Major Bleeding in Outpatients With Stable CAD
Major Bleeding in Outpatients With Stable CAD
There is now clear evidence that bleeding is a key event with important prognostic implications in patients with acute manifestations of CAD) and in patients undergoing myocardial revascularization procedures. Much less is known regarding bleeding events that occur in patients with stable and chronic CAD at a chronological distance from any MI or revascularization. Data from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial provided meaningful information on bleeding rates according to antiplatelet regimens. However, because the patients included in randomized trials are highly selected (patients who required VKA or patients believed to be at particularly high risk of bleeding were excluded from the CHARISMA study), the ability to extrapolate these results to the overall stable CAD population is limited. An analysis of the REACH (Reduction of Atherothrombosis for Continued Health) registry reported risk factors for serious bleeding in a large group of outpatients with various manifestations of atherothrombosis (CAD, cerebrovascular disease, peripheral arterial diseases) or with at least 3 atherosclerosis risk factors in 2003 to 2004. However, to the best of our knowledge, the present study is the first to focus on a contemporary cohort of patients with stable CAD and the first to provide information on major bleeding in a real-life setting.
Our results showed that a BARC type ≥3 bleed is a relatively rare event in stable CAD patients (0.6%/patient-year). It is, however, important to point out that this rate applies to a study population included in an outpatient setting, and that all patients were >1 year from a cardiovascular hospitalization for MI or coronary revascularization at inclusion in the study. The most frequent finding was the incidence of major bleeding episodes related to gastrointestinal bleeding. The data also demonstrated that the occurrence of major bleeding in a stable CAD patient was an independent predictor of death. All physicians following stable CAD patients should, therefore, pay special attention to the determinants of bleeding. Several independent risk factors for major bleeding were identified. As observed in patients with unstable CAD, increasing age, diabetes, and renal insufficiency were associated with an increased risk of bleeding in stable CAD. Long-term oral anticoagulation was the strongest risk factor for bleeding in this stable setting; in particular, we found that the combination of oral anticoagulation with an antiplatelet agent was associated with a major increase in the number of bleeding episodes.
A significant proportion of patients with stable CAD are treated with oral anticoagulation (>10% in the present study), mainly because of atrial fibrillation. Although common practice is to treat such patients with VKA + 1 APT drug (usually aspirin), the 2010 European Society of Cardiology guidelines on atrial fibrillation suggest that, in patients with stable vascular disease (i.e., >1 year with no acute events), VKA monotherapy may be considered, and that in the absence of a subsequent cardiovascular event, concomitant APT should not be prescribed. This was on the basis of evidence that the addition of an APT is associated with a substantial increase in bleeding, with no clear evidence for a decrease in ischemic events. It should be noted, however, that data in patients with stable CAD and modern management (i.e., wide use of coronary revascularization, including drug-eluting stent implantation) were lacking. The American College of Cardiology and the American Heart Association endorsed a similar statement. Recruitment in the present study was performed at the time these guidelines were released. We observed that three-quarters of patients who received a VKA were also treated with an antiplatelet agent; this is concordant with the recent EuroObservational Research Programme Atrial Fibrillation Pilot Registry report, in which APT was still commonly prescribed with oral anticoagulation when there was coexistent CAD. This illustrates that physicians remain hesitant to stop all APTs in stable CAD patients who need oral anticoagulation. However, our follow-up data suggest that this attitude leads to an increased risk of bleeding that does not appear to be balanced by a concomitant decrease in the risk of ischemic complications.
Our data reflect the practice in a regional area in 2010 to 2011. Although this was not a population-based registry, the patients included were treated at research institutions and smaller community hospitals, as well as in private practice. It will have to be determined whether these findings are representative of practices in other parts of the world, and how these trends could change in the era of new drug-eluting stents that lower the risk of thrombosis. In the present study, anticoagulant therapy was limited to VKA, and antiplatelet agents were limited to aspirin and/or clopidogrel; therefore, our results cannot be directly extrapolated to novel oral anticoagulants and antiplatelet agents. In addition, our study only focused on BARC ≥3 bleeds; thus, less severe events that could be associated with prognosis were not analyzed. Further studies are needed to clarify the association of the different BARC classes with outcomes in the outpatient setting, as was recently reported for patients with ST-segment elevation MI.
As with any observational study, the association between treatment and outcomes cannot prove causality. The limitation of adjustment methodology is also acknowledged, and persistent unknown or unmeasured confounding factors may exist. Finally, we also acknowledge that our study had limited power to compare patients receiving VKA alone with patients receiving VKA + APT.
Discussion
There is now clear evidence that bleeding is a key event with important prognostic implications in patients with acute manifestations of CAD) and in patients undergoing myocardial revascularization procedures. Much less is known regarding bleeding events that occur in patients with stable and chronic CAD at a chronological distance from any MI or revascularization. Data from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial provided meaningful information on bleeding rates according to antiplatelet regimens. However, because the patients included in randomized trials are highly selected (patients who required VKA or patients believed to be at particularly high risk of bleeding were excluded from the CHARISMA study), the ability to extrapolate these results to the overall stable CAD population is limited. An analysis of the REACH (Reduction of Atherothrombosis for Continued Health) registry reported risk factors for serious bleeding in a large group of outpatients with various manifestations of atherothrombosis (CAD, cerebrovascular disease, peripheral arterial diseases) or with at least 3 atherosclerosis risk factors in 2003 to 2004. However, to the best of our knowledge, the present study is the first to focus on a contemporary cohort of patients with stable CAD and the first to provide information on major bleeding in a real-life setting.
Our results showed that a BARC type ≥3 bleed is a relatively rare event in stable CAD patients (0.6%/patient-year). It is, however, important to point out that this rate applies to a study population included in an outpatient setting, and that all patients were >1 year from a cardiovascular hospitalization for MI or coronary revascularization at inclusion in the study. The most frequent finding was the incidence of major bleeding episodes related to gastrointestinal bleeding. The data also demonstrated that the occurrence of major bleeding in a stable CAD patient was an independent predictor of death. All physicians following stable CAD patients should, therefore, pay special attention to the determinants of bleeding. Several independent risk factors for major bleeding were identified. As observed in patients with unstable CAD, increasing age, diabetes, and renal insufficiency were associated with an increased risk of bleeding in stable CAD. Long-term oral anticoagulation was the strongest risk factor for bleeding in this stable setting; in particular, we found that the combination of oral anticoagulation with an antiplatelet agent was associated with a major increase in the number of bleeding episodes.
A significant proportion of patients with stable CAD are treated with oral anticoagulation (>10% in the present study), mainly because of atrial fibrillation. Although common practice is to treat such patients with VKA + 1 APT drug (usually aspirin), the 2010 European Society of Cardiology guidelines on atrial fibrillation suggest that, in patients with stable vascular disease (i.e., >1 year with no acute events), VKA monotherapy may be considered, and that in the absence of a subsequent cardiovascular event, concomitant APT should not be prescribed. This was on the basis of evidence that the addition of an APT is associated with a substantial increase in bleeding, with no clear evidence for a decrease in ischemic events. It should be noted, however, that data in patients with stable CAD and modern management (i.e., wide use of coronary revascularization, including drug-eluting stent implantation) were lacking. The American College of Cardiology and the American Heart Association endorsed a similar statement. Recruitment in the present study was performed at the time these guidelines were released. We observed that three-quarters of patients who received a VKA were also treated with an antiplatelet agent; this is concordant with the recent EuroObservational Research Programme Atrial Fibrillation Pilot Registry report, in which APT was still commonly prescribed with oral anticoagulation when there was coexistent CAD. This illustrates that physicians remain hesitant to stop all APTs in stable CAD patients who need oral anticoagulation. However, our follow-up data suggest that this attitude leads to an increased risk of bleeding that does not appear to be balanced by a concomitant decrease in the risk of ischemic complications.
Study Limitations
Our data reflect the practice in a regional area in 2010 to 2011. Although this was not a population-based registry, the patients included were treated at research institutions and smaller community hospitals, as well as in private practice. It will have to be determined whether these findings are representative of practices in other parts of the world, and how these trends could change in the era of new drug-eluting stents that lower the risk of thrombosis. In the present study, anticoagulant therapy was limited to VKA, and antiplatelet agents were limited to aspirin and/or clopidogrel; therefore, our results cannot be directly extrapolated to novel oral anticoagulants and antiplatelet agents. In addition, our study only focused on BARC ≥3 bleeds; thus, less severe events that could be associated with prognosis were not analyzed. Further studies are needed to clarify the association of the different BARC classes with outcomes in the outpatient setting, as was recently reported for patients with ST-segment elevation MI.
As with any observational study, the association between treatment and outcomes cannot prove causality. The limitation of adjustment methodology is also acknowledged, and persistent unknown or unmeasured confounding factors may exist. Finally, we also acknowledge that our study had limited power to compare patients receiving VKA alone with patients receiving VKA + APT.
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