeding complications, including the definitions employed, severity and types of bleeding, as well as the patient characteristics, clinical presentations, and treatment variables that are associated with an increased risk of bleeding. The ultimate goal is to optimize patient outcomes by employing pharmacological and nonpharmacological strategies that minimize bleeding risk while maintaining efficacy. The objective of this article is to present the criteria by which bleeding is expressed and discuss the correlation between bleeding and adverse outcomes, as well as the relative impact of bleeding compared with ischemic events such as myocardial infarction on mortality. Furthermore, the relationship between bleeding and modifications of long-term treatment and methods to predict and prevent bleeding will be explored. J INVASIVE CARDIOL 2010;22:132–141 Key words: acute coronary syndrome; antithrombotic therapy; bleeding; percutaneous coronary intervention Acute coronary syndromes (ACS) are typically secondary to atherothrombosis. Therefore, antithrombotic therapy with antiplatelet (inhibitors of thromboxane A2, adenosine diphosphate, and glycoprotein [GP] IIb/IIIa receptors) and anticoagulant (inhibitors of thrombin and factor Xa) agents are utilized in order to prevent ischemic complications and mortality.1,2 Patients undergoing percutaneous coronary intervention (PCI) are also treated with antithrombotic therapy to prevent ischemic complications associated with the procedure.3 In both ACS and PCI, agents that inhibit different aspects of thrombus formation are typically used in combination, with aspirin, a thienopyridine, an anticoagulant (unfractionated heparin, enoxaparin, fondaparinux, or bivalirudin), and a GP IIb/IIIa receptor antagonist, the currently available pharmacologic options.1 While these potent antithrombotic regimens effectively reduce the risk of thrombotic ischemic complications, they also intrinsically increase the risk of bleeding, particularly in patients with predisposing factors. The need to balance the efficacy and safety of antithrombotic therapy is now even more critical, as bleeding complications have been independently associated with mortality and other adverse outcomes.4–16 Furthermore, newer and more potent antithrombotic agents will need to be carefully evaluated to determine if, and in which patients, their increased efficacy justifies their increased bleeding risk. In order to increase the understanding of the true clinical impact of bleeding, this paper will address how bleeding is defined, the correlation between bleeding and adverse outcomes, the relative value of bleeding compared to ischemic events, and several unresolved issues, including whether bleeding can be predicted or prevented and if bleeding impacts long-term treatment.

Defining Bleeding

Numerous severity indices and definitions have been used to classify bleeding in clinical trials and observational registries (Table 1). Two commonly employed bleeding criteria are the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) and TIMI (Thrombolysis in Myocardial Infarction) scales. However, as these criteria were initially developed to measure short-term bleeding associated with fibrinolytic therapy in ST-elevation myocardial infarction (MI), they may not be completely applicable to newer antithrombotic agents, long-term, oral antiplatelet therapy, or other clinical scenarios such as ACS or PCI.17,18 Partly in response to the limitations of the GUSTO and TIMI scales, clinical trial investigators have devised study-specific definitions of bleeding, examples of which include those used in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events),19 ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy),20 and REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2)7 trials. Based on a recent review of large clinical trials investigating antithrombotic agents in patients with ACS or undergoing PCI, study-specific bleeding criteria seem to be the norm rather than the exception, as nine of the 13 trials identified in one review characterized bleeding using scales other than TIMI or GUSTO.21 While some similarities among the bleeding scales exist, there are also many differences. Major differences include the use of subjective versus laboratory criteria, whether overt bleeding is required to qualify an event, the magnitude of hemoglobin drop required to qualify an event, and the indices used to categorize bleeding (e.g., major vs. life-threatening vs. severe).21 Together, these differences challenge the ability to compare bleeding rates across trials. Furthermore, applying different bleeding criteria to the same bleeding events does not necessarily provide equivalent conclusions.21 For example, applying the trial-specific criteria to bleeding events in the CURE trial of 12,562 patients with non-ST-elevation ACS resulted in a statistically significant excess of major bleeding in clopidogrel plus aspirin recipients compared with those who received aspirin alone, while defining bleeding using the criteria for TIMI major bleeding or GUSTO life-threatening or severe bleeding did not result in statistically significant differences in bleeding rates (Figure 1).19 These results, as well as data from the ACUITY20,22 trial of 13,819 patients with moderate- or high-risk ACS and the REPLACE-2 trial of 6010 patients undergoing urgent or elective PCI,7,16 suggest that the TIMI and GUSTO scales may underestimate rates of clinically important bleeding complications as application of these newer, study-specific definitions results in higher bleeding rates. Importantly, new or unique bleeding definitions should be assessed to determine if they are independently associated with adverse outcomes such as mortality in order to confirm that they are clinically relevant, as were the ACUITY9 and REPLACE-27 definitions.

Physician and Patient Perspectives of Bleeding Importance

While bleeding is certainly of concern to both physicians and patients, the type of bleeding of most importance to each may differ. Clinicians, as well as the bulk of the medical literature, seem more focused on in-hospital bleeding complications of moderate or greater severity, especially those that are associated with transfusion of blood products, the need for medical or surgical intervention, increased length of hospitalization, or increased overall resource utilization.23,24 Major bleeding also increases the probability that intravenous and oral antithrombotic agents will be discontinued.15,25 In contrast, patients may be more concerned about recurrent nuisance bleeding (e.g., epistaxis and bruising) as it impacts their daily life. Nuisance bleeding may cause patients to be less adherent to oral antiplatelet therapy and physicians more likely to discontinue it.23,26,27 Interestingly, patients who experience a bleed and receive follow-up care from a cardiologist are more likely to maintain antiplatelet therapy than those who receive follow up from a primary care physician or no follow up at all,25 suggesting that regular follow up with a cardiologist is critical to optimizing outcomes. Regardless of whether it is physician-directed or a patient’s choice, failure to utilize appropriate long-term oral antiplatelet therapy is detrimental as it increases the likelihood of recurrent ischemic events.9,28,29 A related factor contributing to the relative importance of bleeding is whether bleeding events occur early or late in therapy. Early bleeding events are those that occur in-hospital, typically during or immediately following intravenous and/or oral loading doses of antithrombotic therapy. Conversely, late bleeding events occur post-discharge and are more likely to be associated with maintenance therapy with oral antiplatelet agents. While early bleeding events are typically more frequent and severe than those that occur later, these early events may be easier to detect and manage as patients are hospitalized and have more rapid access to appropriate care and necessary interventions. Even minor, occult bleeding may be easier to identify and treat while patients are hospitalized; in contrast, occult bleeding may go undetected in outpatients because they are not monitored closely for such events.

Correlation between Bleeding and Adverse Outcomes

Bleeding has always been considered an important safety concern for patients with ACS and undergoing PCI maintained on antithrombotic therapy. Until recently, it was thought that the impact of bleeding was acute, i.e., if successfully managed, it had no impact on future adverse events. However, this view now seems unviable as an increasing body of data shows both a short- and long-term correlation between bleeding and adverse cardiovascular outcomes, most notably mortality. As seen in Table 1, OASIS (Organization to Assess Strategies for Ischemic Syndromes) major,6 TIMI major8,11,22 and minor,11 GUSTO mild, moderate, and severe,12,13 and protocol-defined major4,5,7,9,10,14,15,30 bleeding have all been identified as independent predictors of MI and/or mortality. In the ACUITY trial, the rate of stent thrombosis within 30 days of PCI was almost six-fold greater among patients who experienced major bleeding compared with those who did not (3.4% vs 0.6%; p Relative Value of Bleeding in Predicting Mortality Although the available clinical evidence strongly suggests that bleeding independently predicts mortality in ACS and PCI, the relative predictive value of bleeding compared with other factors associated with mortality has not yet been fully defined. Aside from bleeding, there are a number of common, independent predictors of mortality in ACS, including advanced age,4,6,7,9,11,16,33 increased heart rate,6,33 renal insufficiency,4,6,11,33 anemia,4,7,16 systolic pressure abnormalities,6,33 prior stroke,4,6,9 prior heart failure,6,7,33 baseline ST-segment deviation ≥1 mm,4,9,33 and baseline cardiac biomarker elevation.4,9,11,33 Interestingly, several of these independent mortality predictors, including advanced age,6–10,14,15,34 anemia,7,9,16 history of hypertension,6,8,9,14,15 renal insufficiency,6–10,14,15,32 prior stroke,6,14 and baseline ST-segment deviation,9,14,15,32 are also predictors of major bleeding. Other commonly identified predictors of major bleeding in ACS include female gender,4,7,9,10,15 GP IIb/IIIa inhibitor use,9,35 and diabetes.4,9,36 Additional predictors of bleeding in PCI include large sheath size,5,37 long procedure duration,5,7,37 femoral versus radial access,31,37,38 GP IIb/IIIa inhibitor use,5,7,8,10,15 and use of vascular closure devices.5,37 Whether vascular closure devices impact the rate of vascular access site complications is unclear as the body of data is inconclusive. However, a recent analysis of over 4,000 patients with vascular closure devices from the ACUITY trial indicated that vascular closure devices were independently associated with a significant reduction in major access site bleeding (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.61–0.99; p = 0.04).49 Because mortality and bleeding share many of the same independent predictors, it can be challenging to determine the relative value of bleeding compared with other factors in predicting mortality. In an analysis of findings from the Global Registry of Acute Coronary Events (GRACE), which revealed a significant association between major bleeding and in-hospital mortality in patients with ACS, the authors acknowledged that the “true contribution of the bleeding episode itself to the fatal event is unknown.”10 In a subsequent editorial, this opinion was shared by the authors who felt that the nature of the association between bleeding and mortality remains poorly defined.39 One method for assessing the relative value of bleeding in predicting mortality is by determining the overall contribution of bleeding to mortality. Upon multivariate, time-updated Cox modeling of data from the ACUITY trial, the 4.7% of patients who experienced a major bleed within 30 days of randomization had a 3.5-fold increased risk of 1-year mortality compared with those who did not bleed (hazard ratio [HR], 3.5; 95% CI, 2.7–4.4; p Unresolved Issues Several unresolved issues exist with regard to the impact of bleeding on outcomes in ACS and PCI. One is the mechanism behind the relationship between bleeding and thrombosis. While it is possible that bleeding is the result of thrombosis and its treatment, it may also be hypothesized that bleeding occurs first and leads to thrombosis.39 Although evidence exists to support both of these theories, further study would help expand our knowledge in this area. The next unresolved issue is how to predict and prevent bleeding while achieving adequate antithrombotic efficacy in ACS and PCI. As discussed previously, a large body of clinical evidence has identified several demographic, presentation, and treatment factors associated with an increased risk of bleeding. Since one or more of these factors are present in the majority of patients, it is possible that the majority of patients who present with ACS or undergo PCI are at increased risk of bleeding. Therefore, identifying patients who present with multiple factors should help predict those patients most likely to bleed. The issue of whether or not it is possible to prevent bleeding is more complicated. The existence of both modifiable (e.g., choice and number of antithrombotic medications, invasive procedure time, catheter size) and non-modifiable (e.g., age, sex, concomitant disease) risk factors for bleeding suggests that although bleeding risk may be reduced, it cannot be completely eliminated without increasing the risk of ischemic complications. However, rates of bleeding can be improved by careful attention to the choice, dosage, duration, and combinations of antithrombotic therapy42 and performing catheterization and PCI less invasively by using radial versus femoral access,31,37 smaller sheath sizes,5,37 appropriate use of vascular closure devices,5,37,49 and shortening the length of the procedure.5,37 Another question is how outcomes are impacted by treatment alterations secondary to major bleeding. Evidence suggests that patients who experience major bleeding are less likely to receive antithrombotic therapy, which may be correlated with increased mortality.6,15,25 For example, in an analysis of GRACE, patients with ACS who experienced major bleeding were less likely to receive in-hospital antithrombotic therapy after bleeding.15 Furthermore, patients who had major bleeding and discontinued antithrombotic therapy had greater rates of mortality than patients who suffered major bleeding but continued aspirin (52% vs 13%; p ≤ 0.001; OR, 7.55; 95% CI, 4.43–12.88), thienopyridines (58% vs 13%; p Conclusions Mounting clinical evidence clearly suggests that bleeding complications are associated with an increased risk of adverse outcomes, particularly mortality, in ACS and PCI. However, the relative contribution of major bleeding to mortality is not completely clear as many of the factors identified as independent predictors of bleeding have also been identified as independent predictors of mortality, and it is challenging to determine with certainty any cause-and-effect relationship between these predictors.39 Bleeding should be considered to be a relationship between baseline patient characteristics, severity of clinical presentation, antithrombotic regimen, time of exposure, and intervention performed: Bleeding = f (Patient, Clinical Scenario, Drugs, Time, Intervention) This formula highlights the inability to completely eliminate the risk of bleeding due to the contribution of nonmodifiable patient risk factors such as age and sex, among others. However, it also appears intuitive that bleeding risk can indeed be minimized by using the least invasive means possible when performing interventional procedures and carefully choosing the antithrombotic regimen (agents, dosages, and duration) that provides the best balance between efficacy and safety for each patient based on their risk factors. While more potent antithrombotic agents and regimens may result in greater efficacy, they are also generally associated with an increased risk of bleeding complications, which, in turn, are associated with increased morbidity, mortality, and costs. Paradoxically, the possibility exists that these agents may result in outcomes that are inferior to less potent antithrombotic agents or regimens associated with lower rates of bleeding complications.39 Given these concerns, the choice of antithrombotic therapy should be based upon the assessed ischemic and bleeding risk of the individual patient. Acknowledgements. This manuscript was written and edited by the author, who takes full responsibility for its content. Editorial assistance with searching the literature, coordinating revisions, and creating figures and tables in preparation of this manuscript was provided by Melanie Leiby, PhD, and funded by the Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership. The author received no compensation for this work.

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From the Sarah Cannon Research Institute (SCRI), Hospital Corporation of America (HCA), Inc., Nashville, Tennessee, Department of Interventional Cardiology at Centennial Heart, Nashville, Tennessee. S.V. Manoukian has served as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, Eli Lilly & Co, and the Medicines Company. Manuscript submitted July 23, 2009, provisional acceptance September 15, 2009, final version accepted December 22, 2009. Address for correspondence: Steven V. Manoukian, MD, FACC, FSCAI, Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN 37203. Email: steven.manoukian@scresearch.net

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