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

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ClinicalTrials.gov Identifier: NCT03039205
Recruitment Status : Recruiting
First Posted : February 1, 2017
Last Update Posted : April 18, 2019
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Jose Carlos Nicolau, University of Sao Paulo

Tracking Information
First Submitted Date  ICMJE January 23, 2017
First Posted Date  ICMJE February 1, 2017
Last Update Posted Date April 18, 2019
Actual Study Start Date  ICMJE November 7, 2017
Estimated Primary Completion Date December 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
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 [ Time Frame: 8 days (±1) ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03039205 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
  • 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. [ Time Frame: 8 days (±1) ]
    Compare adenosine plasma concentration evaluated by isocratic high-performance liquid chromatographic technique, in patients with coronary artery disease with and without renal dysfunction undergoing treatment with ASA in combination with clopidogrel or ticagrelor.
  • 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 [ Time Frame: 8 days (±1) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 30, 2017)
  • Lipoprotein-a - Lp(a) concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Hemoglobin concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Leukocytes concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Platelet count in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Prothrombin time in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Activated partial thromboplastin time in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Creatinine concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Urea concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Total and free cholesterol concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Free fatty acids concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Cholesterol-ester transfer protein activity in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • LDL-cholesterol concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • HDL cholesterol concentration, size and transport in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Triglycerides concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Fasting glucose concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Glycated hemoglobin in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Ultra-sensitive C-reactive protein (usCRP) concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Interleukin-6 (IL-6) concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Plasminogen activator inhibitor (PAI-1) concentration in the groups with or without renal dysfunction [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: gender (male x female) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: diabetes (present or absent) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: smoking status (yes or no) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: hypertension (presence or absence) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: levels of LDL (<70 or ≥ 70 mg / dl) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: elderly and non-elderly (≥ or <75 years) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: weight (<or ≥ 60 kg) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: body mass index (<30 or ≥ 30kg/m2) [ Time Frame: 8 days (±1) ]
  • Compare platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration in the following subgroups: creatinine clearance (≥60 ml/min, <60 to 30 ml/min and <30 ml/min). [ Time Frame: 8 days (±1) ]
  • Analyze the influence of angiotensin converting enzyme inhibitors or angiotensin receptor subtype 1 (AT1) blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration [ Time Frame: 8 days (±1) ]
  • Analyze the influence of oral hypoglycemic agents on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration [ Time Frame: 8 days (±1) ]
  • Analyze the influence of insulin on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration [ Time Frame: 8 days (±1) ]
  • Analyze the influence of beta-blockers on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration [ Time Frame: 8 days (±1) ]
  • Analyze the influence of proton pump inhibitors (PPI) on platelet aggregation (VerifyNow and Multiplate) and adenosine plasma concentration [ Time Frame: 8 days (±1) ]
  • Analyze, in the studied groups with or without renal dysfunction, the incidence of dyspnea. [ Time Frame: 8 days (±1) ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Platelet Aggregation in Patients With Coronary Artery Disease and Kidney Dysfunction Taking Clopidogrel or Ticagrelor
Official Title  ICMJE Evaluation of Platelet Aggregation and Adenosine Levels in Patients With Coronary Artery Disease and Chronic Kidney Dysfunction Taking Dual Antiplatelet Therapy With Aspirin and Clopidogrel or Ticagrelor
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. 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. 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.

This project aims to validate (or not) these hypotheses, analyzing platelet aggregation and circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin and clopidogrel or ticagrelor.

Detailed Description

Previous publications demonstrated that about 35% to 40% of patients hospitalized with Acute Coronary Syndromes (ACS) have some degree of renal dysfunction. On the other hand, 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. Even at early stages, CKD increases the risk of myocardial infarction and death among different spectra of ACS, and the risk increase is directly proportional to the degree of renal dysfunction. The responsible mechanisms for the increased rate of ischemic events in this population are not completely elucidated. However, accelerated atherosclerosis, oxidative stress, inflammation and increased platelet aggregation, as well as underutilization of therapies such as antithrombotic agents and invasive procedures, are some of the proposed mechanisms.

Antiplatelet therapy is of paramount importance in the treatment of ACS, but its benefit in CKD patients is not well established. The fact that this population is often excluded or underrepresented in large clinical trials, makes the indication for its use be very often extrapolated from studies in patients with preserved renal function.

In recent meta-analysis, Palmer et al. sought to summarize the benefits and risks of antiplatelet agents in patients with CKD, focusing on the occurrence of cardiovascular events (including mortality) and bleeding. The results led them to conclude that: 1) the evidence for the use of antiplatelet agents in patients with CKD and cardiovascular disease is of low quality, 2) in patients with ACS or scheduled for angioplasty already taking acetylsalicylic acid (ASA), 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, and 3) there was a significant 40% increase in the incidence of major bleeding.

In the PLATO trial - "Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes" - ticagrelor, a new reversible inhibitor of the P2Y12 receptor with faster onset of action and greater platelet inhibition power was compared to clopidogrel in over 18,000 patients with high risk ACS. In this publication, patients receiving ticagrelor had a 16% risk reduction on the occurrence of primary composite endpoint (death from vascular causes, myocardial infarction or stroke) without significant increase in the incidence of major bleeding. In a secondary outcome analysis, it was found a significant reduction in mortality from vascular causes and mortality from any cause in patients treated with ticagrelor. Among the high-risk criteria used in the selection of patients for this study, a creatinine clearance <60 ml/min/1.73 m2 was included.

In a following article, considering a pre-specified sub-analysis from the PLATO trial, the results of 3,237 patients who had this high-risk criterion were compared to those obtained for the population with normal renal function. The developed comparisons suggest that the benefit of ticagrelor may be even greater in patients with CKD: when considering the MDRD equation to estimate renal function, the hazard-ratio (HR) for the primary outcome of the study was 0.71 for patients with renal impairment (creatinine clearance <60 ml/min/1.73m2) and 0.90 for those without renal dysfunction (p = 0.03 for interaction). Furthermore, the HRs for mortality were, respectively, 0.79 and 0.91 for patients with and without renal dysfunction (P = 0.02 for interaction). Interestingly, no significant difference between groups relatively to major bleeding was observed, and the incidence of dyspnea was higher in the population without renal dysfunction.

Two hypotheses were considered to explain these results. The first suggests that a greater and more consistent platelet inhibition achieved with ticagrelor would be more effective in reducing ischemic events in this population at increased thrombotic risk. The second hypothesis considers possible pleiotropic effects of ticagrelor besides the reversible inhibition of the P2Y12 receptor. Ticagrelor might be associated with an elevation in serum levels of adenosine through the inhibition of its reuptake by erythrocytes and by increased release of adenosine triphosphate (ATP) from the same erythrocytes, subsequently converted in adenosine by ecto-ATPases. An increase in the concentrations of circulating adenosine could improve myocardial perfusion through coronary vasodilation, and this effect would be more pronounced in patients with renal dysfunction.

Thus, this project aims to validate (or not) these hypotheses, analyzing platelet aggregation and circulating adenosine levels in patients taking dual antiplatelet therapy with aspirin and clopidogrel or ticagrelor.

# Safety: as this protocol was designed for a short-term duration, we do not expect to have many adverse events (AE). An AE is any untoward medical occurrence in a participant that does not necessarily have a causal relationship with the study intervention. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure. AEs will be reported as soon as possible.

Serious adverse events (SAE) are defined as any untoward medical occurrence that meets any one of the following criteria:

  1. Results in death or is life-threatening at the time of the event;
  2. Requires inpatient hospitalization, or prolongs a hospitalization;
  3. Results in a persistent or significant disability/incapacity;
  4. Is a congenital anomaly/birth defect (in a participants offspring); or
  5. Is medically judged to be an important event that jeopardized the subject and, for example, required significant measures to avoid one of the above outcomes.

SAEs will be reported within 24 hours of its information received. The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the investigator(s) and the investigator is responsible for informing the local authorities and ethical committees, of any serious adverse events as per local requirements.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Platelet Aggregation
  • Adenosine
  • Coronary Artery Disease
  • Kidney Dysfunction
  • Antiplatelet Therapy
Intervention  ICMJE
  • Drug: Clopidogrel
    Clopidogrel 600 mg loading dose + 75 mg q.d. for 7 to 9 days
    Other Name: Plavix
  • Drug: Ticagrelor
    Ticagrelor 180 mg loading dose + 90 mg b.i.d. for 7 to 9 days
    Other Name: Brilinta
Study Arms  ICMJE
  • Active Comparator: Chronic kidney dysfunction Clopidogrel
    Patients with creatinine clearance <60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group
    Intervention: Drug: Clopidogrel
  • Active Comparator: Chronic kidney dysfunction Ticagrelor
    Patients with creatinine clearance <60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group
    Intervention: Drug: Ticagrelor
  • Active Comparator: Normal kidney function Clopidogrel
    Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to clopidogrel group
    Intervention: Drug: Clopidogrel
  • Active Comparator: Normal kidney function Ticagrelor
    Patients with creatinine clearance ≥60ml/min/m2 (estimated by MDRD formula) randomized to ticagrelor group
    Intervention: Drug: Ticagrelor
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 30, 2017)
112
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2019
Estimated Primary Completion Date December 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: André Franci, M.D. 55 11 2661-5850 andrefranci@gmail.com
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03039205
Other Study ID Numbers  ICMJE FAPESP 2014/01021-4
4086/14/066 ( Other Identifier: CAPPesq )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Jose Carlos Nicolau, University of Sao Paulo
Study Sponsor  ICMJE University of Sao Paulo
Collaborators  ICMJE Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators  ICMJE
Study Chair: José C Nicolau, M.D. / PhD Heart Institute (InCor) / University of São Paulo
Principal Investigator: André Franci, M.D. Heart Institute (InCor) / University of São Paulo
PRS Account University of Sao Paulo
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP