Oral Anticoagulation After TAVR Doesn’t Reduce Ischemic Cerebral Lesions: AUREA

SAN FRANCISCO, CA—Oral anticoagulation following transcatheter aortic valve replacement fails to lower the incidence of new subclinical cerebral lesions identified on imaging when compared with dual antiplatelet therapy (DAPT), according to the AUREA trial presented today at TCT 2019.

Six days after TAVR, diffusion-weighted magnetic resonance imaging (DW-MRI) revealed that 66.7% of patients treated with dual antiplatelet therapy had new brain lesions versus 84.2% of patients treated with oral anticoagulation, a difference that was not statistically significant (P = 0.15). Similarly, the incidence of new brain lesions on DW-MRI at 3 months was not statistically different between the two antithrombotic approaches.

These results call into question what the antithrombotic treatment strategy should be post-TAVR in patients with severe aortic stenosis and normal sinus rhythm.

“There was no benefit of using oral anticoagulation in this patient population,” lead investigator Victor Alfonso Jiménez Díaz, MD (University Hospital/Hospital Alvaro Cunqueiro, Vigo, Spain), told TCTMD. “The results are very convincing. The incidence of small lesions was comparable [between the two strategies], although the events were numerically higher in patients who received oral anticoagulation. We were surprised. We thought anticoagulation would protect against stroke. The hypothesis is that the stroke we see in patients with atrial fibrillation—thrombus formation in the left atrial appendage—is different than the stroke we’re seeing in patients with normal sinus rhythm after TAVR.”

Díaz said the incidence of small brain lesions detected on DW-MRI following TAVR is quite high, with some suggesting these lesions develop in 60% to 100% of patients who receive a transcatheter heart valve. In their study, three-quarters of those who underwent TAVR had newly identified ischemic lesions on imaging. “The lesions are not really well correlated with clinical outcomes, but what we know is that patients that have cerebral lesions develop early dementia and have a diminished quality of life,” said Díaz.

Prescribing Antithrombotics Post-TAVR in a Evidence-Free Vacuum

The appropriate antithrombotic regimen following TAVR is a hot topic, with US and European guidelines offering an array of weak recommendations. In Europe, the most recent guidelines recommend physicians consider DAPT for the first 3 to 6 months after TAVR (class IIa recommendation) while oral anticoagulation should only be considered for patients with other indications for therapy, such as those with atrial fibrillation. In the United States, there is class IIb recommendation for short-course oral anticoagulation after TAVR in patients at low bleeding risk, while clopidogrel on top of aspirin is considered a reasonable option for 6 months (class IIb recommendation).

“We wanted to really study whether patients in sinus rhythm and an underlying indication for anticoagulation would benefit from the use of oral anticoagulation following TAVR,” said Díaz. “It’s an indication in the US guidelines that you may use oral anticoagulation after TAVR or use dual antiplatelet therapy with aspirin or clopidogrel, but we have to bear in mind that this population has a high risk for bleeding and we need to balance the thrombotic and bleeding events.”

In the trial, investigators randomized 123 intermediate-risk patients (average age 83 years; 52% female) with severe aortic stenosis to DAPT with aspirin and clopidogrel or oral anticoagulation with a vitamin K antagonist.

The incidence of new ischemic lesions at 6 days did not significantly differ between individuals treated with DAPT and those treated with the vitamin K antagonist. Three months after TAVR, 8.2% of the overall population had evidence of new cerebral lesions, but again there was no difference by antithrombotic regimen (6.0% with DAPT vs 10.4% with oral anticoagulation; P = 0.71). The number of new brain lesions identified on DW-MRI also did not differ between the treatment groups at 6 days or 3 months.

In terms of clinical events, there was no difference in the risk of death, stroke, or major bleeding between the DAPT and oral anticoagulation treatment arms at 6 months. Numerically, there were three strokes in the patients treated with DAPT and seven strokes among those treated with oral anticoagulation. Díaz said the absence of major bleeding between groups was reassuring. “Even if you’re not convinced of only using antiplatelet therapy, and you think you’ll protect your patients with oral anticoagulation, it appears safe for 3 months,” Díaz.

Learning From PCI

At their practice, Díaz said DAPT is standard in patients with normal sinus rhythm after TAVR, but for patients with an indication for oral anticoagulation they will also prescribe an antiplatelet agent for 1 to 3 months if they are at low risk for bleeding. The cerebral lesions evident on DW-MRI following TAVR may be a consequence of high platelet reactivity following TAVR, he suggested, in which case an antiplatelet agent might be a more effective strategy for reducing the risk of stroke/TIA. “We strongly believe the platelet pathway for stroke genesis is very important,” he said. “We follow these patients very closely because of the higher risk for bleeding.”

Rishi Puri, MD, PhD (Cleveland Clinic, OH), who was not involved in the trial, said the correct antithrombotic approach following TAVR is simply not yet known. “Should we use anticoagulation? Is it dual antiplatelet therapy for a while and then switch to single antiplatelet therapy? Or do we use oral anticoagulation and then switch to antiplatelet therapy and then which agent?” he said. “I really don’t have the answer. All our clinical practice is based on no evidence whatsoever—it’s simply extrapolation from the PCI field.”

As reported by TCTMD, a small study recently suggested there may be something unique about TAVR-related bleeding, with a mechanism that differs from what’s seen with PCI.

At their center, Puri said they prescribe DAPT for 1 month in patients without an indication for oral anticoagulation and then switch to aspirin. For those with an indication for oral anticoagulation, “I’d be comfortable using a concomitant antiplatelet agent for at least a month and then withdrawing that to continue with oral anticoagulation,” he said. “That’s just my approach for the patients I treat on a daily basis. Is it based on any evidence? No. It’s just touch and feel. We need to undertake the trials to better understand it.”

Even with clinical trials, it’s will remain challenging to understand the appropriate antithrombotic strategy given the heterogeneity of patients undergoing TAVR, said Puri.

“The hemodynamics are different and the underlying [prothesis-patient mismatch] is different, as is the underlying propensity to thrombose or bleed,” said Puri. “It’s really going to come down to a personalized approach. We’re starting to get a little more personalized with PCI and that’s been a long road, but we’re starting to get quite conservative in dialing back antiplatelet agents and using other interesting combinations where we’re dropping aspirin. We’ll probably need to adapt with TAVR.” 

The field recently received some answers last year when the GALILEO trial, which was testing a rivaroxaban-based anticoagulation strategy against antiplatelet therapy in the TAVR setting, was stopped following a review showing a higher risk of death, thromboembolic events, and bleeding in the rivaroxaban arm. The ATLANTIS trial, which is testing apixaban in a similar setting, is still ongoing.

SAN FRANCISCO, CA—Oral anticoagulation following transcatheter aortic valve replacement fails to lower the incidence of new subclinical cerebral lesions identified on imaging when compared with dual antiplatelet therapy (DAPT), according to the AUREA trial presented today at TCT 2019.

Six days after TAVR, diffusion-weighted magnetic resonance imaging (DW-MRI) revealed that 66.7% of patients treated with dual antiplatelet therapy had new brain lesions versus 84.2% of patients treated with oral anticoagulation, a difference that was not statistically significant (P = 0.15). Similarly, the incidence of new brain lesions on DW-MRI at 3 months was not statistically different between the two antithrombotic approaches.

These results call into question what the antithrombotic treatment strategy should be post-TAVR in patients with severe aortic stenosis and normal sinus rhythm.

“There was no benefit of using oral anticoagulation in this patient population,” lead investigator Victor Alfonso Jiménez Díaz, MD (University Hospital/Hospital Alvaro Cunqueiro, Vigo, Spain), told TCTMD. “The results are very convincing. The incidence of small lesions was comparable [between the two strategies], although the events were numerically higher in patients who received oral anticoagulation. We were surprised. We thought anticoagulation would protect against stroke. The hypothesis is that the stroke we see in patients with atrial fibrillation—thrombus formation in the left atrial appendage—is different than the stroke we’re seeing in patients with normal sinus rhythm after TAVR.”

Díaz said the incidence of small brain lesions detected on DW-MRI following TAVR is quite high, with some suggesting these lesions develop in 60% to 100% of patients who receive a transcatheter heart valve. In their study, three-quarters of those who underwent TAVR had newly identified ischemic lesions on imaging. “The lesions are not really well correlated with clinical outcomes, but what we know is that patients that have cerebral lesions develop early dementia and have a diminished quality of life,” said Díaz.

Prescribing Antithrombotics Post-TAVR in a Evidence-Free Vacuum

The appropriate antithrombotic regimen following TAVR is a hot topic, with US and European guidelines offering an array of weak recommendations. In Europe, the most recent guidelines recommend physicians consider DAPT for the first 3 to 6 months after TAVR (class IIa recommendation) while oral anticoagulation should only be considered for patients with other indications for therapy, such as those with atrial fibrillation. In the United States, there is class IIb recommendation for short-course oral anticoagulation after TAVR in patients at low bleeding risk, while clopidogrel on top of aspirin is considered a reasonable option for 6 months (class IIb recommendation).

“We wanted to really study whether patients in sinus rhythm and an underlying indication for anticoagulation would benefit from the use of oral anticoagulation following TAVR,” said Díaz. “It’s an indication in the US guidelines that you may use oral anticoagulation after TAVR or use dual antiplatelet therapy with aspirin or clopidogrel, but we have to bear in mind that this population has a high risk for bleeding and we need to balance the thrombotic and bleeding events.”

In the trial, investigators randomized 123 intermediate-risk patients (average age 83 years; 52% female) with severe aortic stenosis to DAPT with aspirin and clopidogrel or oral anticoagulation with a vitamin K antagonist.

The incidence of new ischemic lesions at 6 days did not significantly differ between individuals treated with DAPT and those treated with the vitamin K antagonist. Three months after TAVR, 8.2% of the overall population had evidence of new cerebral lesions, but again there was no difference by antithrombotic regimen (6.0% with DAPT vs 10.4% with oral anticoagulation; P = 0.71). The number of new brain lesions identified on DW-MRI also did not differ between the treatment groups at 6 days or 3 months.

In terms of clinical events, there was no difference in the risk of death, stroke, or major bleeding between the DAPT and oral anticoagulation treatment arms at 6 months. Numerically, there were three strokes in the patients treated with DAPT and seven strokes among those treated with oral anticoagulation. Díaz said the absence of major bleeding between groups was reassuring. “Even if you’re not convinced of only using antiplatelet therapy, and you think you’ll protect your patients with oral anticoagulation, it appears safe for 3 months,” Díaz.

Learning From PCI

At their practice, Díaz said DAPT is standard in patients with normal sinus rhythm after TAVR, but for patients with an indication for oral anticoagulation they will also prescribe an antiplatelet agent for 1 to 3 months if they are at low risk for bleeding. The cerebral lesions evident on DW-MRI following TAVR may be a consequence of high platelet reactivity following TAVR, he suggested, in which case an antiplatelet agent might be a more effective strategy for reducing the risk of stroke/TIA. “We strongly believe the platelet pathway for stroke genesis is very important,” he said. “We follow these patients very closely because of the higher risk for bleeding.”

Rishi Puri, MD, PhD (Cleveland Clinic, OH), who was not involved in the trial, said the correct antithrombotic approach following TAVR is simply not yet known. “Should we use anticoagulation? Is it dual antiplatelet therapy for a while and then switch to single antiplatelet therapy? Or do we use oral anticoagulation and then switch to antiplatelet therapy and then which agent?” he said. “I really don’t have the answer. All our clinical practice is based on no evidence whatsoever—it’s simply extrapolation from the PCI field.”

As reported by TCTMD, a small study recently suggested there may be something unique about TAVR-related bleeding, with a mechanism that differs from what’s seen with PCI.

At their center, Puri said they prescribe DAPT for 1 month in patients without an indication for oral anticoagulation and then switch to aspirin. For those with an indication for oral anticoagulation, “I’d be comfortable using a concomitant antiplatelet agent for at least a month and then withdrawing that to continue with oral anticoagulation,” he said. “That’s just my approach for the patients I treat on a daily basis. Is it based on any evidence? No. It’s just touch and feel. We need to undertake the trials to better understand it.”

Even with clinical trials, it’s will remain challenging to understand the appropriate antithrombotic strategy given the heterogeneity of patients undergoing TAVR, said Puri.

“The hemodynamics are different and the underlying [prothesis-patient mismatch] is different, as is the underlying propensity to thrombose or bleed,” said Puri. “It’s really going to come down to a personalized approach. We’re starting to get a little more personalized with PCI and that’s been a long road, but we’re starting to get quite conservative in dialing back antiplatelet agents and using other interesting combinations where we’re dropping aspirin. We’ll probably need to adapt with TAVR.” 

The field recently received some answers last year when the GALILEO trial, which was testing a rivaroxaban-based anticoagulation strategy against antiplatelet therapy in the TAVR setting, was stopped following a review showing a higher risk of death, thromboembolic events, and bleeding in the rivaroxaban arm. The ATLANTIS trial, which is testing apixaban in a similar setting, is still ongoing.