Ignite Creation Date:
2024-05-06 @ 12:43 AM
Last Modification Date:
2024-10-26 @ 10:54 AM
Study NCT ID:
NCT01643031
Status:
UNKNOWN
Last Update Posted:
2013-06-17
First Post:
2012-07-15
Brief Title:
Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients With Diabetes and Low Response to Clopidogrel
Sponsor:
Rabin Medical Center
Organization:
Rabin Medical Center
Study Overview
Official Title:
Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients With Diabetes and Low Response to Clopidogrel
Status:
UNKNOWN
Status Verified Date:
2013-06
Last Known Status:
NOT_YET_RECRUITING
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:
MATTIS-D
Brief Summary:
In recent years numerous studies have shown that the response of patients to the anti-platelet drug clopidogrel is widely variable Furthermore patients who do not respond well to the drug resistant have been shown to be at increased risk to develop cardiac events including myocardial infarction and mortality It thus seems reasonable to test the efficacy of the drug by platelet function tests and modify treatment accordingly However a large study that examined a strategy of routine testing of clopidogrel response in thousands of patients GRAVITAS study did not show any clinical benefit This study was limited however by a very low event rate 23 and by the strategy employed to treat patients with low response increasing the clopidogrel dose which is currently known to be ineffective in many patients with low response To overcome these limitations the investigators plan to examine a high risk population - patients with diabetes planned to undergo coronary angiography - and to treat clopidogrel low responders by switching their treatment to the potent anti-platelet drug ticagrelor which has been shown to overcome clopidogrel low response
The investigators hypothesize that patients with diabetes and low response to clopidogrel will benefit clinically from switching therapy to ticagrelor The main endpoint of the study will be the risk of myocardial enzyme elevation following percutaneous coronary intervention PCI a marker which has been strongly associated with poor clinical outcome
The aim of the study is therefore to assess whether a strategy of monitoring platelet function during clopidogrel treatment in patients with diabetes undergoing PCI and modifying treatment to ticagrelor in patients with low response will be associated with reduced risk of myocardial enzyme release
The investigators plan to enroll patients with treated diabetes planned to undergo coronary angiography Patients with acute or recent myocardial infarction will be excluded They will be tested for response to clopidogrel by the VerifyNow P2Y12 assay either on chronic clopidogrel treatment or 12-24 hours after receiving 300 mg clopidogrel Patients with low response to clopidogrel 208 PRU will be randomized to either continued treatment with clopidogrel 75 mgday or switching of treatment to ticagrelor 90 mg twice a day for 30 days followed by continued clopidogrel therapy The primary endpoint will be the rate of troponin of CK-MB cardiac enzymes measured 20-24 hours after the PCI Secondary endpoints will be the occurrence of adverse clinical endpoints - myocardial infarction need for urgent revascularization or mortality at 30 days The investigators aim to enroll 100 patients in each study group ticagrelor vs continued clopidogrel Assuming a clopidogrel low response rate of 40 among patients with diabetes about 500 patients would have to be screened to identify 200 patients with low response
The investigators hypothesize that patients with diabetes and low response to clopidogrel will benefit clinically from switching therapy to ticagrelor The main endpoint of the study will be the risk of myocardial enzyme elevation following percutaneous coronary intervention PCI a marker which has been strongly associated with poor clinical outcome
The aim of the study is therefore to assess whether a strategy of monitoring platelet function during clopidogrel treatment in patients with diabetes undergoing PCI and modifying treatment to ticagrelor in patients with low response will be associated with reduced risk of myocardial enzyme release
The investigators plan to enroll patients with treated diabetes planned to undergo coronary angiography Patients with acute or recent myocardial infarction will be excluded They will be tested for response to clopidogrel by the VerifyNow P2Y12 assay either on chronic clopidogrel treatment or 12-24 hours after receiving 300 mg clopidogrel Patients with low response to clopidogrel 208 PRU will be randomized to either continued treatment with clopidogrel 75 mgday or switching of treatment to ticagrelor 90 mg twice a day for 30 days followed by continued clopidogrel therapy The primary endpoint will be the rate of troponin of CK-MB cardiac enzymes measured 20-24 hours after the PCI Secondary endpoints will be the occurrence of adverse clinical endpoints - myocardial infarction need for urgent revascularization or mortality at 30 days The investigators aim to enroll 100 patients in each study group ticagrelor vs continued clopidogrel Assuming a clopidogrel low response rate of 40 among patients with diabetes about 500 patients would have to be screened to identify 200 patients with low response
Detailed Description:
BACKGOUND The concept of monitoring platelet reactivity in patients treated with clopidogrel and tailoring treatment according to the results has been under intense debate in recent years There is clear and consistent evidence that there is wide variability in the anti-platelet response to clopidogrel and that patients with low response more accurately termed - high on treatment platelet reactivity are at increased risk of adverse cardiac events - mainly stent thrombosis and myocardial infarction However the only large randomized trial that examined a strategy of routing monitoring of platelet reactivity and response to clopidogrel and tailoring treatment accordingly by increasing the clopidogrel maintenance dose - the GRAVITAS study - was negative Thus although from a physiological perspective it seems reasonable to monitor the effects of a drug with such wide variability and poor prognosis associated with low response clinical evidence in support of routine monitoring is lacking When analyzing the negative results of the GRAVITAS study two main factors should be discussed a very low clinical adverse event rate 23 in each of study the groups probably reflecting a low risk patient population and the strategy chosen to overcome high on treatment platelet reactivity HTPR - increasing the maintenance clopidogrel dose from 75 mg daily to 150 mg daily which is currently known to be ineffective in overcoming clopidogrel HTPR in many of the patients
In light of these potential limitations of the GRAVITAS study the investigators propose a study based on the following aspects
1 A potent strategy to overcome clopidogrel HTPR - treatment with ticagrelor which has been clearly shown to overcome low response to clopidogrel
2 Higher risk population - only patients with treated diabetes shown in the BARI-2D study to have a 10-12 rate of major cardiovascular events at 1 year
3 Rather than a composite clinical endpoint the primary endpoint will be the rate of CK-MB or troponin elevation following percutaneous coronary intervention PCI which has been consistently associated with a higher risk of cardiovascular adverse events and occurs at a rate of about 35 in patients with low response to clopidogrel
The aim of the study is to assess whether a strategy of monitoring platelet reactivity during clopidogrel treatment in patients with diabetes undergoing PCI and modifying the treatment to ticagrelor in patients with HTPR is associated with a lower rate of myocardial enzyme elevation following PCI
METHODS
See inclusion and exclusion criteria in the following sections
Patients treated chronically with clopidogrel 75 mg per day will undergo platelet function testing under this treatment regimen Patients who are clopidogrel naïve will be given 300 mg loading of clopidogrel and be tested about 12-24 hours after this loading dose For all patients platelet function testing will be performed before the coronary angiography
Platelet function testing will be performed with the VerifyNow P2Y12 assay Accumetrics Inc using a cutoff value of 208 reaction units to define HTPR
Patients with HTPR will be randomized 11 to receive either ticagrelor or additional clopidogrel
Ticagrelor regimen 180 mg given 1-2 hours before the coronary angiography followed by 90 mg twice a day for 30 days in case PCI was performed After 30 days the patient will be invited to a special research clinic in the hospital and his treatment will be switched to clopidogrel with 300 mg loading and 75 mg a day thereafter for 11 additional months - for a total period of 1 year The 30 day ticagrelor period was chosen because prior studies have shown that platelet hyper-reactivity and low response to clopidogrel are prominent in the first days after PCI and subside significantly within 30 days after the procedure In addition most cases of stent thrombosis occur in the first month following PCI
Clopidogrel regimen 300 mg given 1-2 hours before coronary angiography in addition to the previous 300 mg load or chronic clopidogrel therapy the patient received followed by 75 mg a day for 1 year case PCI was performed
The investigators aim to enroll a total of 200 patients with HTPR who will undergo PCI - 100 patients in each group ticagrelor vs continued clopidogrel Patients who will not undergo PCI will be withdrawn from the study
Choice of stent during PCI will be left to the operators discretion but given the diabetes status of all patients use of drug eluting stents will be encouraged PCI will be performed according to standard practice and operator preferences regarding to access pre- and post dilatation etc Use of glycoprotein IIbIIIa inhibitors will be discouraged unless in bailout situations Patients who will receive glycoprotein IIbIIIa inhibitors will be excluded from the analysis
An additional VerifyNow P2Y12 test will be performed in the 200 patients with initial HTPR 20-24 hours following the PCI at this time point troponin and CK-MB levels will also be evaluated
Primary endpoint rate of elevation of troponin or CK-MB above the upper limit of normal and above 3 times the upper limit of normal measured 20-24 hours after the PCI
Secondary endpoint rate of major adverse cardiovascular endpoints including death myocardial infarction or urgent target vessel revascularization at 30 days
Sample size calculation assuming a rate of CK-MB or troponin elevation post-PCI of 35 among patients with low response to clopidogrel 100 patients in each group would allow detection of a 50 difference in the primary endpoint between the groups 50 reduction in myocardial enzyme elevation rate with ticagrelor with an alpha of 005 and power of 080 Assuming a HTPR rate of 40 using the 208 VerifyNow cutoff value 500 patients would have to be screened in order to identify 200 patients with HTPR not taking into consideration the patients that would not require PCI and be withdrawn from the study
In light of these potential limitations of the GRAVITAS study the investigators propose a study based on the following aspects
1 A potent strategy to overcome clopidogrel HTPR - treatment with ticagrelor which has been clearly shown to overcome low response to clopidogrel
2 Higher risk population - only patients with treated diabetes shown in the BARI-2D study to have a 10-12 rate of major cardiovascular events at 1 year
3 Rather than a composite clinical endpoint the primary endpoint will be the rate of CK-MB or troponin elevation following percutaneous coronary intervention PCI which has been consistently associated with a higher risk of cardiovascular adverse events and occurs at a rate of about 35 in patients with low response to clopidogrel
The aim of the study is to assess whether a strategy of monitoring platelet reactivity during clopidogrel treatment in patients with diabetes undergoing PCI and modifying the treatment to ticagrelor in patients with HTPR is associated with a lower rate of myocardial enzyme elevation following PCI
METHODS
See inclusion and exclusion criteria in the following sections
Patients treated chronically with clopidogrel 75 mg per day will undergo platelet function testing under this treatment regimen Patients who are clopidogrel naïve will be given 300 mg loading of clopidogrel and be tested about 12-24 hours after this loading dose For all patients platelet function testing will be performed before the coronary angiography
Platelet function testing will be performed with the VerifyNow P2Y12 assay Accumetrics Inc using a cutoff value of 208 reaction units to define HTPR
Patients with HTPR will be randomized 11 to receive either ticagrelor or additional clopidogrel
Ticagrelor regimen 180 mg given 1-2 hours before the coronary angiography followed by 90 mg twice a day for 30 days in case PCI was performed After 30 days the patient will be invited to a special research clinic in the hospital and his treatment will be switched to clopidogrel with 300 mg loading and 75 mg a day thereafter for 11 additional months - for a total period of 1 year The 30 day ticagrelor period was chosen because prior studies have shown that platelet hyper-reactivity and low response to clopidogrel are prominent in the first days after PCI and subside significantly within 30 days after the procedure In addition most cases of stent thrombosis occur in the first month following PCI
Clopidogrel regimen 300 mg given 1-2 hours before coronary angiography in addition to the previous 300 mg load or chronic clopidogrel therapy the patient received followed by 75 mg a day for 1 year case PCI was performed
The investigators aim to enroll a total of 200 patients with HTPR who will undergo PCI - 100 patients in each group ticagrelor vs continued clopidogrel Patients who will not undergo PCI will be withdrawn from the study
Choice of stent during PCI will be left to the operators discretion but given the diabetes status of all patients use of drug eluting stents will be encouraged PCI will be performed according to standard practice and operator preferences regarding to access pre- and post dilatation etc Use of glycoprotein IIbIIIa inhibitors will be discouraged unless in bailout situations Patients who will receive glycoprotein IIbIIIa inhibitors will be excluded from the analysis
An additional VerifyNow P2Y12 test will be performed in the 200 patients with initial HTPR 20-24 hours following the PCI at this time point troponin and CK-MB levels will also be evaluated
Primary endpoint rate of elevation of troponin or CK-MB above the upper limit of normal and above 3 times the upper limit of normal measured 20-24 hours after the PCI
Secondary endpoint rate of major adverse cardiovascular endpoints including death myocardial infarction or urgent target vessel revascularization at 30 days
Sample size calculation assuming a rate of CK-MB or troponin elevation post-PCI of 35 among patients with low response to clopidogrel 100 patients in each group would allow detection of a 50 difference in the primary endpoint between the groups 50 reduction in myocardial enzyme elevation rate with ticagrelor with an alpha of 005 and power of 080 Assuming a HTPR rate of 40 using the 208 VerifyNow cutoff value 500 patients would have to be screened in order to identify 200 patients with HTPR not taking into consideration the patients that would not require PCI and be withdrawn from the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None