Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients With Diabetes and Low Response to Clopidogrel

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 (2.3% 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 1:1 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 operator's 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 IIb/IIIa inhibitors will be discouraged, unless in bailout situations. Patients who will receive glycoprotein IIb/IIIa 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 0.05 and power of 0.80. 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).