A Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During TAVI — PTOLEMAIOS  

Aortic Valve Stenosis Clinical Trial

Official title: A Prospective, Multicentre, Randomized, Open Label, Blinded Endpoint, Phase 3 Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During Transcatheter Aortic Valve Implantation (TAVI) OperationS - the PTOLEMAIOS Study.

Status Completed

Clinical Trial Summary

Ticagrelor administered with Acetylsalicylic Acid (ASA) will provide better cerebral protection from microembolization in the cerebral circulation during Transcatheter Aortic Valve Implantation (TAVI) and 30 days afterwards, than Clopidogrel plus ASA. This hypothesis will be investigated by measuring the number of High Intensity Transient Signals (HITS) as assessed with transcranial Doppler (TCD) on middle cerebral arteries.

Clinical Trial Description

TAVI has recently provided a therapeutic alternative to patients with symptomatic aortic stenosis who are inoperable or at high-risk for surgical valve replacement. It has been documented with MRI studies that >70% of the patients undergoing TAVI develop new cerebral infarct lesions. Of these, only a ~3% to ~ 6% represent clinical significant events (transient ischemic attacks, disabling and non-disabling stroke). With the expected expansion of TAVI in lower risk patients and younger age even silent cerebral lesions will be of major importance [7], thus ways to overcome or decrease it will have a rapid and wide penetration. Clinically apparent or "silent" stroke during TAVI may be attributed to a range of different mechanisms. The source of a cerebral ischemia during TAVI is multifactorial. One of the proposed mechanisms is the increased risk of thrombus formation both on the aortic atherosclerotic plaques and on bioprosthetic valve frame and tissue due to inadequate platelet inhibition during or after TAVI. Furthermore, high residual platelet reactivity in the presence of incomplete endothelial coverage of the valve following TAVI may promote formation of fibrin/platelet thrombi. Other mechanisms involve embolization from a variety of origins i.e. atheroembolism from the ascending aorta or aortic arch, calcific emboli from the aortic valve, thromboembolism from catheters. Platelets are the main target of preventative therapy against cerebral ischemic events, owing to the observation that, in addition to promoting arterial thrombosis, platelets have a key role in various nonthrombotic, inflammatory pathways of plaque progression The clinical apparent or "silent" embolic events may be recognized with TCD performed during TAVI as documented in published clinical studies. TCD is an accepted surveillance technique during neurological interventions (such as TAVI, atrial septal defects/patent form ovale closure, carotid endarterectomy). Moreover, studies utilizing TCD during TAVI for evaluation of potential embolization are available. TCD observes HITS that may be quantified and potentially correlated with neurological events. However, it should be noted that this approach is not able to discriminate the exact source or composition of the emboli The use of embolic protection devices (e.g. the Embrella Embolic Deflector system) during TAVI surprisingly showed an increase in the number of cerebral ischemic lesions on postprocedural brain imaging when compared to dual antiplatelet therapy. The first few days post TAVI carry the highest risk for a thromboembolic event, thus special therapeutic and diagnostic approaches should be taken into consideration when regarding this procedure. Similarly, surgical bioprosthetic valve implantation has shown to have a higher risk of thromboembolic events within 3 months of the procedure. The administration of a monotherapy with ASA after biological aortic valve replacement failed to show improvement in the incidence of thromboembolic events. Dual antiplatelet therapy is traditionally started prior to TAVI and continued for 6 months. Nevertheless, in these fragile elderly patients dual antiplatelet therapy increases the risk of haemorrhage. In addition the protection achieved by these agents is questionable and resistance to aspirin and Clopidogrel has been observed in a high percentage. Platelet Function Testing has been proven to characterize the patients at high risk for adverse outcome after percutaneous coronary interventions. However, pharmacological interventions to overcome this increased risk have not been established. The use of Ticagrelor has been proven to reduced cerebral ischemic events in acute coronary syndromes (ACS) without significantly increasing the major bleeding complications, despite the more potent antithrombotic effect. Moreover, total mortality was substantially decreased using Ticagrelor, as the risk of intracranial hemorrhage or fatal stroke was low. In the DISPERSE-2 Trial, slightly higher rates of minor bleeding where observed with Ticagrelor compared to Clopidogrel; however major bleeding events were lower with Ticagrelor. Overall, total bleeding events were similar in the Ticagrelor and Clopidogrel groups, as well as in patients with additional antithrombotic agents or undergoing invasive procedures. However, the administration of Ticagrelor allows for greater flexibility and safety if the need for discontinuation of antiplatelet agents should arise, as it has a half life of only 12 hours [16]. More importantly, Ticagrelor is a reversible platelet inhibitor, in contrast to Clopidogrel and ASA who bind irreversibly to platelet cell membrane receptors and the cyclooxygenase enzyme respectively, and whose effects persist for duration of the platelet life span. Therefore, in case of a bleeding event where antiplatelet therapy needs to be deescalated, monotherapy with Ticagrelor could prove to be the safer option. Ticagrelor has been documented to demonstrate faster onset and more potent inhibition of platelet aggregation than Clopidogrel. These properties of Ticagrelor may contribute to lower rates of thrombotic outcomes compared to Clopidogrel. However, bleeding events are a concern with the more potent antiplatelet agents Ticagrelor and Prasugrel. This risk of bleeding is correlated to the concomitant dosage of ASA, therefore the lowest effective dose of 80mg of ASA was chosen as a background therapy for this study. Compared to Prasugrel, another thienopyridine drug, Ticagrelor has shown to provide a more potent effect on the microcirculation of patients undergoing percutaneous coronary intervention. Moreover, the use of current antiplatelet regimens during and post TAVI has not been well established by clinical data. Currently, there are no guidelines regarding antiplatelet pre- treatment before TAVI. The European Society of Cardiology practice guidelines (2012) suggest that in real-life double antiplatelet regimens are prescribed in the early post-TAVI period, without further issuing a specific recommendation. Even as such and with the wide clinical use of dual antiplatelet therapy perioperatively for TAVI, cases of thrombus formation on bioprosthetic valves have been documented. The manufacturer has attributed these events to suboptimal operative placement of the bioprosthesis, therefore caution must be taken in the positioning of the bioprosthetic valves in order to reduce the formation of emboli that could potentially cause a clinically significant cerebral ischemic event. The use of a more potent dual antiplatelet regimen with Ticagrelor could prove more efficient in this aspect. The present study aims to evaluate whether platelet inhibition with one new antiplatelet agent provides better cerebral protection from microembolization in the cerebral circulation during TAVI, than the currently used Clopidogrel. We hypothesize that treatment with Ticagrelor plus ASA vs. Clopidogrel plus ASA in patients undergoing TAVI will result in fewer HITS as assessed with TCD on middle cerebral arteries. This is the first study to directly compare treatment with Ticagrelor with Acetylsalicylic vs. Clopidogrel with Acetylsalicylic regimen in subjects undergoing TAVI regarding cerebral embolic events as assessed with TCD of both middle cerebral arteries. If significant reduction in HITS number in the Ticagrelor group is proven, this will implicate a possible way to decrease in cerebral ischemic lesions in TAVI subjects. Undoubtedly, as TAVI candidates are increasing in number and decreasing in age, the prevention of neurological consequences is of paramount importance. ;

Related Conditions & MeSH terms

• Aortic Valve Stenosis

• NCT number: NCT02989558
• Study type: Interventional
• Source: University of Athens
• Status: Completed
• Phase: Phase 3
• Start date: December 2016
• Completion date: February 1, 2021