Clinical trial NCT04192552: Perioperative Anticoagulant Use for Surgery Evaluation Study Part 2 Pilot
Official title: Perioperative Anticoagulant (Dabigatran, Rivaroxaban, or Apixaban) Use for Elective Surgery/Procedure Evaluation in Patients With Atrial Fibrillation (AF) Part 2 Randomized Control Trial Pilot
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Atrial Fibrillation
Keywords: anticoagulant
atrial fibrillation
surgery
oral anticoagulant
high risk
blood thinner
DOAC
interruption
discontinue
elective
perioperative
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Hamilton Health Sciences Corporation
name: St. Joseph's Healthcare Hamilton
First posted: 2019-12-10
Enrollment: 201
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients taking apixaban, dabigatran, or rivaroxaban will be randomly assigned to follow 1) PAUSE or 2) ASRA perioperative DOAC management.
Primary purpose: TREATMENT

Brief summary: The proposed PAUSE-2 RCT study is the logical next step to the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study, which was completed on August 31, 2018. Both studies address the perioperative management of patients with atrial fibrillation (AF) who are receiving a direct oral anticoagulant (DOAC) and require an elective surgery/procedure. PAUSE did not address safe management of patients having a high-bleed-risk surgery/neuraxial anesthesia in whom there is concern about bleeding, especially neuraxial-related epidural hematomas that can lead to paralysis; such patients are often managed by the approach recommended by the American Society of Regional Anesthesia (ASRA). In PAUSE-2, investigators will test the hypothesis: (i) for patients having a high-bleed-risk surgery/neuraxial anesthesia, the simpler "PAUSE management" is as safe (non-inferior) to the more complex "ASRA management". PAUSE-2 will establish a standard for perioperative DOAC management in patients having high-bleed-risk surgery or neuraxial anesthesia.

To start, this will be a pilot study of a larger PAUSE-2-RCT. The investigators will be conducting this pilot study to assess the feasibility of the study at this smaller scale.

Detailed description: The proposed PAUSE-2 RCT study is the logical next step to the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study, which was completed on August 31, 2018 and presented at the American Society of Hematology Conference on December 4, 2018. Both studies address the perioperative management of patients with atrial fibrillation (AF) who are receiving a direct oral anticoagulant (DOAC) (apixaban, dabigatran or rivaroxaban) and require an elective surgery/procedure. Standardized, DOAC-specific perioperative management is needed to: (i) minimize patient harm related to serious perioperative adverse events, comprising arterial thromboembolism (A-TE) and major bleeding (MB); and (ii) allow consistent, cost-efficient management that avoids cancelled surgeries/procedures and the need to reverse DOACs. PAUSE did not address safe management of patients having a high-bleed-risk surgery/neuraxial anesthesia in whom there is concern about bleeding, especially neuraxial-related epidural hematomas that can lead to paralysis; such patients are often managed by the approach recommended by the American Society of Regional Anesthesia (ASRA).

In PAUSE-2, the primary question is: (i) In patients having a high-bleed-risk surgery/neuraxial anesthesia, is the simple, shorter-DOAC-interruption PAUSE management as safe as the more complex, longer-interruption ASRA approach? Hypothesis: PAUSE management is non-inferior to ASRA management with expected perioperative risks in both groups of 2.5% for MB (2% non-inferiority margin) and 0.5% for A-TE (1% non-inferiority margin).

In PAUSE-2, the secondary question is: (i) are the PAUSE and ASRA management approaches associated with similar proportions of patients with minimal-to-no residual DOAC levels at surgery, and similar adherence to the DOAC interruption/resumption protocols? Exploratory postulate: PAUSE and ASRA approaches will have similar proportion of patients (±5%) with DOAC levels (\<30, 30-49.9, and ≥50 ng/mL), and protocol adherence to perioperative DOACs interrupted and resumed.

Approximately 201 patients will be recruited for the PAUSE-2 Study pilot. This is 10% of the proposed main study (2,010 participants).

In all patients, a 5 mL blood sample will be taken just before surgery (but will be not available for clinical use and cannot be used for genetic testing). Plasma will be frozen and stored at each clinical site before shipment to the core laboratory at McMaster University for storage and standardized DOAC level measurement.

A focused patient enrolled before the procedure and followed up every week up to completion of their participation at 4 weeks (±5 days). Patients will be enrolled over a 1 year period.

To start, this will be a pilot study of a larger PAUSE-2-RCT. Conducting this pilot study will help assess the feasibility and methodology of the study at this smaller scale. It is important to evaluate the feasibility of recruitment, randomization and retention. As well, investigators need to assess the methodology and implementation of the randomized trial.

Note that the outcome for the pilot study is not to evaluate the safety of the perioperative procedure, but to examine the approach to be used in the intended larger study. The outcomes for the larger study will still be collected.

Eligibility criteria: Inclusion Criteria:

* Adult (age ≥18 years) with AF/flutter who is receiving a DOAC: apixaban 2.5 mg or 5 mg BID; dabigatran 110 mg or 150 mg BID; or rivaroxaban 15 mg or 20 mg QD.
* Undergoing an elective surgery/procedure associated with a high-bleed-risk or any surgery/procedure requiring neuraxial anesthesia (includes regional blocks)
* Patient and their clinician are willing to adhere to DOAC interruption/continuation protocols.
* Patient to resume DOAC after surgery/procedure (i.e., no intent to discontinue DOAC).

Exclusion Criteria:

* Creatinine clearance (CrCl) \<30 mL/min (dabigatran, rivaroxaban) and \<25 mL/min (apixaban) based on the Cockroft-Gault equation, which is recommended for DOAC dosing.
* Patient taking a DOAC that is infrequently used (i.e., edoxaban, \<5% Canadian DOAC market share in 2018) or is not available for clinical use in Canada or Europe (i.e., betrixaban).
* Patient taking a DOAC for a non-AF clinical indication (excluded to maintain study population homogeneity).
* Cognitive impairment or psychiatric illness that precludes collection of follow-up data.
* Inability or unwillingness to provide informed consent.
* Previous participation in PAUSE-2.

Primary outcomes:
measure: Number of patients who had a major bleed
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
measure: Number of patients who had an Arterial Thromboembolism (ATE)
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
Secondary outcomes:
measure: Number of patients who died
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
measure: Number of patients who had a Clinically Relevant Non-Major Bleed
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
measure: Number of patients who had a Minor Bleed
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
measure: Number of patients who had a Venous Thromboembolism (VTE)
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
measure: Number of patients who had an Acute Coronary Syndrome
timeFrame: Each patient will be followed up every 7 days up to completion at 28 days post procedure date
Other outcomes:
measure: Concentrations of Anti-factor Xa
timeFrame: Pre-op day 0
measure: Rate of Diluted Thrombin Time (dTT)
timeFrame: Pre-op day 0
measure: Adherence to the DOAC interruption and resumption protocols
timeFrame: Approximately 1 week pre-op up to completion at 28 days post procedure date
Locations:
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
Study officials:
affiliation: McMaster University/St. Joseph's Healthcare
name: James D Douketis, MD
role: PRINCIPAL_INVESTIGATOR
References: