Speaking at the 2018 CRT meeting (3–6 March, Washington, DC), Victor Alfonso Jiménez Díaz (Cardiovascular Research Unit, Cardiology Department, Hospital Alvaro Cunqueiro University Hospital of Vigo, Vigo, Spain) reported—according to a new study—that ticagrelor could be used to suppress platelet reactivity after transcatheter aortic valve implantation (TAVI). Therefore, potentially, it could be used to reduce thrombotic and haemorrhagic complications. Cardiovascular News spoke to Jiménez Díaz about the study.
Prior to your study, what evidence was available reducing the risk of thrombotic and haemorrhagic complications after TAVI?
Improvements in current percutaneous valves have allowed a decrease in the size of the vascular access sheath required to perform TAVI, leading to a safer and more effective vascular haemostasis. This has had a positive impact on the incidence of vascular and haemorrhagic complications. In addition to this, the refinement in the antithrombotic therapy during the procedure, as well as TAVI technique, have led to a reduction in the incidence of acute ischaemic events. However, the incidence of post-TAVI thrombotic and haemorrhagic complication remains high and, until now, a strategy that provides adequate protection against ischemic events—without significantly increasing the future haemorrhagic risk—has not been defined.
You used platelet reactivity as an endpoint in your study. Why is this a relevant endpoint?
Platelet reactivity has been widely studied in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI), and numerous prior studies have linked high platelet reactivity to a greater risk for ischaemic complications, primarily stent thrombosis, while low platelet reactivity has been associated with greater bleeding events.
The advent of more potent drugs with less variability in their effect has had a positive impact on these phenomena.
Taking into account that the recommendation of dual antiplatelet therapy (DAPT) post-TAVI is based on the knowledge generated from PCI, the measurement of platelet reactivity in patients with severe aortic stenosis who will undergo TAVI and who are currently on the recommended DAPT would be an important parameter to determine its effectiveness in suppressing platelet activity.
To assess for platelet reactivity, you used the VerifyNow assay. What evidence is available for this assay?
All available information comes from patients with coronary heart disease undergoing PCI. Collaborative efforts between groups of American and European researchers have managed to collect and analyse the information available on the use of the VerifyNow assay in more than 20,000 patients with coronary artery disease, demonstrating that high platelet reactivity measured by different platelet function test, including VerifyNow assay, can be considered a risk factor for post-PCI stent thrombosis and myocardial infarction. Furthermore, in clopidogrel non-responders, they demonstrated that increased-dose strategy does not help to overcome high platelet reactivity to clopidogrel and to improve clinical outcomes. They also found a relation of low platelet reactivity to the risk of bleeding.
Based on their analysis, they provide an optimal range of P2Y12-inhibition that can be considered as a therapeutic window, within which the predicted risk of stent thrombosis and major bleeding is the lowest after PCI. These same criteria and cutoffs were used in our study.
What were the key findings of your study?
REAC TAVI was a prospective, multicentre, randomised clinical trial aimed to evaluate the platelet reactivity displayed in patients with severe symptomatic aortic stenosis undergoing TAVI, and the response achieved with the current recommended antiplatelet therapy. So, patients under aspirin and clopidogrel and with high on-treatment platelet reactivity prior TAVI was randomised to receive ticagrelor plus aspirin vs. clopidogrel plus aspirin for three months following TAVI. We also registered the behaviour of platelet reactivity in those patients who were initially responders to clopidogrel prior to TAVI, through a registry group.
The main findings can be summarised in four key messages:
- There is a high incidence of high-platelet reactivity in patients with severe aortic stenosis undergoing TAVI treated with Clopidogrel, with seven out of 10 patients non-being responders to clopidogrel before TAVI. This poor response was maintained during the following three months after the procedure
- In comparison, nine out of 10 patients treated with ticagrelor achieved optimal platelet anti-aggregation at six hours post-TAVI, reaching 100% at five days and maintaining adequate levels of platelet anti-aggregation in all patients during the three months following the TAVI.
- More than a third of patients initially responders to clopidogrel become non-responders after TAVI
- Additionally, there were no significant differences in the incidence of adverse events, including bleeding events between both treatments at three months of follow-up. The poor response to aspirin was also observed in this population, but only in a small proportion of patients.
No significant differences were observed between groups in terms of mortality and major bleeding. Were there any indications that patients in the ticagrelor group had fewer ischaemic events?
There were three major ischaemic events in the study (two strokes and one myocardial infarction), all in patients receiving clopidogrel. However, the study was underpowered for clinical endpoints, so these results must be taken with caution and need to be confirmed by studies designed specifically for this purpose.
What further studies in this area are needed?
Percutaneous treatment of different valvular heart diseases has been established as the therapy of choice in symptomatic patients rejected for surgery or at high surgical risk. Its acceptance and application has been fast and broadly. The use of an antithrombotic therapy following the procedure is mandatory because thromboembolic complications at follow-up are not negligible. But the current recommended antiplatelet therapy has no support from randomised clinical trials. Additionally, this population of patients is in a very delicate balance between thrombotic and haemorrhagic risk, so the implications in choosing an effective and safe therapy is challenging and of paramount importance. Therefore, larger scale studies are needed to determine the best antiplatelet treatment to use in this population and its duration after the procedure.