Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment
NCT ID: NCT04613167
Last Updated: 2020-11-03
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
NA
70 participants
INTERVENTIONAL
2020-11-10
2021-10-01
Brief Summary
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Detailed Description
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The early stage of the atherosclerosis process is characterized by endothelial cell damage, which results in impaired release and function of nitric oxide (NO) from the endothelium. NO is formed by endothelial NO synthetase (NOS-3) from the amino acid L-arginine, which is most pronounced in the vascular wall and is also most important in the process of atherosclerosis. The NOS-3 gene is located on chromosome 7; in the region 7q35-7q36. Functional polymorphisms are those that alter the expression or activity of NOS-3. Among them, rs2070744, rs3918226 and rs1799983 single nucleotide polymorphisms (SNP) are important. Variations in the expression and activity of NOS-3 genetic polymorphisms at exon 7 of the NOS-3 gene are associated with the incidence of myocardial infarction in very young patients who otherwise have a low atheromatous coronary artery load. Variations in the NOS-3 genes cause diversity in NO bioavailability and are responsible for endothelial dysfunction.
A 6-month observational, prospective, and randomized study will include 70 patients with a first acute coronary syndrome (ACS) (including acute transmural myocardial infarction, nontransmural myocardial infarction or unstable angina pectoris) event before age 55 and Lp (a) levels above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L. With the gradual inclusion ("step-wedge") and randomization of patients, the investigators will also provide a control group that will include 30 patients. The investigators will do anamnesis, targeted clinical examination, take blood samples for laboratory measurements, ultrasound measure endothelium-dependent dilatation of the brachial artery and intima media thickness of carotid arteries, measure pulse wave and calculate carotid artery wall stiffness. Patients will be divided into three groups according to a randomization list. The first group will receive alirocumab, the second group evolocumab, and the third group will be the control group and will be included in the treatment after 6 months. During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard treatment. After 6 months, the investigators will repeat all the mentioned investigations. Patients will be informed about the purpose and course of the study before starting it. All will participate voluntarily, without pressure or inappropriate instigation, which they will confirm by signing.
The investigators hypotheses that in patients with early coronary artery disease Lp (a) and Lp (a) polymorphisms are associated with indicators of inflammation and structural-functional properties of the arterial wall; in patients with early coronary artery disease, PCSK9 inhibitors reduce the value of Lp (a), indicators of inflammation and structural and functional involvement of the arterial wall; in patients with early coronary artery disease, the influence of PCSK9 inhibitors on Lp (a), indicators of inflammation and structural-functional properties of the arterial wall depends on the presence of specific polymorphisms for Lp (a).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Alirocumab
The first group of patients will receive 150 mg of alirocumab every two weeks subcutaneously for 6 months
Alirocumab
The first group will receive alirocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Evolocumab
the second group of patients will receive evolocumab 140 mg every two weeks subcutaneously for 6 months
Evolocumab
The second group will receive evolocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Control group
Control group will be included in the treatment after 6 months. During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard guidelines-based treatment
Control group
The third group will receive only optimal guidelines-based secondary preventive treatment. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Interventions
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Alirocumab
The first group will receive alirocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Evolocumab
The second group will receive evolocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Control group
The third group will receive only optimal guidelines-based secondary preventive treatment. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Eligibility Criteria
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Inclusion Criteria
* up to 55 years at the time of first acute coronary syndrome
* concentration Lp (a) above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L
* optimally treated risk factors for cardiovascular events according to currently valid guidelines.
Exclusion Criteria
* documented history of myocardial infarction less than 6 months before enrollment
* secondary dyslipidemia,
* severe renal disease (oGFR \<30 ml / min),
* moderate to severe liver disease (elevated transaminases above 3 times the norm, elevated bilirubin above 2 times the norm, elevated creatinine kinase above 3 times the norm),
* acute illness 6 weeks before inclusion in the study,
* history of allergic reaction to any ingredient in the drug,
* pregnancy and lactation,
* life expectancy less than 12 months,
* unwillingness to participate or lack of availability for follow-up
18 Years
65 Years
ALL
No
Sponsors
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University Medical Centre Ljubljana
OTHER
Responsible Party
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Miran Sebestjen
Professor, principal Investigator
Principal Investigators
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Miran Šebeštjen, prof.
Role: STUDY_CHAIR
University Medical Centre Ljubljana (Slovenia)
Andreja Rehberger Likozar, MD
Role: PRINCIPAL_INVESTIGATOR
University Medical Centre Ljubljana (Slovenia)
Locations
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University Medical Centre Ljubljana-Department of Vascular diseases and dept. of Cardiology
Ljubljana, , Slovenia
Countries
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Central Contacts
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Facility Contacts
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References
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Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec 24;361(26):2518-28. doi: 10.1056/NEJMoa0902604.
Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, Catanese JJ, Buring JE, Devlin JJ, Ridker PM. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009 Apr;203(2):371-6. doi: 10.1016/j.atherosclerosis.2008.07.019. Epub 2008 Jul 26.
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Tada H, Takamura M, Kawashiri MA. Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease. J Atheroscler Thromb. 2019 Jul 1;26(7):583-591. doi: 10.5551/jat.RV17034. Epub 2019 Apr 30.
Machado-Silva W, Alfinito-Kreis R, Carvalho LS, Quinaglia-E-Silva JC, Almeida OL, Brito CJ, Ferreira AP, Cordova C, Sposito AC, Nobrega OT; Brasilia Heart Study Group. Endothelial nitric oxide synthase genotypes modulate peripheral vasodilatory properties after myocardial infarction. Gene. 2015 Sep 1;568(2):165-9. doi: 10.1016/j.gene.2015.05.042. Epub 2015 May 20.
Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O'Shaughnessy KM, Brown MJ. A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999 Oct 5;100(14):1515-20. doi: 10.1161/01.cir.100.14.1515.
Zigra AM, Rallidis LS, Anastasiou G, Merkouri E, Gialeraki A. eNOS gene variants and the risk of premature myocardial infarction. Dis Markers. 2013;34(6):431-6. doi: 10.3233/DMA-130987.
Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene. 2016 Jan 10;575(2 Pt 3):584-99. doi: 10.1016/j.gene.2015.09.061. Epub 2015 Sep 28.
Rehberger Likozar A, Zavrtanik M, Sebestjen M. Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options. Ann Med. 2020 Aug;52(5):162-177. doi: 10.1080/07853890.2020.1775287. Epub 2020 Jun 8.
Rehberger Likozar A, Levstek T, Karun T, Trebusak Podkrajsek K, Zupan J, Sebestjen M. Treatment with PCSK9 inhibitors influences microRNAs expression and changes of arterial wall properties: a randomized controlled trial. Eur J Med Res. 2025 Feb 25;30(1):138. doi: 10.1186/s40001-025-02398-6.
Rehberger Likozar A, Ugovsek S, Sebestjen M. Effects of proprotein convertase subtilisin-kexin type 9 inhibitors on inflammatory and hemostatic parameters in post myocardial infarction patients. Eur J Pharmacol. 2024 Jan 15;963:176232. doi: 10.1016/j.ejphar.2023.176232. Epub 2023 Dec 7.
Likozar AR, Sebestjen M. Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors. Cardiovasc Ultrasound. 2023 Aug 14;21(1):15. doi: 10.1186/s12947-023-00313-9.
Other Identifiers
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GEBI
Identifier Type: -
Identifier Source: org_study_id