Risk of Death and Stroke in Persistent vs Paroxysmal AF
Risk of Death and Stroke in Persistent vs Paroxysmal AF
Characteristics of the patients, stratified by AF type at baseline, are shown in Table 1. Treatment assignment was balanced across AF types. Compared with patients with persistent AF at baseline, those with paroxysmal AF were slightly younger (median age 72 vs. 73 years, P = 0.03), more likely female (45 vs. 39%, P < 0.0001), with lower baseline heart rate (median 72 vs. 76 beats/min, P < 0.0001), and lower rates of diabetes (37 vs. 41%, P = 0.0003) and CHF (56 vs. 64%, P < 0.0001). However, mean CHADS2 (3.5 for each, P = 0.3) and CHA2DS2-VASc (4.9, P = 0.07) scores were both balanced between patients with paroxysmal and persistent AF, and rates of prior thrombo-embolic evens were higher in patients with paroxysmal AF (prior stroke, TIA, or systemic embolism 59 vs. 54%, P < 0.0001). There were also differences in prior vitamin K antagonist therapy (paroxysmal, 56 vs. 64% for persistent, P < 0.0001) and prior chronic aspirin use (paroxysmal, 41 vs. 35% for persistent, P < 0.0001).
There was no imbalance in allocation to rivaroxaban or warfarin by AF type; half of patients with paroxysmal and persistent AF were randomized to rivaroxaban and half were randomized to warfarin.
During the follow-up of patients allocated to warfarin, the TTR was similar between patients with paroxysmal and persistent AF (57 vs. 58%, P = 0.94).
Use of aspirin during the follow-up was balanced between patients with paroxysmal AF (21%) and those with persistent AF (20%). The mean duration of aspirin use during the trial was 19 months in both, and the mean dose was 90 mg for those with paroxysmal AF and 88 mg for those with persistent AF. Electrical cardioversion was performed infrequently–144 in total. There were 58 (2.3%) in the paroxysmal AF group and 86 (0.7%) in the persistent AF group.
Adjusted efficacy and safety outcomes, by AF type, are shown in Table 2. Patients with paroxysmal AF had significantly lower rates of stroke (adjusted HR: 0.78, 95% CI: 0.61–0.99, P = 0.045), all-cause mortality (adjusted HR: 0.79, 95% CI: 0.67–0.94, P = 0.006), and the composite of stroke or systemic embolism or death (adjusted HR: 0.82, 95% CI: 0.71–0.94, P = 0.005). Kaplan–Meier curves for all-cause mortality, stratified by AF type, are shown in Figure 1.
(Enlarge Image)
Figure 1.
Unadjusted Kaplan–Meier event curves for all-cause mortality, by atrial fibrillation type at baseline. AF, atrial fibrillation, HR, hazard ratio; CI, confidence interval.
The results were consistent throughout follow-up. Among patients with paroxysmal AF, there was not any initial greater excess of stroke or systemic embolism during the first month after randomization that could have been attributed to a lower prevalence of anticoagulation by VKA prior to randomization (Figure 1).
Lower hazards for patients with paroxysmal AF were consistent across subgroups of the CHADS2 score, CHF diagnosis, presence of chronic kidney disease, and history of stroke, for the composite end-point of stroke, systemic embolism, or death (Figure 2 and Supplementary material online http://eurheartj.oxfordjournals.org/content/suppl/2014/09/10/ehu359.DC1). There was a significant interaction between AF type and (a) baseline rhythm (AF/atrial flutter vs. sinus/other, Pinteraction = 0.02), and (b) duration of AF diagnosis (≤6 vs. >6 months, Pinteraction = 0.02).
(Enlarge Image)
Figure 2.
Forest plot of the composite end-point of stroke, systemic embolism, or death for paroxysmal vs. persistent atrial fibrillation, stratified by high-risk subgroups. All strata assessed at baseline. AF, atrial fibrillation; AFL, atrial flutter; CHF, congestive heart failure; CKD, chronic kidney disease; ECG, electrocardiogram; SE, systemic embolism.
Adjusted outcomes comparing rivaroxaban vs. warfarin-assigned patients, stratified by AF type, are shown in Table 3. Corresponding Kaplan–Meier curves of the primary end-point, for each of the four groups, are shown in Figure 3. The relative treatment effects of rivaroxaban vs. warfarin were consistent among patients with persistent AF and paroxysmal AF. The number of stroke or systemic embolism events per 100 patient-years in those treated with rivaroxaban compared with warfarin was consistent among patients with paroxysmal AF (1.73% rivaroxaban vs. 1.74% warfarin; adjusted HR: 1.00, 95% CI: 0.65–1.53) and persistent AF (2.03 vs. 2.32%; adjusted HR: 0.88, 0.74–1.06, Pinteraction = 0.60). The number of major bleeding events per 100 patient-years in those treated with rivaroxaban compared with warfarin was consistent among patients with paroxysmal AF (3.43% rivaroxaban vs. 3.19% warfarin; adjusted HR: 1.06, 95% CI: 0.75–1.49) and persistent AF (3.61 vs. 3.49%; adjusted HR: 1.08, 0.92–1.26, Pinteraction = 0.94). All tests of interaction between treatment assignment and AF type were non-significant (Supplementary material online http://eurheartj.oxfordjournals.org/content/suppl/2014/09/10/ehu359.DC1).
(Enlarge Image)
Figure 3.
Unadjusted Kaplan–Meier event curves for stroke or systemic embolism, by atrial fibrillation type and treatment assignment. AF, atrial fibrillation; HR, hazard ratio, CI, confidence interval.
Results
Patient Characteristics
Characteristics of the patients, stratified by AF type at baseline, are shown in Table 1. Treatment assignment was balanced across AF types. Compared with patients with persistent AF at baseline, those with paroxysmal AF were slightly younger (median age 72 vs. 73 years, P = 0.03), more likely female (45 vs. 39%, P < 0.0001), with lower baseline heart rate (median 72 vs. 76 beats/min, P < 0.0001), and lower rates of diabetes (37 vs. 41%, P = 0.0003) and CHF (56 vs. 64%, P < 0.0001). However, mean CHADS2 (3.5 for each, P = 0.3) and CHA2DS2-VASc (4.9, P = 0.07) scores were both balanced between patients with paroxysmal and persistent AF, and rates of prior thrombo-embolic evens were higher in patients with paroxysmal AF (prior stroke, TIA, or systemic embolism 59 vs. 54%, P < 0.0001). There were also differences in prior vitamin K antagonist therapy (paroxysmal, 56 vs. 64% for persistent, P < 0.0001) and prior chronic aspirin use (paroxysmal, 41 vs. 35% for persistent, P < 0.0001).
Treatments During the Follow-up
There was no imbalance in allocation to rivaroxaban or warfarin by AF type; half of patients with paroxysmal and persistent AF were randomized to rivaroxaban and half were randomized to warfarin.
During the follow-up of patients allocated to warfarin, the TTR was similar between patients with paroxysmal and persistent AF (57 vs. 58%, P = 0.94).
Use of aspirin during the follow-up was balanced between patients with paroxysmal AF (21%) and those with persistent AF (20%). The mean duration of aspirin use during the trial was 19 months in both, and the mean dose was 90 mg for those with paroxysmal AF and 88 mg for those with persistent AF. Electrical cardioversion was performed infrequently–144 in total. There were 58 (2.3%) in the paroxysmal AF group and 86 (0.7%) in the persistent AF group.
Outcomes by Atrial Fibrillation Type
Adjusted efficacy and safety outcomes, by AF type, are shown in Table 2. Patients with paroxysmal AF had significantly lower rates of stroke (adjusted HR: 0.78, 95% CI: 0.61–0.99, P = 0.045), all-cause mortality (adjusted HR: 0.79, 95% CI: 0.67–0.94, P = 0.006), and the composite of stroke or systemic embolism or death (adjusted HR: 0.82, 95% CI: 0.71–0.94, P = 0.005). Kaplan–Meier curves for all-cause mortality, stratified by AF type, are shown in Figure 1.
(Enlarge Image)
Figure 1.
Unadjusted Kaplan–Meier event curves for all-cause mortality, by atrial fibrillation type at baseline. AF, atrial fibrillation, HR, hazard ratio; CI, confidence interval.
The results were consistent throughout follow-up. Among patients with paroxysmal AF, there was not any initial greater excess of stroke or systemic embolism during the first month after randomization that could have been attributed to a lower prevalence of anticoagulation by VKA prior to randomization (Figure 1).
Lower hazards for patients with paroxysmal AF were consistent across subgroups of the CHADS2 score, CHF diagnosis, presence of chronic kidney disease, and history of stroke, for the composite end-point of stroke, systemic embolism, or death (Figure 2 and Supplementary material online http://eurheartj.oxfordjournals.org/content/suppl/2014/09/10/ehu359.DC1). There was a significant interaction between AF type and (a) baseline rhythm (AF/atrial flutter vs. sinus/other, Pinteraction = 0.02), and (b) duration of AF diagnosis (≤6 vs. >6 months, Pinteraction = 0.02).
(Enlarge Image)
Figure 2.
Forest plot of the composite end-point of stroke, systemic embolism, or death for paroxysmal vs. persistent atrial fibrillation, stratified by high-risk subgroups. All strata assessed at baseline. AF, atrial fibrillation; AFL, atrial flutter; CHF, congestive heart failure; CKD, chronic kidney disease; ECG, electrocardiogram; SE, systemic embolism.
Outcomes by Treatment Assignment
Adjusted outcomes comparing rivaroxaban vs. warfarin-assigned patients, stratified by AF type, are shown in Table 3. Corresponding Kaplan–Meier curves of the primary end-point, for each of the four groups, are shown in Figure 3. The relative treatment effects of rivaroxaban vs. warfarin were consistent among patients with persistent AF and paroxysmal AF. The number of stroke or systemic embolism events per 100 patient-years in those treated with rivaroxaban compared with warfarin was consistent among patients with paroxysmal AF (1.73% rivaroxaban vs. 1.74% warfarin; adjusted HR: 1.00, 95% CI: 0.65–1.53) and persistent AF (2.03 vs. 2.32%; adjusted HR: 0.88, 0.74–1.06, Pinteraction = 0.60). The number of major bleeding events per 100 patient-years in those treated with rivaroxaban compared with warfarin was consistent among patients with paroxysmal AF (3.43% rivaroxaban vs. 3.19% warfarin; adjusted HR: 1.06, 95% CI: 0.75–1.49) and persistent AF (3.61 vs. 3.49%; adjusted HR: 1.08, 0.92–1.26, Pinteraction = 0.94). All tests of interaction between treatment assignment and AF type were non-significant (Supplementary material online http://eurheartj.oxfordjournals.org/content/suppl/2014/09/10/ehu359.DC1).
(Enlarge Image)
Figure 3.
Unadjusted Kaplan–Meier event curves for stroke or systemic embolism, by atrial fibrillation type and treatment assignment. AF, atrial fibrillation; HR, hazard ratio, CI, confidence interval.