How Serious a Problem is Bleeding in Patients with Acute Coronary Syndromes?
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- Baber, U., Kovacic, J., Kini, A.S. et al. Curr Cardiol Rep (2011) 13: 312. doi:10.1007/s11886-011-0192-3
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Recent studies have highlighted the critical importance of bleeding complications on prognosis in patients with acute coronary syndromes (ACS). In fact, the hazard for an adverse cardiovascular event associated with bleeding is similar to that of a myocardial infarction. Several bleeding risk scores are now available that reliably quantify the probability of an ACS patient experiencing a bleeding complication. Consistent and strong correlates of bleeding include older age, female sex, renal impairment, and an invasive management approach. Although patients who tend to bleed are usually more morbid compared with their non-bleeding counterparts, several lines of experimental and clinical evidence suggest an independent and causal pathway for bleeding-associated cardiovascular risk. Given the frequency and adverse prognosis associated with bleeding, interventions that might reduce such complications are now a major emphasis in the current era of ACS treatment. Recent trials have shown that several novel antithrombotics, bivalirudin and fondaparinux, reduce bleeding risk while maintaining efficacy in reducing ischemic events during ACS. Other promising strategies that continue to be tested include the use of vascular closure devices and transradial arterial access during percutaneous coronary intervention.
KeywordsAcute coronary syndromeBleedingRisk score
Clinical Trial Acronyms
Acute Catheterization and Urgent Intervention Triage Strategy
Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines?
Global Registry of Acute Coronary Events
Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries
Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction
- NCDR ACTION-GWTG
National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry—Get With the Guidelines
Fifth Organization to Assess Strategies in Acute Ischemic Syndromes
Prospective Registry Evaluating Myocardial Infarction: Events and Recovery
Contemporary management of patients with acute coronary syndromes (ACS) involves the combined use of potent antiplatelet and antithrombotic agents coupled with early cardiac catheterization in those at moderate to high risk . Until recently, the primary focus of ACS treatment was limited to the reduction of ischemic complications including recurrent myocardial infarction (MI), urgent revascularization, and cardiac death. Within this context, bleeding was largely thought of as an expected consequence with less prognostic importance than a recurrent ischemic event. However, recent observations over the past several years have challenged this paradigm by clearly demonstrating that bleeding is not only a frequent complication in the current era of ACS treatment but is also associated with substantial cardiovascular risk. Some experts are now recommending that conventional ischemic end points in cardiovascular trials should be expanded to include bleeding events, thereby weighing bleeding and ischemic complications equally . In the present report we review recent evidence supporting this rationale, provide an overview of potential mechanisms of bleeding-associated risk and evolving strategies to reduce bleeding complications.
Bleeding Definitions and Incidence
Reported estimates of bleeding frequency in ACS populations demonstrate substantial variability, ranging from less than 3% in low-risk patients presenting with unstable angina to greater than 20% in higher-risk individuals undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) [3, 4, 5•, 6–8]. In large part this discrepancy reflects the lack of a standardized and uniform metric to measure bleeding events across different populations and presentations. As such, many studies currently categorize bleeding using a combination of traditional schemes such as the Thrombolysis in Myocardial Infarction (TIMI) or GUSTO scales [9, 10]. In contrast, the ACUITY trial defined bleeding using a scale that incorporates elements of existing schemes with other unique attributes. The inherent inconsistencies in assessing bleeding frequency as a result of numerous definitions are best shown when different schemes are applied to the same population. For example, among patients undergoing PCI and randomized to receive bivalirudin in the HORIZONS-AMI trial, the incidence of GUSTO severe, TIMI major, and protocol-defined major bleeding were 0.4%, 3.1% and 4.9%, respectively. Such large differences in major bleeding rates have clear clinical implications in assessing the risk/benefit ratio of antithrombotic agents and in designing clinical studies. Due to these concerns a working group was recently convened to address the need for standardized bleeding definitions in future clinical studies. The final report of their findings and recommendations is eagerly awaited .
Despite these difficulties in measuring the “true” incidence of bleeding in ACS populations, consistent patterns in the level or gradient of bleeding risk have emerged from both observational and randomized trial data over the past several years. First, bleeding risk increases in a dose-dependent fashion with the severity of clinical presentation (ie, lowest for unstable angina, intermediate for non-ST-segment elevation myocardial infarction [NSTEMI], and highest for STEMI). In the ACUITY trial, which only included NSTE-ACS patients, for example, the overall rate of protocol-defined major bleeding was 4.6% . In contrast, the frequency of bleeding among STEMI patients in the HORIZONS-AMI trial, using the same protocol definition as in ACUITY, was 6.6% [13•]. Second, bleeding risk is greater in patients treated with an invasive versus conservative or medical approach. Among patients in the CRUSADE registry, bleeding rates were higher in those treated with an invasive compared with conservative approach across all quintiles of baseline bleeding risk . In addition, invasive therapy is a consistent correlate of greater bleeding complications across different studies, patient populations, and adjunctive pharmacologic treatments. Third, bleeding rates vary by population and are greater in “real-world” practice compared with randomized trial participants. As an example, in the NCDR ACTION-GWTG registry, major bleeding occurred in 11.1% and 8.9% of patients presenting with STEMI and NSTEMI, respectively [15•]. Analogous bleeding rates were 6.6% and 4.6% in the HORIZONS-AMI and ACUITY trials [12, 13•].
Predictors of Bleeding
Selected acute coronary syndrome bleeding risk scores
Strongest clinical predictorsa
Elevated heart rate
Congestive heart failure
Mehran et al. [5•]
30-day protocol-defined major bleeding
Intra-aortic balloon pump
Perhaps the four strongest and most consistent clinical predictors of bleeding include advanced age, female sex, anemia, and chronic kidney disease (CKD). In the randomized ACUITY trial, for example, the odds ratios for each of these parameters associated with 30-day non-coronary artery bypass graft surgery protocol-defined major bleeding were 1.64, 1.92, 1.87, and 1.53, respectively. After combining the NSTE-ACS and STEMI datasets from the ACUITY and HORIZONS-AMI trials, Mehran et al. [5•] found that each of these clinical variables remained significantly associated with major bleeding after multivariable adjustment and were retained in a bleeding risk score. In a separate report based on a “real-world” population, Moscucci et al.  similarly found that advanced age, female gender, renal insufficiency, and history of bleeding were significantly associated with major bleeding after multivariable adjustment.
One potential reason for this clustering of clinical risk factors and enhanced bleeding risk may be related to excess dosing of antithrombotic and/or antiplatelet agents in these patients. In fact, Alexander et al.  found that excess dosing of unfractionated heparin, low molecular weight heparin, and glycoprotein IIb/IIIa inhibitors in the CRUSADE registry was more common among older patients, women, and those with renal insufficiency. Conversely, a biologic basis for these observations is also plausible. Patients with CKD have both qualitative and quantitative platelet abnormalities that increase bleeding potential. In addition, the adverse hemodynamic consequences of tachycardia or impaired myocardial oxygen delivery in patients with obstructive coronary artery disease may be poorly tolerated in anemic patients . Finally, age-related hemostatic changes as a result of aging may also increase bleeding risk.
Procedural and pharmacologic correlates of major bleeding generally reflect either more potent pharmacotherapy or more invasive treatment approach. For example, glycoprotein IIb/IIIa inhibitors are consistent predictors of major bleeding in both randomized and observational reports, which reflects the potent inhibitory effect of these agents on platelet function [8, 12, 13•]. In addition, NSTEMI patients treated invasively with PCI in the GRACE registry were at greater risk of bleeding compared with those treated medically . Furthermore, the use of additional invasive therapies or procedures, such as intra-aortic balloon pump counterpulsation or right heart catheterization, also increase bleeding risk [4, 8].
Impact of Bleeding on Adverse Events
Recent reports involving pooled data from randomized controlled trials and observational registries have clearly shown the adverse prognostic impact of major bleeding during ACS on both mortality and other ischemic events. In fact, the association between bleeding and subsequent risk appears to be similar to that of periprocedural MI, highlighting the critical need for interventions that are not only efficacious but also reduce bleeding risk . In aggregate, existing data suggest a strong, independent and graded association between major bleeding and adverse cardiovascular events that persists for at least 1 year. Moreover, the hazard for mortality associated with bleeding varies based on the baseline risk of the population (randomized trial vs real-world) and type of bleeding definition used.
Combining data from several studies involving NSTEMI patients, Eikelboom et al.  were among the first to rigorously examine the adverse impact of major bleeding on subsequent cardiovascular risk in ACS populations. They found that patients who experienced a protocol-defined major bleed within 30 days of presentation were approximately five times more likely to die compared with those who did not bleed (12.8% vs 2.8%). This association remained independent even after adjusting for baseline risk factors and bleeding propensity (hazard ratio, 5.37; 95% CI, 3.97–7.26). Subsequent reports from the randomized ACUITY and HORIZONS AMI trials have corroborated and extended the findings of Eikelboom et al. . For example, patients with protocol-defined major bleeding in the ACUITY trial  were at a sevenfold increased risk for 30-day mortality compared to those without major bleeding, a magnitude of incremental risk similar to that observed by Eikelboom et al. . Moreover, major bleeding in ACUITY patients was also associated with higher rates of composite ischemia (23.1% vs 6.8%) and stent thrombosis (3.4% vs 0.6%) at 30 days . In a separate study, Mehran et al.  also found that the association between major bleeding and mortality in these patients was durable, extending up to 1 year. The impact of bleeding and mortality was graded, increasing in magnitude with the severity of bleeding. For example, the hazard ratios for 1-year mortality associated with TIMI major, non-TIMI major bleed with transfusion, and non-TIMI major bleed without transfusion in ACUITY and HORIZONS-AMI patients were 4.45, 2.9, and 2.04, respectively .
Although several studies have clearly shown that major bleeding is an independent and consistent correlate of cardiovascular risk in ACS patients, it also appears that the strength of association between bleeding and adverse events is not uniform, varying by the baseline risk of the population and definition used. The hazard ratio for in-hospital mortality associated with major bleeding among unselected patients enrolled in the GRACE registry was 1.9, substantially lower than the HR of 7.5 based on the ACUITY analysis . In part, this discrepancy reflects the higher baseline risk among “real-world” patients in the GRACE registry compared with randomized trial participants. For example, the mortality rate among non-bleeding patients in the GRACE registry was much higher than non-bleeding ACUITY participants (5.4% vs 1.2%, respectively).
The impact of bleeding in ACS also depends on the definition of bleeding that is used. This is not surprising because non-overlapping criteria comprising different bleeding scales identify patients with variable levels of cardiovascular risk. This concept was elegantly demonstrated in a study by Rao et al.  that evaluated the comparative utility of the TIMI and GUSTO bleeding scales on outcomes in NSTE-ACS patients. They found that 1,151 patients who met criteria for GUSTO bleeding did not meet criteria for TIMI bleeding, whereas 765 patients who met criteria for TIMI bleeding did not meet criteria for GUSTO bleeding. The frequency of TIMI minimal, minor, and major bleeding was 12.7%, 8.5%, and 8.2%, respectively, whereas the analogous frequencies of GUSTO mild, moderate, and severe bleeding were 19.2%, 11.4%, and 1.2%, respectively. Moreover, the impact of all levels of TIMI bleeding on outcomes was completely attenuated after adjusting for GUSTO bleeding . These findings suggest that the more clinically based GUSTO scale may be superior in predicting adverse outcomes in ACS patients compared with the more laboratory-based TIMI scheme.
Bleeding and Cardiovascular Risk: Potential Mechanisms
The mechanisms for bleeding-associated cardiovascular risk have not been fully elucidated. Despite numerous reports documenting a strong link between bleeding and adverse events, a causal relationship cannot be inferred because these studies were either observational or post hoc analyses of randomized trials. Therefore, the putative independent association between bleeding and cardiac risk might reflect unmeasured and residual confounding in the sicker and morbid patients who tend to bleed. Although this likely explains a portion of the bleeding-attributable risk, several lines of evidence suggest that bleeding may also be an independent risk factor and not just a risk marker for adverse events. However, demonstrating a truly causal association between bleeding and adverse events is precluded by the inability to conduct the necessary trial.
One direct consequence of bleeding that might amplify cardiovascular risk is less frequent use of recommended antiplatelet medications following an ACS event. Using data from the PREMIER registry, Wang et al. [20•] demonstrated that compared to patients without bleeding, those who bled were less likely to be discharged on either aspirin (82.8% vs 93.3%; P < 0.001) or a thienopyridine (58.8% vs 67.6%; P = 0.002), respectively. The results were similar even among patients who received an intracoronary stent. Interestingly, these patients were also less likely to receive other guideline- and evidence-based secondary preventive therapies, such as β blockers and statins, at the time of discharge. The discrepancies were more pronounced in patients who were followed up by noncardiovascular medical specialists or in those who did not have any follow-up. Although aspirin use remained less common in bleeding patients at 6 months, differences in other medications between bleeding and non-bleeding patients were no longer apparent. However, because bleeding-associated cardiovascular risk does not diminish after 6 months, lack of antiplatelet medication following MI does not fully account for the increased mortality in these patients.
Patients who bleed are more likely to receive red blood cell (RBC) transfusions, which might also increase risk for adverse events in ACS patients. Although transfusion is clearly required in certain clinical scenarios, the optimal threshold for transfusion is not known. Moreover, due to an increase in blood viscosity and other factors, an increase in hemoglobin concentration may not translate into improved tissue oxygenation [21–23]. Structural and biochemical changes in stored RBCs might also adversely impact nitric oxide availability resulting in platelet aggregation and vasoconstriction following transfusion [24, 25]. Consistent with these observations, clinical data have shown that RBC transfusion during ACS is associated with increased cardiovascular risk. For example, data from the CRUSADE registry indicate that RBC transfusion is associated with higher risk of in-hospital death or death and MI . Similarly, Rao et al.  found that RBC transfusion in NSTE-ACS patients was associated with higher mortality when performed for a nadir hematocrit over 25%.
Anemia is an additional consequence of bleeding that might also increase cardiovascular risk. Experimental data suggest that erythropoietin release in the setting of anemia might result in a prothrombotic state that extends beyond the initial bleeding event . In addition, exogenous erythropoietin administration has been linked to higher rates of thrombotic events in several trials involving patients with advanced CKD . Finally, bleeding results in activation of both platelets and the clotting cascade to achieve hemostasis at the site of vascular injury. Systemic amplification of this local response is inhibited by antithrombotic pathways that are largely dependent on a functional vascular endothelium . However, the impact of endothelial dysfunction and coronary artery disease on modulating this natural response to bleeding remains unknown.
Strategies to Reduce Bleeding Risk
Several recent prospective, randomized controlled trials have evaluated the impact of new antithrombotic agents in ACS patients. Results from these trials have shown that bivalirudin, a direct thrombin inhibitor, and fondaparinux, a factor Xa inhibitor, reduce bleeding complications without increasing ischemic event rates in these patients [12, 13, 31].
In the ACUITY trial, approximately 14,000 patients with moderate to high-risk ACS were randomized to heparin plus glycoprotein IIb/IIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone . At 30 days bivalirudin alone was associated with a 14% reduction in the frequency of the net clinical outcome, a composite of both ischemic and bleeding events, compared with heparin plus glycoprotein IIb/IIIa inhibitor (risk ratio, 0.86; 95% CI, 0.77–0.97). This benefit was driven by a substantial 47% reduction in protocol-defined major bleeding in the bivalirudin monotherapy compared with the heparin group. The impact of bivalirudin on reducing bleeding and ischemic complications in STEMI patients treated with primary PCI was further evaluated in the HORIZONS-AMI trial [13•]. Consistent with the findings from ACUITY, bivalirudin was associated with a reduction in the 30-day rate of net adverse clinical events compared with heparin plus glycoprotein IIb/IIIa inhibitors (9.2% vs 12.1%). Again, this benefit was attributable to a large reduction in major bleeding associated with bivalirudin that persists for up to 1 year (4.9% vs 8.3%; relative risk, 0.6; 95% CI, 0.46–0.77). Both cardiac and all-cause mortality were also lower in bivalirudin-treated patients. However, the mortality findings from this study should be interpreted with caution, as the study was not powered for this outcome. In the OASIS-5 trial the comparative efficacy of fondaparinux versus enoxaparin was evaluated in approximately 20,000 NSTE-ACS patients . Similar to the findings from the bivalirudin studies, there were no differences in the rates of composite ischemia between the two groups at 6 months. In contrast, fondaparinux reduced major bleeding by approximately 30% (5.8% vs 4.3%; hazard ratio, 0.72; 95% CI, 0.64–0.82). The reduction in major bleeding translated into greater net clinical benefit and lower mortality at 6 months.
An early invasive approach in moderate to high-risk ACS patients is currently supported by professional societies and guidelines. Because the most common site of bleeding in invasively treated patients is the vascular access site, there has been considerable interest in using a radial approach or vascular closure devices (VCDs) to reduce bleeding complications. A meta-analysis of 23 randomized trials comparing a femoral to radial approach in diagnostic or intervention angiography found a 73% reduction in major bleeding associated with a transradial approach . The benefit of a radial versus femoral approach persisted in the subgroup of studies that only included primary or rescue PCI. The ACUITY investigators also compared outcomes in patients who underwent a femoral (n = 11,989) compared to radial (n = 789) arterial access and found that major bleeding was significantly reduced with the radial approach . Although provocative, these findings are largely limited due to inherent biases that might favor lower complications in patients who are selected to undergo radial versus femoral arterial access.
Although VCDs reduce time to hemostasis and ambulation in patients undergoing angiography, the impact of these devices on bleeding and vascular complications remains controversial [34, 35]. To address this issue, the ACUITY investigators evaluated the impact of VCDs on major access site bleeding (ASB) in 11,621 patients who underwent angiography with or without PCI via the femoral artery . A total of 4,307 (37.1%) patients received a VCD and 7,314 (62.9%) did not. VCD use was associated with a significant reduction major ASB compared with no VCD (2.5% vs 3.3%; P = 0.01). ASB was lowest in patients who received both a VCD and bivalirudin (0.7%). Although these findings suggest a synergistic impact of VCD and bivalirudin on major ASB, other potential vascular complications that might result from VCD use were not analyzed. In addition, VCD use was not randomly allocated but left to the discretion of the operator, introducing the potential for selection bias.
Major bleeding is a common occurrence in the current era of ACS management and is associated with substantial cardiovascular morbidity and mortality. Bleeding risk is not uniform in all patients but can be reliably predicted through several validated risk prediction algorithms. Although bleeding is clearly a marker for greater morbidity that places patients at higher risk for adverse events, independent mechanisms for bleeding-associated risk suggest a putative causal relationship. Recent studies have shown that use of several novel antithrombotic agents reduce bleeding without increasing risk of ischemic events, resulting in an overall net clinical benefit.
No potential conflicts of interest relevant to this article were reported.