A-fib Patients Undergoing TAVR Do Better With OAC Alone: POPular TAVI

For patients who require chronic oral anticoagulation (OAC)—mostly for A-fib—and who undergo TAVR, adding 3 months of clopidogrel to the antithrombotic regimen after the procedure does not appear to have any benefits.

In the POPular TAVI trial, in fact, patients who received clopidogrel on top of their OAC regimen bled more and had numerically higher rates of mortality through 1 year of follow-up, Vincent Nijenhuis, MD (St. Antonius Hospital, Nieuwegein, the Netherlands), reported during the virtual American College of Cardiology (ACC) 2020 Scientific Session.

“Based on these results, we’re fairly confident to say that in patients who have an established indication for oral anticoagulants—most of the time atrial fibrillation—undergoing TAVI, oral anticoagulant alone as compared to oral anticoagulant plus clopidogrel does reduce bleeding,” Jurriën ten Berg, MD, PhD (St. Antonius Hospital), principal investigator of the trial, said during a press conference, noting that a difference was seen in major, life-threatening, or disabling bleeding.

Moreover, the findings—published simultaneously online in New England Journal of Medicine—show that use of “oral anticoagulants alone does not increase the rate of thrombotic events as compared to the combined therapy with clopidogrel,” he said.

Commenting for TCTMD, Howard Herrmann, MD (Hospital of the University of Pennsylvania, Philadelphia), said that it’s not surprising to see that adding clopidogrel to OAC caused more bleeding and that a more pertinent question is whether there was any ischemic benefit.

“Although there didn’t appear to be any benefit to the ischemic endpoints, it was clearly a very small study and it was not powered for the secondary endpoint of ischemic endpoints,” Herrmann said.

He said future studies involving the direct oral anticoagulants (DOACs) that are adequately powered for ischemic endpoints are needed to guide practice, noting that the ongoing ATLANTIS trial will provide some answers.

“Until we have these larger studies, I think it is reasonable to use oral anticoagulants alone in patients with atrial fibrillation after TAVR, particularly given the lack of evidence base for the antiplatelet regimen that the guidelines currently recommend, at least in the absence of a good indication for an antiplatelet agent such as a recent stent or a TIA,” Herrmann said.

Refining Post-TAVR Antithrombotic Therapy

A large proportion of patients undergoing TAVR—about 30%—have A-fib and require chronic OAC to reduce their risk of stroke and thromboembolism. In their paper, the investigators note “current practice guidelines on antithrombotic treatment in patients who have an indication for anticoagulation after TAVI are based on expert opinion and suggest a vitamin K antagonist either alone or in combination with aspirin or clopidogrel.” Although adding clopidogrel to OAC might reduce thromboembolic risk, the more-potent antithrombotic effect would be expected to increase bleeding versus OAC alone.

The POPular TAVI trial, conducted at 17 sites in Europe, was designed to provide randomized evidence to inform this issue. There were two cohorts—A, which included patients without an indication for chronic OAC, and B, which included patients who required chronic OAC. Nijenhuis and ten Berg reported results of cohort B. The investigators enrolled patients who were taking OAC (95% for A-fib) and required TAVR, randomizing them to OAC plus clopidogrel for 3 months or to OAC alone. The modified intention-to-treat analysis included 313 patients (mean age 81 years; 45% women).

The anticoagulant was a vitamin K antagonist (VKA) in 73% of patients, with nearly all of the rest taking a direct oral anticoagulant (DOAC); two patients were treated with low-molecular-weight heparin.

There were two co-primary bleeding outcomes, both of which favored OAC alone through a year of follow-up in superiority analyses:

• Any VARC-2 bleeding (21.7% vs 34.6%; RR 0.63; 95% CI 0.43-0.90)
• Nonprocedural bleeding (21.7% vs 34.0%; RR 0.64; 95% CI 0.44-0.92)

Procedure-related bleeding was defined only as BARC type 4 severe bleeding, which means that most access-site bleeding was considered nonprocedural. There was only one severe procedural bleed recorded in the trial (in the clopidogrel group).

There were also two co-secondary outcomes, both of which established the noninferiority of OAC alone versus OAC plus clopidogrel. Rates were numerically lower with OAC alone:

• CV mortality, nonprocedural bleeding, all-cause stroke, or MI (31.2% vs 45.5%; RR 0.69; 95% CI 0.51-0.92)
• CV mortality, ischemic stroke, or MI (13.4% vs 17.3%; RR 0.77; 95% CI 0.46-1.31)

The authors note that “no clinical inferences can be drawn for these secondary outcome results because of the lack of a plan for correction for multiple comparisons.”

Linking Bleeding to Mortality

Like Herrmann, Sammy Elmariah, MD (Massachusetts General Hospital, Boston), said he was not surprised to see an increase in bleeding among patients who received clopidogrel, adding that one of the more informative elements of the study was the look at secondary ischemic outcomes.

Though the trend toward more events in the clopidogrel group may seem counterintuitive, Elmariah commented to TCTMD, it fits with the literature developing around the link between bleeding and mortality in other settings, like PCI.

The numerical increase in ischemic events in the clopidogrel arm “really suggests to me that when these patients bleed, it really has an adverse impact on their subsequent clinical outcomes. So the detriment is not simply the bleed itself, but also the fact that after these bleeding complications these patients actually do quite poorly, and this trial provides further evidence in support of that emerging concept,” Elmariah said. “I think we have to be quite nuanced in our decisions and perhaps conservative when we treat patients with antiplatelet and anticoagulant agents to make sure that we are not placing our patients at increased risk.”

When asked about the numerical difference in ischemic outcomes favoring OAC alone, ten Berg said it’s difficult to explain because there were no differences between groups in terms of stroke or MI. Death rates, however, tended to favor OAC alone, both for all-cause mortality (13.4% vs 15.4%) and CV mortality (8.3% vs 12.8%); those differences were not statistically significant.

He, too, suggested there might be a link with bleeding. “As we know, these are very complicated patients and it might be that when they have even a minor bleeding it starts a cascade of complications which might in the end lead to death,” ten Berg speculated.

Those considerations aside, Elmariah said POPular TAVI provides evidence in support of current practice patterns in the United States, where the standard is to not give clopidogrel to patients who have an indication for OAC unless there’s another reason to do so (recent DES implantation, for example). Although not specifically addressed in this trial, most patients with an indication for chronic OAC after TAVR would also receive aspirin, he pointed out, but noted that there remains a question about whether aspirin is protective in this scenario.