Platelet Aggregation in Patients With Coronary Artery Disease and Kidney Dysfunction Taking Clopidogrel or Ticagrelor

NCT03039205 | Completed Phase 2

• 2 other identifiers: FAPESP 2014/01021-44086/14/066
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

About 35% of patients hospitalized with Acute Coronary Syndromes (ACS) have some degree of renal dysfunction. Chronic kidney disease (CKD) is not only associated to worse prognosis in ACS patients, but leads also to an increased risk of bleeding, which may importantly influence the risk-benefit ratio of antiplatelet therapy in this population. The responsible mechanisms for increased rate of ischemic events in this population are not completely elucidated. Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in CKD patients is not well established. This population is often excluded or underrepresented in large clinical trials, and the indication of antiplatelet therapy is often extrapolated from studies in patients with preserved renal function. In recent meta-analysis, Palmer et al. sought to evaluate the benefits and risks of antiplatelet agents in patients with CKD and concluded that in patients with ACS or scheduled for angioplasty already taking aspirin, the addition of clopidogrel or glycoprotein IIb / IIIa inhibitors have little or no impact in reducing the incidence of myocardial infarction, death or need for revascularization. In the PLATO trial, ticagrelor (a new reversible inhibitor of P2Y12 receptor with faster onset of action and greater platelet inhibition) was compared to clopidogrel in patients with high risk ACS and was associated to a 16% risk reduction on the occurrence of death from vascular causes, myocardial infarction, or stroke. In a pre-specified sub-analysis, data from patients with CKD were compared to those obtained from the population with normal renal function and suggests that the benefit of ticagrelor may be even greater in patients with CKD. Two hypotheses were considered to explain these results:

1. 1.Greater and more consistent platelet inhibition achieved with ticagrelor would be more effective in reducing ischemic events in this population at increased thrombotic risk;
2. 2.Pleiotropic effects of ticagrelor besides inhibition of the P2Y12 receptor. Ticagrelor might be associated with an elevation in serum levels of adenosine. This could improve myocardial perfusion through coronary vasodilation, and this effect would be more pronounced in patients with renal dysfunction.

Conditions

Platelet Aggregation; Adenosine; Coronary Artery Disease; Kidney Dysfunction; Antiplatelet Therapy

Keywords

Platelet aggregation; Adenosine; Coronary artery disease; Kidney dysfunction; Ticagrelor; Clopidogrel

Outcome Measures

Primary Outcomes (1)

• Platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor

  Compare the level of inhibition of platelet aggregation evaluated by VerifyNow® P2Y12 (difference between clopidogrel and ticagrelor) in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.

  8 days (±1)

Secondary Outcomes (2)

• Adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor.

  8 days (±1)

• Platelet aggregation (difference between clopidogrel and ticagrelor) evaluated by Multiple electrode platelet aggregometry (Multiplate®) in patients with and without renal dysfunction randomized to treatment with either clopidogrel or ticagrelor

  8 days (±1)

Other Outcomes (34)

• Lipoprotein-a - Lp(a) concentration in the groups with or without renal dysfunction

  8 days (±1)

• Hemoglobin concentration in the groups with or without renal dysfunction

  8 days (±1)

• Leukocytes concentration in the groups with or without renal dysfunction

  8 days (±1)

Study Arms (4)

Chronic kidney dysfunction Clopidogrel

ACTIVE COMPARATOR

Patients with creatinine clearance \<60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group

Drug: Clopidogrel

Chronic kidney dysfunction Ticagrelor

ACTIVE COMPARATOR

Patients with creatinine clearance \<60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group

Drug: Ticagrelor

Normal kidney function Clopidogrel

ACTIVE COMPARATOR

Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group

Drug: Clopidogrel

Normal kidney function Ticagrelor

ACTIVE COMPARATOR

Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group

Drug: Ticagrelor

Interventions

Clopidogrel DRUG

Clopidogrel 600 mg loading dose + 75 mg q.d. for 7 to 9 days

Also known as: Plavix

Chronic kidney dysfunction Clopidogrel; Normal kidney function Clopidogrel

Ticagrelor DRUG

Ticagrelor 180 mg loading dose + 90 mg b.i.d. for 7 to 9 days

Also known as: Brilinta

Chronic kidney dysfunction Ticagrelor; Normal kidney function Ticagrelor

Eligibility Criteria

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

You may qualify if:

• Patients in use of aspirin for at least 7 days prior to randomization;
• Documented obstructive coronary artery disease by angiography;
• At least 12 months from the last episode of myocardial infarction (MI);
• Agree to sign the Informed Consent.

You may not qualify if:

• Prior ischemic or hemorrhagic stroke;
• Prior intracranial bleeding;
• Use of oral anticoagulant in the past month;
• Use of dual antiplatelet therapy in the last 30 days;
• Use of NSAIDs and / or dipyridamole in the past month;
• Mandatory use of proton pump inhibitor;
• Known platelet dysfunction or platelets \<100,000 or \>450,000/μL;
• End-stage renal disease undergoing hemodialysis;
• Terminal illness;
• Known liver disease or coagulation disorder;
• Known pregnancy, breast-feeding, or intend to become pregnant during the study period;
• Hypersensitivity to clopidogrel, ticagrelor or any excipients;
• Refusal to sign the Informed Consent;
• Active pathological bleeding.

Sponsors & Collaborators

• University of Sao Paulo: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (1)

Instituto do Coração (InCor) - Hospital das Clínicas da FMUSP

São Paulo, Brazil

Location

Related Publications (20)

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  PMID: 12186803 BACKGROUND

• Freeman RV, Mehta RH, Al Badr W, Cooper JV, Kline-Rogers E, Eagle KA. Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors. J Am Coll Cardiol. 2003 Mar 5;41(5):718-24. doi: 10.1016/s0735-1097(02)02956-x.

  PMID: 12628712 BACKGROUND

• Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004 Sep 23;351(13):1285-95. doi: 10.1056/NEJMoa041365.

  PMID: 15385655 BACKGROUND

• Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol. 2002 Apr 3;39(7):1113-9. doi: 10.1016/s0735-1097(02)01745-x.

  PMID: 11923033 BACKGROUND

• Fox CS, Muntner P, Chen AY, Alexander KP, Roe MT, Cannon CP, Saucedo JF, Kontos MC, Wiviott SD; Acute Coronary Treatment and Intervention Outcomes Network registry. Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry. Circulation. 2010 Jan 26;121(3):357-65. doi: 10.1161/CIRCULATIONAHA.109.865352. Epub 2010 Jan 11.

  PMID: 20065168 BACKGROUND

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  PMID: 15489090 BACKGROUND

• 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. doi: 10.1136/bmj.324.7329.71.

  PMID: 11786451 BACKGROUND

• Basra SS, Tsai P, Lakkis NM. Safety and efficacy of antiplatelet and antithrombotic therapy in acute coronary syndrome patients with chronic kidney disease. J Am Coll Cardiol. 2011 Nov 22;58(22):2263-9. doi: 10.1016/j.jacc.2011.08.051.

  PMID: 22093501 BACKGROUND

• Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, Copetti M, Graziano G, Tognoni G, Jardine M, Webster A, Nicolucci A, Zoungas S, Strippoli GF. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Mar 20;156(6):445-59. doi: 10.7326/0003-4819-156-6-201203200-00007.

  PMID: 22431677 BACKGROUND

• Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30.

  PMID: 19717846 BACKGROUND

• James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, Harrington RA, Horrow J, Katus H, Keltai M, Lewis BS, Parikh K, Storey RF, Szummer K, Wojdyla D, Wallentin L. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010 Sep 14;122(11):1056-67. doi: 10.1161/CIRCULATIONAHA.109.933796. Epub 2010 Aug 30.

  PMID: 20805430 BACKGROUND

• Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16;130(6):461-70. doi: 10.7326/0003-4819-130-6-199903160-00002.

  PMID: 10075613 BACKGROUND

• Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun. 2012 Feb 24;418(4):754-8. doi: 10.1016/j.bbrc.2012.01.093. Epub 2012 Jan 27.

  PMID: 22306816 BACKGROUND

• Montalescot G, Silvain J. Ticagrelor in the renal dysfunction subgroup: subjugated or substantiated? Circulation. 2010 Sep 14;122(11):1049-52. doi: 10.1161/CIRCULATIONAHA.110.974683. Epub 2010 Aug 30. No abstract available.

  PMID: 20805425 BACKGROUND

• Park SH, Kim W, Park CS, Kang WY, Hwang SH, Kim W. A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure. Am J Cardiol. 2009 Nov 1;104(9):1292-5. doi: 10.1016/j.amjcard.2009.06.049.

  PMID: 19840579 BACKGROUND

• Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol. 2012 Sep;52(9):1388-98. doi: 10.1177/0091270011415526. Epub 2011 Sep 29.

  PMID: 21960668 BACKGROUND

• Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.

  PMID: 19923168 BACKGROUND

• Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, Emanuelsson H, Cannon CP, Becker RC, Wallentin L. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol. 2010 Oct 26;56(18):1456-62. doi: 10.1016/j.jacc.2010.03.100.

  PMID: 20832963 BACKGROUND

• Sibbing D, Braun S, Jawansky S, Vogt W, Mehilli J, Schomig A, Kastrati A, von Beckerath N. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost. 2008 Jan;99(1):121-6. doi: 10.1160/TH07-07-0478.

  PMID: 18217143 BACKGROUND

• Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.

  PMID: 35224730 DERIVED

Related Links

• Isocratic high-performance liquid chromatographic determination of plasma adenosine

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

Clopidogrel; Ticagrelor

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Adenosine; Purine Nucleosides; Purines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• José C Nicolau, M.D. / PhD

  Heart Institute (InCor) / University of São Paulo

  STUDY CHAIR

• André Franci, M.D.

  Heart Institute (InCor) / University of São Paulo

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: January 23, 2017
• First Posted: February 1, 2017
• Study Start: November 7, 2017
• Primary Completion: December 19, 2019
• Study Completion: December 19, 2019
• Last Updated: April 24, 2020

Record last verified: 2020-04

Locations

BR (1)