Effectiveness of NextDose for Warfarin Dose Individualization

Single-blind, Randomized Comparison of Warfarin Management Guided by NextDose Versus Management Based on Clinician Experience.

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.

Study Overview

• Status: Unknown
• Conditions: Thrombosis Embolism
• Intervention / Treatment: Device: NextDose (nextdose.org)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ling Xue, MS; Phone Number: +8651267972699 +8651267972699; Email: xueling726@126.com
• Study Contact Backup: Name: Qiong Qin, MS; Phone Number: +8651267973022 +8651267973022; Email: q-q2456@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm; NextDose guided warfarin management taking into consideration covariates (sex, age, weight, height CYP2C9 (rs1057910) and VKORC1 (rs9923231), the dosing and INR history of each patient to predict an individualized dose in accordance with the theory-based warfarin model and target concentration intervention principles. Initial recommended warfarin dose, up to the first INR, will be the maintenance dose predicted from group values, subsequently the NextDose predicted maintenance dose will be recommended. The treating clinician will also be provided with the NextDose report to inform the choice of the prescribed dose.	Device: NextDose (nextdose.org); NextDose guided warfarin management taking into consideration covariates (sex, age, weight, height CYP2C9 (rs1057910) and VKORC1 (rs9923231), the dosing and INR history of each patient to predict an individualized dose in accordance with the theory-based warfarin model and target concentration intervention principles. Initial recommended warfarin dose, up to the first INR, will be the maintenance dose predicted from group values, subsequently the NextDose predicted maintenance dose will be recommended. The treating clinician will also be provided with the NextDose report to inform the choice of the prescribed dose.
No Intervention: Control Arm; Usual standard of care. Clinical experience of the treating physician taking into account the covariates, dosing and INR history of each patient, to determine the initial, and subsequent maintenance doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Time Within Range	The percentage of time spent within the acceptable INR range (± 0.5 of target INR) as estimated using linear interpolation during the 28 days after initiation of warfarin.	28 days after initiation of warfarin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Time Measure	The percentage of time spent within the acceptable INR range at day 90 after initiation of warfarin estimated by linear interpolation.	day 90 after initiation of warfarin
Percentage of Time Measure	The percentage of time spent above and below the acceptable INR range at day 28, and 90 after initiation of warfarin estimated by linear interpolation.	day 28, and 90 after initiation of warfarin
Time to Stable Dose	Number of days to achievement of stable dose (defined as 3 consecutive INR measurements within acceptable range for the same mean daily dose.	90 days after initiation of warfarin
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.	60 days of surgery.
Percentage of prescribed doses within 0.625 mg of the NextDose proposed dose.	Acceptability of NextDose Recommendations	90 days after initiation of warfarin
Mean difference between the prescribed dose and the NextDose proposed dose.	Acceptability of NextDose Recommendations	90 days after initiation of warfarin

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University
• Collaborators: National Natural Science Foundation of China
• Investigators: Principal Investigator: Li Y Miao, PhD, The First Affiliated Hospital of Soochow University; Principal Investigator: Zhen Y Shen, PhD, The First Affiliated Hospital of Soochow University; Study Director: Nick Holford, MBChB, University of Auckland, New Zealand; Study Director: Ling Xue, MS, The First Affiliated Hospital of Soochow University; Study Director: Guangda Ma, MHSc, University of Auckland, New Zealand; Study Director: Ying L Ding, MS, The First Affiliated Hospital of Soochow University; Study Director: Qiong Qin, MS, The First Affiliated Hospital of Soochow University; Study Director: Jacqui Hannam, PhD, University of Auckland, New Zealand

Publications and helpful links

General Publications

• Sheiner LB. Computer-aided long-term anticoagulation therapy. Comput Biomed Res. 1969 Dec;2(6):507-18. doi: 10.1016/0010-4809(69)90030-5. No abstract available.
• Boyle DA, Ludden TM, Carter BL, Becker AJ, Taylor JW. Evaluation of a Bayesian regression program for predicting warfarin response. Ther Drug Monit. 1989;11(3):276-84. doi: 10.1097/00007691-198905000-00010.
• Xue L, Holford N, Ding XL, Shen ZY, Huang CR, Zhang H, Zhang JJ, Guo ZN, Xie C, Zhou L, Chen ZY, Liu LS, Miao LY. Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients. Br J Clin Pharmacol. 2017 Apr;83(4):823-835. doi: 10.1111/bcp.13157. Epub 2016 Nov 25. Erratum In: Br J Clin Pharmacol. 2017 Jul;83(7):1602.
• Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002 Apr 3;287(13):1690-8. doi: 10.1001/jama.287.13.1690.
• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
• Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011 Jan 18;57(3):253-69. doi: 10.1016/j.jacc.2010.12.005. Epub 2011 Jan 7.

Helpful Links

• NextDose

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2020
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 12, 2020

Study Record Updates

• Last Update Posted (Actual): August 19, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: warfarin; PKPD; Bayesian forecasting
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism; Thrombosis; Embolism and Thrombosis
• Other Study ID Numbers: 2020025

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No