Pharmacokinetics, Pharmacodynamics and Safety of Apixaban on Hemodiafiltration
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Blood plasma concentrations of Apixaban before, during and after renal replacement therapy
研究概览
简要总结
Atrial fibrillation (AF) is a prevalent and serious disease in hemodialysis (HD) patients. Untreated AF increases the risk of deaths related to cardiovascular events and multiplies the risk of strokes by 5. Anticoagulation with warfarin significantly reduces the incidence of ischemic strokes in the general population, has a long half-life, and a narrow therapeutic index that requires periodic monitoring. In addition, warfarin treatment is a frequent cause of hospital admission for iatrogenesis. In HD patients, the relationship between stroke prevention benefit and bleeding risk is an unmet medical need. It should be noted that in these patients the risk of bleeding is multiplied by 3 to 10 times compared to the general population. The new direct-acting oral anticoagulants (NACOs), thrombin inhibitors (dabigatran), and activated factor X inhibitors (rivaroxaban, apixaban, edoxaban), do not require regular monitoring, but their plasma concentrations are altered with the deterioration of the renal function. According to its technical data sheets, they do not recommend its use in clinical practice for HD patients. However, the apixaban data sheet includes the results of a pilot clinical trial in the African American population on HD, suggesting that it is a safe anticoagulant drug.
The objective of this clinical trial is to evaluate the pharmacokinetics, pharmacodynamics, and short-term safety (4 weeks) of apixaban in the Spanish population with non-valvular atrial fibrillation and on hemodialysis.
Long-term safety will be assessed in the extension study: prospective cohort study of patients included in the clinical trial. Therefore, this project is comprised of 2 clinical studies (one clinical trial and one extension study) whose objective is to evaluate the pharmacokinetics, pharmacodynamics, and short and long-term safety of apixaban in patients on hemodialysis and with non-valvular atrial fibrillation (FANV).
The results of this project (clinical trial and extension study) will provide evidence on whether apixaban may be the anticoagulant treatment of choice for this type of patient.
详细描述
7.1 CURRENT STATUS OF SCIENTIFIC-TECHNICAL KNOWLEDGE Despite technological advances, cardiovascular disease remains the most frequent cause of death in hemodialysis (HD) patients. The higher prevalence of diabetes, anemia, hyperparathyroidism and hypertension in the population with chronic kidney disease (CKD) favors the appearance of cardiac structural lesions. In addition, hypervolemia and hydroelectrolytic abnormalities increase the risk of arrhythmias. In fact, the annual incidence of atrial fibrillation (AF) in the hemodialysis population is 15 times higher than the general population of the same age and the risk of presenting a thromboembolic complication by a 5-fold increase.
Safely reducing the risk of thromboembolism in patients with AF and CKD is an unmet medical need. Prospective studies conducted in patients with AF have been systematically excluded in patients with a Glomerular Filtration Rate (GFR) <30 ml / min. Importantly, patients with CKD have alterations in hemostasis that predisposes patients to bleeding (reduction of alpha granules in platelets, reduction of endothelial adhesion molecules) and thrombosis (increased fibrinogen). This makes it impossible to extrapolate data from the population with normal kidney function.
Oral anticoagulant treatment with cumarinics such as warfarin, drugs that act as vitamin K antagonists (AVK), have been shown to be effective in reducing the risk of stroke and mortality. However, these drugs are not exempt from major complications since it is difficult to maintain a stable therapeutic index (INR). This frequently leads to the appearance of hemorrhages (the risk is 2 times higher than in HD patients without anticoagulant treatment) due to its reduced therapeutic margin and numerous interactions with drugs and foods, which makes it difficult to predict the pharmacokinetics of these drugs. The use of anticoagulants in patients with AF and in HD is a controversial topic. For example, the Kidney Disease: Improving Global Outcomes (KDIGO2012) guidelines do not recommend its use, while the American College of Cardiology (ACC) / American Heart Association (AHA) / Heart Rhythm Society 2014 guidelines does recommend its use. A recent meta-analysis, which included 7 studies, concluded that warfarin does not reduce the number of strokes and, in addition, was associated with a greater number of hemorrhages. In summary, there is not enough high-quality evidence to recommend warfarin for stroke prevention in patients on hemodialysis with AF. Furthermore, AVKs favor vascular calcifications and have been related to calciphylaxis lesions, CKD-associated pathologies.
7.2. New oral anticoagulants. Apixaban New oral anticoagulants (DOACs) are currently available, such as direct inhibitors of thrombin (dabigatran) and activated factor X (rivaroxaban, apixaban, edoxaban). These drugs have demonstrated their clinical efficacy in patients with GFR> 25 mL/min. DOACs offer the advantage that monitoring of their plasma levels is not necessary. Importantly, administration of dabigatran and rivaroxaban in hemodialysis patients has been associated with an increased risk of bleeding and death compared to warfarin. In contrast, apixaban, a priori, would be the oral anticoagulant of choice in hemodialysis patients.
Apixaban is a direct, selective and reversible coagulation Factor Xa (FXa) inhibitor that is approved to reduce the risk of stroke and systemic embolism in patients with AF of nonvalvular origin without increasing the risk of bleeding. Apixaban has a rapid absorption, a half-life of 12 h, it is metabolized by cytochrome P450 and 25% is eliminated via the kidneys (the rest is eliminated via the digestive tract).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Adults (18 years or older).
- •Body weight ≥ 60 kg.
- •Diagnosis of chronic kidney disease on hemodialysis, clinically stable (with a minimum of 3 months of treatment) and nonvalvular atrial fibrillation in treatment with coumarins.
- •Patient candidate for change of anticoagulant treatment.
- •In women of childbearing age, negative pregnancy test (negative human coriogonadotropine (hCG) urine test).
- •The subject gives informed consent.
排除标准
- •• Pregnant or lactating women.
- •Women of childbearing age (period of time from menarche to postmenopausal status, defined as 12 months absence of menstruation without other medical cause) who do not follow the contraceptive methods recommended by the Clinical Trial Facilitation Group (CTFG) (https://www.hma.eu/fileadm/dateien/Human_Medicines/01): Hormonal contraceptives associated with ovulation inhibitors, intrauterine devices, surgical methods (tubal ligation, vasectomy), abstinence, and barrier methods.
- •Body weight ≤ 60 kg.
- •Presence of liver disease (patients with elevated liver enzyme levels alanine aminotransferase (ALT) / aspartate aminotransferase (AST)> 2x the upper limit of normal, or total bilirubin> 1.5 ULN).
- •Thrombopenia (<100.000 platelets/mL).
- •Be on treatment with other anticoagulants (heparins) or antiplatelet drugs.
- •Be treated with enzyme inhibitors (such as azole antifungals or HIV protease inhibitors) or enzyme inducers (such as rifampin, phenobarbital, carbamazepine, or phenytoin) of CYP3A4 (Cytochrome P450 3A4 oxidase ).
- •History of bleeding episode in the last month.
- •Presence of clinical or analytical alterations not attributable to the stage of kidney disease
- •Participation in another clinical trial of pharmacological treatment.
研究组 & 干预措施
Apixaban
Apixaban treatment, oral, 2.5 mg/12h, 28 days
干预措施: Apixaban 2.5 milligram Oral Tablet (Drug)
结局指标
主要结局
Blood plasma concentrations of Apixaban before, during and after renal replacement therapy
时间窗: 28 days
Determine the plasma concentrations of apixaban before, during and after renal replacement therapy (hemodialysis and hemodiafiltration)
次要结局
- Economic impact of anticoagulant treatment with apixaban compared to anticoagulant treatment with coumarins- part 3(28 days)
- Economic impact of anticoagulant treatment with apixaban compared to anticoagulant treatment with coumarins- part 4(28 days)
- Urine plasma concentrations of Apixaban before, during and after renal replacement therapy(28 days)
- Anti-Factor Xa activity of apixaban (heparin activity (IU/mL))(28 days)
- Number of patients with medical complications with medical complications not directly related to the underlying disease.(28 days)
- Dyalisate concentrations of Apixaban before, during and after renal replacement therapy(28 days)
- Total number of adverse events.(28 days)
- Economic impact of anticoagulant treatment with apixaban compared to anticoagulant treatment with coumarins- part 1(28 days)
- Economic impact of anticoagulant treatment with apixaban compared to anticoagulant treatment with coumarins- part 2(28 days)
研究者
MIGUEL HUESO VAL
Principal Investigator
Hospital Universitari de Bellvitge