TAVR Bleeds Stand Apart From PCI-Related Events

Patients undergoing TAVR appear to have a “hemostatic defect” that uniquely predisposes them to bleeding and involves less thrombin generation and prolonged clotting time as compared to patients receiving PCI, a single-center registry suggests. Moreover, investigators say, their bleeding risk doesn’t hinge on platelet reactivity alone but appears to be driven by some other unknown mechanism.

Platelet activation and leaflet thrombosis—affecting leaflet mobility, thickness, and durability—have captured the lion’s share of interest when it comes to TAVR hemodynamics. But thrombocytopenia, acquired von Willebrand disease, anemia, and other blood-related disorders are relatively common among TAVR candidates and their potential contribution to bleeding complications is less often discussed.

“The theory out there is that when you fix the aortic valve with TAVR or surgery you fix this predisposition to bleeding, [but] that theory has largely been untested,” lead author Harold L. Dauerman, MD (University of Vermont Medical Center, Burlington), explained.

Clinicians should trust their clinical judgement [and] if they think someone is high risk for bleeding going into a TAVR, they should still be worried about bleeding post-TAVR. Harold L. Dauerman

Concerns about hypoattenuated leaflet thickening and leaflet thrombosis have led to a push for more-intense early anticoagulation, while results from the REAC-TAVI trial made a case for stronger antiplatelet therapy, he pointed out. “I thought that this could be dangerous if applied to all patients getting TAVR, because at least a significant proportion have some mechanism for being at risk for bleeding,” Dauerman said. “I just became worried about this because I saw so much bruising and bleeding, [like] GI bleeds, in TAVR patients.”

Davide Capodanno, MD, PhD (University of Catania, Italy), commenting for TCTMD, said, “This is really the first time that someone has looked mechanistically at bleeding, and the methodology of this study is interesting, because they looked at both components of the hemostatic process: platelets and coagulation.” As a small study, it may be particularly vulnerable to confounding, he added. “But anyway, I think it’s a very nice approach.”

Prolonged Clotting Post-TAVR

Dauerman and colleagues compared hematologic parameters in 29 TAVR-treated patients against those of 55 PCI-treated acute MI patients by using blood samples taken 12 to 24 hours after intervention. Patients who had been on oral anticoagulation in the day prior to treatment, who had international normalized ratios greater than 1.5 on the day of blood draw, or who had platelets below 100,000 were excluded.

The researchers measured clotting time and maximum thrombin generation in both platelet-rich and platelet-poor plasma in an attempt to look beyond “known abnormalities in platelet function characterizing patients with aortic stenosis,” they explain in their paper, which is being published as a research letter in the August 13, 2019, issue of the Journal of the American College of Cardiology.

The TAVR group as a whole was older than the PCI group and showed trends toward more PAD and less smoking. Other factors, such as baseline platelet count, renal function, and hemoglobin level were similar in the two cohorts. All PCI patients went on dual antiplatelet therapy, as compared to 72% of the TAVR patients. Around one-quarter of the PCI patients received ticagrelor (Brilinta; AstraZeneca).

Clot time was shorter for PCI than for TAVR, both in platelet-poor plasma (mean 221.47 vs 258.31 seconds; P = 0.002) and platelet-rich plasma (mean 301.32 vs 481.17 seconds; P = 0.0001). Maximum thrombin generation was higher with PCI compared with TAVR in platelet-rich plasma (mean 173.76 vs 140.11; P = 0.008) but not in platelet-poor plasma (mean 407.69 vs 434.18; P = 0.27).

After adjusting for age, PAD, and smoking status, the differences in clot time remained significant for not only the platelet-rich comparison but also in the platelet-poor comparison, where a disparity would not be expected. Overall, this hints “that these patients have intrinsic bleeding abnormalities that extend beyond just the platelet system, things that we don’t know about the coagulation cascade in these patients undergoing TAVR,” Dauerman said.

What’s worth tracking through serial blood testing, he continued, is: “How long does this persist? Is it a permanent thing or, for example, maybe after 30 days clotting time would it be similar between [PCI and TAVR patients]? We don’t know the answer to that, but I would be very concerned about any algorithm or trial that had every single patient post-TAVR go on an oral anticoagulant.”

Clinicians, Trust Your Judgment

Forthcoming data from the GALILEO trial, prematurely halted for harm back in 2018, may provide clarity on the trajectory of bleeding risk after intervention—as well as the best drug regimen—but for now, Dauerman said clinicians should err on the side of caution.

“I don’t think anybody should feel that anything beyond an aspirin a day is mandatory in these TAVR patients,” he advised. “If they have a history of recurrent GI bleeding going into TAVR, I would not put that patient on an oral anticoagulant unless they had another indication that was much [stronger] than a hypothesis of preventing leaflet thrombosis, which is . . . unproven.” Standard of care, Dauerman said, is currently dual antiplatelet therapy for 30 to 90 days.

Asked if an aspirin-alone approach might be reasonable in some cases, based on these data, Capodanno replied, “I think, yes, because [bleeding] is more prevalent than thrombosis.”

Registry data have shown that approximately 30% of TAVR patients experience bleeding over 5-year follow-up, Capodanno noted, so these are clinically relevant questions. Although the situation may change as TAVR extends to lower-risk, younger patients, “for the time being we should be very much aware that bleeding is as important as thrombosis and maybe even more important” when deciding on antithrombotic regimens post-TAVR, he stressed.

It will be very important to explore the outcomes of the GALILEO study and understand which bleeding [type] was increased in which group and why. Davide Capodanno

Capodanno agreed that, given the evidence that there are multiple mechanisms for bleeding in TAVR, “it will be very important to explore the outcomes of the GALILEO study and understand which bleeding [type] was increased in which group and why.”

For Dauerman, the “million dollar question” going forward is whether TAVR patients can be prospectively identified as having a low or high risk of bleeding, with the possibility of individualizing medical therapy. A randomized controlled trial could then home in on the low-risk patients, to compare among aspirin alone, dual antiplatelet therapy, and aspirin plus an anticoagulant.

“In the absence of data, we use a lot of clinical judgement. But I would say that clinicians should trust their clinical judgement [and] if they think someone is high risk for bleeding going into a TAVR, they should still be worried about bleeding post-TAVR,” he concluded.

GALILEO is expected to be presented at a meeting later in 2019.