Stroke Prophylaxis With Apixaban in Chronic Kidney Disease Stage 5 Patients With Atrial Fibrillation

NCT ID: NCT05679024

Last Updated: 2024-10-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

1400 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-02-17

Study Completion Date

2028-12-31

Brief Summary

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Objective: To study the efficacy and safety of apixaban as stroke prophylaxis in patients with chronic kidney disease (CKD) stage 5 and atrial fibrillation (AF) with or without dialysis treatment. The study hypothesis is that compared to no anticoagulation, apixaban reduces the incidence of ischemic stroke without causing an unacceptable increase in fatal or intracranial bleeding events.

The secondary objectives are to evaluate the risk of all-cause mortality, cardiovascular events, and major bleeding in people with CKD stage 5 and AF treated with apixaban compared to standard of care without anticoagulation.

Trial design: Pragmatic Prospective Open Label Randomized Controlled Clinical Trial, phase 3b over 12-72 months.

Trial population: 1000-1400 patients at ≈50 sites in Sweden, Finland, Norway, Iceland and Poland Eligibility criteria: Adults ≥18 years with CKD stage 5 (ongoing treatment with any chronic dialysis treatment OR an estimated glomerular filtration rate (eGFR)\* \<20 ml/min/1.73 m2 at least twice 3 months apart of which at least one occasion is \<15 ml/min/1.73 m2 due to CKD during the last 12 months) and a diagnosis of chronic, paroxysmal, persistent, or permanent AF or atrial flutter (AFL) with CHA2DS2-VASc score ≥2 for men or ≥3 or more for women as an indication for oral anticoagulation.

The exclusion criteria are AF or AFL due to reversible causes, rheumatic mitral stenosis or moderate-to-severe non-rheumatic mitral stenosis at the time of inclusion into the study, a condition other than AF or AFL that requires chronic anticoagulation, contraindications for anticoagulation, active bleeding or serious bleeding within 3 months, planned for surgery within 3 months, and current use of strong inhibitors of both CYP3A4 and P-glycoprotein.

Interventions: Randomization 1:1 to treatment with apixaban 2.5 mg twice daily and standard of care, or standard of care and no anticoagulation.

Outcome measures: primary efficacy (time to first ischemic stroke); primary safety (the composite of time to first intracranial bleeding or fatal bleeding); secondary efficacy (time to all-cause mortality, time to cardiovascular event or cardiovascular death); secondary safety (time to first major bleeding according to International Society on Thrombosis and Hemostasis (ISTH) criteria)

Detailed Description

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Background and rationale: Atrial fibrillation (AF) is common (15-30%) in patients with chronic kidney disease (CKD) and AF prevalence increases with severity of CKD. In late stages of CKD, randomized control trials (RCT) of both efficacy and safety of any anticoagulation therapy, both warfarin and direct oral anticoagulation (DOAC) drugs, for stroke prophylaxis in AF are lacking. The efficacy of warfarin and DOACs have been evaluated in observational trials in patients with stage 5 CKD, but the results have been conflicting, and these studies were all subjected to selection bias in one way or the other. Instead, observational studies have demonstrated several adverse side-effects. Among them an increased number of bleedings including hemorrhagic stroke in patients treated with warfarin, and calciphylaxis, a very serious complications unknown in the normal population linked to the withdrawal of vitamin-K-dependent protection of vascular calcification in CKD. With apixaban treatment several benefits were reported. Firstly, a potential protective effect against ischemic stroke. Secondly, a lower incidence of bleeding complications as observed in the major trials, and thirdly, no disturbance in vitamin K turnover as compared to warfarin treatment. In addition, apixaban treatment does not require routine monitoring and have fewer drug/food interactions. For patients with CKD stage 5, treatment with apixaban appears to have a lower bleeding risk than warfarin treatment.

Rationale to study design: There are no previous randomized controlled clinical trials in this study population. The SACK study is conducted in approximately 50 sites in Sweden, Finland, Norway, Iceland and Poland, and additional European countries, if necessary. In Sweden, the study will be register-randomized (via the national Swedish Renal Register \[SNR\]) whereas the other countries in the study will include patients in a traditional way for clinical trials.

The study design will be an individually randomized two-armed parallel-group design. Apixaban will be prescribed and renewed by the local investigator via regular prescription or distributed by the investigating site at regular intervals in all participating countries. Due to open-label prescription and safety reasons, the study will be conducted as an open-label trial with end-point evaluation. Patients who are randomized to apixaban and those who are randomized to standard of care with no anti-coagulation will receive all other guideline-recommended standard of care treatments. Patients already on prior warfarin or apixaban therapy, or on regular low molecular weight heparin (LMWH) can also be randomized to either treatment arm (their current anticoagulation is discontinued at the inclusion visit) after an individualized risk assessment. At inclusion, patients will provide routine blood samples including hemoglobin, eGFR, and coagulation parameters.

The end of the clinical study for each individual patient is defined as the End of Study (EoS) visit. The EoS for a patient is after 72 months or when 247 primary events have been reached, whichever comes first. An interim analysis will take place after 1000 patient-years with the purpose to evaluate event rate and to be able to closer determine the exact number of patients and duration of the trial. The end of the clinical trial is defined as the last visit of the last subject in the study (LVLS).

A Data and Safety Monitoring Board (DSMB) will supervise this study, and primary safety and efficacy endpoints and major bleedings will additionally be evaluated by independent external reviewers according to a predefined Central Event Adjudication charter.

Exploratory outcomes: Time to first thromboembolic event defined as a composite of deep vein thrombosis, pulmonary embolism, transient ischemic attack Time to dialysis access thrombosis Time to kidney replacement therapy Delayed graft function in patients undergoing kidney transplantation Thrombosis of renal artery or vein in patients undergoing kidney transplantation

Among the secondary safety outcomes are time to major bleeding according to ISTH criteria. We are especially interested in the safety outcomes of the subgroup undergoing a kidney transplantation from the waiting list and therefore we have an extended protocol for those participants.

Conditions

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Chronic Kidney Diseases Atrial Fibrillation Stroke Intracerebral Hemorrhage Major Bleed Cardiovascular Complication Death Kidney Transplant; Complications Thromboses, Venous

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Pragmatic Prospective Open Label Parallel-Group Multicenter Phase 3b Randomized Controlled Clinical Trial
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Apixaban 2.5 mg twice daily and standard of care

Apixaban 2.5 mg twice daily (low dose) and all other standard of care

Group Type ACTIVE_COMPARATOR

Apixaban 2.5 milligram Oral Tablet

Intervention Type DRUG

Oral Tablet

Standard of care and no anticoagulation

All other Standard of care and no anticoagulation

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Apixaban 2.5 milligram Oral Tablet

Oral Tablet

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Signed Written Informed Consent
2. 18 years of age or older
3. Ongoing treatment with any chronic dialysis treatment OR an estimated glomerular filtration rate (eGFR)\* \<20 ml/min/1.73 m2 at least twice 3 months apart of which at least one occasion is \<15 ml/min/1.73 m2 due to CKD during the last year (12 months).
4. Diagnosis of chronic (i.e., repeated) paroxysmal, persistent, or permanent atrial fibrillation (AF) or atrial flutter (AFL)
5. CHA2DS2-VASc score ≥2 or more for men ≥3 or more for women as an indication for oral anticoagulation
6. Women of childbearing potential (WOCBP) should have a negative highly effective pregnancy test at screening and must agree to follow instructions for method(s) of contraception for the duration of treatment

Exclusion Criteria

Participants may not be included in the study if any of the following criteria are met:

1. AF or AFL due to reversible causes (e.g., thyrotoxicosis, pericarditis)
2. Any degree of rheumatic mitral stenosis or moderate-to-severe non-rheumatic mitral stenosis at the time of inclusion into the study
3. Any condition other than AF or AFL that requires chronic anticoagulation (e.g., a prosthetic mechanical heart valve, antiphospholipid syndrome).
4. Any contraindication for anticoagulation including

1. endocarditis
2. documented intolerance for apixaban
3. liver disease with documented coagulation disorder
4. pregnancy or breast feeding
5. Active bleeding or serious bleeding within 3 months, or

1. documented hemorrhagic blood dyscrasia
2. patients currently receiving dual antiplatelet therapy
6. Planned for surgery

1. kidney transplantation with a living donor within 3 months
2. active on the kidney transplant waiting list at a kidney transplant center where apixaban use is prohibited
3. valvular heart disease surgery
7. Current use of strong inhibitors of both CYP3A4 and P-glycoprotein in accordance with the summary of product characteristics (SmPC) of apixaban or regular intake of non-steroidal anti-inflammatory drugs (NSAID) or cyclooxygenase-2 (COX2) inhibitors
8. Any condition or circumstance in which the patient should not participate in the study according to the study investigator (reason documented in the pre-screening protocol)

Being active on the kidney transplant waiting list is not an exclusion criterion if it is allowed according to the current clinical guidelines at the transplant clinic where the patient is registered. The patient must report changes in waiting list status to the investigator promptly.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Region Stockholm

OTHER_GOV

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Marie Evans, Ass Prof

Role: PRINCIPAL_INVESTIGATOR

Karolinska University Hospital

Maria Svensson, Prof

Role: STUDY_CHAIR

Uppsala University

Locations

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Helsingfors University hospital

Helsinki, , Finland

Site Status RECRUITING

Tampere hospital

Tampere, , Finland

Site Status RECRUITING

Turku hospital

Turku, , Finland

Site Status RECRUITING

Landspitali, the National University hospital of Iceland

Reykjavik, , Iceland

Site Status RECRUITING

Oslo Akershus

Oslo, , Norway

Site Status RECRUITING

Oslo Universitetssjukhus Ullevål

Oslo, , Norway

Site Status RECRUITING

Stavanger hospital

Stavanger, , Norway

Site Status RECRUITING

Tromsö hospital

Tromsø, , Norway

Site Status RECRUITING

Vestfold hospital

Tønsberg, , Norway

Site Status ACTIVE_NOT_RECRUITING

Falun hospital

Falun, Dalarna County, Sweden

Site Status RECRUITING

Östersund hospital

Östersund, Jämtland County, Sweden

Site Status NOT_YET_RECRUITING

Lasarettet i Falun

Falun, Region Dalarna, Sweden

Site Status RECRUITING

Mora sjukhus

Mora, Region Dalarna, Sweden

Site Status RECRUITING

Länssjukhuset Kalmar

Kalmar, Region Kalmar Län, Sweden

Site Status NOT_YET_RECRUITING

Kalix hospital

Kalix, Region Norrbotten, Sweden

Site Status RECRUITING

Skånes University hospital Lund

Lund, Region Skåne, Sweden

Site Status RECRUITING

Skånes University hospital Malmö

Malmo, Region Skåne, Sweden

Site Status RECRUITING

Norrland University hospital Umeå

Umeå, Region Västerbotten, Sweden

Site Status RECRUITING

Sundsvall

Sundsvall, Region Västernorrland, Sweden

Site Status RECRUITING

Västmanlands sjukhus Västerås

Västerås, Region Västmanland, Sweden

Site Status NOT_YET_RECRUITING

Borås sjukhus

Borås, Region Västra Götaland, Sweden

Site Status RECRUITING

Sahlgrenska University hospital

Gothenburg, Region Västra Götaland, Sweden

Site Status RECRUITING

Skaraborg hospital Skövde

Skövde, Region Västra Götaland, Sweden

Site Status RECRUITING

University hospital Örebro

Örebro, Region Örebro Län, Sweden

Site Status RECRUITING

Linköping University hospital

Linköping, Region Östergötland, Sweden

Site Status RECRUITING

Länssjukhuset Ryhov

Jönköping, , Sweden

Site Status RECRUITING

Karlshamns sjukhus

Karlshamn, , Sweden

Site Status RECRUITING

Karlstad Central hospital

Karlstad, , Sweden

Site Status RECRUITING

Norrköpings sjukhus

Norrköping, , Sweden

Site Status RECRUITING

Skellefteå hospital

Skellefteå, , Sweden

Site Status NOT_YET_RECRUITING

Karolinska Universitetssjukhuset

Stockholm, , Sweden

Site Status RECRUITING

Danderyd sjukhus AB

Stockholm, , Sweden

Site Status RECRUITING

Akdemiska sjukhuset Uppsala

Uppsala, , Sweden

Site Status RECRUITING

Varberg hospital

Varberg, , Sweden

Site Status RECRUITING

Countries

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Finland Iceland Norway Sweden

Central Contacts

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Marie Evans, Ass Prof

Role: CONTACT

+46760520852

Caroline Moberg

Role: CONTACT

Facility Contacts

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Helsingfors U hospital, MD

Role: primary

Satu Mäkelä, MD

Role: primary

Tapio Hellman, MD

Role: primary

Sunna Snaedal, MD, PhD

Role: primary

Asta Jonasdottir, MD, PhD

Role: backup

Kristyna Parker, MD

Role: primary

Benedict Ronning, PhD

Role: primary

Eva Staal

Role: primary

Ludvig Rinde

Role: primary

Anna Sahlander, MD

Role: primary

Jan Flesche, MD

Role: primary

Anna Sahlander, MD

Role: primary

Hans Furuland, MD

Role: primary

Nikolaos Rigas, MD

Role: primary

Nils Sundberg, MD

Role: primary

Mårten Segelmark, Prof

Role: primary

Anders Christenssen, Prof

Role: primary

Andreas Jonsson, MD

Role: primary

Frida Welander, MD

Role: primary

Josefin Mörtberg, MD

Role: primary

Achim Barth, MD

Role: primary

Gregor Guron, Prof

Role: primary

Anna Wärme, MD

Role: primary

Piotr Jacuszewski, MD

Role: primary

Fredrik Uhlin, RN

Role: primary

Maria Stendahl, PhD

Role: primary

Jonas Andersson, MD

Role: primary

Johan Isaksson, MD

Role: primary

Fredrik Sundelin, MD

Role: primary

Cecilia Johansson, MD, PhD

Role: primary

Marie Evans, PhD

Role: primary

+4612382550

Karin Bergen, MD

Role: primary

Kerstin Martala, RN

Role: primary

Oscar Bratt, MD

Role: primary

References

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Natale P, Palmer SC, Ruospo M, Longmuir H, Dodds B, Prasad R, Batt TJ, Jose MD, Strippoli GF. Anticoagulation for people receiving long-term haemodialysis. Cochrane Database Syst Rev. 2024 Jan 8;1(1):CD011858. doi: 10.1002/14651858.CD011858.pub2.

Reference Type DERIVED
PMID: 38189593 (View on PubMed)

Other Identifiers

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EU CT 2022-501600-10-00

Identifier Type: -

Identifier Source: org_study_id

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