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

NCT02989558 | Completed Phase 3

• 1 other identifier: D5130C00173
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Aortic Valve Stenosis

Outcome Measures

Primary Outcomes (1)

• The number of confirmed HITS, as assessed by Transcranial Doppler (TCD), between the two treatment groups during the TAVI procedure.

  The primary objective is to identify any potential differences between the two treatment groups, subjects receiving Ticagrelor with ASA vs. those receiving Clopidogrel with ASA, in preventing cerebrovascular embolic events during the TAVI procedure, as assessed by measuring the number of HITS with an operative transcranial continuous-function Doppler.

  During the TAVI procedure

Secondary Outcomes (4)

• The incidence of cerebral embolic events between the two treatment groups, as assessed by HITS measured by TCD at subject discharge.

  At day 5, an average at discharge. Data about HITS

• the incidence of cerebral embolic events in each treatment group, during the TAVI procedure, and at subject discharge.

  At day 1, procedure day and at day 5, an average at discharge. Data about HITS

• The differences between the two treatment groups in induced platelet inhibition, at the day of the procedure.

  At day 1, procedure day. Data about platelet inhibition

• The differences between the two treatment groups in induced platelet inhibition, at subject discharge.

  At day 5, an average at discharge. Data about platelet inhibition

Study Arms (2)

Ticagrelor plus ASA

ACTIVE COMPARATOR

Subjects in the Ticagrelor group will receive ASA 80mg qd 7 days prior to the TAVI procedure and for 90 days and Ticagrelor 90mg bid 1 day prior to the TAVI procedure and for 90 days.

Drug: Ticagrelor plus ASA

Clopidogrel plus ASA

ACTIVE COMPARATOR

Subjects in the Clopidogrel group will receive ASA 80mg qd 7 days prior to the TAVI procedure and for 90 days and Clopidogrel as a loading dose of 300 mg 1 day prior to the TAVI procedure and thereafter 75mg qd for 90 days.

Drug: Clopidogrel plus ASA

Interventions

Ticagrelor plus ASA DRUG

Subjects in the Ticagrelor group will receive ASA 80mg qd 7 days prior to the TAVI procedure and for 90 days and Ticagrelor 90mg bid 1 day prior to the TAVI procedure and for 90 days.

Also known as: Brilique plus aspirin

Ticagrelor plus ASA

Clopidogrel plus ASA DRUG

Subjects in the Clopidogrel group will receive ASA 80mg qd 7 days prior to the TAVI procedure and for 90 days and Clopidogrel as a loading dose of 300 mg 1 day prior to the TAVI procedure and thereafter 75mg qd for 90 days.

Also known as: Clopidogrel plus aspirin

Clopidogrel plus ASA

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The subject (or where unable to do so, their legally acceptable representative) must be able to provide written informed consent prior to any study specific criteria, stating that he or she understands the purpose of and the procedures required for the study and is willing to participate in the study.
• Female and/or male subjects aged 18 years or older.
• High risk (EuroSCOREa ≥18, or considered inoperable) for surgical aortic valve replacement.
• Is expected to benefit from the placement of TAVI.
• Does not suffer from any disease or condition that would limit his/her life expectancy of \<6 months.
• The subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Hemoglobin ≥ 10 g/dL
• Platelets ≥ 100 X 103 cells/μL
• Absolute neutrophil count (ANC) ≥ 1000 cells/μL
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels must be within 1.5 times the upper limit of normal (ULN) range for the laboratory conducting the test.
• Total bilirubin ≤ 2x ULN.

You may not qualify if:

• Have scheduled any elective surgery in the next 4 months following screening procedures.
• History of hypocoagulopathy.
• Previous thromboembolism or known hypercoagulopathy (acquired or congenital).
• Antiplatelet therapy, other than ASA, within 7 days before randomization that cannot be discontinued due to the underlying disease.
• History of gastric or duodenal ulcer disease verified by endoscopy or barium meal double-contrast technique within the 3 months.
• Moderate or severe hepatic impairment.
• Known hypersensitivity to any of the investigational products or their components.
• Presence of any other clinically significant disease or disorder which, in the opinion of the Investigator (by its nature or by being inadequately controlled), might put the subject at risk due to participation in the study, or may influence the conduct or the interpretation of the results of the study or the subject's ability to complete the study.
• Any identified contraindication for using Ticagrelor, Clopidogrel or ASA.
• History or recent findings of atrial fibrillation.
• Significant carotid artery disease on either internal carotid artery, as defined by a \>50 % diameter reduction on carotid ultrasonography.
• Unwillingness to receive or intolerant to any blood products.
• Previous trauma or surgery to either femoral vein.
• Major surgical procedure or trauma within the 30 days prior to enrolment.
• Mechanical heart valve (any location).

Sponsors & Collaborators

• University of Athens: lead

Study Sites (1)

1st Department of Cardiology, Hippokration Hospital

Athens, Greece

Location

Related Publications (19)

• Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007 Nov 6;50(19):1852-6. doi: 10.1016/j.jacc.2007.07.058. Epub 2007 Oct 23.

  PMID: 17980251 BACKGROUND

• Kowalczyk M, Banach M, Mikhailidis DP, Hannam S, Rysz J. Ticagrelor--a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors? Med Sci Monit. 2009 Dec;15(12):MS24-30.

  PMID: 19946242 BACKGROUND

• Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006 May;27(9):1038-47. doi: 10.1093/eurheartj/ehi754. Epub 2006 Feb 13.

  PMID: 16476694 BACKGROUND

• Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014 Oct;34(10):1077-90. doi: 10.1002/phar.1477. Epub 2014 Aug 28.

  PMID: 25164528 BACKGROUND

• Ghanem A, Muller A, Nahle CP, Kocurek J, Werner N, Hammerstingl C, Schild HH, Schwab JO, Mellert F, Fimmers R, Nickenig G, Thomas D. Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging. J Am Coll Cardiol. 2010 Apr 6;55(14):1427-32. doi: 10.1016/j.jacc.2009.12.026. Epub 2010 Feb 24.

  PMID: 20188503 BACKGROUND

• Samim M, Agostoni P, Hendrikse J, Budde RP, Nijhoff F, Kluin J, Ramjankhan F, Doevendans PA, Stella PR. Embrella embolic deflection device for cerebral protection during transcatheter aortic valve replacement. J Thorac Cardiovasc Surg. 2015 Mar;149(3):799-805.e1-2. doi: 10.1016/j.jtcvs.2014.05.097. Epub 2014 Oct 17.

  PMID: 25455466 BACKGROUND

• Rodes-Cabau J, Kahlert P, Neumann FJ, Schymik G, Webb JG, Amarenco P, Brott T, Garami Z, Gerosa G, Lefevre T, Plicht B, Pocock SJ, Schlamann M, Thomas M, Diamond B, Merioua I, Beyersdorf F, Vahanian A. Feasibility and exploratory efficacy evaluation of the Embrella Embolic Deflector system for the prevention of cerebral emboli in patients undergoing transcatheter aortic valve replacement: the PROTAVI-C pilot study. JACC Cardiovasc Interv. 2014 Oct;7(10):1146-55. doi: 10.1016/j.jcin.2014.04.019.

  PMID: 25341709 BACKGROUND

• Brueck M, Kramer W, Vogt P, Steinert N, Roth P, Gorlach G, Schonburg M, Heidt MC. Antiplatelet therapy early after bioprosthetic aortic valve replacement is unnecessary in patients without thromboembolic risk factors. Eur J Cardiothorac Surg. 2007 Jul;32(1):108-12. doi: 10.1016/j.ejcts.2007.03.031. Epub 2007 Apr 20.

  PMID: 17449264 BACKGROUND

• Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF; DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007 Nov 6;50(19):1844-51. doi: 10.1016/j.jacc.2007.07.053. Epub 2007 Oct 23.

  PMID: 17980250 BACKGROUND

• Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graffagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, Granett J, Shuaib A, Koudstaal PJ, Theroux P, Van de Werf F, Sigmon K, Pieper K, Vallee M, Willerson JT; Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion Trial Investigators. Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation. 2003 Jul 29;108(4):399-406. doi: 10.1161/01.CIR.0000084501.48570.F6. Epub 2003 Jul 21.

  PMID: 12874182 BACKGROUND

• Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, Davlouros P, Hahalis G. Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. Circ Cardiovasc Interv. 2013 Jun;6(3):277-83. doi: 10.1161/CIRCINTERVENTIONS.113.000293. Epub 2013 Jun 4.

  PMID: 23735473 BACKGROUND

• Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Lung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M; ESC Committee for Practice Guidelines (CPG); Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg. 2012 Oct;42(4):S1-44. doi: 10.1093/ejcts/ezs455. Epub 2012 Aug 25. No abstract available.

  PMID: 22922698 BACKGROUND

• Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003 Jun 17;107(23):2908-13. doi: 10.1161/01.CIR.0000072771.11429.83. Epub 2003 Jun 9.

  PMID: 12796140 BACKGROUND

• Butler K, Maya J, Teng R. Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients. Curr Med Res Opin. 2013 May;29(5):569-77. doi: 10.1185/03007995.2013.781502. Epub 2013 Apr 2.

  PMID: 23448616 BACKGROUND

• Zafar MU, Farkouh ME, Fuster V, Chesebro JH. Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets. J Interv Cardiol. 2009 Aug;22(4):385-9. doi: 10.1111/j.1540-8183.2009.00475.x. Epub 2009 May 28.

  PMID: 19496900 BACKGROUND

• Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O'Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jun 10;63(22):2438-88. doi: 10.1016/j.jacc.2014.02.537. Epub 2014 Mar 3. No abstract available.

  PMID: 24603192 BACKGROUND

• Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB; Valve Academic Research Consortium-2. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg. 2013 Jan;145(1):6-23. doi: 10.1016/j.jtcvs.2012.09.002. Epub 2012 Oct 16.

  PMID: 23084102 BACKGROUND

• Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.

  PMID: 21670242 BACKGROUND

• Erdoes G, Basciani R, Huber C, Stortecky S, Wenaweser P, Windecker S, Carrel T, Eberle B. Transcranial Doppler-detected cerebral embolic load during transcatheter aortic valve implantation. Eur J Cardiothorac Surg. 2012 Apr;41(4):778-83; discussion 783-4. doi: 10.1093/ejcts/ezr068. Epub 2011 Dec 1.

  PMID: 22423058 BACKGROUND

MeSH Terms

Conditions

Aortic Valve Stenosis

Interventions

Ticagrelor; Aspirin; Clopidogrel

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• EMMANOUIL VAVOURANAKIS, Ass. Prof

  University of Athens, 1st Department of Cardiology, Hippokration Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 3, 2016
• First Posted: December 12, 2016
• Study Start: December 1, 2016
• Primary Completion: February 1, 2020
• Study Completion: February 1, 2021
• Last Updated: March 3, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

GR (1)