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

NCT03021928 | Unknown Phase 3 DMC FDA Drug

• 1 other identifier: 2017-09-0035
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 15

Brief Summary

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

Conditions

Stroke

Keywords

Stroke; Atrial Fibrillation; Anticoagulation; NOAC

Outcome Measures

Primary Outcomes (2)

• Recurrent IschemicEvent

  Any symptomatic ischemic stroke or systemic embolism as evidenced by either CT or MRI

  30 days

• Hemorrhagic Event

  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 Outcomes (2)

• Modified Rankin Scale

  30 days

• Modified Rankin Scale

  90 days

Study Arms (4)

72 hours (Day 3-4)

EXPERIMENTAL

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

132 hours (Day 6)

EXPERIMENTAL

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

228 hours (Day 10)

EXPERIMENTAL

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

324 hours Day 14.

EXPERIMENTAL

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

Interventions

Time-To-Treatment Randomization OTHER

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.

132 hours (Day 6); 228 hours (Day 10); 324 hours Day 14.; 72 hours (Day 3-4)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• New disabling neurological deficit attributable to new ischemic stroke.
• Minimum lesion diameter of 1.5cm on qualifying imaging. If lesion not visible on imaging, NIHSS must be greater than 4.
• Non-valvular atrial fibrillation (paroxysmal, persistent, or permanent).
• 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.
• Treating physician plans to anticoagulate with a FDA-approved novel oral anticoagulant (NOAC): apixaban, dabigatran, edoxaban, or rivaroxaban, or other FDA-approved NOAC.
• 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.
• Ability to randomize within 60 hours of symptom onset.

You may not qualify if:

• 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.
• 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.
• 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.
• Symptomatic edema expected from size and location of ischemic stroke.
• Decreased level of consciousness present or expected.
• Life expectancy less than 90 days.
• Follow-up in person or by telephone for 90 days is not feasible.

Sponsors & Collaborators

• University of Texas at Austin: lead
• Lone Star Stroke Research Consortium: collaborator
• Texas Department of State Health Services: collaborator

Study Sites (15)

Dell Seton Medical Center at The University of Texas

Austin, Texas, 78701, United States

Location

Seton Medical Center Austin

Austin, Texas, 78705, United States

Location

St. David's Medical Center

Austin, Texas, 78705, United States

Location

CHI St. Joseph Health Regional Hospital

Bryan, Texas, 77802, United States

Location

Texas Health Presbyterian Hospital

Dallas, Texas, 75231, United States

Location

Parkland Memorial Hospital

Dallas, Texas, 75235, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

UT Southwestern William P. Clements Hospital

Dallas, Texas, 75390, United States

Location

UT Southwestern Zale Lipshy University Hospital

Dallas, Texas, 75390, United States

Location

Texas Tech University Health Science Center - El Paso University Medical Center

El Paso, Texas, 79905, United States

Location

Texas Health Harris Methodist Hospital

Fort Worth, Texas, 76104, United States

Location

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Seton Medical Center Hays

Kyle, Texas, 78640, United States

Location

Seton Medical Center Williamson

Round Rock, Texas, 78665, United States

Location

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (16)

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• The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997 May 31;349(9065):1569-81.

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• Lee JH, Park KY, Shin JH, Cha JK, Kim HY, Kwon JH, Oh HG, Lee KB, Kim DE, Ha SW, Cho KH, Sohn SI, Oh MS, Yu KH, Lee BC, Kwon SU. Symptomatic hemorrhagic transformation and its predictors in acute ischemic stroke with atrial fibrillation. Eur Neurol. 2010;64(4):193-200. doi: 10.1159/000319048. Epub 2010 Aug 12.

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• January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014 Dec 2;130(23):2071-104. doi: 10.1161/CIR.0000000000000040. Epub 2014 Mar 28. No abstract available.

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• Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S; RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010 Dec;9(12):1157-1163. doi: 10.1016/S1474-4422(10)70274-X. Epub 2010 Nov 6.

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  PMID: 22315271 BACKGROUND

• Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30.

  PMID: 27573206 BACKGROUND

• Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0. Epub 2013 Dec 4.

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• Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, Rueckert C, Pezzini A, Poli L, Padovani A, Csiba L, Szabo L, Sohn SI, Tassinari T, Abdul-Rahim AH, Michel P, Cordier M, Vanacker P, Remillard S, Alberti A, Venti M, Scoditti U, Denti L, Orlandi G, Chiti A, Gialdini G, Bovi P, Carletti M, Rigatelli A, Putaala J, Tatlisumak T, Masotti L, Lorenzini G, Tassi R, Guideri F, Martini G, Tsivgoulis G, Vadikolias K, Liantinioti C, Corea F, Del Sette M, Ageno W, De Lodovici ML, Bono G, Baldi A, D'Anna S, Sacco S, Carolei A, Tiseo C, Acciarresi M, D'Amore C, Imberti D, Zabzuni D, Doronin B, Volodina V, Consoli D, Galati F, Pieroni A, Toni D, Monaco S, Baronello MM, Barlinn K, Pallesen LP, Kepplinger J, Bodechtel U, Gerber J, Deleu D, Melikyan G, Ibrahim F, Akhtar N, Mosconi MG, Bubba V, Silvestri I, Lees KR. Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study. Stroke. 2015 Aug;46(8):2175-82. doi: 10.1161/STROKEAHA.115.008891. Epub 2015 Jun 30.

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• Warach SJ, Davis LA, Lawrence P, Gajewski B, Wick J, Shi F, Shang TT, Olson DM, Prasad S, Birnbaum L, Richardson JM, Savitz SI, Goldberg MP, Cruz-Flores S, Alba I, Anderson J, Kimmel B, Venkatasubba Rao CP, King B, Dula AN, Milling TJ. Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: A Pragmatic, Response-Adaptive Randomized Clinical Trial. JAMA Neurol. 2025 May 1;82(5):470-476. doi: 10.1001/jamaneurol.2025.0285.

  PMID: 40163159 DERIVED

Related Links

• Website for the Lone Star Stroke Consortium

MeSH Terms

Conditions

Stroke; Atrial Fibrillation

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Steven Warach, MD, PhD

  University of Texas at Austin

  PRINCIPAL INVESTIGATOR

• Truman J Milling, MD

  University of Texas at Austin

  PRINCIPAL INVESTIGATOR

• Patrick Lawrence, BS

  University of Texas at Austin

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director; Professor

Study Record Dates

• First Submitted: January 12, 2017
• First Posted: January 16, 2017
• Study Start: June 14, 2017
• Primary Completion: August 3, 2023
• Study Completion: December 1, 2023
• Last Updated: August 8, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)