Viewing Study NCT05122455



Ignite Creation Date: 2024-05-06 @ 4:53 PM
Last Modification Date: 2024-10-26 @ 2:18 PM
Study NCT ID: NCT05122455
Status: RECRUITING
Last Update Posted: 2023-06-23
First Post: 2021-10-19

Brief Title: Effects of Edoxaban on Platelet Aggregation
Sponsor: University of Sao Paulo
Organization: University of Sao Paulo

Study Overview

Official Title: Effects of Edoxaban on Platelet Aggregation in Patients With Stable Coronary Artery Disease
Status: RECRUITING
Status Verified Date: 2023-06
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: Edoxaban
Brief Summary: Rationale The interaction between nonvitamin K oral anticoagulants NOACs and platelet aggregation is complex The direct activated factor X inhibitors factor Xa inhibitors an NOAC antagonizes thrombin generation one of most important platelet agonist so that factor Xa inhibitors has a potential effect in decreasing thrombin-mediated platelet aggregation On the other hand patients who experience ACS continue to have a hypercoagulable state for long periods after the index event The COMPASS trial showed that in patients with stable coronary artery disease SCAD Rivaroxaban a direct anti-Xa inhibitor in addition to antiplatelet agent compared to antiplatelet therapy alone reduced the composite endpoint of myocardial infarction stroke and death

Objective Analyze the role of edoxaban on platelet aggregation in SCAD patients

Methods and Results This is a prospective non-randomized interventional study of SCAD patients taking low-dose acetylsalicylic acid ASA Subjects initially will receive in the following sequence ASA 100 mg once daily QD plus edoxaban 60 mg QD clopidogrel 75 mg QD alone clopidogrel 75 mg QD plus edoxaban 60 mg QD and edoxaban 60 mg QD alone Platelet function will be assessed by standard of care technology at baseline and after each intervention phase by Multiplate-ADP primary endpoint Multiplate-Aspi and Multiplate-TRAP In addition to immature platelets fraction IPF and count IPC Coagulability will be assessed at baseline and after each intervention phase by thromboelastogram TEG assessment Specifically after the phases in which edoxaban will be administered activated factor X FXa level and Plasminogen activator inhibitor-1 PAI-1 will be evaluated in addition to previous Finally inflammatory markers will be at same way assessed at baseline and after intervention each phase ultrasensitive C-reactive protein us-PCR

Keywords edoxaban direct factor Xa inhibitor stable coronary artery disease aspirin clopidogrel platelet aggregation
Detailed Description: 1 Introduction

Stable coronary artery disease SCAD is the leading cause of deaths attributable to cardiovascular disease in the United States 720000 new coronary events are expected - defined as the first acute myocardial infarction AMI hospitalized or death from SCAD - and approximately 335000 recurring events per year

Patients who survive the initial phase of acute coronary syndrome ACS remain at risk of cardiac complications sudden death re infarction or recurrent rest angina complications related to the development of coronary thrombosis

The most common cause of coronary thrombosis is plaque rupture followed by plaque erosion The plaque rupture represents a stimulus for both thrombosis and coagulation because thrombin activates platelets and converts fibrinogen into fibrin characteristic of the white arterial thrombus Therefore the process of arterial thrombus generation involves both platelet aggregation and blood coagulation

The importance of the coagulation system underlying plaque complications was addressed by Ardissino et al in the Global Use of Strategies To Open ocluded coronary artteries GUSTO IIb a prospective multicenter cohort study that evaluated the importance of persistently elevated thrombin generation for outcome in 319 consecutive patients with ACS In this study the authors concluded that after an episode of ACS thrombin generation levels were significantly correlated with a worse U-shaped result

Orbe et al showed that patients with a previous history of ACS being treated with platelet antiaggregants generated a higher amount of thrombin earlier and faster when compared to stable patients Their results suggest that these patients could benefit from more potent antithromboticanticoagulant agents to prevent thrombin activation and generation Different anticoagulant drugs have been studied for secondary prevention after ACS to reduce mortality and recurrence of ischemic events

Directly activated X factor inhibitors factor Xa inhibitors antagonize thrombin generation Two representatives of this class rivaroxaban and apixaban were evaluated in the context of ACS

Atlas ACS-2 a phase III trial was designed to evaluate the effect of low-dose rivaroxaban 25-5 mg twice daily versus placebo in 15526 patients with recent ACS The primary outcome composed of cardiovascular death AMI or stroke was significantly reduced with both doses compared to placebo 89 vs 107 HR 084 P 0008 Major hemorrhagic events were higher with rivaroxaban in both doses when compared with placebo 21 vs 06 P 0001 there were fewer fatal hemorrhagic events with the lowest dose of rivaroxaban compared to the highest dose 01 vs 04 respectively P 004

APPRAISE-2 was a randomized double-blind placebo-controlled phase III study that compared apixaban 5 mg twice daily with placebo in addition to standard antiplatelet therapy in patients with recent ACS It was discontinued prematurely after recruiting 7392 patients because major bleeding events were significantly greater in the apixaban group 13 apixaban vs 05 control HR 259 P 0001 in the absence of a counterbalance reduction in recurrent ischemic events primary endpoint cardiovascular death AMI or ischemic stroke 75 event rate in the apixaban v group 79 in the placebo group HR 095 P 051

In patients with SCAD the phase III COMPASS study involved 27395 subjects randomized to receive rivaroxaban 25 mg twice daily plus aspirin ASA 100 mg once daily rivaroxaban 5 mg twice daily or ASA 100 mg once a day The incidence of the primary composite endpoint of cardiac death stroke or AMI was significantly lower in the rivaroxaban plus aspirin group compared to the aspirin-only group 41 versus 54 HR 076 P 0001 On the other hand major bleeding events were significantly higher in the rivaroxaban plus aspirin group compared to the aspirin only group HR 17 P 0001 but intracranial and fatal bleeding events were similar in both groups In patients with an indication for anticoagulation after an ACS episode eg patients with atrial fibrillation guidelines recommend the use of triple antithrombotic therapy double antiplatelet in addition to anticoagulant initially followed by dual antithrombotic therapy for 1 month to one year and after 1 year only keep the anticoagulant However in cases of very high ischemic risk especially if there is a low hemorrhagic risk some choose to keep the antiplatelet drug at the same time and the antiplatelet drug can be maintain

Therefore the demonstration of antiplatelet activity in a factor Xa inhibitor would be useful in order to reinforce its use in isolation after the first year of the acute episode even in patients with high ischemic risk It has been shown in vitro that edoxaban a direct factor Xa inhibitor is a potent inhibitor of tissue factor-induced platelet aggregation and its use has increased the antiplatelet effects of clopidogrel and aspirin Despite this in vitro demonstration there are no in vivo studies analyzing the action of this drug on platelet reactivity The present project was designed to provide information on this important issue analyzing the role of edoxaban on platelet aggregation in patients with SCAD or a history of AMI for more than 12 months

21 Primary objective To compare platelet aggregability in patients with SCAD using the Multiplate-TRAP method at the start of ASA use and after 10 2 days of the association of edoxaban and ASA

22 Secondary objective

Comparison of platelet aggregability in different scenarios

111 Measured by Multiplate-ADP Multiplate-Aspi at baseline and after 10 2 days of edoxaban and ASA

112 Measured by Multiplate-ADP Multiplate-Aspi and Multiplate-TRAP before and after 10 2 days of edoxaban and clopidogrel compared to clopidogrel alone 113 Measured by Multiplate-ADP Multiplate-Aspi and Multiplate-TRAP before and after 10 2 days of edoxaban only compared to AAS only 114 Measured by Multiplate-ADP Multiplate-Aspi and Multiplate-TRAP before and after 10 2 days of edoxaban only compared to clopidogrel alone 115 Measured by Multiplate-ADP Multiplate-Aspi and Multiplate-TRAP before and after 10 2 days of edoxaban plus clopidogrel compared to 10 2 days of edoxaban and AAS

23 Other secondary goals 116 Dosage of the following parameters

1 Total immature platelets IPC and fractions IPF and inflammatory markers ultrasensitive CRP after each intervention phase
2 Thromboelastography TEG after each intervention phase
3 Dosing of plasminogen activator inhibitor type 1 PAI-1 and factor Xa activity after each intervention phase in which edoxaban is administered
4 Analyze the primary objective of the study in the following subgroups

Gender malefemale
Diabetes presence or not
Current or not smoking
Elderly 65 years old and non-elderly

3 Methods 31 Study design Prospective open intervention non-randomized study that will be conducted at Heart Institute InCor HCFMUSP

After signing the free and informed consent form the patient will undergo a physical examination and be classified by the HAS-BLED according to the risk of bleeding then blood samples will be collected for safety assessment complete blood count coagulation kidney and liver function tests

Eligible patients for the study will be evaluated at five more visits in addition to the screening visit In four of the remaining visits there will be different interventions first visit second visit third visit and fourth visit

The following laboratory tests will be performed at the beginning and after each intervention phase Multiplate-ADP Multiplate-Aspi Multiplate-TRAP IPF and IPC Ultrasensitive PCR and TEG Specifically after the phases in which edoxaban will be administered FXa and PAI-1 level activity will be further evaluated

32 Study procedures

During the intervention phases eligible patients will sequentially receive ASA 100 mg 1xday edoxaban 60 mg 1xday for a period of 10 2 days Subsequently ASA and edoxaban will be suspended and clopidogrel 75 mg once a day will be administered for 10 2 days washout period of the ASA Subsequently it will be associated with edoxaban 60 mg once a day to clopidogrel 75 mg once a day for 10 2 days and finally only edoxaban 60 mg once a day for 10 2 days will be administered After the end of the interventions the ASA 100 mg once a day will be restarted All study medications and procedures will be fully paid for by those responsible for the study without any burden to the Unified Health System or to Supplementary Health

Criteria for stopping current medication

The study drug should be discontinued in the event of major bleeding defined by the presence of at least one of the following criteria fall in hemoglobin level greater than or equal to 20gdL or transfusion of two or more units of packed red blood cells bleeding from a critical site or organ such as intracranial intraspinal intraocular pericardial intraarticular intramuscular with compartment syndrome retroperitoneal or fatal hemorrhage

Bleeding that does not meet the criteria for major bleeding but that has been associated with a medical intervention an unscheduled contact visit with a physician or associated with discomfort for the subject such as pain or impairment of activities of daily living will be considered clinically relevant but not severe bleeding

33 Selection The patients included will be selected from the outpatient clinics of the Heart Institute InCor HCFMUSP and from the database of the Thematic project Platelet aggregation and antiaggregation in patients with coronary artery disease SDC 4086 14066 FAPESP 201401021-4 of the InCor Acute Coronary Disease Unit

34 Inclusion criteria

1 Patients aged between 18 and 75 years
2 Confirmed diagnosis of CAD using ASA 100 mg once a day The following will be considered for SCAD diagnosis previous history of type 1 AMI at least one year ago according to the fourth universal definition of myocardial infarction andor coronary angioplasty andor coronary artery bypass graft surgery myocardium andor coronary angiography showing at least 50 obstruction in one of the main epicardial vessels
3 Agreement to sign the free and informed consent form

35 Exclusion criteria

Clinically active bleeding or clinically significant bleeding in the last year
Peptic ulcer active in the last 60 days
Previous history of high gastrointestinal bleeding
Hemoglobin 10 g dl at randomization
Platelets 100000 or 500000 µL
Need for lumbar puncture
Atrial fibrillation
Metal valve prosthesis
Percutaneous coronary intervention PCI in the last 3 months with conventional stent and in the last 6 months with drug-eluting stent
Surgical myocardial revascularization CABG in the last 90 days
Percutaneous coronary intervention PCI or surgical myocardial revascularization CABG planned within the next 60 days
Previous hemorrhagic stroke
Moderate or severe liver failure associated with coagulation disorders Child-Pugh B or C
Hypersensitivity to edoxaban or formula components
Pregnant women or women of childbearing potential
Chronic kidney disease glomerular filtration rate estimated at 50 mLmin173m² calculated using the Cockcroft-Gault equation
Current or last 30 days use of anticoagulant or antiplatelet therapy except ASA
Weight 60 kg
HAS-BLED score 3 points
Concomitant use of P-glycoprotein inhibitors such as azithromycin clarithromycin erythromycin itraconazole ketoconazole verapamil quinidine except amiodarone
Concomitant use of P-glycoprotein inducers such as Rifampicin
Known abuse of alcohol drugs or medications in the 12 months prior to consent for this study
Cancer therapy 5 years prior to consent for this study
Medicines that will further increase the risk of bleeding such as nonsteroidal anti-inflammatory drugs
Participation in another study within 30 days of signing the consent form

36 Procedures

Blood samples

All blood samples will be collected between 800 am and 1200 pm 2 to 4 hours after the last drug ingestion after 30 minutes of rest by antecubital venipuncture with a 21-gauge needle Within 2 hours after collection platelet function tests Multiplate will be performed The other samples will be centrifuged at 3000 rpm stored in aliquots and subsequently frozen at -80 degrees Celsius for further analysis by enzyme immunoassay ELISA

Description of laboratory tests

1 Multiple electrode aggregometry - MEA Multiplate from Roche a volume of 30 ml of blood will be collected in a hirudin tube 300 µL of this sample is diluted with 300 µL of 09 NaCl and incubated in a test cuvette at 37C for 3 minutes Then as recommended by the manufacturer platelet aggregation will be induced by the addition of arachidonic acid ASPItest ADP ADPtest or TRAP-6 TRAPtest The platelet aggregation response will be continuously recorded for 6 minutes The increase in impedance due to the fixation of platelets to the electrodes is detected for each sensor unit separately and transformed into aggregation units AU which are plotted Approximately 8 AU corresponds to 1 Ohm Aggregation measured with Multiplate is quantified as AU and area under the curve AUC of aggregation units AU min Multiplate displays and documents aggregation tracings providing a qualitative assessment of platelet function
2 PCRus will be determined by the IMMULITE automated analyzer Immulite DPC medLAB Los Angeles USA
3 PAI-1 inhibits the serine protease urokinase uPA and tissue plasminogen activator tPA resulting in the inhibition of fibrinolysis The elevation of plasma PAI-1 has been described as a prothrombotic factor in arterial and venous thromboembolic disorders Furthermore high levels of PAI-1 are associated with an increased incidence of acute coronary syndromes The determination of plasma PAI-1 will be performed by ELISA
4 ROTEM The viscoelastic properties of the clot such as clot formation clotting time and clot formation time clot strength maximum clot firmness alpha angle and clot lysis will be determined using the ROTEM delta device Instrumentation Laboratory Bedford MA USA
5 Anti-XA The Liquid Anti-Xa chromogenic method will be performed with specific calibrators and controls for edoxaban manufacturer Stago Diagnostica Stago France in automated coagulation equipment STA-R and STA Compact Diagnostica Stago France STA Liquid Anti-Xa are intended for the quantitative determination in plasma of edoxaban measuring its direct anti-Xa activity in a competitiveness study

Edoxaban levels are given in ngmL The detection limit on the STA-R and STA Compact is 20 ngmL and the linearity range extends up to 400 ngmL The test will be performed on platelet poor plasma PPP

4 Sample size

Previous publications analyzing platelet aggregation in patients with CAD by Multiplate-TRAP Roche showed a mean platelet reactivity of 102 26 AUC Assuming that the standard deviation of the difference is the same standard deviation as the mean and a 20 decrease in platelet aggregability after the use of edoxaban an alpha error of 001 two-tailed considering the multiplicity adjustment by Bonferroni - see below and a power of 95 a sample size of 57 patients was obtained Based on these calculations and considering possible losses to follow-up approximately 20 we propose a sample of 70 patients to be analyzed in this study

5 Statistical analysis The results will be presented as number and percentage categorical variables continuous variables will be presented as means SD Gaussian distribution or medians and interquartile values non-Gaussian distribution Due to the paired design the interest groups will not be independent from each other Because of this comparisons between them in relation to continuous variables will be made using the Student t test for paired samples for variables with normal distribution or the Wilcoxon signed rank test for non-Gaussian distribution variables Due to the multiplicity of hypotheses 5 in total the sample size calculation has already been adjusted by Bonferroni leading to an overall type 1 error of 5 Therefore for each individual comparison edoxaban aspirin versus aspirin edoxaban clopidogrel versus clopidogrel etc a p001 will be considered statistically significant Regarding the tests the multiplicity adjustment will take into account the Multiplate-TRAP while Multiplate-ADP and Multiplate-Aspi will be considered exploratory

6 Ethical issues This protocol is in accordance with the recommendations contained in the Declaration of Helsinki and was approved together with the Informed Consent Form attached by the Scientific Committee of InCor and by the Research Ethics Committee of HCFMUSP CAAE43768921600000068

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: False
Is a FDA Regulated Device?: False
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: False
Is an FDA AA801 Violation?: None