Impact of Pre-treatment With 600mg of Clopidogrel (Plavix) on the Incidence of Ischemic and Hemorrhagic Complications in Patients Undergoing Elective Percutaneous Coronary Revascularization.--Prospective Randomized Trial.
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Cumulative Incidence of bleeding and major vascular complications
研究概览
简要总结
Patients who have stents placed in their coronary arteries require treatment with at least two medications to prevent platelets from sticking to the stainless steel stent and forming a blood clot that can result in a heart attack. The 2 anti-platelet medications used for most patients with stents are aspirin and clopidogrel (Plavix). These are usually prescribed for 1-12 months (the length of time depends on the number and types of stents implanted). Although the typical long-term dose of clopidogrel is 75 mg by mouth once daily, a larger dose (known as a loading dose) is usually given at the start of treatment to help the medication take effect more quickly.
Prior to January 2006, most patients at the Beth Israel Deaconess Medical Center (BIDMC) who were undergoing PCI and who had not already been taking clopidogrel would receive a loading dose of 300-600 mg of clopidogrel in the cardiac catheterization procedure room immediately after the angioplasty and stenting portion of the procedure. However, several recent studies suggest that administering clopidogrel 600 mg at least two hours prior to an angioplasty procedure can reduce the rate of complications afterwards (especially reducing the chances of detectable damage to the heart muscle).
The main purpose of this study is to see whether giving a loading dose of clopidogrel 600 mg to outpatients scheduled to undergo cardiac catheterization with coronary angiography can decrease the risk of procedure-related complications during the 14 days following the cardiac catheterization compared to a strategy of giving clopidogrel 600 mg after the procedure only to those who undergo angioplasty. We will focus our attention particularly on detecting damage to heart muscle following angioplasty (which might be expected to improve with a loading dose of clopidogrel before the procedure) and on bleeding and other groin complications (which might worsen with clopidogrel loading before the procedure).
The drug clopidogrel has been approved by the Food and Drug Administration (FDA) for use in patients with a recent or ongoing heart attack, narrowings in major blood vessels outside the heart, or recent stroke with a loading dose of 300 mg followed by 75 mg once daily. It has been used in several large studies with a loading dose of 600 mg without a significant increase in major adverse effects. However, we do not yet know if it is useful or safe when given as a loading dose of 600 mg before cardiac catheterization for outpatients with stable symptoms and who are not thought to be in the midst of a heart attack.
详细描述
SIGNIFICANCE AND BACKGROUND FOR THE STUDY The benefits of dual anti-platelet therapy with full dose aspirin and a thienopyridine have been firmly established in patients undergoing coronary stenting. Leon showed reduction in the combined end-point of death, myocardial infarction, target vessel revascularization and stent thrombosis from 3.5% with aspirin alone to 2.3% with aspirin and ticlopidine. This benefit was associated, however, with an increased rate of bleeding and vascular complications of 5.5% with aspirin+ticlopidine versus 1.8% with aspirin alone. Multiple other studies have evaluated the safety and efficacy of the thienopyridine clopidogrel in percutaneous coronary intervention (PCI). In patients at intermediate risk (without elevation of troponin-T prior to PCI), pretreatment with clopidogrel several hours before the procedure reduced the event rate and obviated the need for additional glycoprotein IIb/IIIa receptor inhibition (ISAR-REACT). In the Clopidogrel for the Reduction of Events During Observation (CREDO) Study, investigators showed that the benefit of pretreatment with 300 mg of clopidogrel was only seen when the pretreatment was instituted at least 12 hours pre-procedure (optimally 24 hours before the PCI). However, survival analysis in this study showed a cumulative event rate at 30 days of 8.3% in the placebo arm, 7.8% in those administered clopidogrel within 15 hours of the procedure, and 3.5% in those administered clopidogrel more that 15 hours before the index PCI.
Subsequently, the benefit of higher doses of clopidogrel was studied both ex vivo and in clinical studies (PRONTO). A 600 mg dose of clopidogrel achieved adequate platelet inhibition within 2 hours of administration, unlike 300 mg that required at least 3 to 6 hours to achieve full effect Subsequent data from the ISAR-REACT investigators in 2,159 patients showed that the benefit of 600 mg of clopidogrel was not time dependent. The trial focused on the possible additional benefit of glycoprotein IIb/IIIa inhibition in these patients who had all been pre-treated with 600 mg of clopidogrel. More recently, ISAR-REACT-2 showed that clopidogrel pretreatment in moderate to high risk PCI patients reduced the combined endpoint event rate (relative to placebo) from 11.7% to 5.7% in patients treated with glycoprotein IIb/IIIa inhibitors and from 15.5% to 7.6% in those not receiving glycoprotein IIb/IIIa inhibition. The recently published Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis (ALBION) Trial showed in a low risk group of patients that 600 mg and 900 mg doses of clopidogrel provide faster and greater platelet inhibition than 300 mg as assessed by biochemical assays. The study was underpowered to demonstrate clinical benefits, but it showed a trend towards reduction in troponin-I release as a marker of necrosis from 58% to 42% in the higher dose clopidogrel groups. There was no demonstrable increase in major bleeding complications (2.9% in both 300 and 900 mg groups), but there was a statistically insignificant increase in minor bleeding in the 900 mg dose group.
Our investigation will evaluate the safety and efficacy of pre-treatment (≥2 hours) with 600 mg of clopidogrel in 600 outpatients undergoing elective cardiac catheterization with coronary angiography in our institution who have no evidence of high risk features such as ischemic ST segment deviations, unstable angina, recent myocardial infarction, or abnormal troponin-T levels. The benefit of clopidogrel in patients who undergo interventions may be offset by the bleeding complications encountered, especially in patients who do not undergo coronary angioplasty. Our trial is designed to assess this potential benefit-risk trade-off. Unlike the ALBION trial, we will focus on clinical outcomes using a larger sample size. Our hypothesis is that pretreatment with 600 mg of clopidogrel will significantly reduce the incidence of ischemic complications in patients undergoing PCI, but with possible increase in hemorrhagic and vascular complications in the overall population.
In addition, we will also examine whether the use of 5 French arterial sheaths in cases that do not go onto intervention offsets the increase in bleeding risk, if any, associated with pretreatment with 600 mg of clopidogrel. Very large diameter arterial sheaths (e.g., 10 French) have been associated with higher vascular complication rates, but whether 5 French sheaths offer lower vascular complication rates than 6 French sheaths is uncertain. Nearly all PCIs at our institution are performed using 6 French sheaths (which have larger lumens, more accommodating of angioplasty equipment and higher injection rates of iodinated contrast). Patients who undergo PCI following diagnostic angiography using a 5 French sheath will require exchange for a larger 6 French arterial sheath. On the other hand, patients who do not need angioplasty after coronary angiography will not require any exchange of their arterial sheath, and those with smaller sheath sizes may well have less vascular and bleeding complications.
DESCRIPTION OF RESEARCH PROTOCOL Design: This is a prospective randomized clinical trial comparing ischemic, hemorrhagic and vascular outcomes in outpatients undergoing elective cardiac catheterization with coronary angiography following 1:1 randomization to pretreatment with 600 mg clopidogrel vs. no pretreatment (and clopidogrel dosing post-procedure if a PCI is performed). Patients will provide written informed consent prior to enrollment and randomization. Since some operators may feel strongly about using glycoprotein IIb/IIIa inhibition in patients who did not receive clopidogrel well in advance of the PCI, blinding of the loading strategy and use of a placebo are not feasible. A separate 1:1 randomization will assign patients to undergo cardiac catheterization using 5 or 6 French arterial introducing sheaths. Since the arterial sheath sizes are color-coded, catheter sizes are imprinted on each catheter, and the operator must know the arterial sheath size in case alternate catheters are required, blinding of sheath size assignment is also not feasible. The investigator adjudicating and abstracting the outcomes data such as bleeding and ischemic complications for analysis will be blinded, however, to the clopidogrel reimen and randomization in order to avoid any bias.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient less than 18 years of age
- •Patient referred as an outpatient for elective cardiac catheterization with coronary angiography and ad hoc percutaneous coronary intervention (if coronary anatomy suitable)
- •Patient has stable angina or a stress test suggestive of ischemia and/or prior myocardial infarction
- •Anticipated femoral arterial approach for the cardiac catheterization procedure
- •Patient provides written informed consent
排除标准
- •Patients will be excluded if any of the following are present:
- •Use of clopidogrel or ticlopidine during the 14 days prior to the scheduled procedure
- •Known hypersensitivity to clopidogrel (regardless of desensitization) or to any other components of Plavix
- •Contraindication to clopidogrel, including
- •Pre-existing bleeding disorder or hematological dyscrasia
- •INR >1.4 immediately prior to the scheduled procedure
- •Platelet count <50 K/uL
- •Significant bleeding during the 14 days prior to the scheduled procedure
- •Surgery or invasive procedure at a non-compressible location during the 30 days prior to the scheduled procedure
- •Anticipated need for surgery or other invasive procedure within 30 days following the scheduled procedure
- •Patient states unwillingness to undergo transfusion of red blood cells even in the event of life threatening bleeding
- •Unstable cardiac status
- •Patient was admitted for a cardiac condition and referred as an inpatient for cardiac catheterization
- •Myocardial infarction diagnosed as occurring during the 30 days prior to the scheduled procedure
- •Pre-procedure troponin-T >0.01 ng/mL
- •Unstable angina
- •i. Ischemic symptoms at rest ii. Ischemic symptoms with mild exertion (e.g., walking one to two level blocks or climbing one flight of stairs) e. Pre-procedure electrocardiogram with ST segment changes indicative of ongoing myocardial injury or ischemia
- •Chronic renal failure (which may raise troponin-T levels)
- •Patient currently undergoing dialysis
- •Serum creatinine >2 mg/dL
- •Estimated glomerular filtratation rate (eGFR using the MDRD formula) <45 mL/min/1.73 m2
- •Procedural factors
- •Patient does not require coronary angiography as part of the scheduled cardiac catheterization
- •Patient is not a candidate for percutaneous coronary intervention during the same procedure as the diagnostic coronary angiography
- •Anticipated need for arterial access using brachial, radial or other non-femoral approach
- •Anticipated need to access the femoral artery via a femoral bypass graft
- •Anticipated need for an arterial sheath 6 French in size or larger (e.g., planned evaluation of aortic stenosis or hypertrophic cardiomyopathy)
- •Anticipated need for heparin anticoagulation during the diagnostic cardiac catheterization procedure (e.g., crossing a stenosed aortic valve with a 0.035" wire, planned intra-vascular ultrasound or pressure wire study)
- •Woman of child-bearing potential who does not have a negative pregnancy test immediately prior to the scheduled procedure
- •Participation in another non-observational clinical study that has not yet completed all mandatory follow-up (i.e., patients who are participating in a "natural history" observational registry where no active therapy is being investigated may participate)
- •Prior participation in this study
- •Inability to provide written informed consent or demonstrate understanding of the risks and benefits associated with participation in this study
研究组 & 干预措施
Clopidogrel 600 mg pre-treatment
Patients will receive 600 mg Clopidogrel load >2 hours pre-angiography with possibility for ad hoc PCI based on angiographic results
干预措施: clopidogrel 600 mg (Drug)
No clopidogrel 600 mg pretreatment
Patients will receive 600 mg Clopidogrel load after PCI, if performed
干预措施: clopidogrel 600 mg (Drug)
5Fr arterial access sheath
Patients will have angiography performed using 5Fr sheath. If PCI required, sheath will be upsized.
干预措施: arterial access sheath (Device)
6Fr arterial access sheath
Patients will have angiography performed using 6Fr sheath
干预措施: arterial access sheath (Device)
结局指标
主要结局
Cumulative Incidence of bleeding and major vascular complications
时间窗: 14 days
as described in protocol
Cumulative Incidence of major cardiac events
时间窗: 14 days
includes death, MI, TVR, stent throbmosis
次要结局
- Clinical stent thrombosis(14 days)
- Composite vascular complications endpoint:(14 days)
- Composite TIMI bleeding endpoint:(14 days)
研究者
Donald Cutlip
Professor of Medicine
Beth Israel Deaconess Medical Center