Major Bleeding in Outpatients With Stable CAD
The baseline characteristics of the patients included in the CORONOR study have been reported previously and are summarized in Table 1. Most patients were men, with a mean age of 66.9 ± 11.5 years. Most patients underwent at least 1 coronary revascularization procedure before inclusion. There was wide prescription of major secondary prevention drugs (i.e., beta-blockers, statins, and angiotensin system antagonists). Almost all patients received at least 1 antithrombotic treatment (99.3%). The majority received antiplatelet therapy (APT) alone (n = 2,798; 67.4%; aspirin, n = 2,025; clopidogrel, n = 773). Although these patients had no recent coronary events, a substantial proportion received dual antiplatelet treatment (i.e., aspirin and clopidogrel; n = 861; 20.8%). Altogether, 11.1% received a vitamin K antagonist (VKA). Among these patients, most (n = 342) received the combination of a VKA and an antiplatelet agent (VKA + APT) (aspirin, n = 308; clopidogrel, n = 34), whereas 119 received a VKA alone. Of note, no patient received prasugrel, ticagrelor, or new oral anticoagulants at inclusion.
At follow-up, there were 271 deaths (119 cardiovascular and 152 noncardiovascular), 91 MIs, and 48 strokes. The combined endpoint of cardiovascular death, MI, or nonhemorrhagic stroke occurred in 226 patients. There were 51 major bleeding events during the 2-year follow-up (0.6 per 100 patient-years). As shown in Table 2, most events were BARC type 3a bleeds; there were 12 fatal bleeds (type 5). In most of the cases, the site of bleeding was gastrointestinal (54.9%). The site of fatal bleeding was intracranial in 6 patients, gastrointestinal in 4 patients, retroperitoneal in 1 patient, and pericardial in 1 patient. Figure 1 illustrates the timing of the bleeding events and shows that the risk of bleeding was constant throughout the follow-up. During the follow-up, 6 additional deaths occurred among the patients who experienced major bleeding, giving a total of 18 (35.3%) deaths. The time interval between the bleeding event and death was 12 ± 19 days for the 12 patients with type 5 bleeding, and 174 ± 142 days in the 6 patients who died after type 3 to 4 bleeding. When used as a time-dependent variable, major bleeding was associated with a significant increase in mortality (unadjusted HR: 6.78; 95% CI: 4.2 to 10.94; p < 0.0001); major bleeding remained significantly associated with mortality (HR = 2.89; 95% CI 1.73 to 4.83; p < 0.0001) when adjusted for age, sex, diabetes mellitus, previous heart failure, and the estimated glomerular filtration rate (eGFR).
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Figure 1.
Time Frame for Bleeding Events
BARC classes are detailed in the footnote of Table 2. BARC = Bleeding Academic Research Consortium.
The patients who experienced major bleeding were older and more frequently had angina, a history of hypertension, diabetes mellitus, and multivessel CAD. The patients who bled also more frequently underwent drug-eluting stent implantation, aortic or peripheral intervention, were hospitalized for decompensated heart failure, had a lower left ventricular ejection fraction and eGFR, more often received VKA, and were less frequently on statin therapy (Table 1). As shown in Table 3, 4 variables were identified as independent predictors of major bleeding by multivariate analysis: treatment with VKA, diabetes mellitus, age (positive association), and eGFR (negative association). The impact of antithrombotic treatments on the risk of major bleeding is shown in Figure 2. The increased bleeding risk associated with VKA treatment was particularly evident in patients who received the combination of VKA + APT, whereas there was no significant increase in bleeding in patients who received VKA alone. In contrast, as shown in Figure 3, there was no difference in the risk of the combined endpoint of cardiovascular death, MI, or nonhemorrhagic stroke in patients treated with VKA + APT versus patients treated with VKA alone (adjusted HR: 1.15; 95% CI: 0.58 to 2.27; p = 0.697).
(Enlarge Image)
Figure 2.
Major Bleeding in Stable Coronary Artery Disease Patients According to Antithrombotic Treatments
(A) Kaplan-Meier curves during follow-up. (B) Age- and sex-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for major bleeding in the different groups. The MAPT group served as the reference group. MAPT = mono-antiplatelet therapy; DAPT = dual-antiplatelet therapy; VKA = vitamin K antagonist; VKA + APT = vitamin K antagonist and antiplatelet therapy.
(Enlarge Image)
Figure 3.
Cardiovascular Death, Myocardial Infarction, or Nonhemorrhagic Stroke in Stable Coronary Artery Disease Patients Treated With Vitamin K Antagonists According to Antiplatelet Use
Kaplan-Meier curves with hazard ratios (HRs) during follow-up. HR (95% confidence interval) for VKA + APT versus VKA alone. *Analyses were adjusted for age, sex, diabetes mellitus, previous heart failure, and estimated glomerular filtration rate. Abbreviations as in Figure 2.
Results
The baseline characteristics of the patients included in the CORONOR study have been reported previously and are summarized in Table 1. Most patients were men, with a mean age of 66.9 ± 11.5 years. Most patients underwent at least 1 coronary revascularization procedure before inclusion. There was wide prescription of major secondary prevention drugs (i.e., beta-blockers, statins, and angiotensin system antagonists). Almost all patients received at least 1 antithrombotic treatment (99.3%). The majority received antiplatelet therapy (APT) alone (n = 2,798; 67.4%; aspirin, n = 2,025; clopidogrel, n = 773). Although these patients had no recent coronary events, a substantial proportion received dual antiplatelet treatment (i.e., aspirin and clopidogrel; n = 861; 20.8%). Altogether, 11.1% received a vitamin K antagonist (VKA). Among these patients, most (n = 342) received the combination of a VKA and an antiplatelet agent (VKA + APT) (aspirin, n = 308; clopidogrel, n = 34), whereas 119 received a VKA alone. Of note, no patient received prasugrel, ticagrelor, or new oral anticoagulants at inclusion.
At follow-up, there were 271 deaths (119 cardiovascular and 152 noncardiovascular), 91 MIs, and 48 strokes. The combined endpoint of cardiovascular death, MI, or nonhemorrhagic stroke occurred in 226 patients. There were 51 major bleeding events during the 2-year follow-up (0.6 per 100 patient-years). As shown in Table 2, most events were BARC type 3a bleeds; there were 12 fatal bleeds (type 5). In most of the cases, the site of bleeding was gastrointestinal (54.9%). The site of fatal bleeding was intracranial in 6 patients, gastrointestinal in 4 patients, retroperitoneal in 1 patient, and pericardial in 1 patient. Figure 1 illustrates the timing of the bleeding events and shows that the risk of bleeding was constant throughout the follow-up. During the follow-up, 6 additional deaths occurred among the patients who experienced major bleeding, giving a total of 18 (35.3%) deaths. The time interval between the bleeding event and death was 12 ± 19 days for the 12 patients with type 5 bleeding, and 174 ± 142 days in the 6 patients who died after type 3 to 4 bleeding. When used as a time-dependent variable, major bleeding was associated with a significant increase in mortality (unadjusted HR: 6.78; 95% CI: 4.2 to 10.94; p < 0.0001); major bleeding remained significantly associated with mortality (HR = 2.89; 95% CI 1.73 to 4.83; p < 0.0001) when adjusted for age, sex, diabetes mellitus, previous heart failure, and the estimated glomerular filtration rate (eGFR).
(Enlarge Image)
Figure 1.
Time Frame for Bleeding Events
BARC classes are detailed in the footnote of Table 2. BARC = Bleeding Academic Research Consortium.
The patients who experienced major bleeding were older and more frequently had angina, a history of hypertension, diabetes mellitus, and multivessel CAD. The patients who bled also more frequently underwent drug-eluting stent implantation, aortic or peripheral intervention, were hospitalized for decompensated heart failure, had a lower left ventricular ejection fraction and eGFR, more often received VKA, and were less frequently on statin therapy (Table 1). As shown in Table 3, 4 variables were identified as independent predictors of major bleeding by multivariate analysis: treatment with VKA, diabetes mellitus, age (positive association), and eGFR (negative association). The impact of antithrombotic treatments on the risk of major bleeding is shown in Figure 2. The increased bleeding risk associated with VKA treatment was particularly evident in patients who received the combination of VKA + APT, whereas there was no significant increase in bleeding in patients who received VKA alone. In contrast, as shown in Figure 3, there was no difference in the risk of the combined endpoint of cardiovascular death, MI, or nonhemorrhagic stroke in patients treated with VKA + APT versus patients treated with VKA alone (adjusted HR: 1.15; 95% CI: 0.58 to 2.27; p = 0.697).
(Enlarge Image)
Figure 2.
Major Bleeding in Stable Coronary Artery Disease Patients According to Antithrombotic Treatments
(A) Kaplan-Meier curves during follow-up. (B) Age- and sex-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for major bleeding in the different groups. The MAPT group served as the reference group. MAPT = mono-antiplatelet therapy; DAPT = dual-antiplatelet therapy; VKA = vitamin K antagonist; VKA + APT = vitamin K antagonist and antiplatelet therapy.
(Enlarge Image)
Figure 3.
Cardiovascular Death, Myocardial Infarction, or Nonhemorrhagic Stroke in Stable Coronary Artery Disease Patients Treated With Vitamin K Antagonists According to Antiplatelet Use
Kaplan-Meier curves with hazard ratios (HRs) during follow-up. HR (95% confidence interval) for VKA + APT versus VKA alone. *Analyses were adjusted for age, sex, diabetes mellitus, previous heart failure, and estimated glomerular filtration rate. Abbreviations as in Figure 2.