Impact of LDL-cholesterol Lowering on Platelet Activation

Familial Hypercholesterolemia Clinical Trial

Official title:

Impact of LDL-cholesterol Lowering on Platelet Activation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03331666
• Other study ID #: AAAR1041
• Status: Terminated
• Phase: Phase 4
• Start date: November 16, 2018
• Est. completion date: February 4, 2020

Study information

• Verified date: March 2021
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol.

The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.

Description:

Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: February 4, 2020
• Est. primary completion date: February 4, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects who have a clinical diagnosis of familial hypercholesterolemia (FH)

• Subjects who are referred to Dr. Ginsberg's Lipid Practice for treatment with PCSK9 inhibitor

• Subjects with LDL cholesterol levels >100 mg/dl on baseline treatment with statins and/or ezetimibe

Exclusion Criteria:

• Children under 18 years of age

Related Conditions & MeSH terms

• Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Evolocumab
140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia

Locations

Country	Name	City	State
United States	Columbia University Medical Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Columbia University	Amgen

Country where clinical trial is conducted

United States, 

References & Publications (20)

Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29. — View Citation

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Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study. JACC Cardiovasc Interv. 2013 Feb;6(2):169-79. doi: 10.1016/j.jcin.2012.09.013. — View Citation

Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. Pharmacodynamic effects of adjunctive high dose atorvastatin on double dose clopidogrel in patients with high on-treatment platelet reactivity depending on diabetes mellitus status. J Thromb Thrombolysis. 2014 May;37(4):427-34. doi: 10.1007/s11239-013-0966-0. — View Citation

Owens AP 3rd, Passam FH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, Williams JC, Hubbard BK, Dutton JA, Wang J, Tobias PS, Curtiss LK, Daugherty A, Kirchhofer D, Luyendyk JP, Moriarty PM, Nagarajan S, Furie BC, Furie B, Johns DG, Temel RE, Mackman N. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest. 2012 Feb;122(2):558-68. doi: 10.1172/JCI58969. Epub 2012 Jan 3. — View Citation

Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015 Mar 16;11(1):115-21. doi: 10.5114/aoms.2015.49216. Epub 2015 Mar 14. — View Citation

Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21. — View Citation

Puccetti L, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palazzuoli A, Angori P, Auteri A, Bruni F. Time-dependent effect of statins on platelet function in hypercholesterolaemia. Eur J Clin Invest. 2002 Dec;32(12):901-8. — View Citation

Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1405-10. — View Citation

Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15. — View Citation

Sikora J, Kostka B, Marczyk I, Krajewska U, Chalubinski M, Broncel M. Effect of statins on platelet function in patients with hyperlipidemia. Arch Med Sci. 2013 Aug 30;9(4):622-8. doi: 10.5114/aoms.2013.36905. Epub 2013 Aug 8. — View Citation

Undas A, Brummel-Ziedins KE, Potaczek DP, Stobierska-Dzierzek B, Bryniarski L, Szczeklik A, Mann KG. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost. 2006 Nov;4(11):2397-404. Epub 2006 Aug 14. — View Citation

Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation. 2013 Jan 15;127(2):251-7. doi: 10.1161/CIRCULATIONAHA.112.145334. Review. — View Citation

Wada H, Mori Y, Kaneko T, Wakita Y, Nakase T, Minamikawa K, Ohiwa M, Tamaki S, Tanigawa M, Kageyama S, et al. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol. 1993 Oct;44(2):112-6. — View Citation

Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1. Review. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU))	ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU	Day 7, Day 14, Day 21, Day 28, Day 84
Primary	Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU))	ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU)	Day 7, Day 14, Day 21, Day 28, Day 84