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Ticagrelor bests clopidogrel for suppressing high platelet reactivity after TAVR
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Ticagrelor plus aspirin, when compared with clopidogrel plus aspirin, resulted in faster and more sustained suppression of high platelet reactivity in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, according to the REAC-TAVI trial.
The study enrolled patients with severe aortic stenosis undergoing TAVR from November 2015 to May 2017 at seven centers in Spain. All patients were on aspirin 100 mg daily and needed to be on clopidogrel maintenance dosing of 75 mg daily for at least 4 days before TAVR, and those who were not on clopidogrel were pretreated with a 300-mg loading dose.
Of the 68 patients included, 48 had high platelet reactivity at baseline and were randomly assigned aspirin plus ticagrelor (Brilinta, AstraZeneca) or continued on aspirin plus clopidogrel. The 20 remaining patients without high platelet reactivity were deemed clopidogrel responders and were included in the registry cohort. The primary endpoint was a platelet reaction unit level lower than 208 in at least 70% of patients on ticagrelor.
Víctor Alfonso Jiménez Díaz, MD, MPH, interventional cardiologist, clinical research coordinator, Cardiovascular Research Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Spain, and colleagues measured platelet reactivity at 6 hours, 24 hours, 5 days, 30 days and 90 days after TAVR. At all time points, patients in the ticagrelor group had lower platelet reactivity than patients in the clopidogrel group and the registry cohort (P < .001). Additionally, all patients receiving ticagrelor, compared with 21% of patients receiving clopidogrel, achieved platelet reaction unit levels lower than 208 (net difference, 79%; P < .001). At the end of treatment, platelet reaction unit levels were lower by an average of 170 in the ticagrelor group vs. the clopidogrel group.
There were also more responders among patients on ticagrelor vs. clopidogrel throughout the treatment period.
The researchers also noted variations in the registry group, including an increase of 53 in platelet reaction unit level and a 33% decrease in clopidogrel responders during the first month after TAVR, throughout treatment.
Fifty-five adverse events occurred in the study, with no significant differences in major bleeding, CV death or other Valve Academic Research Consortium-2 defined events among study groups at 4 months. There was only one in-hospital major bleeding in a patient with low platelet reactivity at 6 hours after TAVR.
Clinical implications
The researchers concluded that their data suggest high rates of residual platelet reactivity despite treatment with clopidogrel after TAVR, including a significant increase during the first month after the procedure that may last up to 3 months. This finding indicates that the efficacy of clopidogrel in these patients may be questionable.
“Based on expert consensus and in the absence of randomized trials, the American and European guidelines have recommended the use of DAPT for the first 3 to 6 months after TAVR. The rationale for using DAPT is the potential platelet-mediated origin of thrombus formation after TAVR. However, the evidence base supporting DAPT after TAVR is scarce and, in essence, it reproduces the knowledge from trials in the field of PCI,” Jiménez Díaz wrote in an email to Cardiology Today’s Intervention.
“In this regard, platelet reactivity has been widely studied in patients with CAD undergoing PCI, and numerous prior studies have linked high platelet reactivity to a greater risk for ischemic complications, primarily stent thrombosis, while low platelet reactivity has been associated with greater bleeding events. The advent of more potent antiplatelet drugs with less variability in their effect, such as ticagrelor, has had a positive impact on these phenomena.”
Jiménez Díaz and colleagues noted that the REAC-TAVI results confirm the superior potency of ticagrelor over clopidogrel for achieving prompt and potent platelet inhibitory effects.
“Lack of compelling evidence exists on the efficacy of aspirin plus clopidogrel as antithrombotic treatment in patients with severe aortic stenosis undergoing TAVR. High platelet reactivity to clopidogrel is present in a considerable number of patients with aortic stenosis prior TAVR and more than one-third of patients who are initially responders to clopidogrel become non-responders during the treatment period post-TAVR. Ticagrelor overcomes high platelet reactivity in all TAVR patients with a sustained effect during the entire treatment period,” he said.
The researchers highlighted several limitations of the study. For instance, although the high platelet reactivity cutoff point used in the study was recommended for the evaluation for thrombotic events in CAD, the cutoff for evaluating thrombotic events in patients undergoing TAVR remains unknown. The study was also not powered to assess clinical endpoints.
"Larger clinical trials are needed to assess the safety and clinical implications of these findings,” Jiménez Díaz said.
Need for further study
During the past decade, use of TAVR has expanded significantly, according to Jiménez Díaz.
“Its acceptance and application have been fast and broad, and it could further increase as TAVR indications may gradually extend after completion of the large, low-surgical-risk patient trials. Hence, the antithrombotic regimen after successful TAVR is of the utmost importance to prevent ischemic events, but it should also minimize the risk of bleeding,” Jiménez Díaz told Cardiology Today’s Intervention. “The TAVR population is in a very delicate balance between thrombotic and hemorrhagic risk, so the implications in choosing an effective and safe therapy is challenging and extremely relevant. Therefore, larger-scale studies are needed to determine the best antiplatelet treatment to use in this population and its duration after the procedure. An important aspect is to determine the appropriate high platelet reactivity cut-off point in TAVR patients, which may be different from what is known to be in post-PCI patients. The impact of other factors on high platelet reactivity, such as the type of valve used, as well as certain comorbidities (diabetes, renal failure) and some clinical characteristics should be also studied in detail.”
The implications of REAC-TAVI confirm information from previous studies regarding high platelet reactivity in both PCI and TAVR cohorts, Davide Capodanno, MD, PhD, from the division of cardiology, C.A.S.T., P.O. “G. Rodolico”, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele,” University of Catania in Italy, and Dominick J. Angiolillo, MD, PhD, professor of medicine, medical director of the Cardiovascular Research Program and program director of the Interventional Cardiology Fellowship Program at the University Florida College of Medicine – Jacksonville and a Cardiology Today’s Intervention Editorial Board member, wrote in an accompanying editorial.
However, the study also raises questions. For example, data do not yet demonstrate a link between high platelet reactivity and ischemic events after TAVR, suggesting there is no urgency to suppress on-clopidogrel high platelet reactivity after TAVR, they wrote. Further, low platelet reactivity may contribute to the risk for bleeding after TAVR and one would expect more thrombotic complications to be observed in real-world practice.
“If DAPT will finally prove to outperform aspirin at a reasonable bleeding cost, then the full potential for other investigations reproducing the history of DAPT trials for PCI will be unraveled,” Capodanno and Angiolillo wrote. “Indeed, issues such as pretreatment, drug choice and dosing, duration, platelet function testing and de-escalation have been deeply investigated in the field of PCI but have not been tackled in the field of TAVR, a virgin territory for DAPT and antithrombotic therapy trials.” – by Melissa Foster
Disclosures: The study was sponsored by the Spanish Society of Cardiology and supported by AstraZeneca. Jiménez Díaz and the other authors report no relevant financial disclosures. Capodanno reports he has received speaker honoraria from Bayer, AstraZeneca and Boehringer Ingelheim and consultant fees or honoraria from Abbott Vascular, AstraZeneca and Bayer. Angiolillo reports he has received consultant fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PLx Pharma, Pfizer, Sanofi and The Medicines Company; he has participated in review activities for CeloNova and St. Jude Medical; and he has received institutional grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical and Renal Guard Solutions.
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