Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation (START)

August 4, 2023 updated by: Steven Warach, MD, PhD, University of Texas at Austin

Title:

Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation (START): a pragmatic, adaptive randomized clinical trial.

Primary Objective:

• To determine the optimal time to initiate anticoagulation with a Non-Vitamin K Oral Anticoagulant (NOAC) after ischemic stroke in patients with non-valvular atrial fibrillation.

Secondary Objectives:

  • To compare the rates of primary adverse outcomes in a per protocol analysis
  • To compare 30 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
  • To compare 90 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
  • To explore the optimal timing in subgroups of age, sex, outcome category, and NOAC choice

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Long-term oral anticoagulation is standard for secondary stroke prevention in patients with atrial fibrillation (AFib). However, there is limited data and no consensus on the timing of when to initiate anticoagulation therapy, and concern that starting too soon risks symptomatic hemorrhagic transformation. These data are derived almost exclusively from heparins and Vitamin K antagonists (e.g.,warfarin). Now that NOACs have become the mainstay of stroke prophylaxis in AFib and have more rapid and consistent anticoagulation and fewer strokes (hemorrhagic especially), the question of optimal timing of NOAC initiation is of increasing importance.

The primary aim is to determine the time-to-treatment interval with the lowest associated risk for adverse events in the context of anticoagulation therapy with NOACs for acute stroke patients with non-valvular AFib. The question will be investigated with a prospective, adaptive, randomized, controlled "dose-exploration" trial with the time to treatment with NOAC therapy treated as the incremental "dose".

An adaptive, pragmatic trial will be performed that will not deviate from the treating physicians' usual practice except for randomizing the time to start the NOAC. Data collection will be limited to those fields necessary for the planned primary and secondary analyses.

The composite primary outcome event will be any of the following within 30 days of the index stroke: Ischemic Events (symptomatic ischemic stroke or systemic embolism) or Hemorrhagic Events (symptomatic hemorrhagic transformation of index ischemic stroke, other symptomatic intracranial hemorrhage, or major extracranial hemorrhage).

Four time-to-treatment intervals, i.e. study arms, between 2 and 14 days will be investigated: 72 (+/- 24) hours, 132 (+/- 12) hours, 228 (+/- 12) hours, and 324 (+/- 12) hours. An innovative adaptive design will be used which includes response adaptive randomization and modeling of ischemic and hemorrhagic outcome events. The ischemic and hemorrhagic events within the composite primary endpoint are modeled separately using their known monotonic property that the risk of an event increases (ischemic) or decreases (hemorrhage) as the time-to-treatment interval lengthens. Interim analysis will occur after 100 subjects are randomized and have the primary outcome, where the primary outcome will be analyzed and new randomization probabilities will be calculated to favor the arms that have a better risk-profile. Thereafter, interim analyses will occur after 50 subjects are randomized under the new randomization probabilities, and further new randomization probabilities will be calculated to favor the arms that have a better risk-profile.

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Texas
      • Austin, Texas, United States, 78705
        • Seton Medical Center Austin
      • Austin, Texas, United States, 78701
        • Dell Seton Medical Center at The University of Texas
      • Austin, Texas, United States, 78705
        • St. David's Medical Center
      • Bryan, Texas, United States, 77802
        • CHI St. Joseph Health Regional Hospital
      • Dallas, Texas, United States, 75235
        • Parkland Memorial Hospital
      • Dallas, Texas, United States, 75246
        • Baylor University Medical Center
      • Dallas, Texas, United States, 75231
        • Texas Health Presbyterian Hospital
      • Dallas, Texas, United States, 75390
        • UT Southwestern William P. Clements Hospital
      • Dallas, Texas, United States, 75390
        • UT Southwestern Zale Lipshy University Hospital
      • El Paso, Texas, United States, 79905
        • Texas Tech University Health Science Center - El Paso University Medical Center
      • Fort Worth, Texas, United States, 76104
        • Texas Health Harris Methodist Hospital
      • Houston, Texas, United States, 77030
        • The University of Texas Health Science Center at Houston
      • Kyle, Texas, United States, 78640
        • Seton Medical Center Hays
      • Round Rock, Texas, United States, 78665
        • Seton Medical Center Williamson
      • San Antonio, Texas, United States, 78229
        • The University of Texas Health Science Center at San Antonio

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. New disabling neurological deficit attributable to new ischemic stroke.
  2. Minimum lesion diameter of 1.5cm on qualifying imaging. If lesion not visible on imaging, NIHSS must be greater than 4.
  3. Non-valvular atrial fibrillation (paroxysmal, persistent, or permanent).

  4. Not currently anticoagulated and/or will not be anticoagulated prior to starting their NOAC at the randomized time of initiation (except for DVT prophylaxis).

    Note: Patients who had been taking an anticoagulant prior to their qualifying index event (for any reason) are eligible for START, assuming the drug is no longer having a therapeutic effect in the patient's system by 48 hours from stroke onset.

  5. Treating physician plans to anticoagulate with a FDA-approved novel oral anticoagulant (NOAC): apixaban, dabigatran, edoxaban, or rivaroxaban, or other FDA-approved NOAC.
  6. Qualifying brain CT or MRI scan < 48hr from stroke onset (time last known well). If patient has been treated with thrombolytic or endovascular therapy for this stroke, then the qualifying scan is that which is performed after therapy to rule out clinically significant hemorrhagic transformation.
  7. Ability to randomize within 60 hours of symptom onset.

Exclusion Criteria:

  1. Any clinical or imaging evidence of spontaneous intracranial hemorrhage in the previous 6 months.

    Note: Patients with hemorrhagic transformation of current or previous ischemic stroke may be included per Investigator's judgment. Sporadic microbleeds may be included per Investigator's judgment. As a general recommendation, a cerebral microbleed is considered to be ≤ 5mm, but sometimes up to 10mm, in greatest diameter on gradient recalled echo (GRE), or T2*, MRI sequences. Any blood visualized on a CT will be classified as a macrobleed.

  2. Infarct volume (estimated) is greater than 50% of middle cerebral artery territory on qualifying scan. If the full extent of the lesion is not visible, any patient with a NIHSS > 23 must be excluded.

    Note: The lesion does not need to be restricted to the mCA, but if the lesion volume is estimated to be greater than half of the mCA territory, the patient should be excluded.

    Note: In non-EVT patients, any NIHSS following the index stroke may be used to qualify the patient for START. For example, a patient that presents with a NIHSS of 10 who then receives tPA and improves to a NIHSS of 2 is still eligible for START. For patients whom had endovascular therapy, the qualifying NIHSS assessment is that which is obtained with their qualifying scan following therapy.

  3. Anticipated need for major surgery over the next 30 days that would require delay, discontinuation, or extended suspension of anticoagulant of more than 5 days.
  4. Symptomatic edema expected from size and location of ischemic stroke.
  5. Decreased level of consciousness present or expected.
  6. Life expectancy less than 90 days.
  7. Follow-up in person or by telephone for 90 days is not feasible.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 72 hours (Day 3-4)
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 72 (+/-24) hours correlates to starting treatment on Day 3-4.
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 72 (+/- 24) hours, 132 (+/- 12) hours, 228 (+/- 12) hours, and 324 (+/- 12) hours.
Experimental: 132 hours (Day 6)
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 132 (+/- 12) hours correlates to starting treatment on Day 6.
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 72 (+/- 24) hours, 132 (+/- 12) hours, 228 (+/- 12) hours, and 324 (+/- 12) hours.
Experimental: 228 hours (Day 10)
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 228 (+/- 12) hours correlates to starting treatment on Day 10.
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 72 (+/- 24) hours, 132 (+/- 12) hours, 228 (+/- 12) hours, and 324 (+/- 12) hours.
Experimental: 324 hours Day 14.
Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 324 (+/- 12) hours starts Day 14.
Other: Time-To-Treatment Randomization
The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 72 (+/- 24) hours, 132 (+/- 12) hours, 228 (+/- 12) hours, and 324 (+/- 12) hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recurrent IschemicEvent
Time Frame: 30 days
Any symptomatic ischemic stroke or systemic embolism as evidenced by either CT or MRI
30 days
Hemorrhagic Event
Time Frame: 30 days
Any symptomatic hemorrhagic transformation of index ischemic stroke, other symptomatic intracranial hemorrhage, or major extracranial hemorrhage as evidenced by CT or MRI
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Modified Rankin Scale
Time Frame: 30 days
A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.
30 days
Modified Rankin Scale
Time Frame: 90 days
A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas at Austin

Collaborators

Lone Star Stroke Research Consortium
Texas Department of State Health Services

Investigators

  • Principal Investigator: Steven Warach, MD, PhD, Dell Medical School at The University of Texas at Austin
  • Principal Investigator: Truman J Milling, MD, Dell Medical School at The University of Texas at Austin
  • Study Chair: Patrick Lawrence, BS, Dell Medical School at The University of Texas at Austin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 14, 2017

Primary Completion (Actual)

August 3, 2023

Study Completion (Estimated)

December 1, 2023

Study Registration Dates

First Submitted

January 12, 2017

First Submitted That Met QC Criteria

January 12, 2017

First Posted (Estimated)

January 16, 2017

Study Record Updates

Last Update Posted (Actual)

August 8, 2023

Last Update Submitted That Met QC Criteria

August 4, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2017-09-0035

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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