Apixaban Advantage Before AF Cardioversion Hinted in EMANATE Trial

September 12, 2017

BARCELONA, SPAIN — A randomized trial tentatively pointing to fewer strokes vs standard therapy when a new oral anticoagulant (NOAC) is used before cardioversion for atrial fibrillation (AF) may edge the field forward in a few ways[1].

In contrast to prior NOAC studies in the same clinical setting, the current trial used apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and was limited to anticoagulant-naïve patients or those with <48 hours anticoagulant exposure.

Also, the 1500-patient open-label EMANATE trial supports an accelerated cardioversion schedule in which the procedure can be performed as soon as 2 hours after the start of bolus-dosed apixaban, with or without transesophageal echocardiography (TEE) or CT to show or rule out potentially embolic atrial thrombus.

That strategy, usually more attractive than the 3 to 4 weeks of anticoagulation the guidelines recommend before cardioversion, unless imaging shows no thrombus, was allowed in EMANATE for patients who started on apixaban with 10-mg or 5-mg bolus doses.

There were no strokes in EMANATE's 753 patients who received apixaban but six among the 747 patients assigned to standard anticoagulants (P=0.0164), including five ischemic strokes and one intracranial bleed. Overall there were three and six major bleeds, respectively, and two deaths on apixaban vs one among controls. No cases of extracranial systemic emboli were seen.

Among the 342 patients who received apixaban bolus dosing with accelerated cardioversion, there was one death, one major bleed, and four clinically relevant nonmajor bleeds.

A similarly accelerated approach was used in last year's randomized ENSURE-AF trial of edoxaban (Savaysa/Lixiana, Daiichi Sankyo), which nonetheless saw no significant outcome advantage for the NOAC. Clinical outcomes in the same clinical setting were also similar across groups for rivaroxaban (Xarelto, Janssen) in the randomized 2014 trial X-VERT, in which cardioversion was allowed after 1 week of the NOAC.

In EMANATE and those other NOAC trials, the usual-care comparator was a standard parenteral anticoagulant with or without an oral vitamin-K antagonist (VKA), typically given for at least 3 weeks unless atrial thrombus is ruled out by imaging, consistent with guidelines. Thrombus rule-out by imaging can be followed soon by cardioversion.

Also like those other trials, EMANATE was statistically underpowered for clinical outcomes, principal investigator Dr Michael D Ezekowitz (Thomas Jefferson University, Philadelphia, and Lankenau Medical Center, Wynnewood, PA) noted for theheart.org | Medscape Cardiology.

Ezekowitz, who presented the EMANATE results here at the European Society of Cardiology (ESC) 2017 Congress, and others at the sessions pointed out that an enrollment upward of an impractical 40,000 patients would have been needed for a statistically adequate comparison.

The trial nonetheless supports using apixaban as anticoagulant pretreatment in patients slated for AF cardioversion, according to Ezekowitz.

Site-Investigator Discretion

Importantly, he said in an interview, investigators at each trial site could decide whether to accelerate the apixaban-cardioversion schedule or to screen for atrial thrombi with imaging for individual patients.

"Generally speaking" using standard anticoagulation or even apixaban, he said, "if you want to expedite the process, you do a TEE." In EMANATE, patients assigned to apixaban may or may not have had TEE or CT and may or may not have received the NOAC with "regular" dosing or bolus dosing.

The former consisted of 5 mg twice daily, reduced to 2.5 mg twice daily in the presence of at least two of three prespecified risk factors (age >80, weight <60 kg, or serum creatinine >1.5 mg/dL) for at least five doses prior to cardioversion.

Discretionary bolus dosing, done in 45.4% of apixaban recipients, which featured an initial apixaban dose of 10 mg (reduced to 5 mg in some for the same reasons) all at once, could be followed by cardioversion in 2 or more hours.

Regardless of assigned oral anticoagulant, the trial's patients showed a mean CHA2DS2-VASc score of about 2.4, although it was 4.4 among the 11 patients who received the 5-mg apixaban bolus.

Regardless of apixaban dosing and for all patients assigned to standard anticoagulation, cardioversion was delayed if discretionary imaging disclosed atrial thrombus. "We encourage investigators to continue assigned medication in patients identified with thrombus and repeat imaging studies after 3 weeks," according to the trial's "rationale and design" publication[2].

Need for Imaging?

Neither the investigators nor other interviewed experts seemed to advocate cardioversion without imaging guidance, regardless of anticoagulation strategy. The EMANATE protocol "encouraged an image-guided approach" regardless of randomized treatment.

Indeed, such imaging can be "a quite simple noninvasive test" and therefore as a safety precaution in practice would probably be a wise thing to do routinely, ESC officer Dr Sarah C Clarke (Papworth Hospital, Cambridge, UK), not connected to EMANATE, said in an interview.

And among apixaban recipients who didn't have imaging but did get the bolus doses, "there may have been some who got a cardioversion that had thrombus in their left atrial appendage," according to Clarke. Without imaging, she noted, no one knows whether that happened, "but it doesn't look like it caused any adverse effects."

Of the 840 patients across the trial in whom cardioversion was guided by imaging, 30 assigned to apixaban and 31 to standard anticoagulants showed evidence of atrial thrombus. The assigned anticoagulation regimen was then continued, with repeat imaging a mean of 37 days later in 23 and 18 patients, respectively. By then, thrombus was no longer visible in about half of patients, 52% of those with follow-up imaging in the apixaban group and 56% of those on standard anticoagulants.

Questions About the End Points

EMANATE seems to shore up evidence that regardless of imaging, anticoagulation before AF cardioversion can sometimes be much briefer than 3 to 4 weeks, Clarke said. Apixaban was given for about 48 hours or, with bolus dosing, potentially for just a couple of hours, before attempting to achieve sinus rhythm, she noted.

Although generally supportive of the trial, Dr Jens Cosedis Nielsen (Aarhus University Hospital, Denmark), assigned discussant for Ezekowitz's presentation of EMANATE, pointed out some of its limitations.

Sure, it was underpowered, he said, although a randomized superiority or noninferiority NOAC trial with the tens of thousands of patients needed for adequate statistical strength "is not realistic, and I would question whether it was ethical to put that much money into such a trial."

But also, EMANATE did not prespecify a primary end point, he noted. There were "protocol-specified outcomes" site investigators were to look for and that were independently and blindly adjudicated: acute stroke, systemic embolism, death from any cause, major bleeding, and clinically relevant nonmajor bleeding.

And whereas stroke/systemic embolism as an end point hinted at superiority for apixaban, Nielsen said, "if we combine the end points, take also death into the equation, it is no longer significant, nor is it if we take death and bleeds into the equation."

Those observations "preclude us from taking any hard conclusions from this trial," he said. "However, I think that EMANATE adds to the growing evidence suggesting that NOACs are a viable alternative to help therapy in patients undergoing cardioversion for AF."

EMANATE was sponsored by Pfizer and Bristol-Myers Squibb. Ezekowitz disclosed receiving consulting fees from Boehringer Ingelheim, Armetheon, Pfizer, Sanofi, Bristol-Myers Squibb, Portola, Daiichi-Sankyo, Medtronic, Johnson & Johnson, and Janssen Scientific Affairs; and grant support from Boehringer Ingelheim, Pfizer, and Bristol-Myers Squibb. He also noted that he is co–principal investigator or on the executive committee for a number of clinical trials in the area of oral anticoagulants and/or atrial fibrillation. Nielson reported that he has no relevant financial relationships.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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