The Effect of Intravenous Cangrelor and Oral Ticagrelor on Platelets, the Microcirculation and Myocardial Damage in Patients Admitted With STEMI Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Pilot Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Degree of Platelet Inhibition Measured
研究概览
简要总结
Major heart attacks are caused by a number of factors, the two major of which are furring up of a coronary artery with atheroma and then sudden clot formation on this area leading to a blockage and interruption of blood flow. The clots that lead to heart attacks are largely made of clotting blood cells (platelets) that in health repair blood vessels and inhibit spontaneous bleeding. One of the main treatment strategies for heart attacks is to make these cells less "sticky". Aspirin is a main stay of anti-platelet treatment in the United Kingdom (UK) and in addition one of three other oral antiplatelet agents acting on the same platelet activation pathway (P2Y12 receptor) is licensed for use. When a patient is admitted with a major heart attack, they are treated with emergency primary percutaneous coronary intervention (PPCI) a technique where a wire and balloon are used to reopen the coronary artery and then usually a stent (a slotted metal tube) is placed to keep the artery open. Aspirin and one of the P2Y12 inhibitor agents are given to prevent further clots and all have been shown to reduce negative events following heart attacks and angioplasty with stent insertion. There are increasing data, including from our own institution, showing that in the setting of heart attacks, the oral P2Y12 inhibitors are poorly absorbed and have little effect at the time of most need, i.e. soon after dosing while the primary PCI is being performed.
All three current P2Y12 inhibitor agents are taken in tablet form immediately before the emergency PPCI procedure. It appears that in healthy stable patients these agents take at least 30 min to 2 hours to have an adequate effect. In heart attack patients the angioplasty procedure is usually performed well within this timescale. Furthermore, patients who are having a heart attack do not have normal drug absorption with blood being diverted away from the stomach and gut activity being suppressed by other drugs such as morphine.
In this current study, patients with major heart attacks will be given our standard oral agent, Ticagrelor, or the newer intravenous agent Cangrelor prior to PPCI.
详细描述
The success of modern treatment for ST-segment elevation myocardial infarction (STEMI) is dependent, in part, on the adequate suppression of platelet activity. Primary percutaneous coronary intervention (PPCI) for STEMI management has led to marked reductions in morbidity and mortality (1, 2). Aspirin is the mainstay anti-platelet agent. It is rapidly absorbed in the upper gastrointestinal (GI) tract and results in a measurable inhibition of platelet function within 60 minutes (3, 4). The advent of the platelet P2Y12 inhibitors has led to further improvement in outcomes in patients with acute coronary syndromes (ACS) undergoing PCI with reduced ischaemic complications (5) albeit at an increase in rate of bleeding complications. These agents have a synergistic effect on platelet function with the addition of Clopidogrel to Aspirin leading to approximately 20% reduction in negative cardiovascular events (6).
Activation of platelets leads to a conformational change in the surface glycoprotein IIb/IIIa receptor that allows cross bridging with fibrinogen and rapid aggregation (platelet thrombus formation) (7, 8) During PPCI, thrombus formation and dispersion can have a major impact on outcome. Intravenous platelet IIb/IIIa receptor antagonists such as Abciximab were initially shown to have a positive impact on primary angioplasty outcomes leading to a class IIa indication within the European Society of Cardiology (ESC) guidelines for use in the treatment of STEMI with angioplasty (9).
As oral antiplatelet inhibition has improved (specifically with the addition of Clopidogrel, Prasugrel or Ticagrelor) there has been a concomitant reduction in the use of intravenous IIb/IIIa agents during PCI for patients with ACS. This has been partly informed by later studies suggesting that the additive value of these agents to dual anti-platelet therapy is questionable (10).
In addition, the extra bleeding complications are seen by some to be excessive (11).
Current NICE recommendations for the treatment of STEMI include Aspirin plus one of the P2Y12 agents Clopidogrel, Prasugrel or Ticagrelor.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients presenting with STEMI eligible for PPCI
- •Able to give verbal assent pre procedure and written consent following the procedure.
- •Age ≥18 years
- •No contraindication to Cangrelor or Ticagrelor
- •Thienopyridine naïve
- •If a patient gives verbal assent but is unable to provide a written consent at a later stage due to incapacitation, presumed consent will be continued. The reasons why a patient becomes incapacitated and becomes unable to provide a written consent will be recorded during data collection.
排除标准
- •Be unable to provide verbal assent and written consent
- •Allergic to Aspirin or any of the P2Y12 antagonists in the trial
- •Have pre-existing cardiogenic shock
- •Previous myocardial infarction
- •Have a concurrent septic or inflammatory disease e.g. rheumatoid arthritis, lupus, and pneumonia.
- •Already taking a P2Y12 inhibitor
- •Known bleeding diathesis
- •Significant active bleeding
- •History of intracranial hemorrhage
- •Patients who are being treated with formal anticoagulation (Vitamin K antagonist, Factor II or Xa inhibitors) or have an indication for anticoagulation during the first four hours of the study period. Example is patients known to have atrial fibrillation, pulmonary embolism or deep vein thrombosis.
- •Known severe renal dysfunction requiring renal replacement therapy.
研究组 & 干预措施
Oral Ticagrelor
Patients in the oral Ticagrelor arm will receive Ticagrelor at a loading dose of 180mg followed by maintenance dose of 90mg twice daily for 12 months.
干预措施: Ticagrelor (Drug)
Intravenous Cangrelor
Patients in the intravenous Cangrelor arm will receive Cangrelor as an initial bolus dose given as per body weight followed by an intravenous infusion for no longer than three hours, they will then switch to oral Ticagrelor given at maintenance dose of 90mg twice daily for 12 months
干预措施: Cangrelor (Drug)
结局指标
主要结局
Degree of Platelet Inhibition Measured
时间窗: Measured at 4, 24 and 36 hours post dosing
P2Y12 inhibition was measured using VerifyNow™ rapid platelet function analyzer at the time of infarct vessel balloon inflation, 4 hours following study drug loading and at 24-36 hours. A single value was calculated by using the mean/average value. Results are expressed as P2Y12 reaction units (PRU), indicating the degree of ADP- mediated aggregation specific to the P2Y12 receptor. PRU values of ≥208 are indicative of a suboptimal response and are associated with poor clinical outcomes including death, MI and stroke at one year.
次要结局
- Index of Microvascular Resistance (IMR) Measurement(1 hour)
- Measurement of Thrombolysis in Myocardial Infarction (TIMI)(3 Months)
- ST Segment Resolution by ECG(90-120 minutes post PPCI)
- The Impact of Cangrelor vs Ticagrelor on Initial Myocardial Infarct Size Based on Peak Troponin(24-36 hours)