Clinical trial NCT04510805: Effectiveness of NextDose for Warfarin Dose Individualization
Official title: Single-blind, Randomized Comparison of Warfarin Management Guided by NextDose Versus Management Based on Clinician Experience.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Thrombosis Embolism
Keywords: warfarin; PKPD; Bayesian forecasting
Lead sponsor: The First Affiliated Hospital of Soochow University
Sponsor class: OTHER
Collaborators: name: National Natural Science Foundation of China
First posted: 2020-08-12
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Current warfarin dose individualization methods tend to be empirical, rather than based upon pharmacological and statistical principles. A theory-based model of warfarin pharmacokinetics and pharmacodynamics (PKPD) has been developed for dose individualization when used in conjunction with a Bayesian forecasting tool (NextDose).

This study compares standard of care clinician judgement for warfarin management with the use of a web-based dosing tool (NextDose). Computer-assisted anticoagulant dosing has been shown to be helpful using empirical models. This study will evaluate a theory-based model which has shown superior performance over empirical models in predicting clinical doses of warfarin. The study is also guided by quality and service improvement principles.
Primary purpose: TREATMENT

Brief summary: Objectives:

To understand whether the implementation of warfarin dose management using NextDose (nextdose.org) at The First Affiliated Hospital of Soochow University (Suzhou, China) improves the quality of anticoagulation therapy.

Endpoint Primary

1. Percentage of time within the acceptable INR range estimated using linear interpolation during the 28 days after initiation of warfarin.

Secondary 2.1 Percentage of Time Measures 2.2 Time to Stable Dose 2.3 Safety Outcomes 2.4 Acceptability of NextDose Recommendations Exploratory 3.1 Percentage of Time Measures 3.2 Time to Stable Dose 3.3 Safety Outcomes 3.4 Acceptability of NextDose Recommendations 3.5 Model Evaluation 3.6 INR Variability

Population:

240 participants of any sex between the age of 18 and 80 years. Patients requiring treatment with warfarin following cardiac surgery.

Detailed description: Objectives:

To understand whether the implementation of warfarin dose management using NextDose (nextdose.org) at The First Affiliated Hospital of Soochow University (Suzhou, China) improves the quality of anticoagulation therapy.

Endpoint Primary

1. Percentage of time within the acceptable INR range estimated using linear interpolation during the 28 days after initiation of warfarin.

   Secondary 2.1 Percentage of Time Measures
   1. Percentage of time within the acceptable INR Range estimated using linear interpolation during the 90 days after initiation of warfarin.
   2. Percentage of time spent above and below the acceptable INR range at day 28, and 90 after initiation of warfarin estimated by linear interpolation.

   2.2 Time to Stable Dose a. Number of days to achievement of stable dose (defined as 3 consecutive INR measurements within acceptable range for the same mean daily dose).

   2.3 Safety Outcomes a. Number of participants who experience at least one of the following safety events: major bleeding within 30 days, INR of 4 or greater within 30 days, death within 30 days, and symptomatic or asymptomatic VTE confirmed by objective testing within 60 days of surgery.

   2.4 Acceptability of NextDose Recommendations
   1. Percentage of prescribed doses within 0.625 mg of the NextDose proposed dose.
   2. Mean difference between the prescribed dose and the NextDose proposed dose. Exploratory 3.1 Percentage of Time Measures

   a. The percentage of time spent within, above and below the acceptable INR range estimated by numerical integration with the Bayesian parameter estimates of the PKPD model at day 28 and at day 90 after initiation of warfarin.

   3.2 Time to Stable Dose a) Days to first INR measurement within the acceptable range. b) Days to second consecutive INR measurement within the acceptable range. c) Number of dose adjustments to achievement of stable dose (3 consecutive INR measurements within acceptable range for the same mean daily dose).

   d) Total number of dose adjustments at day 90. e) Total number of INR measurements at day 90. 3.3 Safety Outcomes

   a) Incidence of minor and major bleeding events. b) Incidence of thromboembolic events. c) 30 day all-cause mortality. d) 90 day all-cause mortality. e) 90 day cardiovascular mortality. f) Number of warfarin doses withheld due to high INR (as determined by the treating clinician).

   3.4 Acceptability of NextDose Recommendations a) Percentage of prescribed doses within 20% of the NextDose proposed dose. 3.5 Model Evaluation

   a) Predictive performance of the model for patients with steady-state warfarin doses below 2 or above 7 mg/day.

   3.6 INR Variability

   a) INR variability as described by Lind et al. (the standard deviation of transformed INR values).

   Population:

240 participants of any sex between the age of 18 and 80 years. Patients requiring treatment with warfarin following cardiac surgery.

Eligibility criteria: Inclusion Criteria:

* Scheduled to undergo cardiac surgery with planned warfarin anticoagulation for at least three months.
* Age ≥ 18 and \< 80 years.
* Written informed consent has been obtained.

Exclusion Criteria:

* Allergy to warfarin tablet or excipients.
* Enrollment or planned enrollment in other research that would conflict with full participation in the study or confound the observation or interpretation of the study findings.
* Patients who in the opinion of the recruiting clinician are:

  * unwilling or unable to comply with the protocol requirements and/or,
  * considered unreliable concerning the requirements for follow-up during the study and/or, compliance with drug administration.
* Patient with life expectancy less than the expected duration of the trial due to concomitant disease.
* Contraindication to warfarin therapy. The following are examples but not an exhaustive list:

  * Pregnancy.
  * Cerebral infarction or cerebral haemorrhage (from patients' medical record) within the 3 months prior to heart valve replacement
  * Severe heart failure (New York Heart Function Class IV)
  * Severe renal failure (CLcr (Cockcroft-Gault) ≤20mL / min)
  * Severe liver failure (Child-Pugh≥10)
  * Abnormal liver function (elevated transaminase more than three times the upper limit of the local hospital clinical laboratory).

Primary outcomes:
measure: Percentage of Time Within Range
timeFrame: 28 days after initiation of warfarin
Secondary outcomes:
measure: Percentage of Time Measure
timeFrame: day 90 after initiation of warfarin
measure: Percentage of Time Measure
timeFrame: day 28, and 90 after initiation of warfarin
measure: Time to Stable Dose
timeFrame: 90 days after initiation of warfarin
measure: Number of participants who experience at least one of the following safety events:
timeFrame: 60 days of surgery.
measure: Percentage of prescribed doses within 0.625 mg of the NextDose proposed dose.
timeFrame: 90 days after initiation of warfarin
measure: Mean difference between the prescribed dose and the NextDose proposed dose.
timeFrame: 90 days after initiation of warfarin
Other outcomes:
Locations:
Study officials:
affiliation: The First Affiliated Hospital of Soochow University
name: Li Y Miao, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Soochow University
name: Zhen Y Shen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Auckland, New Zealand
name: Nick Holford, MBChB
role: STUDY_DIRECTOR
affiliation: The First Affiliated Hospital of Soochow University
name: Ling Xue, MS
role: STUDY_DIRECTOR
affiliation: University of Auckland, New Zealand
name: Guangda Ma, MHSc
role: STUDY_DIRECTOR
affiliation: The First Affiliated Hospital of Soochow University
name: Ying L Ding, MS
role: STUDY_DIRECTOR
affiliation: The First Affiliated Hospital of Soochow University
name: Qiong Qin, MS
role: STUDY_DIRECTOR
affiliation: University of Auckland, New Zealand
name: Jacqui Hannam, PhD
role: STUDY_DIRECTOR
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