Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04952792 |
| Other study ID # |
2018-002991-41 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
May 20, 2021 |
| Est. completion date |
December 15, 2022 |
Study information
| Verified date |
September 2023 |
| Source |
Hospital Universitari de Bellvitge |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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).
Pharmacokinetic and pharmacodynamic studies of apixaban in patients with severe chronic
kidney disease (CrCr= 15 mL/min) and in Hemodialysis observed an increase in exposure (area
under the curve of plasma concentration vs. time was 44% and 36% respectively). This
increased exposure is directly correlated with increased anti-Factor Xa activity. However, no
changes were observed in terms of t1/2 (12 hours), maximum concentration (Cmax) or the
presence of adverse effects. In a standard conventional hemodialysis session, the exposure to
apixaban is decreased by 14%. A subsequent study observed the trend towards stability of
apixaban levels after the administration of a reduced dose of apixaban 2.5mg/12h for a week
in a sustained manner, therefore it has been suggested that it can be used in HD without the
need for modify the dose. It should be borne in mind that all the studies that have analyzed
the behavior of apixaban in HD have been carried out in the African American population of
the United States, where the use of convective techniques (HDF) that allow greater
elimination of medium and high molecular weight and that can modify the behavior of drugs
with strong binding to plasma proteins. Apixaban could be affected by this phenomenon as it
is a drug with strong protein binding (UPP 86%). In Catalonia, 65% of patients are on renal
replacement therapy with HDF..
According to the technical data sheet (Section 5.2. Pharmacokinetic properties), in patients
with renal insufficiency: "renal insufficiency had no manifest effect on the relationship
between plasma concentration and anti-Factor Xa activity of apixaban", and in patients with
end-stage renal disease: "theArea under the Curve (AUC) of apixaban was increased by 36%
compared to that observed in subjects with normal renal function, when a single 5mg dose of
apixaban was administered immediately after hemodialysis. Hemodialysis, started 2 hours after
administration of a single 5mg dose of apixaban, decreased the AUC by 14% in these CKD
subjects, corresponding to an apixaban clearance of 18 mL/min during hemodialysis. Therefore,
hemodialysis is unlikely to be an effective measure to manage apixaban overdose." Apixaban
appears to be a safe anticoagulant in hemodialysis patients. It should be noted that this
study was conducted in the African American population (87.5%), so we do not know if these
data could be extrapolated to the Spanish population. Apixaban was marketed in May 2011 and
is indicated for "the prevention of stroke and systemic embolism in adult patients with
nonvalvular atrial fibrillation (NVAF) with one or more risk factors such as stroke or
previous transient ischemic attack (TIA); age ≥75 years; hypertension; mellitus diabetes;
symptomatic heart failure (NYHA scale: ≥2). However, there is no information on the
modification of its efficacy with the type of hemodialysis technique, and therefore if it
could be used in clinical practice in hemodialysis patients.
7.3. Work Hypothesis
1. Apixaban is a safe oral anticoagulant in patients in our setting with chronic kidney
disease (undergoing hemodiafiltration or hemodialysis) and nonvalvular atrial
fibrillation.
2. Considering that severe renal dysfunction increases the AUC of apixaban by 36% and
hemodialysis treatment only decreases exposure to the drug by 14%, the recommended dose
of apixaban for patients on hemodialysis or hemodiafiltration is 2.5 mg/12h.
3. Apixaban is an effective oral anticoagulant in patients in our setting with chronic
kidney disease (being treated with hemodiafiltration or hemodialysis) and nonvalvular
atrial fibrillation:
1. Plasma apixaban concentrations are stable in patients in our setting with chronic
kidney disease (undergoing hemodiafiltration or hemodialysis) and nonvalvular
atrial fibrillation.
2. The anti-Factor Xa activity of apixaban is not affected in patients in our setting
with chronic kidney disease (being treated with hemodiafiltration or hemodialysis)
and nonvalvular atrial fibrillation.
