Risk of Death and Stroke in Persistent vs Paroxysmal AF
Risk of Death and Stroke in Persistent vs Paroxysmal AF
Of the 14 264 patients randomized in the ROCKET-AF trial, a sizable minority (18%) had paroxysmal AF at baseline. While patients with persistent AF had some higher-risk features, compared with those with paroxysmal AF, CHADS2 and CHA2DS2-VASc scores were equivalent. After adjustment, thrombo-embolic and mortality outcomes were consistently higher in patients with persistent AF, and this association endured across high-risk subgroups (including patients with prior stroke). There did not appear to be significant differences in event rates between rivaroxaban and dose-adjusted warfarin, across AF type.
Several prior cohorts have suggested no difference in outcomes between patients with paroxysmal or persistent AF. However, there are important distinctions of these studies. For example, in the GISSI-AF post hoc analysis, a total of 1234 patients were studied, and antithrombotic rates varied significantly between paroxysmal and persistent (76 vs. 96%, P < 0.0001). Furthermore, mean CHADS2 scores were dramatically lower compared with those in ROCKET-AF (1.4 vs. 3.5). Similarly, a post hoc analysis of the ACTIVE-W trial included patients with mean CHADS2 scores of 1.8–2.0; and while anticoagulation was not uniform by design, there were imbalances of the randomization scheme between paroxysmal and persistent AF patients (65% warfarin for paroxysmal vs. 85% for sustained AF, P < 0.0001). Lastly, in an analysis of 5533 patients in the Euro Heart Survey, the authors identified dramatic differences in the use of oral anticoagulation rates across several AF types (ranging from 45 to 79%, P < 0.001), and highly dynamic subsequent management in these patients. Overall, these studies have been significantly smaller than the present analysis (limiting their relative power); they frequently have lower risk and more heterogeneous populations (confounding comparisons); and most importantly, none of these previously reported analyses included consistently anticoagulated patients. The use of anticoagulation in all patients likely had a significant impact on our findings, as historical stroke/TIA events and anticoagulation use trended in opposite directions in paroxysmal AF patients in our cohort—they were less likely to be previously exposed to anticoagulation but more likely to have had prior stroke or TIA. Following uniform anticoagulation between the groups (at randomization), our data demonstrate that patients with persistent AF have worse outcomes, including thrombo-embolic events and mortality.
Our findings extend observations from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) and Apixaban for Reduction in Stroke and Other Thrombo-embolic Events in Atrial Fibrillation (ARISTOTLE) trials—patients enrolled in ROCKET-AF had substantially higher CHADS2 scores than either of those trials (mean 3.5 in ROCKET-AF vs. 2.1 in RE-LY and ARISTOTLE). In our analysis, CHADS2 scores, CHA2DS2-VASc scores, and the intensity of anticoagulation were all balanced between patients with paroxysmal AF and those with persistent AF. Even in patients at such high stroke risk, those with persistent AF still demonstrated worse survival and higher risk of thrombo-embolic events. Furthermore, the effect on mortality appears to be a sustained phenomenon, as event curves continue to separate out to 2.5 years of follow-up.
These data provide important insights into the risks associated with more advanced forms of AF (i.e. those with persistent AF). While the risk of stroke has been clear and remains present in patients with paroxysmal AF, it was not clear that outcomes are worse in patients with persistent AF once stroke risk is treated with oral anticoagulation. Our data demonstrate that, in the setting of adequate anticoagulation with either dose-adjusted warfarin or rivaroxaban, persistent AF is associated with worse outcomes, and this finding has important implications for overall AF treatment strategies aimed at improving outcomes, including survival. It suggests that the worse outcomes associated with advanced AF are unlikely to be attributable to stroke risk alone, and may instead be related to electromechanical or haemodynamic sequelae of the rhythm. Notable prior studies have failed to demonstrate a substantive survival benefit to maintaining sinus rhythm; however, several concerns have been raised with these data and they were not specific to advanced AF. Our analysis suggests there is an opportunity for improving outcomes of patients with advanced AF, potentially through disease-state modification. Rhythm control strategies such as catheter ablation have been shown to slow progression, and may provide an opportunity to improve clinical outcomes. There is also emerging evidence supporting the use of such procedures in patients with persistent AF. However, strategies such as risk factor modification may also provide additional opportunities to slow the disease progression.
The lower risk of thrombo-embolic events and death in patients with paroxysmal AF, compared with persistent AF, was particularly pronounced in two subgroups—patients with the diagnosis of AF >6 months prior to baseline, and those with rhythms other than AF or atrial flutter on baseline ECG (Pinteraction <0.05 for each). While these remain hypothesis-generating results only, there are potential explanations that deserve further study. The effect of AF duration may reflect diagnostic biases in patients with more recent diagnoses, but both AF duration and ECG rhythm may also reflect measures of burden of AF arrhythmia. Patients not in AF or atrial flutter at baseline represent those with AF less likely to be captured on any single ECG. Burden of AF has been an intensely studied topic, and one of great debate. The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) study suggested as little as 6 min of AF increased stroke risk, and additional studies have demonstrated some dose–response effect—that is, more AF portends worse thrombo-embolic outcomes. Yet to date, neither AF type nor AF burden is included in guideline-recommended risk stratification for thrombo-embolism prophylaxis. This is likely due in part to the difficulties of defining and measuring paroxysmal episodes of AF, and additional studies of the implications of AF burden for treatment decisions are required. However, patients with paroxysmal AF remain at significant risk of stroke, relative to patients without AF, and current evidence does not support withholding anticoagulation in these patients. In contrast, our data suggest that the use of more aggressive stroke prevention in patients with persistent AF, who are otherwise at lower risk, deserves further study.
The treatment effects of rivaroxaban vs. adjusted-dose warfarin were not different between patients with paroxysmal vs. persistent AF. This finding is consistent with prior data, suggesting both groups benefit from oral anticoagulation, particularly among patients at high risk of stroke at baseline. However, those patients at the highest risk of adverse outcome often derive the greatest benefit from aggressive therapies; in our analysis, patients with persistent AF were at substantially higher risk of thrombo-embolic events and death. This may explain, in part, the variance in the hazards of rivaroxaban vs. dose-adjusted warfarin by AF type. However, none of the differences was statistically significant and wider confidence intervals indicate relatively under-powered assessments.
The current study represents a post hoc analysis of the ROCKET-AF trial, and is largely hypothesis generating. The classification of AF type was made at the site level at baseline and there may be variation (despite pre-specified definitions) or changes in AF type or burden over time that are not captured. Additionally, patients with paroxysmal AF represented a minority of the overall cohort, and power to detect differences in outcomes by treatment may be limited relative to the overall trial population. This is particularly pronounced for patients with low CHA2DS2-VASc scores—low numbers of patients and events limits additional analyses at this low-risk end of the spectrum. Furthermore, although treatment assignment was balanced and multivariable adjustment was performed, we cannot exclude significant, unmeasured confounding in the comparison between paroxysmal and persistent AF patients. Lastly, generalizability may be limited: these data are derived from a randomized trial population; few warfarin-treated patients had TTR >70%; and patients were generally of high stroke risk.
Discussion
Of the 14 264 patients randomized in the ROCKET-AF trial, a sizable minority (18%) had paroxysmal AF at baseline. While patients with persistent AF had some higher-risk features, compared with those with paroxysmal AF, CHADS2 and CHA2DS2-VASc scores were equivalent. After adjustment, thrombo-embolic and mortality outcomes were consistently higher in patients with persistent AF, and this association endured across high-risk subgroups (including patients with prior stroke). There did not appear to be significant differences in event rates between rivaroxaban and dose-adjusted warfarin, across AF type.
Several prior cohorts have suggested no difference in outcomes between patients with paroxysmal or persistent AF. However, there are important distinctions of these studies. For example, in the GISSI-AF post hoc analysis, a total of 1234 patients were studied, and antithrombotic rates varied significantly between paroxysmal and persistent (76 vs. 96%, P < 0.0001). Furthermore, mean CHADS2 scores were dramatically lower compared with those in ROCKET-AF (1.4 vs. 3.5). Similarly, a post hoc analysis of the ACTIVE-W trial included patients with mean CHADS2 scores of 1.8–2.0; and while anticoagulation was not uniform by design, there were imbalances of the randomization scheme between paroxysmal and persistent AF patients (65% warfarin for paroxysmal vs. 85% for sustained AF, P < 0.0001). Lastly, in an analysis of 5533 patients in the Euro Heart Survey, the authors identified dramatic differences in the use of oral anticoagulation rates across several AF types (ranging from 45 to 79%, P < 0.001), and highly dynamic subsequent management in these patients. Overall, these studies have been significantly smaller than the present analysis (limiting their relative power); they frequently have lower risk and more heterogeneous populations (confounding comparisons); and most importantly, none of these previously reported analyses included consistently anticoagulated patients. The use of anticoagulation in all patients likely had a significant impact on our findings, as historical stroke/TIA events and anticoagulation use trended in opposite directions in paroxysmal AF patients in our cohort—they were less likely to be previously exposed to anticoagulation but more likely to have had prior stroke or TIA. Following uniform anticoagulation between the groups (at randomization), our data demonstrate that patients with persistent AF have worse outcomes, including thrombo-embolic events and mortality.
Our findings extend observations from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) and Apixaban for Reduction in Stroke and Other Thrombo-embolic Events in Atrial Fibrillation (ARISTOTLE) trials—patients enrolled in ROCKET-AF had substantially higher CHADS2 scores than either of those trials (mean 3.5 in ROCKET-AF vs. 2.1 in RE-LY and ARISTOTLE). In our analysis, CHADS2 scores, CHA2DS2-VASc scores, and the intensity of anticoagulation were all balanced between patients with paroxysmal AF and those with persistent AF. Even in patients at such high stroke risk, those with persistent AF still demonstrated worse survival and higher risk of thrombo-embolic events. Furthermore, the effect on mortality appears to be a sustained phenomenon, as event curves continue to separate out to 2.5 years of follow-up.
These data provide important insights into the risks associated with more advanced forms of AF (i.e. those with persistent AF). While the risk of stroke has been clear and remains present in patients with paroxysmal AF, it was not clear that outcomes are worse in patients with persistent AF once stroke risk is treated with oral anticoagulation. Our data demonstrate that, in the setting of adequate anticoagulation with either dose-adjusted warfarin or rivaroxaban, persistent AF is associated with worse outcomes, and this finding has important implications for overall AF treatment strategies aimed at improving outcomes, including survival. It suggests that the worse outcomes associated with advanced AF are unlikely to be attributable to stroke risk alone, and may instead be related to electromechanical or haemodynamic sequelae of the rhythm. Notable prior studies have failed to demonstrate a substantive survival benefit to maintaining sinus rhythm; however, several concerns have been raised with these data and they were not specific to advanced AF. Our analysis suggests there is an opportunity for improving outcomes of patients with advanced AF, potentially through disease-state modification. Rhythm control strategies such as catheter ablation have been shown to slow progression, and may provide an opportunity to improve clinical outcomes. There is also emerging evidence supporting the use of such procedures in patients with persistent AF. However, strategies such as risk factor modification may also provide additional opportunities to slow the disease progression.
The lower risk of thrombo-embolic events and death in patients with paroxysmal AF, compared with persistent AF, was particularly pronounced in two subgroups—patients with the diagnosis of AF >6 months prior to baseline, and those with rhythms other than AF or atrial flutter on baseline ECG (Pinteraction <0.05 for each). While these remain hypothesis-generating results only, there are potential explanations that deserve further study. The effect of AF duration may reflect diagnostic biases in patients with more recent diagnoses, but both AF duration and ECG rhythm may also reflect measures of burden of AF arrhythmia. Patients not in AF or atrial flutter at baseline represent those with AF less likely to be captured on any single ECG. Burden of AF has been an intensely studied topic, and one of great debate. The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) study suggested as little as 6 min of AF increased stroke risk, and additional studies have demonstrated some dose–response effect—that is, more AF portends worse thrombo-embolic outcomes. Yet to date, neither AF type nor AF burden is included in guideline-recommended risk stratification for thrombo-embolism prophylaxis. This is likely due in part to the difficulties of defining and measuring paroxysmal episodes of AF, and additional studies of the implications of AF burden for treatment decisions are required. However, patients with paroxysmal AF remain at significant risk of stroke, relative to patients without AF, and current evidence does not support withholding anticoagulation in these patients. In contrast, our data suggest that the use of more aggressive stroke prevention in patients with persistent AF, who are otherwise at lower risk, deserves further study.
The treatment effects of rivaroxaban vs. adjusted-dose warfarin were not different between patients with paroxysmal vs. persistent AF. This finding is consistent with prior data, suggesting both groups benefit from oral anticoagulation, particularly among patients at high risk of stroke at baseline. However, those patients at the highest risk of adverse outcome often derive the greatest benefit from aggressive therapies; in our analysis, patients with persistent AF were at substantially higher risk of thrombo-embolic events and death. This may explain, in part, the variance in the hazards of rivaroxaban vs. dose-adjusted warfarin by AF type. However, none of the differences was statistically significant and wider confidence intervals indicate relatively under-powered assessments.
Limitations
The current study represents a post hoc analysis of the ROCKET-AF trial, and is largely hypothesis generating. The classification of AF type was made at the site level at baseline and there may be variation (despite pre-specified definitions) or changes in AF type or burden over time that are not captured. Additionally, patients with paroxysmal AF represented a minority of the overall cohort, and power to detect differences in outcomes by treatment may be limited relative to the overall trial population. This is particularly pronounced for patients with low CHA2DS2-VASc scores—low numbers of patients and events limits additional analyses at this low-risk end of the spectrum. Furthermore, although treatment assignment was balanced and multivariable adjustment was performed, we cannot exclude significant, unmeasured confounding in the comparison between paroxysmal and persistent AF patients. Lastly, generalizability may be limited: these data are derived from a randomized trial population; few warfarin-treated patients had TTR >70%; and patients were generally of high stroke risk.
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