Atrial Fibrillation Treated With Vitamin K Antagonism
Atrial Fibrillation Treated With Vitamin K Antagonism
Of the 14 264 patients enrolled in ROCKET AF, 2468 (17.3%) had prior MI at baseline. Table 1 shows the baseline demographics of patients with and without prior MI. Patients with prior MI tended to be older, male, and more often had risk factors for atherosclerosis and used antiplatelet agents. Among warfarin-treated patients with prior MI and those without prior MI, the median (25th, 75th percentiles) time the INR was in the therapeutic range (2.0–3.0, inclusive) was 59.1 (44.9, 71.5%) and 57.6 (42.6, 70.4%), respectively.
Stroke, cardiac, and bleeding outcomes are shown in Table 2 and Figure 1 for patients with and without prior MI. Patients with and without prior MI had similar rates of stroke and non-central nervous system embolism. Patients with prior MI had more recurrent CV events and higher mortality. These patients also had higher rates of major bleeding. After adjustment for differences in baseline characteristics, participants with prior MI remained at elevated risk for recurrent CV events (HR 1.64, 95% CI 1.21–2.24; P = 0.002) (Supplementary material online, Table S1).
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Figure 1.
Clinical outcomes in patients with and without prior myocardial infarction.
Major bleeding rates in patients with and without baseline use of aspirin and/or a thienopyridine were 4.59 and 3.73 for patients with prior MI vs. 4.27 and 2.97 for patients without prior MI (interaction P value = 0.408).
Table 3 shows CV outcomes by randomly assigned treatment in the overall trial. Patients assigned to rivaroxaban tended to have lower rates of CV events with a non-significant 14% reduction in the hazard of CV death, MI, or UA [HR 0.86, 95% CI 0.73–1.00; P = 0.051 (adjusted HR 0.88, 95% CI 0.75–1.03; adjusted P = 0.103)].
Table 4 shows cardiac, stroke, and bleeding outcomes in patients with and without prior MI by treatment assignment and the MI by treatment interaction P values. Several interaction P values are <0.05, suggesting a differential treatment effect of rivaroxaban compared with warfarin in patients with prior MI. A reduction of all-cause mortality with rivaroxaban was observed in patients without prior MI, while this was not seen among patients with prior MI (interaction P = 0.0296). For major or NMCR bleeding and NMCR bleeding, excess bleeding with rivaroxaban was observed only among patients with prior MI (interaction P = 0.0352 and 0.0427, respectively). Consistent reductions in intracranial haemorrhage and fatal bleeding were observed with rivaroxaban in patients with and without prior MI.
The Kaplan–Meier curves for CV death, MI, and UA in patients with and without prior MI by treatment assignment are shown in Figure 2. A Kaplan–Meier plot that was adjusted for selected baseline characteristics is provided as Supplementary material online, Figure S1. After adjustment, there was some evidence that rivaroxaban vs. warfarin was more beneficial in preventing CV events in those without prior MI than in those with prior MI, but this was non-significant (HR among those without prior MI 0.79, 95% CI 0.65–0.96; HR among those with prior MI 1.06, 95% CI 0.82–1.36; interaction P = 0.075). The Kaplan–Meier curves for CV death, MI, and UA by treatment and by antiplatelet use at baseline are shown in Supplementary material online, Figure S2. Event rates tended to be higher for patients with aspirin or clopidogrel use at baseline and lowest in patients on neither at baseline, although the number of patients on clopidogrel at baseline was low. Supplementary material online, Figure S3, shows the principal safety outcome in the same subgroups. Similar trends are observed with the highest event rates in patients on both aspirin and clopidogrel at baseline.
(Enlarge Image)
Figure 2.
Cardiovascular death, myocardial infarction, and unstable angina in patients with and without prior myocardial infarction by treatment assignment.
Because aspirin and prior MI are likely strongly linked and concomitant use of aspirin and anticoagulant therapies are of particular clinical interest, the relationship between aspirin use and outcomes was modelled in two ways (Supplementary material online, Tables S2 and S3). The first model included all patients in the safety population and contained aspirin use at study entry. The second model was a 30-day landmark analysis with an indicator for aspirin use 30 days after randomization because the use of aspirin at baseline could have been altered because of inclusion in the study and initiation of anticoagulant therapy. The time point of 30 days was chosen because aspirin use should be consistent by this time. In both models, aspirin use was associated with higher event rates, but the treatment effect of rivaroxaban compared with warfarin did not differ depending on whether aspirin was used (interaction P values all >0.3).
Overall, a total of 227 MIs occurred while on study drug treatment for a median of 0.8 (0.4, 1.4) years following study drug initiation. The use of fibrinolytic therapy; use of percutaneous coronary intervention (PCI) within 2 h of the time of MI; and the use of antiplatelet, anticoagulant, and other cardiac medications are shown in Supplementary material online, Table S4. In total, 22 patients were treated with lytic therapy and none of these had intracranial hemorrhage within 5 days of lytic use. Few patients were treated with PCI. About half of the patients were treated with aspirin and the use of other cardiac medications was low. Overall, 84 patients had study drug permanently stopped within 5 days of MI, 74 had study drug temporarily stopped, and 69 remained on study drug through the MI event.
Supplementary material online, Table S5, shows aspirin and thienopyridine use at baseline and 30 days. Overall, 36.5% of patients were on aspirin at randomization and ~60% of those remained on aspirin at 30 days post-enrollment with a similar distribution between treatment groups. Few patients were on thienopyridine at baseline since use within 5 days of randomization was an exclusion criterion. A total of 126 (0.9%) patients were on both aspirin and a thienopyridine at randomization and 58 (0.4%) were on both at 30 days; these were protocol deviations since the use of a thienopyridine during the course of the study was only allowed for those receiving a coronary artery stent.
Supplementary material online, Table S6, shows the proportion of patients on antiplatelet therapy within the 30 days prior to MI or the principal safety endpoint (major or NMCR bleeding). Approximately 30% of patients were on aspirin or thienopyridine therapy prior to these events.
Results
Of the 14 264 patients enrolled in ROCKET AF, 2468 (17.3%) had prior MI at baseline. Table 1 shows the baseline demographics of patients with and without prior MI. Patients with prior MI tended to be older, male, and more often had risk factors for atherosclerosis and used antiplatelet agents. Among warfarin-treated patients with prior MI and those without prior MI, the median (25th, 75th percentiles) time the INR was in the therapeutic range (2.0–3.0, inclusive) was 59.1 (44.9, 71.5%) and 57.6 (42.6, 70.4%), respectively.
Stroke, cardiac, and bleeding outcomes are shown in Table 2 and Figure 1 for patients with and without prior MI. Patients with and without prior MI had similar rates of stroke and non-central nervous system embolism. Patients with prior MI had more recurrent CV events and higher mortality. These patients also had higher rates of major bleeding. After adjustment for differences in baseline characteristics, participants with prior MI remained at elevated risk for recurrent CV events (HR 1.64, 95% CI 1.21–2.24; P = 0.002) (Supplementary material online, Table S1).
(Enlarge Image)
Figure 1.
Clinical outcomes in patients with and without prior myocardial infarction.
Major bleeding rates in patients with and without baseline use of aspirin and/or a thienopyridine were 4.59 and 3.73 for patients with prior MI vs. 4.27 and 2.97 for patients without prior MI (interaction P value = 0.408).
Table 3 shows CV outcomes by randomly assigned treatment in the overall trial. Patients assigned to rivaroxaban tended to have lower rates of CV events with a non-significant 14% reduction in the hazard of CV death, MI, or UA [HR 0.86, 95% CI 0.73–1.00; P = 0.051 (adjusted HR 0.88, 95% CI 0.75–1.03; adjusted P = 0.103)].
Table 4 shows cardiac, stroke, and bleeding outcomes in patients with and without prior MI by treatment assignment and the MI by treatment interaction P values. Several interaction P values are <0.05, suggesting a differential treatment effect of rivaroxaban compared with warfarin in patients with prior MI. A reduction of all-cause mortality with rivaroxaban was observed in patients without prior MI, while this was not seen among patients with prior MI (interaction P = 0.0296). For major or NMCR bleeding and NMCR bleeding, excess bleeding with rivaroxaban was observed only among patients with prior MI (interaction P = 0.0352 and 0.0427, respectively). Consistent reductions in intracranial haemorrhage and fatal bleeding were observed with rivaroxaban in patients with and without prior MI.
The Kaplan–Meier curves for CV death, MI, and UA in patients with and without prior MI by treatment assignment are shown in Figure 2. A Kaplan–Meier plot that was adjusted for selected baseline characteristics is provided as Supplementary material online, Figure S1. After adjustment, there was some evidence that rivaroxaban vs. warfarin was more beneficial in preventing CV events in those without prior MI than in those with prior MI, but this was non-significant (HR among those without prior MI 0.79, 95% CI 0.65–0.96; HR among those with prior MI 1.06, 95% CI 0.82–1.36; interaction P = 0.075). The Kaplan–Meier curves for CV death, MI, and UA by treatment and by antiplatelet use at baseline are shown in Supplementary material online, Figure S2. Event rates tended to be higher for patients with aspirin or clopidogrel use at baseline and lowest in patients on neither at baseline, although the number of patients on clopidogrel at baseline was low. Supplementary material online, Figure S3, shows the principal safety outcome in the same subgroups. Similar trends are observed with the highest event rates in patients on both aspirin and clopidogrel at baseline.
(Enlarge Image)
Figure 2.
Cardiovascular death, myocardial infarction, and unstable angina in patients with and without prior myocardial infarction by treatment assignment.
Because aspirin and prior MI are likely strongly linked and concomitant use of aspirin and anticoagulant therapies are of particular clinical interest, the relationship between aspirin use and outcomes was modelled in two ways (Supplementary material online, Tables S2 and S3). The first model included all patients in the safety population and contained aspirin use at study entry. The second model was a 30-day landmark analysis with an indicator for aspirin use 30 days after randomization because the use of aspirin at baseline could have been altered because of inclusion in the study and initiation of anticoagulant therapy. The time point of 30 days was chosen because aspirin use should be consistent by this time. In both models, aspirin use was associated with higher event rates, but the treatment effect of rivaroxaban compared with warfarin did not differ depending on whether aspirin was used (interaction P values all >0.3).
Overall, a total of 227 MIs occurred while on study drug treatment for a median of 0.8 (0.4, 1.4) years following study drug initiation. The use of fibrinolytic therapy; use of percutaneous coronary intervention (PCI) within 2 h of the time of MI; and the use of antiplatelet, anticoagulant, and other cardiac medications are shown in Supplementary material online, Table S4. In total, 22 patients were treated with lytic therapy and none of these had intracranial hemorrhage within 5 days of lytic use. Few patients were treated with PCI. About half of the patients were treated with aspirin and the use of other cardiac medications was low. Overall, 84 patients had study drug permanently stopped within 5 days of MI, 74 had study drug temporarily stopped, and 69 remained on study drug through the MI event.
Supplementary material online, Table S5, shows aspirin and thienopyridine use at baseline and 30 days. Overall, 36.5% of patients were on aspirin at randomization and ~60% of those remained on aspirin at 30 days post-enrollment with a similar distribution between treatment groups. Few patients were on thienopyridine at baseline since use within 5 days of randomization was an exclusion criterion. A total of 126 (0.9%) patients were on both aspirin and a thienopyridine at randomization and 58 (0.4%) were on both at 30 days; these were protocol deviations since the use of a thienopyridine during the course of the study was only allowed for those receiving a coronary artery stent.
Supplementary material online, Table S6, shows the proportion of patients on antiplatelet therapy within the 30 days prior to MI or the principal safety endpoint (major or NMCR bleeding). Approximately 30% of patients were on aspirin or thienopyridine therapy prior to these events.
