ASpirin vs Triflusal for Event Reduction In Atherothrombosis Secondary Prevention (ASTERIAS)

Atherothrombosis Clinical Trial

— ASTERIAS  

Official title:

Comparison of Triflusal With Aspirin in the Secondary Prevention of Atherothrombotic Events

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02616497
• Other study ID #: Asp-Trifl-1
• Status: Completed
• Phase: Phase 4
• First received: November 20, 2015
• Last updated: April 13, 2018
• Start date: September 2015
• Est. completion date: March 28, 2018

Study information

• Verified date: April 2018
• Source: University of Ioannina
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Investigation of the efficacy and safety of triflusal in comparison with aspirin in patients with stable coronary artery disease (CAD) and in those with a history of an acute non-cardioembolic ischemic stroke.

Description:

Triflusal, 2-(acetyloxy)-4-(trifluoromethyl) benzoic acid, is an antiplatelet agent with a chemical structure similar to aspirin, but with a different pharmacokinetic and pharmacodynamic profile. The drug is administered orally and its bioavailability ranges from 83% to 100%. It binds almost entirely (99%) to plasma proteins and crosses readily organic barriers. Triflusal is deacetylated in the liver, forming its main metabolite 2-hydroxy-4-trifluoromethyl benzoic acid (HTB). In contrast to the inactive aspirin metabolite salicylic acid, HTB exhibits antiplatelet activity and has a long plasma half-life of approximately 40h. Triflusal irreversibly inhibits COX-1 and reduces TxA2 production, but to a lesser extent compared with aspirin. It inhibits COX-1 and AA metabolism selectively in platelets, preserving PGI2 synthesis in vascular endothelial cells 1. Except of platelet COX-1 triflusal and in particular HTB inhibit phosphodiesterase, the enzyme that degrades the cyclic nucleotides, cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP), both of which inhibit platelet function.

Triflusal has similar to aspirin efficacy for the secondary prevention of vascular events in patients with acute myocardial infarction (MI) and stroke, while it reduces the incidence of intracranial and gastrointestinal haemorrhage compared with aspirin. It should be noted that triflusal is well tolerated in patients with aspirin-induced asthma.

Aspirin (acetyl salicylic acid) remains for over 50 years the cornerstone of antiplatelet therapy due to its proven clinical benefit and very good cost effectiveness profile. Aspirin selectively and irreversibly acetylates the hydroxyl group of a single serine residue at position 529 within the polypeptide chain of PGH synthase-1. Thus aspirin inhibits the COX-1 activity but it does not affect the hydroperoxidase activity PGH synthase-1. By blocking COX-1, the production of TXA2 is reduced, leading to reduced platelet aggregation. Aspirin improves clinical outcome in all cardiovascular syndromes in primary and secondary prevention, including acute events. In high-risk patients, aspirin substantially reduces the risk of vascular death by ~15% and non-fatal vascular events by ~30% as it reported by a meta-analysis of over 100 large-scale randomized trials. Several studies the last years have suggested that a proportion of patients (5 to 65%) exhibit a hyporesponsiveness (resistance) to aspirin treatment which could be associated with recurrent ischemic events. Aspirin resistance may result from several causes, such as low compliance, interference with non-steroid anti-inflammatory drugs (NSAIDS) and protein glycation occurring in type 2 diabetes mellitus. Increased platelet turnover observed in various diseases such as ACS, peripheral arterial disease and diabetic angiopathy associated with faster re-appearance of newly formed, non aspirinated platelets, may also account for aspirin resistance.

Although triflusal is chemically related to aspirin and has similar effectiveness, it appears to have a better tolerability profile than aspirin. Results from large-scale clinical trials and a meta-analysis suggest that its use may be preferable to that of aspirin, in several clinical settings where antiplatelet therapy is indicated. Furthermore, in selected populations, such as in geriatric patients, because of an increased risk of bleeding complications, in patients suffering from asthma, chronic sinusitis and nasal polyps, or in cases of aspirin resistance, triflusal may be a choice worth considering. Furthermore, when combination antiplatelet-fibrinolytic or antiplatelet-anticoagulant therapy is needed, clinical data support triflusal use based on its efficacy and better safety than aspirin. Unlike aspirin, triflusal, also, less likely affect the efficacy of antihypertensive drugs, especially angiotensin converting enzyme inhibitors. The aim of the present trial is to investigate the efficacy and safety of triflusal in comparison with aspirin in patients with stable coronary artery disease (CAD) and in those with a history of an acute non-cardioembolic ischemic stroke.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1220
• Est. completion date: March 28, 2018
• Est. primary completion date: February 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with a stable coronary artery disease (CAD)

• Patients with a history of non-cardioembolic ischemic stroke.

Exclusion Criteria:

• Hypersensitivity reaction or contraindication to triflusal or aspirin

• Active bleeding or history of severe bleeding (peptic ulcer, trauma or intracranial hemorrhage)

• Blood coagulation disorders

• Uncontrolled severe hypertension

• Pregnancy or breastfeeding

• Liver disease (alanine or aspartate aminotransferase more than 3 times the upper normal limit)

• Malignancy that may potentially increase the risk of hemorrhage

• Drug or alcohol abuse

• HIV infection

• Chronic disorders requiring long-term treatment with systemic nonsteroidal anti-inflammatory drugs (NSAIDs).

Related Conditions & MeSH terms

• Atherothrombosis

Intervention

Drug:
• Aspirin
COX-1 inhibitor
• Triflusal
COX-1 inhibitor

Locations

Country	Name	City	State
Greece	Atherothrombosis Research Centre / Laboratory of Biochemistry, University of Ioannina	Ioannina

Sponsors (1)

Lead Sponsor	Collaborator
University of Ioannina

Country where clinical trial is conducted

Greece, 

References & Publications (20)

Acikel S, Yildirir A, Aydinalp A, Demirtas K, Bal U, Kaynar G, Ozin B, Karakayali H, Muderrisoglu H, Haberal M. Incidence of aspirin resistance and its relationship with cardiovascular risk factors and graft function in renal transplant recipients. Transplant Proc. 2008 Dec;40(10):3485-8. doi: 10.1016/j.transproceed.2008.06.108. — View Citation

Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P. Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009 May-Jun;50(3):199-207. Review. — View Citation

Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86. Erratum in: BMJ 2002 Jan 19;324(7330):141. — View Citation

Antonijoan RM, Gich I, Azaro A, Sainz S, Balanzó J, Izquierdo I, Borja J, Donado E, Blanch I, Barbanoj MJ. Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study. Eur J Clin Pharmacol. 2011 Jul;67(7):663-9. doi: 10.1007/s00228-011-1004-9. Epub 2011 Feb 16. — View Citation

Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabin J, Torres F. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004296. Review. — View Citation

Cruz-Fernández JM, López-Bescós L, García-Dorado D, López García-Aranda V, Cabadés A, Martín-Jadraque L, Velasco JA, Castro-Beiras A, Torres F, Marfil F, Navarro E. Randomized comparative trial of triflusal and aspirin following acute myocardial infarction. Eur Heart J. 2000 Mar;21(6):457-65. — View Citation

Culebras A, Rotta-Escalante R, Vila J, Domínguez R, Abiusi G, Famulari A, Rey R, Bauso-Tosselli L, Gori H, Ferrari J, Reich E; TAPIRSS investigators. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology. 2004 Apr 13;62(7):1073-80. — View Citation

Di Minno G. Aspirin resistance and platelet turnover: a 25-year old issue. Nutr Metab Cardiovasc Dis. 2011 Aug;21(8):542-5. doi: 10.1016/j.numecd.2011.04.002. Epub 2011 Jul 13. — View Citation

Feher G, Feher A, Pusch G, Lupkovics G, Szapary L, Papp E. The genetics of antiplatelet drug resistance. Clin Genet. 2009 Jan;75(1):1-18. doi: 10.1111/j.1399-0004.2008.01105.x. Epub 2008 Nov 29. Review. — View Citation

Kalantzi KI, Tsoumani ME, Goudevenos IA, Tselepis AD. Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives. Expert Rev Clin Pharmacol. 2012 May;5(3):319-36. doi: 10.1586/ecp.12.19. Review. — View Citation

Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008 Jan 26;336(7637):195-8. doi: 10.1136/bmj.39430.529549.BE. Epub 2008 Jan 17. Review. — View Citation

Matías-Guiu J, Ferro JM, Alvarez-Sabín J, Torres F, Jiménez MD, Lago A, Melo T; TACIP Investigators. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke. 2003 Apr;34(4):840-8. Epub 2003 Mar 20. — View Citation

Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010 Feb;9(2):154-69. doi: 10.1038/nrd2957. Review. — View Citation

Murdoch D, Plosker GL. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. Drugs. 2006;66(5):671-92. Review. — View Citation

Papathanasiou A, Goudevenos J, Tselepis AD. Resistance to aspirin and clopidogrel: possible mechanisms, laboratory investigation, and clinical significance. Hellenic J Cardiol. 2007 Nov-Dec;48(6):352-63. Review. — View Citation

Pérez-Gómez F, Alegría E, Berjón J, Iriarte JA, Zumalde J, Salvador A, Mataix L; NASPEAF Investigators. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol. 2004 Oct 19;44(8):1557-66. — View Citation

Simon DI, Jozic J. Drug-eluting stents and antiplatelet resistance. Am J Cardiol. 2008 Nov 3;102(9 Suppl):29J-37J. doi: 10.1016/j.amjcard.2008.09.007. Review. — View Citation

Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med. 2007 Aug 13-27;167(15):1593-9. Review. — View Citation

Undas A, Siudak Z, Topór-Madry R, Lesniak M, Tracz W. Simvastatin administration reduces thromboxane production in subjects taking aspirin: links between aspirin resistance and thrombin generation. Int J Cardiol. 2012 Jan 12;154(1):59-64. doi: 10.1016/j.ijcard.2010.09.093. Epub 2010 Oct 29. — View Citation

Valle M, Barbanoj MJ, Donner A, Izquierdo I, Herranz U, Klein N, Eichler HG, Müller M, Brunner M. Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers. Eur J Clin Pharmacol. 2005 Apr;61(2):103-11. Epub 2005 Feb 12. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of death from vascular causes, myocardial infarction (MI), or stroke (ischaemic or haemorrhagic) during the twelve month treatment period	Number of participants who suffer from the primary efficacy end point which is the composite of death from vascular causes, myocardial infarction(MI), or stroke during the twelve month treatment period	12 months
Primary	Rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria during the twelve month treatment period	Number of participants who suffer from the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria during the twelve month treatment period	12 months
Secondary	Composite of death from any cause, MI, or stroke during the twelve month treatment period	Number of participants who suffer from the secondary efficacy end point which is the composite of death from any cause, MI, or stroke during the twelve month treatment period	12 months
Secondary	Hypersensitivity or intolerance to study drugs during the twelve month treatment period	Number of participants who suffer from the secondary safety end points which are hypersensitivity or intolerance to study drugs during the twelve month treatment period	12 months