Epidemiology and Management of Bleeding in Acute Myocardial Infarction

Introduction

Clinical outcomes after acute coronary syndrome (ACS) have significantly improved over time. A significant proportion of the reduction in mortality has been the result of development and adoption of potent anticoagulant and antiplatelet therapies coupled with invasive risk stratification in high-risk patients (see Chapter 13 ). In addition, the use of secondary prevention strategies to control risk factors has further improved long-term outcomes (see Chapter 34 ). Although antithrombotic medications reduce the risk for recurrent ischemic events, they increase the risk for bleeding and need for blood transfusion. Paradoxically, bleeding events are associated with a subsequent higher risk for myocardial infarction (MI), stroke, stent thrombosis, and death. Randomized trials of “bleeding avoidance strategies” (BAS) in patients with ACS have demonstrated a reduction in adverse events, including mortality. Because of the availability of BAS, use of management strategies that reduce ischemia while minimizing bleeding have the potential to further improve outcomes. This chapter summarizes the epidemiology and management of bleeding events in ACS and MI.

Epidemiology of Bleeding

Reported Incidence of Bleeding: Influence of Definitions

The reported incidence of major bleeding events among patients with ACS varies greatly depending on the definition used, the fidelity with which the events are identified, the types of antithrombotic therapies used, and whether invasive risk stratification with revascularization is pursued. Before discussing the incidence of bleeding in ACS, it is important to review how bleeding is defined. Several schemas exist, but a few have been consistently used to identify bleeding events across randomized trials or registries that include ACS patients. Bleeding events as defined by several of these classification systems have also been correlated with other adverse events such as recurrent MI, stroke, stent thrombosis, and death (see section on Bleeding and Outcomes ).

Most bleeding definitions are made up of specific data elements that broadly fall into three categories: changes in hemoglobin or hematocrit; clinical events (e.g., gastrointestinal bleeding or intracranial hemorrhage); and consequences (e.g., blood transfusion or fatal bleeding). The extremes of bleeding definitions could focus solely on either changes in hemoglobin or on clinical events, and either could “cast the net” too widely—that is, identify events that would not be considered bleeding events by most clinicians or too narrowly by identifying only the most severe bleeding events and missing other less severe, but clinically important, events. Most definitions include combinations of all three categories. Table 29-1 displays commonly used bleeding definitions across randomized trials and registries.

TABLE 29-1

Sample Bleeding Definitions in Acute Coronary Syndrome Clinical Trials and Registries

Trial/Definition	Patient Population	Intervention	Bleeding Definition
TIMI	ACS, PCI	N/A	Major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL Fatal bleeding (bleeding that directly results in death within 7 d)
			Minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL Requiring medical attention Any overt sign of hemorrhage that meets 1 of the following criteria and does not meet criteria for a major or minor bleeding event, as defined previously: Requiring intervention (medical practitioner–guided medical or surgical treatment to stop or treat bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or study drug) Leading to or prolonging hospitalization Prompting evaluation (leading to an unscheduled visit to a health care professional and diagnostic testing, either laboratory or imaging) Minimal Any overt bleeding event that does not meet the preceding criteria Bleeding in the setting of CABG Fatal bleeding (bleeding that directly results in death) Perioperative intracranial bleeding Reoperation after closure of the sternotomy incision for the purpose of controlling bleeding Transfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver transfusion will not be counted in calculations of blood products Chest tube output >2 L within a 24-h period
GUSTO	ACS, PCI	N/A	Severe or life-threatening Intracerebral hemorrhage Resulting in substantial hemodynamic compromise requiring treatment Moderate Requiring blood transfusion, but not resulting in hemodynamic compromise Mild Bleeding that does not meet previous criteria
SYNERGY	NSTE-ACS	Enoxaparin vs. heparin	TIMI and GUSTO
PURSUIT	NSTE-ACS	Eptifibatide/heparin vs. heparin	TIMI and GUSTO
CURE	NSTE-ACS	Aspirin vs. aspirin + clopidogrel	Major bleeding Life-threatening Fatal Intracranial Requiring surgical intervention Results in hypotension Decrease in Hgb ≥5 g/dL Requires ≥4 U of blood Other major Requires transfusion of 2 or 3 U Intraocular
GUSTO IIb	NSTE-ACS	Hirudin vs. heparin	GUSTO
CURRENT-OASIS 7	NSTE-ACS	High-dose aspirin vs. low-dose aspirin; high-dose clopidogrel vs. standard dose clopidogrel	Severe bleeding Fatal Requiring transfusion ≥4 U of PRBCs or equivalent whole blood Resulting in hemoglobin drop ≥ 5 g/dL Leading to hypotension that requires inotropes Requiring surgery Symptomatic intracranial hemorrhage Other major bleeding Requiring transfusion of 2 to 3 U Significantly disabling, intraocular bleeding leading to significant loss of vision
OASIS-5	NSTE-ACS	Fondaparinux vs. enoxaparin	Major bleeding Fatal, intracranial, retroperitoneal, intraocular leading to vision loss Decrease in Hgb ≥3 g/dL adjusted for transfusion Transfusion of 2 U of red blood cells
ACUITY and HORIZONS-MI	NSTE-ACS	Bivalirudin alone vs. heparin or enoxaparin + GP IIb/IIIa vs. bivalirudin + GP IIb/IIIa	Major bleeding Intracranial or intraocular bleeding Hemorrhage at the access site, requiring intervention Hematoma with a diameter of ≥5 cm Reduction in Hgb levels of ≥4 g/dL without an overt bleeding source or ≥3 g/dL with such a source Reoperation for bleeding Transfusion of a blood product
ACTION-GWTG	ACS	N/A	Absolute Hgb decrease of ≥4 g/dL (baseline to nadir) Intracranial hemorrhage Documented or suspected retroperitoneal bleed Any red cell blood transfusion with baseline Hgb ≥9 g/dL, or any red cell transfusion with Hgb <9 g/dL and a suspected bleeding event
CRUSADE	NSTE-ACS	N/A	Major bleeding Absolute decrease in hematocrit concentration by 12% from baseline Intracranial hemorrhage Retroperitoneal bleeding Red blood cell transfusion because of bleeding
GRACE	NSTE-ACS		Life-threatening bleeding requiring a transfusion of >2 U red blood cells Resulting in a decrease in hematocrit of >10% Occurring intracerebrally Resulting in stroke or death
TRITON TIMI 38	NSTE-ACS		TIMI
PLATO	NSTE-ACS		Major life-threatening Fatal Intracranial Intrapericardial with cardiac tamponade Resulting in hypovolemic shock or severe hypotension that requires pressors or surgery Clinically overt or apparent bleeding associated with decrease in hemoglobin >5 g/dL Requiring transfusion of ≥4 U whole blood or PRBCs Other major Significantly disabling (e.g., intraocular with permanent vision loss) Associated drop in hemoglobin of 3–5 g/dL Requiring transfusion of 2–3 U whole blood or PRBCs Any major Any 1 of the previous criteria

ACS , Acute coronary syndrome; CABG , coronary artery bypass grafting; GP , glycoprotein; Hgb , hemoglobin; MRI , magnetic resonance imaging; NSTE , non–ST-segment elevation; PCI , percutaneous coronary intervention; PRBC , packed red blood cell.

Established Definitions

Thrombolysis in Myocardial Infarction and Global Use of Strategies to Open Occluded Arteries Definitions

Historically, the most commonly used definitions were the Thrombolysis in Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded arteries (GUSTO) bleeding scales. The TIMI definition was developed in the context of fibrinolytic therapy for ST-elevation MI (STEMI) and was generally based on decreases in hemoglobin. The categorization for TIMI bleeding originally consisted of minimal, minor, and major bleeding, defined according to the degree of hemoglobin change. Because intracranial hemorrhage is the most feared complication of fibrinolytic therapy, it was included as part of the TIMI major bleeding definition. Since its original development, the TIMI bleeding definition has evolved to include a qualifier that bases the required decrease in hemoglobin on whether a clinically overt bleeding event has occurred ( Table 29-1 ). The GUSTO definition was also developed in the context of fibrinolytic therapy for STEMI, and was based solely on clinical events. GUSTO bleeding is categorized as mild, moderate, or severe, and again, intracranial hemorrhage is considered severe according to the GUSTO definition. Other definitions listed in Table 29-1 combine elements of the TIMI and GUSTO definitions and add others (e.g., access site hematoma).

The existence of multiple bleeding definitions contributes to the variations in the reported rates of bleeding. When two or more definitions are used in the same study, the assessment of the safety of a management strategy can be confusing. One example of this is the SYNERGY trial, which compared enoxaparin with unfractionated heparin in 9978 ACS patients without persistent ST-segment elevation who were slated to undergo early invasive risk stratification. The primary efficacy endpoint was 30-day death or MI; the primary safety endpoint was bleeding defined according to both the TIMI and GUSTO scales. There was no significant difference in 30-day death or MI between the two strategies; however, the bleeding data showed disparate findings. There was no significant difference in GUSTO severe bleeding or transfusion rates (i.e., GUSTO moderate bleeding), but there was a significant excess of TIMI major bleeding among patients assigned to enoxaparin. These results challenged any firm conclusion about the relative safety of enoxaparin over unfractionated heparin and underscored the influence of definition on reported bleeding rates.

Capture of Bleeding Events

Another factor that may affect the incidence of bleeding is the methods for detecting events. Clinical trials often use independent clinical events committees that review source documents (medical charts) to detect adverse events. This minimizes the risk of bias at the site level. In contrast, registries generally do not use adjudication and rely on site-identified events. This is particularly true of registries in which the primary purpose is quality improvement rather than comparing the effectiveness of one treatment with another. As such, the rates of bleeding are often higher in clinical trials than in registries, despite the inclusion of higher risk patients in the latter. For example, the rate of postprocedural major bleeding among patients who underwent primary percutaneous coronary intervention (PCI) for STEMI assigned to unfractionated heparin plus glycoprotein IIb/IIIa inhibitors in the HORIZONS-MI trial was 8.4%, whereas the rate of bleeding among patients who underwent primary PCI in the National Cardiovascular Data Registry’s Cath-PCI registry was approximately 4% to 5%. Certainly, this difference is driven in part by the differences in definitions, but it is also likely caused by variations in the way the events were identified and reported.

Bleeding Academic Research Consortium Definition

To overcome some of the challenges posed by different bleeding definitions, several groups have attempted to develop a standardized approach to classifying and reporting bleeding events. Rather than developing a new definition, the Academic Research Consortium (ARC) proposed a list of standardized data elements that should be recorded in the case report form for a clinical trial of antithrombotic therapy (or the data collection form of a registry of ACS). These data elements can then either be reported separately or combined to reconstruct other bleeding definitions. The ARC, which originally consisted of members from four academic research organizations that designed and executed pivotal trials of drug-eluting stents, developed a set of standardized definitions for endpoints used in coronary stent trials. Periprocedural bleeding was not considered in their initial deliberations; however, subsequent iterations of ARC have developed definitions for bleeding endpoints for ACS trials, transcatheter valve trials, and peripheral arterial disease trials. The Bleeding Academic Research Consortium (BARC) definition of bleeding for use in ACS trials is shown in Table 29-2 .

TABLE 29-2

Bleeding Academic Research Consortium Definition of Bleeding

Type 0: no bleeding
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a health care professional
Type 2: any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least 1 of the following criteria: (1) requiring nonsurgical, medical intervention by a health care professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation
Type 3
- Type 3a
  - Overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided hemoglobin drop is related to bleed), corrected for transfusion
  - Any transfusion with overt bleeding
- Type 3b
  - Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is related to bleed), corrected for transfusion
  - Cardiac tamponade
  - Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid)
  - Bleeding requiring intravenous vasoactive agents
- Type 3c
  - Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal)
  - Subcategories confirmed by autopsy or imaging or lumbar puncture
  - Intraocular bleed compromising vision
Type 4: CABG-related bleeding
- Perioperative intracranial bleeding within 48 h
- Reoperation after closure of sternotomy for the purpose of controlling bleeding
- Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period
- Chest tube output ≥2 L within a 24-h period
Type 5: fatal bleeding
- Type 5a
  - Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious
- Type 5b
  - Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation

CABG , coronary artery bypass grafting.

Bleeding Incidence

After considering the differences in definitions across studies, the estimated incidence of bleeding during acute management of ACS is between 1% and 12%; any attempt to report a single number as the rate of ACS-related bleeding complications is likely to be misleading. Moreover, the incidence of bleeding in ACS patients may change with evolution of therapy over time and may be decreasing. One can use either clinical trials or registries to estimate the incidence of bleeding. In the SYNERGY trial, which included ACS patients who underwent an early invasive strategy, the rate of major or severe bleeding ranged between 2.7% (GUSTO severe) to 9.1% (TIMI major) among patients assigned to enoxaparin. Similarly, in the PLATO trial, the rates of TIMI major bleeding and protocol-defined PLATO major bleeding were 7.9% and 11.6%, respectively, among patients assigned to ticagrelor. Another source of information on bleeding complications is registry data. The ACTION–Get With the Guidelines registry is a nationally representative quality improvement registry for ACS that tracks and reports in-hospital bleeding complications (see Table 29-1 for definitions). The incidence of bleeding in this registry is 10.8%. Clinicians should be cognizant of the factors that influence the reporting of bleeding rates, and either use one definition to survey their own practice, or participate in an ACS registry like the ACTION-Get With the Guidelines registry to receive bleeding data on their patients benchmarked against a registry average.

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