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

Stroke Clinical Trial

— START  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03021928
• Other study ID #: 2017-09-0035
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 14, 2017
• Est. completion date: December 2023

Study information

• Verified date: August 2023
• Source: University of Texas at Austin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: December 2023
• Est. primary completion date: August 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrial Fibrillation
• Ischemic Stroke
• Stroke

Intervention

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.

Locations

Country	Name	City	State
United States	Dell Seton Medical Center at The University of Texas	Austin	Texas
United States	Seton Medical Center Austin	Austin	Texas
United States	St. David's Medical Center	Austin	Texas
United States	CHI St. Joseph Health Regional Hospital	Bryan	Texas
United States	Baylor University Medical Center	Dallas	Texas
United States	Parkland Memorial Hospital	Dallas	Texas
United States	Texas Health Presbyterian Hospital	Dallas	Texas
United States	UT Southwestern William P. Clements Hospital	Dallas	Texas
United States	UT Southwestern Zale Lipshy University Hospital	Dallas	Texas
United States	Texas Tech University Health Science Center - El Paso University Medical Center	El Paso	Texas
United States	Texas Health Harris Methodist Hospital	Fort Worth	Texas
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	Seton Medical Center Hays	Kyle	Texas
United States	Seton Medical Center Williamson	Round Rock	Texas
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas

Sponsors (3)

Lead Sponsor	Collaborator
University of Texas at Austin	Lone Star Stroke Research Consortium, Texas Department of State Health Services

Country where clinical trial is conducted

United States, 

References & Publications (15)

Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso V, Diener HC, Lees KR; VISTA collaborators. Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol. 2015 Jul;22(7):1048-55. doi: 10.1111/ene.12577. Epub 2014 Oct 16. — View Citation

Bohmann F, Mirceska A, Pfeilschifter J, Lindhoff-Last E, Steinmetz H, Foerch C, Pfeilschifter W. No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke. PLoS One. 2012;7(7):e40804. doi: 10.1371/journal.pone.0040804. Epub 2012 Jul 24. — View Citation

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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. Erratum In: Lancet Neurol. 2011 Jan;10(1):27. — View Citation

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. Erratum In: Circulation. 2014 Dec 2;130(23):e270-1. — View Citation

Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996 Oct;27(10):1765-9. doi: 10.1161/01.str.27.10.1765. — View Citation

Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014 Jul;45(7):2160-236. doi: 10.1161/STR.0000000000000024. Epub 2014 May 1. Erratum In: Stroke. 2015 Feb;46(2):e54. — View Citation

Kim TH, Kim JY, Mun HS, Lee HY, Roh YH, Uhm JS, Pak HN, Lee MH, Joung B. Heparin bridging in warfarin anticoagulation therapy initiation could increase bleeding in non-valvular atrial fibrillation patients: a multicenter propensity-matched analysis. J Thromb Haemost. 2015 Feb;13(2):182-90. doi: 10.1111/jth.12810. Epub 2015 Jan 7. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Sandercock PA, Counsell C, Kane EJ. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2015 Mar 12;2015(3):CD000024. doi: 10.1002/14651858.CD000024.pub4. — View Citation

Shibazaki K, Kimura K, Aoki J, Saji N, Sakai K. Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation. J Neurol Sci. 2013 Aug 15;331(1-2):90-3. doi: 10.1016/j.jns.2013.05.016. Epub 2013 Jun 3. — View Citation

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. — View Citation

You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, Halperin JL, Lip GYH. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e531S-e575S. doi: 10.1378/chest.11-2304. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrent IschemicEvent	Any symptomatic ischemic stroke or systemic embolism as evidenced by either CT or MRI	30 days
Primary	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	Modified Rankin Scale	A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.	30 days
Secondary	Modified Rankin Scale	A modified Rankin scale (mRS) assessment will be performed by a qualified staff member.	90 days

External Links

•   Website for the Lone Star Stroke Consortium