Major Bleeding in Acute Coronary Syndromes

Abstract: Treatment of acute coronary syndrome has been based on the prevention of ischemic complications by means of antithrombotic therapy and invasive strategies. The desired reduction reached in the recurrence of ischemic events reveals its price, an increase in the occurrence of major bleeding. Initially tolerated as a benign complication, it is now shown to be an important predictor of mortality. Greater attention dedicated to the prognostic impact of bleeding is recent, motivated by the development of new antithrombotic agents. Detailed analysis of the risk factors for myocardial infarction or bleeding is an important issue and allows institution of individualized approach.

J INVASIVE CARDIOL 2011;23(11):485-490

Key words: acute coronary syndrome, hemorrhage, thrombolytic therapy, complications

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The lessons arising from evidence-based medicine have been found to be indispensable in the implementation and refinement of the best patient care strategies. As the number and complexity of the therapies advance, especially in a context where the longevity of the population and the presence of comorbidities are increasingly expanding, an inherent increase is observed in the risk of complications and adverse events, particularly in the scope of cardiovascular diseases.

The treatment of acute coronary syndromes (ACS) has been traditionally based on the prevention or minimization of ischemic complications, by means of aggressive antithrombotic therapy and invasive stratification, accompanied, when appropriate, by either a percutaneous or surgical revascularization strategy.^1,2 Yet, the desired reduction reached in the recurrence of ischemic events reveals its price, which is an increase in the occurrence of bleeding complications.^3,4 Initially interpreted and tolerated as a benign complication, major bleeding is now shown to be an important predictor of mortality and ischemic events.⁵

Greater attention dedicated to the prognostic impact of bleeding is a recent topic, motivated mainly by the development of new antithrombotic agents with diverse efficacy and safety profiles. Some drugs demonstrated reduction in hemorrhagic complications accompanied by maintenance of anti-ischemic efficacy,^6,7 while others were associated with greater effectiveness, however at the cost of higher bleeding rates.⁸ Thus, this leads to a setting where the detailed analysis of the risk factors for myocardial infarction (MI) or bleeding complications will be a preponderant issue and will allow the institution of an individualized approach in attending the patient with ACS.

New Standardized Bleeding Definitions

Contemporary randomized clinical trials evaluating the effectiveness of antithrombotic agents in the treatment of ACS adopt the occurrence of major bleeding as a safety outcome.⁹ However, different definitions of bleeding have been applied to supplant the relative limitations of the original concepts proposed by Thrombolysis in Myocardial Infarction (TIMI) criteria,¹⁰ which are based essentially on laboratorial data, such as drop in hemoglobin and hematocrit, and by the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria,¹¹ which focus in the clinical repercussions arising from a bleeding complication (Table 1). The absence of uniformity and consistency among the definitions limits the possibility of comparing security data among the studies and consequently the implementation of practical recommendations and guidelines to be followed.

The Bleeding Academic Research Consortium (BARC), an independent group including members of academic research organizations, cardiovascular professional societies, pharmaceutical and cardiovascular device manufacturers, the National Institutes of Health, and the FDA (CDER and Center for Devices and Radiological Health), was idealized with the intention of reviewing the existing definitions and developing standards for the analysis of hemorrhagic complications.¹² Among the recommendations of the panel, the consensus around the challenge of creating a single definition of major bleeding to be adopted stands out since the analyzed population is extremely variable as to its characteristics, clinical profile, follow-up time length, and due to the constant temporary modifications in clinical therapy and treatment strategies considered appropriate at its time. Thus, the collection and report of elements related to the period of bleeding, its location (gastrointestinal, genitourinary, intracranial, vascular access), laboratorial parameters and its consequences (death, blood transfusion, permanent sequela) is considered essential, making it possible to gather all necessary information, independent of the definition used in each study, compare the data obtained in different studies, and obtain essential parameters to the development of tools that aid in the standardization of treatment.

Recently, BARC participants proposed 5 bleeding types, which will need prospective validation in future studies.¹³ Type 0 is no bleeding. Type 1 is bleeding that “is not actionable” and does not cause the patient to seek medical attention. Type 2 bleeding includes any clinically overt sign of hemorrhage that “is actionable” and requires diagnostic studies, hospitalization, or treatment by a health care professional. Type 3 bleeding is divided into 3 categories, a through c, and includes clinical, laboratory, and/or imaging evidence of bleeding with specific health care provider responses. Type 3a bleeding includes any transfusion with overt bleeding and overt bleeding plus a hemoglobin drop of ≥3 to <5 g/dL (provided the hemoglobin drop is related to bleeding). Type 3b bleeding includes overt bleeding plus a hemoglobin drop of ≥5 g/dL (provided the hemoglobin drop is related to bleeding), cardiac tamponade, bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid), and bleeding requiring intravenous vasoactive drugs. Type 3c bleeding includes intracranial hemorrhage and intraocular bleeding compromising vision. Type 4 bleeding is coronary artery bypass grafting (CABG)-related (within 48 hours), and type 5 bleeding is fatal. Fatal bleeding is categorized as intracranial, gastrointestinal, retroperitoneal, pulmonary, pericardial, genitourinary, or other (Table 2). This new, hierarchically graded consensus classification for bleeding, once validated, will overcome the limitations presented today and will allow consistent reporting of bleeding in future clinical investigations as well as a better comprehension of the determinant mechanisms of poor prognosis associated with this adverse event. 

Bleeding Statistics in ACS

During the past few decades, efforts have been made in improving the care of ACS patients. Refinements in antithrombotic therapy resulted in an optimal treatment regime constituted by oral antiplatelet drugs, parenteral antithrombin agents, and often glycoprotein IIb/IIIa receptor blockers. As a result, the risk of major adverse ischemic complications decreased, but was accompanied by an increased risk of bleeding complications.

Early major ACS trials reported different rates of bleeding. In the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, the additional platelet inhibition with eptifibatide was associated with an increased incidence of TIMI major bleeding compared to placebo (10.6% vs 9.1%, P=.02).¹⁴ Tirofiban, in combination with aspirin alone, was associated with a 0.4% TIMI major bleeding rate in the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study.¹⁵ However, the addition of heparin to aspirin and tirofiban promoted a substantial increase in bleeding complications (4.0%) in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study.¹⁶ The landmark Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-Thrombolysis in Myocardial Infarction 18 trial demonstrated the superiority of an early invasive strategy in comparison to a conservative strategy, accompanied by a TIMI major bleeding rate below 2.0%.¹⁷

More recent randomized studies involving ACS patients with non-ST segment elevation MI (NSTEMI) showed similar major bleeding rates varying between 2-5%,^5,7 especially among higher-risk subgroups,  similar to the prevalence of refractory ischemia, MI, or death observed in these casuistics. However, the application of rigorous and restrictive inclusion and exclusion criteria confers a non-representative condition of real-world practice to this selected population. In this context, consecutive and controlled registries continue providing a real scenario of contemporary practice, becoming sources of information that allow the critical analysis of the application of a therapeutic strategy.

The recent publication of the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry Get with the Guidelines (NCDR ACTION Registry-GWTG)¹⁸ evaluated 72,699 patients with NSTEMI and 48,943 with ST-segment elevation MI (STEMI), treated in 360 North-American hospitals between January 2007 and June 2009. The authors reported a major bleeding rate of approximately 9% among patients with NSTEMI and 12% among those with STEMI, notably influenced by the presence of comorbidities, as well as by the use of invasive strategies.

Important paradoxes were also verified between the experience acquired from randomized trials and current medical practice: 1) unfractionated heparin remains the most used agent in ACS in spite of repeated demonstrations of the superiority of alternative antithrombotic regimes; 2) low-molecular-weight heparin in elderly patients and those with renal dysfunction continues to be the most common medication used in these subgroups in spite of the known risk of bleeding attributed to its use, frequently without the proper dose-adjustment; 3) persistence in the practice of crossover between different types of antithrombotic treatment in the same patient, with its inherent greater risk of bleeding.

Nevertheless, the expressive bleeding rate in this report, observing the fact that patients transferred among institutions, as well as the cases of coronary artery bypass grafting-related bleeding were excluded from the analysis, suggests that the real prevalence of major bleeding among ACS patients may be even greater.

Predictors of Bleeding After ACS

Major bleeding is currently the most common non-cardiac complication observed in the treatment of ACS patients. The identification of clinical characteristics and particularities of the antithrombin therapy associated with an increased risk of hemorrhagic complications would make it possible to adopt prevention strategies, especially among those exposed to greater risk.

In this way, different studies exposed the main predictors of major bleeding in the treatment of ACS. Investigators from Global Registry of Acute Coronary Events (GRACE),¹⁹ in a sample including 24,045 ACS patients, of which 933 (3.9%) developed an episode of major bleeding during hospitalization, pointed out the following independent predictors of bleeding: advanced age, female sex, previous bleeding episode, renal failure, fibrinolysis, IIb/IIIa inhibitors use, and percutaneous coronary intervention (PCI). The most frequent bleeding sites were gastrointestinal (31.5%) and those related to the vascular access site (23.8%), with the latter more prevalent among patients who underwent invasive coronary procedures. The occurrence of major bleeding was significantly associated with greater in-hospital mortality (18.6% vs 5.1%, P<.001; RR = 1.64; 95% CI, 1.18-2.28).

Advanced age would predispose to a greater risk of bleeding due to injuries located in the vessels and systemic diffuse vessel disease. The collagen and amyloid deposits in the aging arterial tunica media may cause brittle, leaky vessels that are less inclined to constrict and are more prone to bleed, especially following fibrinolysis and antithrombotic therapy or PCI. Although the relationship between the female sex and bleeding is difficult to determine, it is believed that the smaller body and vessel size, reduced creatinine clearance, higher prevalence of comorbidities, higher risk of drug overdosing, differences in pharmacological response to antithrombotics compared with men, propensity to vascular complications following PCI, greater mean age at the moment of admission, and a lower threshold for transfusion due to smaller base levels of hemoglobin would justify these findings. Patients with renal failure are more susceptible to excess dosing of antithrombotic drugs, due to reduced clearance of administered antithrombotic agents, have more diffuse and advanced arterial disease, plaquetary dysfunction, and abnormalities in the coagulation.

Antithrombotic therapy, on the other hand, would be influenced by pharmacodynamic and pharmacokinetic characteristics of the agents, as exemplified in the Organization to Assess Ischemic Syndromes (OASIS)-5 randomized trial.⁶ In this study, which compared fondaparinux, a selective factor Xa inhibitor, to enoxaparin in the treatment of 20,078 patients with NSTEMI, fondaparinux was associated with a significant reduction of fatal bleeding, major bleeding and necessity for blood transfusion at 9 days, with significant impact in mortality at 6 months.

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY)⁷ study involved 13,819 ACS patients submitted to early invasive strategy, randomized to an antithrombotic therapy constituted by unfractionated heparin and IIb/IIIa inhibitors, bivalirudin and IIb/IIIa inhibitors, or isolated bivalirudin. The prognostic impact of a major bleeding episode was comparable to a recurring MI in the subsequent mortality rate (11.7% vs 9.1%, respectively), independent of the antithrombotic agent used.²⁰ In addition, the authors identified 5 predictors of reinfarction, including increase in cardiac biomarkers, positive family history of coronary artery disease, advanced age, ST-segment elevation ≥1 mm, and previous MI, while 8 variables related to greater risk of bleeding were identified. The following stood out in order of statistical significance: female sex, anemia, advanced age, use of unfractionated heparin and IIb/IIIa inhibitors instead of isolated bivalirudin, elevated serum creatinine, increased leukocyte count, absence of previous PCI, previous stroke, ST-segment elevation ≥1 mm, and the routine use of IIb/IIIa inhibitors. The conclusions of the study pave the way for a decision concerning the best antithrombotic strategy to be used aiding individual evaluation for risk of ischemic or hemorrhagic events.

Adoption of Bleeding Risk Scores

Although ischemic risk stratification tools to determine the best treatment options for patients with NSTEMI are thoroughly described and validated (e.g., TIMI,²¹ GRACE²²), the risk stratification for major bleeding is still limited.

Some existing models are not representative of all risk subgroups and, therefore, cannot be applied in an unrestricted manner. Using data from the multicenter studies Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-1 e 2,^23,24 Nikolsky et al²⁵ proposed a bleeding risk score for patients submitted to PCI through femoral access (www.bleedingriskscore.org). In multivariate analysis obtained from the characteristics of 5395 patients, the predictors of major bleeding were use of intra-aortic balloon pump, administration of IIb/IIIa inhibitors, advanced age, female sex, chronic renal failure, anemia, and the use of low-molecular-weight heparin in the 48 hours preceding the procedure. The occurrence of major bleeding varied from 0.9% to 22.2%, depending on the risk score, with an average of 1% for those categorized as very low risk and 5.4% among those at high risk.

More recently, investigators of the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE)²⁶ registry developed and validated a risk stratification tool for in-hospital major bleeding among NSTEMI patients. Having a database constituted by 89,134 patients, within 485 North American hospitals, the authors demonstrated that the independent predictors of major bleeding were baseline hematocrit <36%, creatinine clearance, heart rate, systolic blood pressure, female sex, signs of congestive heart failure at admission, previous vascular disease (previous peripheral artery disease or previous stroke), and diabetes mellitus.

The rates for major bleeding were 3.1% in very low-risk patients, 5.5% in those at low risk, 8.6% at intermediate risk, 11.9% at high risk, and an expressive 19.5% among those at very high risk. Considering only the variables present at admission, this is presented as an easily applicable and useful tool in predicting patient risk, in addition to the analysis of the risk of ischemic events, allowing a tailored therapeutic strategy, adapted to the individualized risk profile (www.crusadebleedingscore.org).

Although it is coherent to justify the association between major bleeding and mortality by the coexistence of comorbidities and risk factors in the population common to the occurrence of these outcomes, today an accumulation of evidence is observed that points to direct or indirect influence of bleeding as a greater determinant of subsequent adverse ischemic events. The localization (intracranial) or the intensity (gastrointestinal, retroperitoneal) of the bleeding may itself result in death. However, other consequences may exhibit harmful effects to the ACS patients or those submitted to invasive coronary procedures.²⁷

Interactions between platelets and the coagulation cascade produce a fast hemostatic response at the vascular injury site. A systemic amplification of this localized response is prevented by different mechanisms. Deficiencies in these protective antithrombotic pathways may cause a state of hypercoagulability induced by bleeding and consequently predispose to the occurrence of ischemic events. Experimental data suggest that a stimulus to the synthesis and liberation of erythropoietin in response to anemia induced by bleeding may sustain a systemic prothrombotic state beyond the acute phase, exemplified by the greater risk of thrombotic events among critically ill patients treated with recombinant erythropoietin. Finally, antiplatelet agents such as acetylsalicylic acid and thienopyridines, as well as other antithrombotic agents, may be suspended after a hemorrhagic event, increasing the risk of potentially fatal ischemic complications, such as stent thrombosis.

Blood transfusions to correct anemia in patients hospitalized due to ACS, similar to an episode of major bleeding, are independently associated with greater early and late mortality.^28,29 Stored red blood cells exhibit depletion of 2,3-diphosphoglyceric acid, increasing the affinity of hemoglobin by the oxygen, thus reducing its offer to the tissue. Recent data suggest that structural and biochemical modifications observed in stored erythrocytes could result in an even greater impact in its in vivo function. Provoked alterations in the natural deformability of erythrocytes would promote greater aggregation and consequent viscosity in the microvascular bed, leading to ischemia. The transport of nitric oxide by the erythrocytes also significantly alters after storage, endangering the capacity of vasodilatation and regional increase of flow once a hypoxic atmosphere is detected.

Other mechanisms involved with a worse prognosis among transfused patients would be the prothrombotic effects associated with the transfusion of red blood cells, stimulation of plaquetary activation and aggregation,³⁰ immunosupressor effects, predisposition to infections, and severe hemolytic reactions, especially secondary to large transfused volumes.

Collectively, innumerous studies have shown a robust association between the occurrence of major bleeding and the necessity of blood cell transfusion with greater mortality in patients admitted with ACS or submitted to PCI. The reduction of major bleeding, a relatively frequent complication in the current scenario and possibly underestimated in randomized clinical trials, translated in greater survival and better short- and long-term prognosis. Thus, its prevention today represents a goal to be reached in the treatment of patients with ACS, through the balance between the risks and benefits of the pharmacological and invasive strategies offered.

Bleeding avoidance strategies, classified into three broad categories — pharmacology, procedure, and technology — are shown to be feasible and applicable to the clinical practice:³¹

• The identification of patients with greater propensity for complications, applying bleeding risk scores, would aid in making cautious and precise decisions in cases classified as high risk;
• New antithrombotic agents with unique profile of security and efficacy that combines anti-ischemic potency, comfort dosage, and reduction of the bleeding rates (e.g., fondaparinux, bivalirudin, ticagrelor). In this situation, an individualized evaluation of the most appropriate strategy is best suited, including the type of agent chosen, as well as the prescription for the proven beneficial and safe dosage;
• Lower-dose unfractionated heparin, fluoroscopically- or ultrasound-guided femoral access reduces vascular complications; 
• The adoption of radial access in detriment to femoral in performing coronary diagnostic and therapeutic procedures was shown to reduce major bleeding rates by 73%,³² notably among patients exposed to greater risks, such as those with ACS;
• Vascular closure devices reduce time to hemostasis, provide more comfort and early ambulation, although exhibited inconsistent data regarding safety;
• Continuous efforts have been used in the collection and storage techniques of blood cell derivatives, aiming to improve their quality. In spite of this, the inconsistency of the available results and the absence of a conclusive randomized trial that supports the benefit of blood transfusion in anemic patients with ACS stimulates a critical analysis to the criteria imposed of transfusion, based on hematocrit or hemoglobin values many times arbitrary, especially among patients that present themselves stable and with no evidence of recurring ischemia.

Conclusions

From what was exposed, we are now faced with the need of a return to and valorization of a fundamental principle in medical practice — discerning clinical judgment. Through it, we may evaluate the patient in an individualized and tailored manner, seeking to identify characteristics that allow the appropriate implementation of pharmacological and invasive strategies, capable of maintaining the tenuous balance between efficacy and safety.

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From ¹Santa Casa de Marília, Marília, Brazil, ²Hospital do Coração de Londrina, Londrina, Brazil, and  ³Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 27, 2011, provisional acceptance given August 3, 2011, final version accepted August 29, 2011.
Address for correspondence: Pedro Beraldo de Andrade, MD, Invasive Cardiology, Santa Casa de Marília Av. Vicente Ferreira, 828-Cascata, Marília, São Paulo, Brazil 17515-900. Email: pedroberaldo@gmail.com