Stroke Risk Lower for Paroxysmal vs Persistent or Permanent AF: ENGAGE AF-TIMI 48

Marlene Busko

January 23, 2017

DALLAS, TX — Patients who had paroxysmal atrial fibrillation (AF) had a significantly lower risk of stroke/systemic embolic event (SEE; the primary outcome) as well as all-cause death over a median 2.8-year follow-up than patients with persistent or permanent AF, in a new study[1].

These findings from a prespecified analysis of the ENGAGE AF-TIMI 48 trial were published online January 11, 2017 in Circulation: Arrhythmia and Electrophysiology.

This study adds "marked evidence" that individuals with paroxysmal AF have a lower risk of stroke and 3-year mortality than patients with persistent or permanent AF, lead author Dr Mark S Link (UT Southwestern Medical Center, Dallas), told heartwire from Medscape. The Kaplan Meir curves for outcomes were "very convincing" and showed a clear, early separation for outcomes with paroxysmal AF vs nonparoxysmal AF that continued to widen over time.

Dr Mark S Link

The study also showed that the benefits of edoxaban vs warfarin were preserved even for paroxysmal AF, "so it still dropped the risk of stroke relative to warfarin," he added.

This was the largest novel oral anticoagulant (NOAC) trial with the longest follow-up and hundreds of outcomes and provides important information, Drs Stefan H Hohnloser and Mate Vamos (JW Goethe University, Frankfurt, Germany) write in an accompanying editorial[2]. It showed that paroxysmal AF was associated with a lower risk of stroke and all-cause mortality, and edoxaban had the same efficacy and safety in patients with different types of AF.

While two studies that should shed light on the shortest duration of AF that warrants anticoagulation therapy are still ongoing, this and other studies still suggest that "subjects with clinically documented paroxysmal AF should receive anticoagulation treatment, preferably with a NOAC, similar to subjects with persistent or permanent AF," they conclude.

"When you are sitting with a patient and discussing anticoagulation, the frequency of AF can now play a part in that decision," Link said. For example, if a patient has a CHA2DS2-VASc score of 1 or 2 and has persistent AF, "I'd be more inclined to offer them anticoagulation than if they had paroxysmal AF," he said. On the other hand, "patients with a CHA2DS2-VASc score of 3 or more should receive anticoagulation therapy no matter what type of AF they have."

AF Patterns and Stroke Risk, Conflicting Results

The CHA2DS2-VASc score for estimating stroke risk in patients with AF does not consider the pattern of AF, and prior studies have reported conflicting results for this risk in patients with different types of AF, Link and colleagues write.

Most recent NOAC trials—such as the SPORTIF, ARISTOTLE, ROCKET-AF, and AVERROES trials—have reported that patients with paroxysmal AF had a lower risk of stroke/SEE than patients with persistent AF.

In contrast, in the RE-LY trial, the risk of stroke/SEE was 1.32%/year in patients with paroxysmal AF, which was not statistically significantly lower than the rates of 1.55%/year and 1.49%/year among patients with persistent AF and permanent AF, respectively.

Link and colleagues examined data from the 21,105 subjects in the ENGAGE AF-TIMI 48 trial, which comprised 5366 patients (25%) with paroxysmal AF (episodes <7 days), 4868 patients (23%) with persistent AF (lasting 1 week to 1 year), and 10,865 patients (51%) with permanent AF (lasting ≥1 year or failed electric cardioversion).

The patients had a mean age of 71 and had a CHADS2 score >2.

There were more than 650 stroke and SEE events. Patients with paroxysmal AF had a significantly lower risk of thromboembolism and a similar risk of major bleeding as other patients.

Outcomes for Patients with Paroxysmal, Persistent, or Permanent AF at Baseline

Outcome Paroxysmal AF (%/y) Persistent AF (%/y) Permanent AF (%/y) P a P b
Stroke/SEE 1.49 1.83 1.95 0.015 0.004
Stroke, SEE, CV death 3.16 4.57 4.49 <0.001 <0.001
All-cause death 2.99 4.41 4.41 <0.001 <0.001
Major bleeding 2.86 2.65 2.73 0.42 0.87
SEE=systemic embolic event
a. For risk of outcome with paroxysmal AF vs persistent AF, after multivariable adjustment
b. For risk of outcome with paroxysmal AF vs permanent AF, after multivariable adjustment

Subclinical AF is the next frontier in this line of research, Link remarked. Various studies have suggested that stroke risk begins when AF episodes last 5 minutes, 24 hours, or 40 seconds, so the question is when do short AF episodes start increasing the risk of stroke. "That's a very relevant clinical question, because if you have an increased risk of stroke you should be anticoagulated," he said.

Ongoing research should provide more clues. "Unanswered questions are currently [being] explored in two large-scale prospective trials," Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESIA) and Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH), Hohnloser and Vamos note.

Daiichi-Sankyo Pharma funded the ENGAGE AF-TIMI 48 trial. Link has no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Hohnloser reports receiving consulting fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific, Daiichi Sankyo, Gilead, Johnson & Johnson, Medtronic, Pfizer, Portola, Sanofi, Servier, St Jude Medical, and Zoll Medical. Vamos reports receiving lecture fees from Bayer, Pfizer, and Spectranetics.

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