Interventional Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in High-risk Patients With Atrial Fibrillation (PRAGUE-17 Study)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- Combined endpoint: stroke OR systemic cardioembolic event OR clinically significant bleeding OR cardiovascular death OR procedure or device-related complications
研究概览
简要总结
Atrial fibrillation (AF) is the most common cardiac arrhythmia with a prevalence of 1-2%. Without antithrombotic treatment, the annual risk of a cardioembolic event is 5-6%. The source of a cardioembolic event is a thrombus, which usually forms in the left atrial appendage (LAA). The prevention of cardioembolic events involves treatment with anticoagulant drugs, which were limited to, until recently, vitamin K antagonists (e.g. warfarin). Anticoagulant treatment with warfarin can lead to adverse bleeding events, some of which can be life threatening. Recently, two new options for thrombus prevention have been developed. The first is the novel anticoagulants (NOAC), which were associated with slightly better safety profiles due to a lower frequency of intracranial bleeding in large randomized trials . The second option involves interventional occlusion of the LAA. The aim of this project is to compare the LAA occlusion intervention to NOAC pharmacological treatment in a randomized multicenter study of AF patients at high risk of a cardioembolic event.
详细描述
Interventional left atrial appendage closure vs. novel anticoagulation agents in high-risk patients with atrial fibrillation (PRAGUE-17 study)
INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a prevalence of 1-2% in the general population; additionally, the incidence increases with age. (1) Among the elderly 75 years and older, its incidence is 12%. (2) AF is associated with a five-fold risk of a cardioembolic event; approximately 20% of all strokes are due to AF. (3) The annual risk of stroke in AF patients is 5 -6 % in AF patients without antithrombotic treatment. Moreover, a stroke due to AF is typically more severe, i.e. associated with worse neurological deficits. (4) Not only does the incidence of AF increase with age, the risk of strokes in AF patients also increases with age with age: in patients between 50-59 years, the risk of stroke is about 1.5%, while in patients between 80 - 90, the risk increases to about 23%. (5) The source of an embolic stroke is a thrombus, which forms in the left atrium (LA) due to insufficient mechanical contraction of LA. Most often thrombi arise in the left atrial appendage (LAA); according to data from autopsies and findings from transesophageal echocardiography (TEE) in AF patients, approximately 90% of all left atrial thrombi arise in the LAA. (6) In addition to insufficient mechanical contraction of LA, the pro-coagulant status of patients also plays an important role in thrombus development. A patient's risk profile is characterized according to the CHA2DS2-VASc score. Each letter presents one recognized risk factor (C - congestive heart failure or left ventricular dysfunction, H - hypertension, A - age > 75 years (2 points), D - diabetes, S - history of stroke (2 points), V - present vascular disease (atherosclerosis), A - age > 65 years, Sc- female sex. In the CHA2DS2-VASc scoring system, each risk factor is evaluated as either 1 or 2 points. The sum of all points presents the annual risk of a cardioembolic event, in percent. The prevention of strokes or other systemic cardioembolic events (thrombus can embolize to peripheral artery of upper or lower extremity, artery supplying gastrointestinal tract, renal artery etc.) involve treatment using anticoagulant drugs, which were, until recently, vitamin K antagonists only (e.g. warfarin). These drugs block the effect of vitamin K in the liver, which in turn blocks the production of coagulant factors II, VII, IX, and X. As a result, the coagulation cascade is slowed. The efficacy of warfarin is estimated using International Normalized Ratio (INR); the effective INR to prevent thrombus formation in AF patients is between 2.0 and 3.0. The amount of vitamin K in food varies, which can lead to variations in INR despite a stable warfarin dose. This represent one of the disadvantages of warfarin treatment. In large randomized trials, in which all patients are very carefully followed, only 65% of INR values were successfully maintain between 2.0 and 3.0. (7) In real clinical praxis, it was shown that only 50% of all INR values are within the desired range. (8) This can easily lead to both overtreatment and undertreatment of patients. Vitamin K antagonism is thought to be effective when 70% of INR values are maintained in the therapeutic range. (9) Another disadvantage of warfarin treatment involves dietary restrictions.
Recently, several new drugs that can block coagulation have been discovered, and are appropriately named novel anticoagulants (NOAC). These new drugs include direct thrombin (factor IIa) inhibitors, such as dabigatran, and inhibitors of factor Xa, such as rivaroxaban and apixaban. In contrast to warfarin, they block a single step in the coagulation cascade. The dosing of these drugs does not have to be adjusted based on laboratory tests, like warfarin. Stable concentrations of these drugs are achieved by once or twice daily dosing, according to their half-lives. Dosing only needs to be adjusted when there is significant comorbidity (i.e. renal or liver function) and no dietary restrictions are needed. In large prospective multicenter studies, NOAC were non-inferior to warfarin, i.e. prevention of systemic cardioembolic events was similar between patients treated by warfarin and NOAC. (10) (11) (12) (13) Additionally, NOAC were associated with slightly better safety profiles relative to the lower frequency of intracranial bleeding. (10) (11) (12) (13)
The prevention of thrombus formation in the fibrillating atrium by anticoagulation has been shown to be effective; however, adverse bleeding events can occur with both warfarin (even in the therapeutic range) and NOAC. The frequency of any (major or minor) bleeding during NOAC treatment is approximately 15-18% per year; severe bleeding can lead to hospitalization or even death.
The risk of bleeding can be estimated using the HAS-BLED scoring system. Each letter presents a risk factor for bleeding (H - hypertension, A - abnormal liver or renal function, S - history of stroke, B - history of bleeding, L - labile INR, E - elderly patients, and D - drugs, alcohol consumption). Patients with HAS-BLED scores > 3 are considered to be at high risk of bleeding.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 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
- •history of significant bleeding (i.e. bleeding which required intervention or hospitalization), even in the absence of anticoagulation treatment at the time of the bleeding event, or
- •a cardioembolic event, which occurred on anticoagulation, or
- •a high risk profile of the patient, defined as a CHA2DS2-VASc score ≥ 3 and a HAS-BLED score ≥ 2
排除标准
- •thrombus in the LA or LAA;
- •mechanical valve prosthesis;
- •mitral stenosis;
- •previous LAA ligation during cardiac surgery;
- •life expectancy less than 2 years;
- •comorbidities other than AF, which present an indication for anticoagulation;
- •patent foramen ovale with atrial septal aneurysm
- •mobile plaque in the aorta;
- •symptomatic atherosclerosis of the carotid artery;
- •pericardial effusion greater than 10 mm;
- •clinically significant bleeding within the 30 days prior to the scheduled procedure;
- •stroke or other cardioembolic event within the 30 days prior to the scheduled procedure;
- •acute coronary syndrome within the 90 days prior to the scheduled procedure,
- •significant valvular disease,
- •creatinine clearance less than 30 ml/min
研究组 & 干预措施
LAAO group
Patients will be treated interventionally by left atrial appendage occlusion (LAAO). LAAO will be done using Amulet or Watchman device.
干预措施: Left atrial appendage closure (Device)
NOAC group
Patients will be treated by novel anticoagulants (NOAC).
干预措施: NOAC (Drug)
结局指标
主要结局
Combined endpoint: stroke OR systemic cardioembolic event OR clinically significant bleeding OR cardiovascular death OR procedure or device-related complications
时间窗: From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient
The primary endpoint is the combination of stroke, other systemic cardiovascular event, clinically significant ISTH major or non-major bleeding (ISTH major: a decrease in hemoglobin level of 20 g/l or more over a 24-hour period, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding; ISTH non-major: requiring hospitalization or invasive procedure, which doesn´t meet the ISTH major criteria), cardiovascular death or procedure or device-related complications (i.e. a pericardial effusion with a need for drainage, surgical or pericardiocentesis; cardioembolic event during the procedure; significant periprocedural bleeding (such as major vascular bleeding with a need for surgical revision, or blood concentrate transfusion); device embolization, or thrombus of the device with a consequent cardioembolic event).
次要结局
- Systemic cardioembolic event(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- Stroke(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- Economical comparison - all costs associated with the treatment and adverse events(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- Clinically significant bleeding (ISTH major)(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- Cardiovascular death(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- Minor bleeding(From the date of randomization until the date of 6 month follow-up visit of the last enrolled patient)
- An procedure or device-related complications(Within 6 months after the procedure)
研究者
Pavel Osmancik
3. Faculty of Medicine and University Hospital Kralovske Vinohrady
Charles University, Czech Republic