Ticagrelor: Better Platelet Blockade Post-TAVR?

WASHINGTON, DC—As many as two-thirds of patients undergoing transcatheter aortic valve replacement have a high degree of platelet reactivity and clopidogrel fails to achieve adequate platelet inhibition in the majority of these patients, according to the results of a new study.

In contrast, more than 90% of patients treated with ticagrelor (Brilinta, AstraZeneca) in the study had adequate platelet inhibition 6 hours after TAVR and all patients had suppressed platelet reactivity 5 days after the procedure.

“Patients with aortic stenosis have a lot of high on-treatment platelet reactivity, probably more than acute coronary syndrome patients,” lead investigator Victor Jimenez Diaz, MD (University Hospital of Vigo, Spain), told TCTMD. “And clopidogrel is not effective for the blockade of platelets. It’s not working well in more than 70% of these patients, but ticagrelor could be a good option to treat high on-treatment platelet reactivity.” 

Diaz said use of ticagrelor after TAVR, which is off-label, appears to be safe, with no signs of increased procedural or in-hospital bleeding complications, and no increased risk of major bleeding at 30 and 90 days. However, he cautioned, the study is small and underpowered for clinical endpoints. “At least with the information we have, it’s reassuring,” he told TCTMD.

Lots of Questions About Post-TAVR Therapy

Presenting the results of REAC-TAVI at CRT 2018, Diaz said there is no standardized recommendation for antithrombotic treatment after TAVR. The 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update on the management of patients with valvular heart disease suggests clopidogrel 75 mg may be reasonable in the first 6 months after TAVR, in addition to lifelong aspirin (class IIb, level of evidence C). The European guidelines suggest dual antiplatelet therapy for 3 to 6 months followed by lifelong aspirin therapy (class IIa, level of evidence C).

“The recommendations have no support from randomized clinical trials,” said Diaz. “Most of the things we know about antiplatelet therapy in TAVI patients comes from the PCI world and that’s not a good way to compare patient-to-patient, because TAVI patients are a completely different population. They probably share a high prothrombotic environment, but TAVI patients have a lot of comorbidities and the therapy likely needs to be tailored.”

In REAC-TAVI, a multicenter, randomized trial, the researchers identified 65 patients with severe symptomatic aortic stenosis undergoing TAVR. Of those, 46 patients had high baseline on-treatment platelet reactivity, which was assessed using the VerifyNow P2Y12 assay (Accriva Diagnostics) and aspirin assays. In total, 24 patients were randomized to standard dual antiplatelet treatment with clopidogrel 75 mg and aspirin 100 mg and 22 patients were randomly assigned to ticagrelor 90 mg twice daily and aspirin.

At 6 hours, 24 hours, 5 days, 1 month, and 3 months, mean platelet reactivity levels were significantly lower among patients treated with ticagrelor.

Using a P2Y12 reaction unit (PRU) cutoff of 208, which identified those with high on-treatment platelet reactivity, individuals treated with clopidogrel had mean PRU values above the threshold over the entire study period. Comparatively, mean PRU values for those treated with ticagrelor were 129 at 6 hours, 104 at 24 hours, and 64 at 3 months. Overall, just 21% of those treated with clopidogrel had adequate platelet inhibition at 3 months, compared with 100% of ticagrelor patients.

The group is attempting to conduct a large-scale clinical trial testing ticagrelor against clopidogrel and would also like to assess subclinical leaflet thrombosis among patients treated with the more potent antiplatelet agent. “We’re refining the procedural techniques and we’re improving the devices, and we should improve the antithrombotic treatment after TAVI,” he said. 

What’s Wrong, GALILEO?

Several trials are assessing the best antithrombotic regimen after TAVR, including GALILEO, AUREA, and POPULAR-TAVI, among others. GALILEO investigators, for example, are testing two antithrombotic treatment strategies in TAVR-treated patients: the direct oral anticoagulant rivaroxaban (Xarelto, Bayer/Janssen) 10 mg plus aspirin against a strategy that includes clopidogrel 75 mg and aspirin. Patients in the trial do not have an indication for oral anticoagulation, Diaz pointed out, and he questioned whether this is the right approach.

“The problem is, patients have a thrombotic risk but also a high risk of bleeding,” he said. “Putting these patients on anticoagulation could be something we don’t like too much, particularly after an interventional procedure using large-bore catheters. It’s not something that’s really desirable, especially for patients with no indication for anticoagulation besides TAVI.”  

Moderating the late-breaking clinical trial session, Jeffrey Popma, MD (Beth Israel Deaconess Medical Center, Boston, MA), questioned whether GALILEO might be studying the wrong antithrombotic treatment regimen. The REAC-TAVI data are “very, very provocative,” he said. “You get much better platelet inhibition with the combination of ticagrelor and aspirin than clopidogrel [and aspirin], and yet our standard has been clopidogrel as the generic class of antiplatelet agent. It’s very intriguing.”

Danny Dvir, MD (University of Washington Medical Center, Seattle), who has studied valve deterioration and durability, pointed out that several analyses have suggested dual antiplatelet therapy offers no protection against subclinical thrombosis identified on 4-D computed tomography. He does not believe leaflet thickening is likely to be prevented with an even more potent antiplatelet agent like ticagrelor. Dvir also pointed out, though, that surgeons have largely abandoned the use of oral anticoagulation after surgical aortic valve replacement.

Asked what he thinks would likely be the correct antithrombotic strategy after TAVR, Howard Herrmann, MD (University of Pennsylvania Perelman School of Medicine, Philadelphia), said he doesn’t know, but that he believes it’s unlikely to be dual antiplatelet therapy.

Ron Waksman, MD (MedStar Heart & Vascular Institute, Washington, DC), was also impressed by the REAC-TAVI findings. “Clopidogrel probably doesn’t work and yet most of us give it,” he said. “The issue with ticagrelor is that it’s completely off label and then you also worry about the bleeding and how long you can prescribe it.”