Best Anticoagulant in the TAVR Patient With A-fib? Small Study Makes Case for Apixaban

Patients with atrial fibrillation undergoing transcatheter aortic valve replacement are at an increased risk of death and other adverse outcomes when compared with patients in normal sinus rhythm having the procedure, according to a new analysis. Additionally, the study showed that A-fib patients treated with apixaban (Eliquis, Bristol-Myers Squibb) have better safety outcomes than those treated with warfarin, including significantly less life-threatening bleeding.

Although the study found an advantage with the novel oral anticoagulant over the vitamin K antagonist, investigators led by Julia Seeger, MD (University of Ulm, Germany), caution that the results are not based on a randomized trial but rather on single-center registry data. Larger studies, they say, “are needed to confirm these initial exploratory findings.”

Haris Riaz, MD (Cleveland Clinic, OH), who was not involved in this analysis but has studied the safety of oral anticoagulation after TAVR, agreed that the findings should be considered hypothesis-generating only, particularly since the results are limited by study design and sample size. He said he was not surprised by the increased risk of death among TAVR patients with A-fib, mainly because the arrhythmia generally implies a sicker patient population. 

“The bigger issue here is if the use of apixaban confers a lower event rate for hazardous endpoints as the authors have suggested,” said Riaz. He noted that the association between warfarin and a higher rate of adverse safety outcomes could suggest those treated with the older drug were a sicker patient population (for example, physicians would feel more comfortable prescribing warfarin given that it's well studied), the true superiority of apixaban, or a combination of both. “Only a randomized controlled trial can address this research question,” he noted.

Net Safety Benefit With Apixaban

The new analysis, published online yesterday in JACC: Cardiovascular Interventions, included 617 patients who underwent TAVR. Of these patients, 345 were in normal sinus rhythm and 272 had A-fib. 

The 30-day safety endpoint, which included all-cause mortality, all stroke, life-threatening bleeding, acute kidney injury, coronary obstruction, major vascular complications, and valve dysfunction requiring intervention, occurred in 11.0% of patients in normal sinus rhythm and 23.2% of patients with A-fib (P < 0.01). There was no significant difference in mortality at 30 days, but at 12 months, the mortality rate was significantly higher among TAVR-treated patients with A-fib when compared with those in normal sinus rhythm (19.1% vs 7.8%; P = 0.01). 

The combined secondary endpoint of all-cause mortality and stroke was also significantly higher among patients with A-fib, a difference driven by mortality.  

Of the 272 patients with A-fib, 141 were given apixaban and 131 the vitamin K antagonist. The apixaban-treated patients were less likely to have a history of MI, stroke/ intracerebral bleeding, or renal replacement therapy, but other baseline characteristics were similar. The 30-day safety endpoint occurred significantly less often among patients treated with apixaban (13.5% vs 30.5%; P < 0.01). The rate of life-threatening bleeding was also significantly lower among the apixaban-treated patients (3.5% vs 5.3%), as was the rate of acute kidney injury (2.1% vs 8.4%; P < 0.01 for both). 

There was a trend toward a lower rate of stroke at 30 days in the apixaban-treated patients, but the difference was not statistically significant. At 30 days and 12 months, there was no difference in all-cause mortality between the apixaban- and warfarin-treated patients. 

Warfarin Alone Also a Pretty Good Option

Speaking with TCTMD, Josep Rodés-Cabau, MD (Laval University, Quebec City, Canada), said the increased risk of adverse safety outcomes, including mortality at 12 months, after TAVR in patients with A-fib is well documented. The more pertinent question is the correct antithrombotic treatment for these A-fib patients given the need to balance the risk of stroke versus the risk of bleeding. In early TAVR experience, physicians prescribed triple therapy, a cocktail of aspirin, clopidogrel, and warfarin.  

“Very rapidly we realized this was associated with an excessive risk of bleeding,” said Rodés-Cabau. “The patients we are treating—the elderly, frail—don’t tolerate these types of combinations.” 

Nowadays, multiple clinical guidelines for A-fib patients undergoing TAVR recommend a vitamin K antagonist plus a single antiplatelet agent. Rodés-Cabau and colleagues published a study last summer showing that concomitant antiplatelet therapy in TAVR patients prescribed warfarin did not reduce the risk of stroke, major adverse cardiovascular events, or death but did increase the risk of life-threatening bleeding. 

“Warfarin alone was probably a pretty good option if you don’t need antiplatelet therapy, and many of these patients don’t because they don’t have significant coronary artery disease or they have stable coronary artery,” he said, referring to their data. “If they have a stent, then it’s a very different scenario.”

Rodés-Cabau added that A-fib patients are being treated more and more with novel oral anticoagulants. The current findings showing an advantage with apixaban, while provocative, need to be validated in another study, particularly since older, frailer patients, including those with multiple comorbidities, are unlikely to receive the new agents. More study is also needed to determine if there is any difference in adverse events between apixaban- and warfarin-treated patients who receive different antiplatelet combinations.  

Lots of Information Coming Soon

In an editorial accompanying the study, Lars Søndergaard, MD, and Fadi Sawaya, MD (Copenhagen University Hospital, Denmark), note that the value of oral anticoagulation after TAVR, even among those without A-fib, has been reemphasized given recent reports of subclinical leaflet thrombosis in bioprosthetic aortic valves. The upcoming GALILEO study, which includes a 4-D computed tomography substudy, will attempt to address the potential effect of rivaroxaban (Xarelto, Janssen Pharmaceuticals) on leaflet thickening and motion abnormalities.  

The editorialists say the new data contributes to ongoing debate about the optimal antithrombotic regimen in post-TAVR patients, including those with A-fib. Several studies are ongoing, including ARTE and POPULAR-TAVI, both of which are studying a single antiplatelet (either aspirin or clopidogrel alone) agent versus dual antiplatelet therapy. Other strategies are being tested in A-fib patients; for example, AVATAR is testing oral anticoagulation alone versus anticoagulation plus aspirin after TAVR. Other studies, including cohort B of POPULAR-TAVI and ATLANTIS, are ongoing.

“A wealth of information will be uncovered from this potpourri of trials in the next few years, and one can foresee a change in the way we approach and manage patients after TAVR, both those with A-fib and those in sinus rhythm,” write Søndergaard and Sawaya.

For Rodés-Cabau, more data are welcome, particularly since A-fib is very common among patients he encounters. It is estimated A-fib is present in approximately one-third of patients undergoing TAVR.