Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment

NCT04613167 | Unknown DMC

• 1 other identifier: GEBI
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of study is to examine the relationship between lipid subfractions, inflammation and structural-functional properties of the arterial wall in patients with premature coronary heart disease, to study genetic polymorphisms that determine lipid subfractions concentration on the functional and morphological properties of the arterial vascular wall in patients with early coronary heart disease, to study the effect of alirocumab and evolocumab on lipid subfractions, inflammation and structural-functional properties of arterial wall in patients with early coronary atherosclerosis and to study the influence of NOS-3 gene expression on the functional and morphological properties of the arterial vascular wall in the same patients. Impaired blood fat metabolism and chronic inflammation are intertwined as possible causes of atherosclerosis. Lipoprotein (a) (Lp (a)) is an important risk factor for coronary heart disease and a prognostic predictor in patients after myocardial infarction, but recent research suggests that subtilisin-kexin convertase type 9 (PCSK9) inhibitors are the only drugs that significantly reduce serum Lp (a) concentration. However, there are no data on the relationship between Lp (a) values and polymorphisms for Lp (a), indicators of inflammation and impaired arterial function, and response to treatment with various PCSK9 inhibitors in patients with early coronary heart disease.

Conditions

Acute Coronary Syndrome; Premature Coronary Heart Disease; Lipoproteinemia; Inflammation; Genetic Polymorphisms

Keywords

Coronary heart disease; Acute coronary syndrome; Lipoprotein (a); Genetics; Secondary prevention; Endothelium; Inflammation; Genetic polymorphisms; NO synthetase; Dyslipidemia

Outcome Measures

Primary Outcomes (3)

• Ultrasound functional and morphological properties of the arterial wall and Lp (a) concentration

  Functional and morphological characteristics of arterial wall will correlate to Lp (a) concentrations.

  Baseline

• Concentration of Lp (a) and SNP in the LPA gene

  The serum concentration of Lp (a) will correlate with single nucleotide polymorphisms (SNP) in the LPA gene

  Baseline

• The effect of alirocumab or evolocumab on functional and morphological properties of arterial wall after 6 months

  Both drugs will improve functional and morphological properties of arterial wall in with no difference between the drugs. We expect the improvements in each drug group will be in correlation with the decrease of Lp (a) concentration.

  6 months

Study Arms (3)

Alirocumab

EXPERIMENTAL

The first group of patients will receive 150 mg of alirocumab every two weeks subcutaneously for 6 months

Drug: Alirocumab

Evolocumab

EXPERIMENTAL

the second group of patients will receive evolocumab 140 mg every two weeks subcutaneously for 6 months

Drug: Evolocumab

Control group

EXPERIMENTAL

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

Drug: Control group

Interventions

Alirocumab DRUG

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.

Alirocumab

Evolocumab DRUG

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.

Evolocumab

Control group DRUG

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.

Control group

Eligibility Criteria

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

You may qualify if:

• at least 6 months after acute coronary syndrome,
• 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.

You may not qualify if:

• Age \<18 years or \> 65 years,
• 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),
• 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

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Study Sites (1)

University Medical Centre Ljubljana-Department of Vascular diseases and dept. of Cardiology

Ljubljana, 1000, Slovenia

RECRUITING

Related Publications (20)

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  PMID: 30986377 BACKGROUND

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  PMID: 14064818 BACKGROUND

• Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412-23. doi: 10.1001/jama.2009.1063.

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• Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR. Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors. Clin Res Cardiol Suppl. 2019 Apr;14(Suppl 1):45-50. doi: 10.1007/s11789-019-00099-z.

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• Maranhao RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq Bras Cardiol. 2014 Jul;103(1):76-84. doi: 10.5935/abc.20140101.

  PMID: 25120086 BACKGROUND

• Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with elevated and normal Lp(a) concentration. Metabolism. 2019 Jul;96:8-11. doi: 10.1016/j.metabol.2019.04.010. Epub 2019 Apr 14.

  PMID: 30995439 BACKGROUND

• Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016 Apr;57(4):526-37. doi: 10.1194/jlr.R061648. Epub 2015 Dec 4.

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• Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692-711. doi: 10.1016/j.jacc.2016.11.042.

  PMID: 28183512 BACKGROUND

• 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.

  PMID: 20032323 BACKGROUND

• 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.

  PMID: 18775538 BACKGROUND

• Ober C, Nord AS, Thompson EE, Pan L, Tan Z, Cusanovich D, Sun Y, Nicolae R, Edelstein C, Schneider DH, Billstrand C, Pfaffinger D, Phillips N, Anderson RL, Philips B, Rajagopalan R, Hatsukami TS, Rieder MJ, Heagerty PJ, Nickerson DA, Abney M, Marcovina S, Jarvik GP, Scanu AM, Nicolae DL. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res. 2009 May;50(5):798-806. doi: 10.1194/jlr.M800515-JLR200. Epub 2009 Jan 5.

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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.

  PMID: 31061262 BACKGROUND

• 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.

  PMID: 26002446 BACKGROUND

• 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.

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• 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.

  PMID: 23594558 BACKGROUND

• 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.

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• 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.

  PMID: 32453609 BACKGROUND

• 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.

  PMID: 40001082 DERIVED

• 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.

  PMID: 38070635 DERIVED

• 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.

  PMID: 37580777 DERIVED

MeSH Terms

Conditions

Acute Coronary Syndrome; Inflammation; Coronary Disease; Dyslipidemias

Interventions

alirocumab; evolocumab; Control Groups

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Miran Šebeštjen, prof.

  University Medical Centre Ljubljana (Slovenia)

  STUDY CHAIR

• Andreja Rehberger Likozar, MD

  University Medical Centre Ljubljana (Slovenia)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Miran Šebeštjen, prof.

CONTACT

+38615228541; miran.sebestjen@guest.arnes.si, miran.sebestjen@kclj.si

Andreja Rehberger Likozar, MD

CONTACT

+38615228012; rehbergerandreja@gmail.com, andreja.rehbergerlikozar@kclj.si

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, principal Investigator

Study Record Dates

• First Submitted: October 6, 2020
• First Posted: November 3, 2020
• Study Start: November 10, 2020
• Primary Completion: June 30, 2021
• Study Completion: October 1, 2021
• Last Updated: November 3, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

SL (1)