A large, international, randomized, placebo-controlled trial to assess the impact of dabigatran ( a direct thrombin inhibitor) and omeprazole ( a proton-pump inhibitor) in patients suffering myocardial injury after noncardiac surgery.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 3,200
- 试验地点
- 16
- 主要终点
- To determine the effect of dabigatran versus placebo on the risk of a major vascular complication and, to determine the effect of omeprazole versus placebo on the risk of a major upper gastrointestinal complication in patients who have suffered MINS and are followed on average for 1 year.
研究概览
简要总结
Magnitude of the ProblemWorldwide, over 200 million adults undergo major noncardiac surgery annually,5, 6 and more than 10 million of these patients will suffer MINS during the first 30 days after surgery.5 Myocardial injury is the most common major vascular complication after noncardiac surgery. We recently completed a large (8351 patients) multicenter international (190 centres in 23 countries) perioperative prophylactic RCT that compared the impact of a beta-blocker versus placebo (i.e., the POISE Trial).7 In the placebo group of the POISE Trial 1.4% of patients suffered a vascular death, 0.5% suffered a stroke, 0.5% suffered a nonfatal cardiac arrest, and 5.7% suffered a myocardial injury in the first 30 days.7 Despite the magnitude of this problem, there is not a single established effective and safe intervention to improve the outcome of patients suffering MINS. The striking absence of effective interventions reflects the lack of large RCTs evaluating potential interventions. MINS is therefore a major neglected public health problem.
Why we should find a treatment for MINSMyocardial injury after noncardiac surgery (MINS) differs from non-operative myocardial infarction in two ways; it has a poorer prognosis (patients suffering MINS are 2 times more likely to die within 30 days compared to non-operative myocardial infarction in the emergency room) and paradoxically its treatment is less intensive.1, 8-10 This difference in the intensity of treatment is likely influenced by several factors including: (1) a majority of patients suffering MINS do not experience ischemic symptoms,1, 11 potentially influencing physicians’ perception of the severity of the event; (2) there is debate as to the pathophysiology of MINS 12(although emerging evidence does suggest that coronary arterial thrombosis is an important mechanism of MINS);5 and (3) no randomized controlled trial (RCT) has evaluated an intervention to manage MINS, and hence physicians are uncertain about the risk-benefit ratio of potential interventions (e.g., interventions that are effective in the management of non-operative myocardial infarction).5 From a human and economic perspective, it is a tragedy that some patients undergoing noncardiac surgery for important reasons (e.g., to obtain a cure of their cancer or to become mobile after a new prosthetic joint) fail to obtain these benefits, because they suffer MINS that ultimately takes their life. There is an urgent need for clinical trials to identify effective therapies to improve the outcomes of patients suffering MINS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Double Blind Double Dummy
入排标准
- 年龄范围
- 45.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •INCLUSION CRITERIA Patients are eligible if they:
- •have undergone noncardiac surgery;
- •are ≥45 years of age;
- •have suffered MINS based upon fulfilling one of the following criteria1 A.
- •Elevated troponin or CK-MB measurement with one or more of the following defining features i.
- •ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness of breath, pulmonary edema); ii.
- •development of pathologic Q waves present in any two contiguous leads that are >30 milliseconds; iii.
- •electrocardiogram (ECG) changes indicative of ischemia (i.e., ST segment elevation [>2 mm in leads V1, V2, or V3 OR >1 mm in the other leads], ST segment depression [>1 mm], OR symmetric inversion of T waves >1 mm) in at least two contiguous leads; iv.
- •new LBBB; or v.
- •new or presumed new cardiac wall motion abnormality on echocardiography or new or presumed new fixed defect on radionuclide imaging B.
- •Elevated troponin measurement after surgery with no alternative explanation (e.g., pulmonary embolism, sepsis) to myocardial injury; AND
- •provide written informed consent to participate while still in hospital after their index surgery and within 5 days of suffering their MINS.
排除标准
- •EXCLUSION CRITERIA We will exclude patients meeting any of the following criteria:
- •hypersensitivity or known allergy to dabigatran;
- •history of intracranial, intraocular, or spinal bleeding;
- •hemorrhagic disorder or bleeding diathesis;
- •known hepatic impairment or liver disease expected to have an impact on survival;
- •condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart valve, venous thromboembolism, atrial fibrillation);
- •currently using or plan to initiate rifampicin, cyclosporine, itraconazole, tacrolimus, ketoconazole, or dronedarone;
- •women who are pregnant, breastfeeding, or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study;
- •investigator considers the patient unreliable regarding requirement for study follow-up or study drug compliance; OR
- •previously enrolled in the MANAGE Trial.
- •We will also exclude patients in whom any of the following criteria persist beyond 5 days of their suffering MINS:
- •the attending surgeon believes it is not safe to initiate therapeutic dose anticoagulation therapy;
- •the attending physician believes ASA, intermittent pneumatic compression, or elastic stockings are not sufficient for venous thromboembolism (VTE) prophylaxis and that the patient requires a prophylactic-dose anticoagulant;
- •the patient has an indwelling epidural or spinal catheter that cannot be removed, or the first dose of dabigatran will occur within 4 hours of epidural catheter removal; OR
- •estimated glomerular filtration rate (eGFR) <35 ml/min as estimated by calculated creatinine clearance.
- •it is expected that the patient will undergo cardiac catheterization for MINS.
- •Exclusion Criteria Specific to Patients in the Omeprazole Factorial Component of the Trial We will exclude patients meeting any of the following criteria:
- •esophageal or gastric variceal disease; OR
- •patient declines participation in the omeprazole arm of MANAGE.
结局指标
主要结局
To determine the effect of dabigatran versus placebo on the risk of a major vascular complication and, to determine the effect of omeprazole versus placebo on the risk of a major upper gastrointestinal complication in patients who have suffered MINS and are followed on average for 1 year.
时间窗: one year
次要结局
- To determine the effect of dabigatran on each of the following individual secondary outcomes after MINS and an average of 1 year of follow-up: all-cause mortality, vascular mortality, myocardial infarction, stroke, cardiac revascularization procedure, symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or symptomatic deep venous thrombosis), amputation, peripheral arterial thrombosis, and rehospitalization for vascular reasons.(one year)