Aspirin Versus Aspirin and Fondaparinux Prior to Early Invasive Strategy in Patients With NSTEMI
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 5,076
- 试验地点
- 11
- 主要终点
- Composite endpoint of mortality, new myocardial infarction, and clinical deterioration resulting in acute CAG
研究概览
简要总结
The main goal of this study is to compare two treatments in patients with a specific type of heart attack called Non-ST-elevation Myocardial Infarction (NSTEMI). The investigators want to find out whether using aspirin alone is as effective and safer than using aspirin together with a second blood thinner called fondaparinux.
Both treatments will be given before a scheduled heart procedure called coronary angiography (CAG), which may include balloon dilation and stent placement (PCI) if needed.
The current guidelines recommend using aspirin in combination with a second blood thinner like fondaparinux before CAG and possible PCI. However, these recommendations are based on studies from the 1990s, a time when invasive procedures were not standard practice for these patients. In contrast, nearly all patients with NSTEMI in Denmark (96%) now undergo CAG within 72 hours. This change in practice raises questions about whether the older studies still provide a valid foundation for today's guidelines.
The study aims to answer two questions:
- Is aspirin alone as effective as aspirin combined with fondaparinux before early CAG and possible PCI?
- Is aspirin alone safer, with a lower risk of severe bleeding, compared to the combination treatment?
To answer these questions, the investigators will enroll about 5,000 patients with NSTEMI. Participants will be randomly assigned to receive either aspirin alone or aspirin with fondaparinux. The investigators will monitor them for 30 days to compare outcomes such as death, new heart attacks, the need for urgent CAG before the scheduled, and severe bleeding.
详细描述
Background The current guidelines from European Society of Cardiology (2023) (ESC) and American Heart Association (2014) (AHA) provide a Class-I recommendation for the administration of aspirin together with an anticoagulant in the immediate treatment of Non-ST-Elevation Myocardial Infarction (NSTEMI). For patients scheduled for coronary angiography (CAG) within 24 hours, the recommendation is to initiate unfractionated heparin (UFH) bolus of 70-100 U/kg followed by an adjustable infusion until an activated partial thromboplastin time (APPT) of 60-80 seconds. Patients not planned for CAG within 24 hours are recommended to be treated with fondaparinux 2.5 mg subcutaneous (s.c.) once a day until potential revascularization with percutaneous coronary intervention (PCI) or discharge. According to the clinical guidelines from Danish Society of Cardiology (DSC), fondaparinux is recommended as the first choice for all patients with NSTEMI in Denmark, and heparin is rarely used on this indication.
A plaque rupture in NSTEMI results not only in the activation of platelets but also in the activation of the coagulation cascade through exposure of tissue factor in the extrinsic pathway. This cascade leads to activation of Factor VII and X, which cleave prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, leading to thrombus formation. Fondaparinux, a synthetic pentasaccharid, directly binds to and enhances the effect of antithrombin, specifically inhibiting activated factor X disrupting the coagulative cascade. Fondaparinux has a half-life of about 17 hours, compared to just 1.5 hours for UFH. This makes the administration and monitoring of UFH treatment substantially more difficult and time-consuming compared to treatment with fondaparinux.
The evidence behind the Class-I recommendation for anticoagulant treatment in patients with NSTEMI is based on two meta-analyses: Oler et al. (1996) and Eikelboom et al. (2000).
The meta-analysis from Oler et al. included six studies that investigated the effect of combination therapy with aspirin and heparin compared with aspirin alone in patients with Non-ST-elevation Acute Coronary Syndrome (NSTEACS), comprising unstable angina pectoris (UAP) and Non-ST-Elevation Myocardial Infarction (NSTEMI). The study showed no statistically significant reduction in the relative risk (RR) = 0.67 (95% CI 0.44-1.02) for new myocardial infarction (MI) or death. However, the results indicated a trend towards a potential positive effect of the combination treatment with both heparin and aspirin.
The indication of a possibly positive effect of combination treatment with both aspirin and anticoagulants was further strengthened with the publication of the FRISC I study (1996), which included 1506 patients with NSTEACS. This was twice as many patients as in all the studies included in the meta-analysis by Oler et al. The patients in the FRISC I study were randomized to treatment with either aspirin and placebo or aspirin and dalteparin (low molecular weight heparin [LMWH]). The primary endpoint was the occurrence of death or new MI within 6 days. The results showed a significant reduction in the primary endpoint, with a odds ratio (OR) of 0.37 (95% CI 0.20-0.68, p = 0.001).
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
- •Diagnosis of NSTEMI verified by:
- •Rise or/and fall in cardiac troponin (cTN) and
- •Symptoms of acute ischemia or ECG-changes compatible with acute ischemia.
- •Age above 18 years old
- •Expected remaining lifespan above 1 year
- •Informed consent
排除标准
- •Treatment with any anticoagulants before enrollment and randomization
- •Including any direct anticoagulant (DOAC), LMWH, UFH or warfarin.
- •Not possible with CAG and PCI within 72 hours
- •Unsuitable for CAG and possible PCI due to poor condition
- •Estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73m2
- •Known liver disease
- •Active bleeding or high risk of bleeding where treatment with Fondaparinux is contraindicated.
- •Anemia (B-Hemoglobin < 6.0 mmol/l)
- •Pregnancy or breastfeeding
- •Endocarditis
- •Indication for acute CAG before enrollment and randomization:
- •ST-elevation Myocardial Infarction (STEMI)
- •Patients classified as "Very High Risk" according to ESC guidelines, defined as(1):
- •Hemodynamic instability (in need of inotropic support) or cardiogenic shock (DANGER-SHOCK criteria (20)) at time of admission.
- •Acute heart failure because of presumed acute ischemia
- •Life-threatening arrhythmias or cardiac arrest
- •Mechanical complications (such as papillary muscle rupture with acute mitral regurgitation, free wall rupture and interventricular rupture)
研究组 & 干预措施
Standard Treatment - Aspirin and Fondaparinux
Standard treatment regime with Aspirin in combination with Fondaparinux.
干预措施: Aspirin (Drug)
Aspirin alone
Treatment with aspirin alone. The intervention is removal of treatment with fondaparinux
干预措施: Aspirin (Drug)
Standard Treatment - Aspirin and Fondaparinux
Standard treatment regime with Aspirin in combination with Fondaparinux.
干预措施: Fondaparinux Sodium (Drug)
结局指标
主要结局
Composite endpoint of mortality, new myocardial infarction, and clinical deterioration resulting in acute CAG
时间窗: The primary endpoints will be assessed after day 30.
Composite of 30-day mortality, 30-day new MI, and clinical deterioration resulting in acute CAG. The endpoints will be assessed through review of the patient's medical journal. New Myocardial infarction (MI): Defined as a new MI after the early invasive strategy. Clinical deterioration resulting in acute CAG: Defined as conversion to acute coronary angiography (CAG) before the scheduled. Indication for acute CAG is based on the ESC guidelines of "very high risk" NSTEMI (1):
次要结局
- All-cause mortality(Up to 10 years)
- New Myocardial Infarction(Up to 10 years)
- Cerebrovascular accident (CVA)(Up to 30 days)
- Length of hospital stay(Up to 30 days)
- Left Ventricular Ejection Fraction at Discharge(Up to 30 days)