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 BleedingNumerous 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 ImportanceWhile 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 OutcomesBleeding 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.
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: firstname.lastname@example.org
1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148–e304. 2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction, writing on behalf of the 2004 Writing Committee. Circulation 2008;117:296–329. 3. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: A report of the American College of Cardiology/American Heart Association task force on Practice Guidelines: 2007 Writing group to review new evidence and update the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 Writing Committee. Circulation 2008;117:261–295. 4. Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: A risk model from the ACUITY trial. Eur Heart J 2009;30:1457–1466. 5. Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding complications after percutaneous coronary intervention. Incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994–2005. JACC Intervent 2008;1:202–209. 6. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774–782. 7. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 2007;100:1364–1369. 8. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930–935. 9. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: An analysis from the ACUITY Trial. J Am Coll Cardiol 2007;49:1362–1368. 10. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815–1823. 11. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: Appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51:690–697. 12. Rao SV, O'Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:809–816. 13. Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96:1200–1206. 14. Segev A, Strauss BH, Tan M, et al. Predictors and 1-year outcome of major bleeding in patients with non-ST-elevation acute coronary syndromes: Insights from the Canadian Acute Coronary Syndrome Registries. Am Heart J 2005;150:690–694. 15. Spencer FA, Moscucci M, Granger CB, et al. Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction? Circulation 2007;116:2793–2801. 16. Voeltz MD, Patel AD, Feit F, et al. Effect of anemia on hemorrhagic complications and mortality following percutaneous coronary intervention. Am J Cardiol 2007;99:1513–1517. 17. Serebruany VL, Atar D. Assessment of bleeding events in clinical trials — Proposal of a new classification. Am J Cardiol 2007;99:288–290. 18. Rao SV, Eikelboom JA, Granger CB, et al. Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1193–1204. 19. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 20. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–2216. 21. Steinhubl SR, Kastrati A, Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J 2007;154:3–11. 22. Manoukian SV, Feit F, Voeltz MD, et al. Abstract 2217: Impact of the ACUITY and TIMI major bleeding definitions on one-year mortality in patients with acute coronary syndromes. Circulation 2007;116(16 Suppl):II-482. 23. Ng H, Crowther M. New anticoagulants and the management of their bleeding complications. Transfusion alternatives in transfusion medicine 2006;8(Suppl. 1):12–19. 24. Rao SV, Kaul PR, Liao L, et al. Association between bleeding, blood transfusion, and costs among patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2008;155:369–374. 25. Wang TY, Xiao L, Alexander KP, et al. Antiplatelet therapy use after discharge among acute myocardial infarction patients with in-hospital bleeding. Circulation 2008;118:2139–2145. 26. Roy P, Bonello L, Torguson R, et al. Impact of “nuisance” bleeding on clopidogrel compliance in patients undergoing intracoronary drug-eluting stent implantation. Am J Cardiol 2008;102:1614–1617. 27. Serebruany VL, Midei MG, Meilman H, et al. Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial. Int J Clin Pract 2006;60:863–866. 28. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130. 29. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation 2006;113:2803–2809. 30. Manoukian SV, Feit F, Voeltz MD, et al. Major bleeding is associated with increased one-year mortality and ischemic events in patients wtih acute coronary syndromes undergoing percutaneous coronary intervention: The ACUITY trial. Presented at TCT 2007. Washington, D.C. 31. Chase AJ, Fretz EB, Warburton WP, et al. Association of the arterial access site at angioplasty with transfusion and mortality: The M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart 2008;94:1019–1025. 32. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555–1562. 33. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: Estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004;291:2727–2733. 34. Lopes RD, Alexander KP, Manoukian SV, et al. Advanced age, antithrombotic strategy, and bleeding in non-ST-segment elevation acute coronary syndromes: Results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;53:1021–1030. 35. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108–3116. 36. Feit F, Manoukian SV, Ebrahimi R, et al. Safety and efficacy of bivalirudin monotherapy in patients with diabetes mellitus and acute coronary syndromes: A report from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2008;51:1645–1652. 37. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69:73–83. 38. Hamon M, Rasmussen LH, Manoukian SV, et al. Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: The ACUITY trial. EuroInterv 2009;5:115–120. 39. Berger PB, Manoukian SV. Bleeding is bad.... Isn't it? Circulation 2007;116:2776–2778. 40. Giugliano RP, Giraldex RR, Morrow DA, et al. The relative contribution of clinical factors, treatments, bleeding, and CV complications to mortality in 20,323 patients receiving fibrinolysis for STEMI. J Am Coll Cardiol 2008;51(Suppl. A):A209. 41. Cohen M. Predictors of bleeding risk and long-term mortality in patients with acute coronary syndromes. Curr Med Res Opin 2005;21:439–445. 42. Manoukian SV, Voeltz MD, Eikelboom J. Bleeding complications in acute coronary syndromes and percutaneous coronary intervention: predictors, prognostic significance, and paradigms for reducing risk. Clin Cardiol 2007;30(10 Suppl 2):II24–II34. 43. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015. 44. Effient [package insert]. Indianapolis, IN: Eli Lilly & Co; Parsippany, NJ: Daiichi Sankyo, Inc., 2009. 45. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: A TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008;51:2028–2033. 46. Kaul S, Shah PK, Diamond GA. Abstract 4014: Timing of Benefit with Prasugrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Reanalysis of TRITON-TIMI 38 Results. Circulation 2008;118(18 Suppl):S818–S819. 47. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–2230. 48. Lincoff AM, Steinhubl SR, Manoukian SV, et al. Influence of timing of clopidogrel treatment on the efficacy and safety of bivalirudin in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention — An analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. JACC Intervent 2008;1:639–648. 49. Sanborn TA, Ebrahimi R, Manoukian SV, et al. Impact of femoral vascular closure devices and antithrombotic therapy on access site bleeding in acute coronary syndromes: The ACUITY trial. Circ Cardiovasc Interv 2010;3:57–62.