Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients With Diabetes and Low Response to Clopidogrel
试验速览
- 阶段
- 4 期
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- 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.
研究概览
简要总结
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 (2.3%), 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 mg/day), 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.
详细描述
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:
- A potent strategy to overcome clopidogrel HTPR - treatment with ticagrelor, which has been clearly shown to overcome low response to clopidogrel.
- 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).
- 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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 30 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with diabetes treated with oral hypoglycemic medications and/or insulin.
- •Aged 30-80 years.
- •Patients with stable angina and a positive non-invasive test, or patients with unstable angina, all planned to undergo coronary angiography.
- •Treated with aspirin 75-100 mg per day.
排除标准
- •Any myocardial infarction (STEMI or non-STEMI) as the indication for the cardiac catheterization. Thus, only troponin-negative and CK-MB negative patients will be included.
- •Any contraindications to ticagrelor or clopidogrel.
- •Anemia (Hg<10 g/dL) or thrombocytopenia (<100,000 / mm3)
- •Chronic renal failure (Cr ≥ 2.5 mg/dL)
研究组 & 干预措施
Ticagrelor
Patients randomized to the ticagrelor group will receive ticagrelor at a dose of 180 mg given 1-2 hours before the coronary angiography, followed by 90 mg twice a day for 30 days after the PCI. After 30 days the patient will be invited to a special research clinic in the hospital and his treatment will be switched back to clopidogrel (to complete 1 year of treatment).
干预措施: Ticagrelor (Drug)
Continued Clopidogrel
Patients randomized to continued clopidogrel treatment will be given an additional 300 mg of clopidogrel loading 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 after the PCI
干预措施: Continued clopidogrel (Drug)
结局指标
主要结局
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.
时间窗: 20-24 hours after the PCI
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.
次要结局
- Rate of major adverse cardiovascular endpoints including death, myocardial infarction or urgent target vessel revascularization at 30 days(30 days)
研究者
eli lev
Prof. Eli Lev, Director, Cardiac catheterization laboratory, Hasharon Hospital, Rabin Medical Center, Israel
Rabin Medical Center