Outcomes of Apixaban vs Warfarin by Type of AF
Outcomes of Apixaban vs Warfarin by Type of AF
At study entry, 2786 (15.3%) patients had paroxysmal AF and 15 412 (84.7%) had persistent or permanent AF. The median duration of AF prior to study entry for the overall population was 840 days (25th, 75th percentiles: 140, 2269); 489 (145, 1721) for patients with paroxysmal AF, and 914 (139, 2372) for patients with persistent or permanent AF. The baseline characteristics by type of AF are presented in Table 1. New onset AF within 14 days before randomization was present in 31 (1.1%) patients with paroxysmal AF and 824 (5.4%) patients with persistent or permanent AF. Compared with patients with paroxysmal AF, those with persistent or permanent AF were older and were less often women, more often had a history of heart failure and a higher CHADS2 score, and less often had a history of prior myocardial infarction, hypertension, and vascular disease. There was a trend towards a higher rate of prior stroke, TIA, or systemic embolism among patients with paroxysmal AF. Prior clinically relevant or spontaneous bleeding was evenly distributed between the two groups.
Of patients with paroxysmal AF, 1347 (7.55%) were randomized to apixaban and 1412 (7.76%) to warfarin. Of patients with persistent or permanent AF, 7744 (42.55%) were randomized to apixaban and 7668 (42.14%) to warfarin. Of patients with paroxysmal AF, 47.9% were vitamin K antagonist-naïve vs. 41.9% of patients with persistent or permanent AF. In the warfarin group, patients with paroxysmal AF had a mean TTR of 61.7 and a median TTR of 65.0 and patients with persistent or permanent AF had a mean TTR of 62.3 and a median TTR of 66.0 during the trial (P-value for difference of means = 0.30).
Table 1 shows medications and procedures by type of AF at baseline. Compared with patients with paroxysmal AF, those with persistent or permanent AF less often received amiodarone, any antiarrhythmic medication, aspirin, clopidogrel, and statins. Patients with persistent or permanent AF more often received a beta-blocker, digoxin, and warfarin. The use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a calcium channel blocker was evenly distributed between the two groups. Patients with paroxysmal AF more often had a prior history of electrical cardioversion and AF ablation. During the follow-up, 627 (22.5%) patients with paroxysmal AF were managed with rhythm control and 2158 (77.5%) were managed with rate control. Of patients with persistent or permanent AF, 1020 (6.6%) were managed with rhythm control and 14 391 (93.4%) were managed with rate control.
As shown in Figure 1, there was a consistent reduction in stroke or systemic embolism (P for interaction 0.71), all-cause mortality (P for interaction 0.75), and major bleeding (P for interaction 0.50) with apixaban compared with warfarin for both types of AF. Longer duration of AF was associated with a piecewise linear reduction in the risk of death [P-value for death <0.001; HR: 0.83, 95% CI (0.76, 0.90) per 1 year increase in duration between 0–2 years; HR: 1.01, 95% CI (0.99, 1.04) beyond 2 years]. There was no association between AF duration and any other endpoint. This association was sustained after controlling for age (P-value <0.001). The benefit from apixaban was consistent compared with warfarin in all of the studied endpoints, regardless of the duration of AF at study entry (P-value for all interactions >0.13).
(Enlarge Image)
Figure 1.
Outcomes by type of atrial fibrillation and study treatment.
As shown in Table 2 and Figure 2, the rates of stroke or systemic embolism, all-cause mortality, and the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding were significantly lower in patients with paroxysmal AF than patients with persistent or permanent AF [HR: 0.65, 95% CI (0.48, 0.87), P = 0.003; HR: 0.72, (95% CI 0.61, 0.85), P = 0.0002; HR: 0.77, (95% CI: 0.68, 0.87), P < 0.0001, respectively]. There was also a trend towards a lower risk of major bleeding in the paroxysmal AF group [HR: 0.83, 95% CI (0.68, 1.02), P = 0.078]. Adjusting for potential confounders, the risk of stroke or systemic embolism was still significantly lower for paroxysmal AF than for persistent or permanent AF [HR: 0.70, 95% CI (0.51, 0.93), P = 0.015]. There was a trend towards a higher risk of all-cause mortality and the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding in patients with persistent or permanent AF (P = 0.066 and P = 0.068, respectively).
(Enlarge Image)
Figure 2.
Outcomes by type of atrial fibrillation. (A) Stroke or systemic embolism. (B) Major bleeding, (C) All-cause mortality (D) the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding.
The majority of patients had data entered on ≤2 ECGs during the follow-up; 10 696 (69.4%) in the persistent or permanent AF group and 1877 (67.4%) in the paroxysmal AF group. The proportion of patients with AF on all subsequent ECGs was 81.6% in the persistent or permanent AF group and 17.5% in the paroxysmal AF group (P < 0.0001). The proportion of patients in AF at the 1-year ECG was 87.8% in the persistent or permanent AF group vs. 23.6% on the paroxysmal AF group (P < 0.0001). Of patients with paroxysmal AF at study entry, 700 (30.9%) had AF on their last trial ECG; and of patients with persistent or permanent AF at study entry, 10 733 (87.3%) had AF on their last trial ECG.
Results
Baseline Characteristics
At study entry, 2786 (15.3%) patients had paroxysmal AF and 15 412 (84.7%) had persistent or permanent AF. The median duration of AF prior to study entry for the overall population was 840 days (25th, 75th percentiles: 140, 2269); 489 (145, 1721) for patients with paroxysmal AF, and 914 (139, 2372) for patients with persistent or permanent AF. The baseline characteristics by type of AF are presented in Table 1. New onset AF within 14 days before randomization was present in 31 (1.1%) patients with paroxysmal AF and 824 (5.4%) patients with persistent or permanent AF. Compared with patients with paroxysmal AF, those with persistent or permanent AF were older and were less often women, more often had a history of heart failure and a higher CHADS2 score, and less often had a history of prior myocardial infarction, hypertension, and vascular disease. There was a trend towards a higher rate of prior stroke, TIA, or systemic embolism among patients with paroxysmal AF. Prior clinically relevant or spontaneous bleeding was evenly distributed between the two groups.
Treatment
Of patients with paroxysmal AF, 1347 (7.55%) were randomized to apixaban and 1412 (7.76%) to warfarin. Of patients with persistent or permanent AF, 7744 (42.55%) were randomized to apixaban and 7668 (42.14%) to warfarin. Of patients with paroxysmal AF, 47.9% were vitamin K antagonist-naïve vs. 41.9% of patients with persistent or permanent AF. In the warfarin group, patients with paroxysmal AF had a mean TTR of 61.7 and a median TTR of 65.0 and patients with persistent or permanent AF had a mean TTR of 62.3 and a median TTR of 66.0 during the trial (P-value for difference of means = 0.30).
Table 1 shows medications and procedures by type of AF at baseline. Compared with patients with paroxysmal AF, those with persistent or permanent AF less often received amiodarone, any antiarrhythmic medication, aspirin, clopidogrel, and statins. Patients with persistent or permanent AF more often received a beta-blocker, digoxin, and warfarin. The use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a calcium channel blocker was evenly distributed between the two groups. Patients with paroxysmal AF more often had a prior history of electrical cardioversion and AF ablation. During the follow-up, 627 (22.5%) patients with paroxysmal AF were managed with rhythm control and 2158 (77.5%) were managed with rate control. Of patients with persistent or permanent AF, 1020 (6.6%) were managed with rhythm control and 14 391 (93.4%) were managed with rate control.
Outcomes
As shown in Figure 1, there was a consistent reduction in stroke or systemic embolism (P for interaction 0.71), all-cause mortality (P for interaction 0.75), and major bleeding (P for interaction 0.50) with apixaban compared with warfarin for both types of AF. Longer duration of AF was associated with a piecewise linear reduction in the risk of death [P-value for death <0.001; HR: 0.83, 95% CI (0.76, 0.90) per 1 year increase in duration between 0–2 years; HR: 1.01, 95% CI (0.99, 1.04) beyond 2 years]. There was no association between AF duration and any other endpoint. This association was sustained after controlling for age (P-value <0.001). The benefit from apixaban was consistent compared with warfarin in all of the studied endpoints, regardless of the duration of AF at study entry (P-value for all interactions >0.13).
(Enlarge Image)
Figure 1.
Outcomes by type of atrial fibrillation and study treatment.
As shown in Table 2 and Figure 2, the rates of stroke or systemic embolism, all-cause mortality, and the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding were significantly lower in patients with paroxysmal AF than patients with persistent or permanent AF [HR: 0.65, 95% CI (0.48, 0.87), P = 0.003; HR: 0.72, (95% CI 0.61, 0.85), P = 0.0002; HR: 0.77, (95% CI: 0.68, 0.87), P < 0.0001, respectively]. There was also a trend towards a lower risk of major bleeding in the paroxysmal AF group [HR: 0.83, 95% CI (0.68, 1.02), P = 0.078]. Adjusting for potential confounders, the risk of stroke or systemic embolism was still significantly lower for paroxysmal AF than for persistent or permanent AF [HR: 0.70, 95% CI (0.51, 0.93), P = 0.015]. There was a trend towards a higher risk of all-cause mortality and the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding in patients with persistent or permanent AF (P = 0.066 and P = 0.068, respectively).
(Enlarge Image)
Figure 2.
Outcomes by type of atrial fibrillation. (A) Stroke or systemic embolism. (B) Major bleeding, (C) All-cause mortality (D) the composite endpoint of stroke or systemic embolism, all-cause mortality, and major bleeding.
Follow-up Electrocardiogram Data
The majority of patients had data entered on ≤2 ECGs during the follow-up; 10 696 (69.4%) in the persistent or permanent AF group and 1877 (67.4%) in the paroxysmal AF group. The proportion of patients with AF on all subsequent ECGs was 81.6% in the persistent or permanent AF group and 17.5% in the paroxysmal AF group (P < 0.0001). The proportion of patients in AF at the 1-year ECG was 87.8% in the persistent or permanent AF group vs. 23.6% on the paroxysmal AF group (P < 0.0001). Of patients with paroxysmal AF at study entry, 700 (30.9%) had AF on their last trial ECG; and of patients with persistent or permanent AF at study entry, 10 733 (87.3%) had AF on their last trial ECG.
