Predicting Bleeding in High-Risk Patients With ACS
Predicting Bleeding in High-Risk Patients With ACS
In this large population of patients post ACS and at high risk for recurrent ischaemic events in whom a majority were receiving dual oral antiplatelet therapy, the addition of the oral anticoagulant apixaban resulted in an increased risk of bleeding when compared with placebo. Bleeding occurred more frequently with apixaban in a variety of locations, including mucosal surfaces (eg, epistaxis, gingival), skin (eg, bruising, haematoma), gastrointestinal, genitourinary (eg, haematuria), intracranial and others. Multivariable models demonstrated that, in addition to study treatment itself, several clinical factors (eg, increasing age, history of smoking, renal dysfunction, elevated white cell count) and aspects of prerandomisation management (eg, use of dual oral antiplatelet therapy, coronary revascularisation) were associated with bleeding events over the course of the trial.
In the overall APPRAISE-2 trial population, the proportion of patients who experienced TIMI major or minor and ISTH major or CRNM bleeding was approximately 2% while any bleeding occurred in approximately 13% of patients, indicating that the majority of bleeding events in the trial were minor. There was a marked increase in the rate of major and any bleeding events shortly (≤30 days) after ACS. Rates of bleeding were at least 50-fold higher in the short compared with 'late' post-ACS indexed hospitalisation period. However, the risk of late bleeding persisted after the initial indexed event and bleeding occurring >30 days after ACS accounted for more than half of all TIMI, ISTH and any bleeding events in the study. Treatment with apixaban was associated with significantly higher rates of bleeding events in both short-term and long-term follow-up. Gastrointestinal bleeding was the most common source of major bleeding in APPRAISE-2.
In APPRAISE-2, use of apixaban was associated with an increase in fatal bleeds and a fourfold greater number of ICH when compared with placebo. While direct comparisons are not available, and the patient populations, concomitant therapies, study drugs and doses, and treatment durations differed, it is interesting to note that risk of bleeding (including fatal bleeding) and ICH in patients receiving apixaban was comparable with the threefold to fourfold increase in bleeding observed with other factor Xa and direct thrombin inhibitors in a large Phase III and several smaller Phase II studies, respectively. Further, a previous meta-analysis indicated that the addition of warfarin to aspirin after ACS was associated with an almost twofold increased risk of bleeding when compared with aspirin alone. Thus, risk of bleeding in the high ischaemic risk patients with ACS on oral anticoagulation together with single or dual antiplatelet therapy in APPRAISE-2 did not appear to be substantially different from that observed in previous studies of similar or lower ischaemic risk post-ACS populations.
In APPRAISE-2, patients with any bleeding or ISTH-classified bleeding events tended to be older and were more likely to have additional comorbidities (eg, smoking, hypertension, impaired renal function and atrial fibrillation). In addition, patients experiencing bleeding events were more likely to have an elevated white cell count and have undergone PCI for the indexed event and received dual oral antiplatelet therapy prior to randomisation. Indeed, the APPRAISE-2 trial included higher-risk patients with ACS and provided a longer-term bleeding assessment when compared with previous large, randomised and observational studies where predictors of bleeding were identified. A number of common predictors of short-term bleeding after ACS and/or PCI have been derived from pooled analysis of clinical trials and from large observational cohorts. Common predictors of short-term bleeding included older age, female sex, body weight, renal dysfunction, history of diabetes, baseline anaemia, prior vascular disease, use of oral anticoagulants, presenting blood pressure and congestive heart failure or shock on admission. Thus, characteristics that predispose to bleeding appear to be similar across the spectrum of moderate-risk to high-risk patients with ACS and consistent between 'real world' and clinical trial populations. Additionally, characteristics of patients with ACS which predispose to short-term bleeding appear to confer risk for long-term bleeding events as well.
Both increased age and renal dysfunction have been consistently correlated with higher risk of post-ACS bleeding. Age >75 years has been associated with 1.9-fold to 3.3-fold increased risk of non-coronary artery bypass grafting (CABG) major bleeding in patients receiving contemporary ACS treatment. Similarly, impaired renal function has been associated with a more than fourfold increase in non-CABG major bleeding. Additionally, the risk of bleeding appears to rise incrementally by 4%–21% for every 5-year increase in age and by 6% for every 10 mL/min reduction in creatinine clearance.
Dual oral antiplatelet therapy has also been shown to increase risk of bleeding after ACS. When compared with aspirin alone, there is an estimated 0.6%–1.2% increase in the absolute risk of bleeding with the addition of clopidogrel; use of the newer P2Y12 receptor inhibitors prasugrel and ticagrelor, while more effective in reducing cardiovascular events, were also shown to further increase risk of bleeding post ACS when compared with clopidogrel.
Management with an invasive revascularisation strategy for index events has also been shown to increase risk of bleeding after ACS, and post-ACS bleeding was more likely with early revascularisation regardless of the anticoagulation therapy used. Early invasive therapy is an independent predictor of major bleeding, with an OR of >1.6 when compared with a conservative treatment strategy for ACS, which may be attributable to increased use of anticoagulation and access site bleeding.
The effects of prior smoking on bleeding predisposition in patients with ACS and those at high risk of vascular disease have been inconsistent. While some observational studies have shown a lower risk of bleeding among recent smokers receiving clopidogrel, in the APPRAISE-2 cohort, smoking was an independent predictor of increased bleeding risk. Smoking may increase bleeding risk by the induction of cytochrome P450 system enzymes resulting in increased conversion of clopidogrel to its active metabolite, thereby augmenting platelet inhibition. Finally, consistent with previous reports, we observed that an elevated white cell count was associated with an increased risk of short-term bleeding.
In contrast to APPRAISE-2, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) study did find a significant reduction in major adverse cardiovascular events with rivaroxaban superimposed on standard ACS therapy. However, it should be noted that the other major clinical trials involving adjunctive treatment of novel oral anticoagulants in this setting, including the Randomized Dabigatran Etexilate Dose-Finding Study in Patients With Acute Coronary Syndromes (REDEEM) with dabigatran and the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) with vorapaxar, found increased bleeding with additional therapy without reductions in primary composite ischaemic endpoints. It is possible that an increase in major bleeding may have contributed to greater ischaemic events in the treatment arms of these trials resulting in an absence of effect on cardiovascular outcomes observed in these trials. Therefore, it is possible that a lower dose of apixaban may have reduced major bleeding events and consequently reduced ischaemic outcomes.
Although the risk of recurrent ischaemia after ACS is increased in patients with high-risk features, so too is the predisposition towards bleeding events. Major bleeding events after ACS have even been shown to be prognostic for recurrent ischaemia, with rates of future ischaemic events being threefold to fivefold higher after bleeding. This is unsurprising as risk factors for bleeding identified in this study, including age, smoking, white cell count and renal impairment, have all been associated with increased risk of future ischaemic events. Similarly, patient characteristics such as heart rate, systolic blood pressure, congestive heart failure and renal function are included in both the Global Registry of Acute Coronary Events (GRACE) ischaemic and CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) bleeding stratification scores. Considering the substantial overlap in risk factors for bleeding and ischaemia, attempts to reduce ischaemic events in higher-risk patients with increasingly aggressive pharmacological therapies, such as apixaban added to standard therapy including frequent use of dual oral antiplatelet therapy in APPRAISE-2, will likely come at a cost of increased bleeding with resultant prognostic implications.
Discussion
In this large population of patients post ACS and at high risk for recurrent ischaemic events in whom a majority were receiving dual oral antiplatelet therapy, the addition of the oral anticoagulant apixaban resulted in an increased risk of bleeding when compared with placebo. Bleeding occurred more frequently with apixaban in a variety of locations, including mucosal surfaces (eg, epistaxis, gingival), skin (eg, bruising, haematoma), gastrointestinal, genitourinary (eg, haematuria), intracranial and others. Multivariable models demonstrated that, in addition to study treatment itself, several clinical factors (eg, increasing age, history of smoking, renal dysfunction, elevated white cell count) and aspects of prerandomisation management (eg, use of dual oral antiplatelet therapy, coronary revascularisation) were associated with bleeding events over the course of the trial.
Bleeding Outcomes in APPRAISE-2
In the overall APPRAISE-2 trial population, the proportion of patients who experienced TIMI major or minor and ISTH major or CRNM bleeding was approximately 2% while any bleeding occurred in approximately 13% of patients, indicating that the majority of bleeding events in the trial were minor. There was a marked increase in the rate of major and any bleeding events shortly (≤30 days) after ACS. Rates of bleeding were at least 50-fold higher in the short compared with 'late' post-ACS indexed hospitalisation period. However, the risk of late bleeding persisted after the initial indexed event and bleeding occurring >30 days after ACS accounted for more than half of all TIMI, ISTH and any bleeding events in the study. Treatment with apixaban was associated with significantly higher rates of bleeding events in both short-term and long-term follow-up. Gastrointestinal bleeding was the most common source of major bleeding in APPRAISE-2.
In APPRAISE-2, use of apixaban was associated with an increase in fatal bleeds and a fourfold greater number of ICH when compared with placebo. While direct comparisons are not available, and the patient populations, concomitant therapies, study drugs and doses, and treatment durations differed, it is interesting to note that risk of bleeding (including fatal bleeding) and ICH in patients receiving apixaban was comparable with the threefold to fourfold increase in bleeding observed with other factor Xa and direct thrombin inhibitors in a large Phase III and several smaller Phase II studies, respectively. Further, a previous meta-analysis indicated that the addition of warfarin to aspirin after ACS was associated with an almost twofold increased risk of bleeding when compared with aspirin alone. Thus, risk of bleeding in the high ischaemic risk patients with ACS on oral anticoagulation together with single or dual antiplatelet therapy in APPRAISE-2 did not appear to be substantially different from that observed in previous studies of similar or lower ischaemic risk post-ACS populations.
Predictors of Major Bleeding in APPRAISE-2
In APPRAISE-2, patients with any bleeding or ISTH-classified bleeding events tended to be older and were more likely to have additional comorbidities (eg, smoking, hypertension, impaired renal function and atrial fibrillation). In addition, patients experiencing bleeding events were more likely to have an elevated white cell count and have undergone PCI for the indexed event and received dual oral antiplatelet therapy prior to randomisation. Indeed, the APPRAISE-2 trial included higher-risk patients with ACS and provided a longer-term bleeding assessment when compared with previous large, randomised and observational studies where predictors of bleeding were identified. A number of common predictors of short-term bleeding after ACS and/or PCI have been derived from pooled analysis of clinical trials and from large observational cohorts. Common predictors of short-term bleeding included older age, female sex, body weight, renal dysfunction, history of diabetes, baseline anaemia, prior vascular disease, use of oral anticoagulants, presenting blood pressure and congestive heart failure or shock on admission. Thus, characteristics that predispose to bleeding appear to be similar across the spectrum of moderate-risk to high-risk patients with ACS and consistent between 'real world' and clinical trial populations. Additionally, characteristics of patients with ACS which predispose to short-term bleeding appear to confer risk for long-term bleeding events as well.
Both increased age and renal dysfunction have been consistently correlated with higher risk of post-ACS bleeding. Age >75 years has been associated with 1.9-fold to 3.3-fold increased risk of non-coronary artery bypass grafting (CABG) major bleeding in patients receiving contemporary ACS treatment. Similarly, impaired renal function has been associated with a more than fourfold increase in non-CABG major bleeding. Additionally, the risk of bleeding appears to rise incrementally by 4%–21% for every 5-year increase in age and by 6% for every 10 mL/min reduction in creatinine clearance.
Dual oral antiplatelet therapy has also been shown to increase risk of bleeding after ACS. When compared with aspirin alone, there is an estimated 0.6%–1.2% increase in the absolute risk of bleeding with the addition of clopidogrel; use of the newer P2Y12 receptor inhibitors prasugrel and ticagrelor, while more effective in reducing cardiovascular events, were also shown to further increase risk of bleeding post ACS when compared with clopidogrel.
Management with an invasive revascularisation strategy for index events has also been shown to increase risk of bleeding after ACS, and post-ACS bleeding was more likely with early revascularisation regardless of the anticoagulation therapy used. Early invasive therapy is an independent predictor of major bleeding, with an OR of >1.6 when compared with a conservative treatment strategy for ACS, which may be attributable to increased use of anticoagulation and access site bleeding.
The effects of prior smoking on bleeding predisposition in patients with ACS and those at high risk of vascular disease have been inconsistent. While some observational studies have shown a lower risk of bleeding among recent smokers receiving clopidogrel, in the APPRAISE-2 cohort, smoking was an independent predictor of increased bleeding risk. Smoking may increase bleeding risk by the induction of cytochrome P450 system enzymes resulting in increased conversion of clopidogrel to its active metabolite, thereby augmenting platelet inhibition. Finally, consistent with previous reports, we observed that an elevated white cell count was associated with an increased risk of short-term bleeding.
Ischaemic Events With Combined Novel Oral Anticoagulants and Dual Antiplatelet Therapy in ACS
In contrast to APPRAISE-2, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) study did find a significant reduction in major adverse cardiovascular events with rivaroxaban superimposed on standard ACS therapy. However, it should be noted that the other major clinical trials involving adjunctive treatment of novel oral anticoagulants in this setting, including the Randomized Dabigatran Etexilate Dose-Finding Study in Patients With Acute Coronary Syndromes (REDEEM) with dabigatran and the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) with vorapaxar, found increased bleeding with additional therapy without reductions in primary composite ischaemic endpoints. It is possible that an increase in major bleeding may have contributed to greater ischaemic events in the treatment arms of these trials resulting in an absence of effect on cardiovascular outcomes observed in these trials. Therefore, it is possible that a lower dose of apixaban may have reduced major bleeding events and consequently reduced ischaemic outcomes.
Limitations to Anticoagulation in Targeting Ischaemia Alone
Although the risk of recurrent ischaemia after ACS is increased in patients with high-risk features, so too is the predisposition towards bleeding events. Major bleeding events after ACS have even been shown to be prognostic for recurrent ischaemia, with rates of future ischaemic events being threefold to fivefold higher after bleeding. This is unsurprising as risk factors for bleeding identified in this study, including age, smoking, white cell count and renal impairment, have all been associated with increased risk of future ischaemic events. Similarly, patient characteristics such as heart rate, systolic blood pressure, congestive heart failure and renal function are included in both the Global Registry of Acute Coronary Events (GRACE) ischaemic and CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) bleeding stratification scores. Considering the substantial overlap in risk factors for bleeding and ischaemia, attempts to reduce ischaemic events in higher-risk patients with increasingly aggressive pharmacological therapies, such as apixaban added to standard therapy including frequent use of dual oral antiplatelet therapy in APPRAISE-2, will likely come at a cost of increased bleeding with resultant prognostic implications.
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