Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06045858 |
| Other study ID # |
23-164 |
| Secondary ID |
2023-507544-37-0 |
| Status |
Not yet recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
June 30, 2024 |
| Est. completion date |
June 30, 2027 |
Study information
| Verified date |
May 2024 |
| Source |
University Hospital, Caen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction:
Several randomised controlled trials have demonstrated that novel oral anticoagulants (NOACs)
are safer compared to vitamin K antagonists for the management of non valvular atrial
fibrillation (NVAF) to prevent thromboembolic events, in the general population. There is a
growing interest in the use of apixaban in patients with End-Stage Renal-Disease (ESRD)
undergoing peritoneal dialysis but there is a lack of randomised data in this population.
Design: APIDP2 is a prospective parallel randomised, open-label, blinded endpoint trial.
Participants: Patients with ESRD undergoing chronic Peritoneal Dialysis who have NVAF.
Setting: A total of 178 participants will be recruited from 20 French peritoneal dialysis
centers.
Intervention: Eligible patients will be randomly assigned to receive either apixaban at a
reduced dose 2.5mg twice daily (dose determined with the previous pharmacokinetic study
APIDP1 of apixaban in PD patients) or dose-adjusted to INR target [2-3] coumadin therapy.
Anticoagulation to prevent thromboembolic events will be initiated or changed according to
the randomisation for a duration of one year.
The primary outcome is a major or clinically relevant non-major bleeding from randomisation
up to Month 12, assessed according to ISTH score. Secondary outcomes encompass an efficacy
composite criterion combining stroke or TIA, cardiovascular death, and thrombosis including
myocardial infarction cumulated at 12 months. Bleeding events will be also classified
according to GUSTO and TIMI criteria and pharmacodynamics outcomes will evaluate the time
within the INR target range of [2-3] in the warfarin arm over one year, and AntiXa apixaban
activity in case of bleeding events and at 1, 6, and 12 months of follow-up in the apixaban
arm.
Primary outcome analysis: To demonstrate that apixaban is safer than warfarin at one year,
assuming two interim analyses after 60 and 118 patients, a bilateral alpha risk of 5% and a
power of 80%, 178 patients are needed in this randomised trial (effect size found in the
ARISTOTLE study among patients with CrCl [25-30]ml/min), i.e. 89 patients per group.
Description:
The prevalence of AF in the general population is estimated to range around 1% depending on
age, reaching 8% in patients over 80 years old. This prevalence is of 20% and 14% in patients
on hemodialysis and peritoneal dialysis.
In addition, AF is associated with higher morbidity and mortality rates in patients with
advanced chronic kidney disease, in contrast with patients with preserved kidney function,
with a higher risk of both bleeding and clotting.
In the general population, the novel oral anticoagulants (NOACs) demonstrated a greater
safety over warfarin and among 269 patients with CrCl (Creatinine Clearance) 25 to 30 mL/min
included in ARISTOTLE trial: apixaban caused less bleeding than warfarin.
Furthermore, warfarin has been recognized as a risk factor for calcific uremic arteriolopathy
(calciphylaxis), a rare yet serious complication. Additionally, patients in ESRD appear to
have low adherence to warfarin therapy, with time of INR in target range of only 44 to 51% in
three randomised controlled trials.
Considering the complex pathophysiology underlying the excess risk of stroke in patients with
advanced CKD and the known complications of warfarin therapy, the use of NOACs in these
populations may present an appealing alternative.
Four significant reviews conducted in 2022 and 2023, based on randomised controlled trials
and cohort studies, assessed both thrombotic and bleeding outcomes associated with
anticoagulant use in advanced chronic kidney disease. These reviews highlights the necessity
for more randomised controlled trials (RCTs).
The two most significant cohorts to date that compared warfarin versus NOACs yielded
important findings are:
- Siontis et al.: they conducted a study involving a larger cohort (2,351 versus 7,053)
and found a reduction in major bleeding events with apixaban compared to warfarin, with
similar efficacy in dialysis patients.
- Wetmore et al.: they included 3,130 patients versus 9,086, and also found a reduction in
major bleeding events with apixaban compared to warfarin in dialysis patients, while
maintaining similar efficacy.
In 2023, a thirth cohort study was published, involving 4,313 apixaban users with stage 4 and
5 kidney disease. This study found that the use of 5mg apixaban was associated with a higher
risk of bleeding, with no difference in efficacy. These findings supported European dosing
recommendations of 2.5mg twice daily, which differ from the U.S. recommendation of 5mg twice
daily in patients with atrial fibrillation and severe chronic kidney disease.
Additionally, two recent meta-analyses included the three randomised controlled trials
comparing the safety of NOACs versus warfarin. These analyses encompassed a total of 341
patients with atrial fibrillation and end-stage renal disease, with 176 in the NOAC group and
165 in the warfarin group. The results indicated that safety and efficacy outcomes were
comparable, with no significant differences in stroke, mortality, or bleeding incidences.
In terms of cardiology recommendations, two meta-analyses involving a total of 10,445
patients with end-stage renal disease (ESRD) and 24,335 patients on dialysis, comparing those
who received VKA with those who received no anticoagulation, revealed no significant benefit
in preventing ischemic stroke but did indicate an increased risk of bleeding. Consequently,
the ESC guidelines do not provide any recommendations regarding the use of NOACs in patients
with atrial fibrillation (AF) who also have ESRD or are undergoing dialysis.
The results obtained from randomised controlled trials (RCTs) conducted on hemodialysis
patients cannot be extrapolated to peritoneal dialysis patients. The two patient populations
are distinct, as peritoneal dialysis patients do not receive heparin-based anticoagulation,
which may increase the risk of bleeding events. Additionally, peritoneal dialysis patients do
not have arteriovenous fistulas that could potentially lead to bleeding.
Regarding apixaban pharmacokinetics, a preliminary PK study in 2016 by Wang suggested that
hemodialysis has a moderate impact on apixaban's plasma concentration. Subsequently,
Mavrakanas conducted another PK study, revealing that hemodialysis was linked to
supratherapeutic levels of apixaban and recommended a dose reduction.
However, as there was a lack of data on the pharmacokinetics of apixaban in end-stage renal
disease (ESRD) patients undergoing peritoneal dialysis, researchers initiated the APIDP1
study with 12 peritoneal dialysis patients. The results showed a very low peritoneal dialysis
apixaban clearance, resulting in significantly higher mean AUC in patients treated with PD,
73% higher (p=0.01) than the mean AUC of healthy controls matched by age, weight, and sex.
Fung et al. subsequently reported similar pharmacokinetic findings : a proportion of PD
patients had supratherapeutics levels even when the reduced dosage 2.5mg twice a day was use.
Then Lidgard and Shen, in a 2023 editorial, emphasized the importance of reducing the
apixaban dosage for stroke prevention in atrial fibrillation patients undergoing PD
treatment, regardless of their age or weight.
Then, APIDP group aimed to conduct a phase III study to compare the safety of apixaban at the
reduced dose to adjusted-warfarin in ESRD patients treated with chronic peritoneal dialysis.
The study name is APIDP2, the protocol was prepared in accordance to Recommendations for
Interventional Trials (SPIRIT) guidelines. The complete study protocol and the SPIRIT
checklist are attached as supplement. The flow diagram of the study is illustrated in figure
1.
Objectives To determine in ESRD patients treated with chronic peritoneal dialysis whether
apixaban 2.5mg twice daily or dose-adjusted to INR target [2-3] warfarin is safer at one
year.
Methods
Trial design APIDP2 is a phase III study with a parallel enrolment, PROBE (prospective
randomised open blinded-endpoint) design, one year of follow-up. Open-label administration of
anticoagulation was choice because the need to adjust warfarin to targeted international
normalized ratio (INR).
Setting Recruitment is scheduled to commence in June 2024 with a total of 178 randomised
patients to be included. Considering the suitability of the 20 centers, it is anticipated
that data collection will be completed around June 2027.
