Treat Stroke to Target (TST)

• ClinicalTrials.gov Identifier: NCT01252875
• Recruitment Status: Completed
• First Posted: December 3, 2010
• Last Update Posted: August 6, 2019
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Pfizer; AstraZeneca; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: December 2, 2010
• First Posted Date: December 3, 2010
• Last Update Posted Date: August 6, 2019
• Actual Study Start Date: March 15, 2010
• Actual Primary Completion Date: May 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2019)

recurrent ischemic stroke or stroke of undetermined origin, myocardial infarction, urgent coronary or carotid revascularization following new symptoms requiring hospitalization, and vascular death. [ Time Frame: each 6 months ]

recurrent ischemic stroke or stroke of undetermined origin, myocardial infarction, urgent coronary or carotid revascularization following new symptoms requiring hospitalization, and vascular death.

Original Primary Outcome Measures (submitted: December 2, 2010)

Recurrent of non fatal stroke, non fatal IM, and vascular death [ Time Frame: each three weeks until target is not achieved then each 6 months ]

Recurrent of non fatal stroke, non fatal IM, and vascular death

Current Secondary Outcome Measures (submitted: May 29, 2019)

• Recurrent nonfatal ischemic stroke [ Time Frame: each 6 months ]
  Recurrent nonfatal ischemic stroke
• Nonfatal myocardial infarction [ Time Frame: each 6 months ]
  Nonfatal myocardial infarction
• Recurrent ischemic stroke, fatal or non [ Time Frame: each 6 months ]
  Recurrent ischemic stroke, fatal or non
• Recurrent ischemic stroke or TIA [ Time Frame: each 6 months ]
  Recurrent ischemic stroke or TIA
• Intracranial hemorrhage (intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma) [ Time Frame: each three weeks until target is not achieved then each 6 months ]
  Intracranial hemorrhage (intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma)
• All stroke (ischemic or hemorrhagic) [ Time Frame: each three weeks until target is not achieved then each 6 months ]
  All stroke (ischemic or hemorrhagic)
• Any major coronary events (including fatal and nonfatal myocardial infarction) [ Time Frame: each 6 months ]
  Any major coronary events (including fatal and nonfatal myocardial infarction)
• Any coronary heart disease end-point (myocardial infarction, hospitalization for acute corornary symptoms, coronary revascularization procedure) [ Time Frame: each 6 months ]
  Any coronary heart disease end-point (myocardial infarction, hospitalization for acute corornary symptoms, coronary revascularization procedure)
• Any revascularisation procedure (coronary, carotid, or peripheral artery)) [ Time Frame: each 6 months ]
  Any revascularisation procedure (coronary, carotid, or peripheral artery))
• Carotid artery revascularization procedure (urgent following new symptoms or elective) [ Time Frame: each 6 months ]
  Carotid artery revascularization procedure (urgent following new symptoms or elective)
• Vascular death (ischemic stroke or undetermined stroke, fatal myocardial infarction, other vascular deaths, sudden death, death of undetermined cause, i.e., without other cause documented such as cancer, infection, accident, suicide, etc…) [ Time Frame: each 6 months ]
  Vascular death (ischemic stroke or undetermined stroke, fatal myocardial infarction, other vascular deaths, sudden death, death of undetermined cause, i.e., without other cause documented such as cancer, infection, accident, suicide, etc…)
• All causes deaths [ Time Frame: each 6 months ]
  All causes deaths
• Primary endpoint plus intracranial hemorrhage [ Time Frame: each 6 months ]
  Primary endpoint plus intracranial hemorrhage
• New onset diabetes [ Time Frame: each 6 months ]
  New onset diabetes

Original Secondary Outcome Measures (submitted: December 2, 2010)

Recurrent of fatal and non fatal stroke, stroke and TIA. [ Time Frame: each three weeks until target is not achieved then each 6 months ]

Recurrent of fatal and non fatal stroke, stroke and TIA, major coronary event (MI, sudden death, coronary revascularization for an ACS), any coronary endpoints (MI, hospitalization for ACS, coronary revascularization), any revascularization procedures (coronary, carotid, peripheral), carotid revascularization (either surgical or endovascular), vascular death, total death

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treat Stroke to Target
• Official Title: EVALUATION OF TWO SECONDARY CARE STRATEGIES AFTER STROKE OR TRANSIENT ISCHEMIC ATTACK (TIA): ACHEIVED TARGET LDL-C TO 100 mg/dL (+/- 10,mg/dL) OR LESS THAN 70 mg/dL.

Brief Summary

The aim of this study is the evaluation of two usual care strategies after stroke or TIA : achieved target LDL-C of 100 mg/dL (+/-10 mg/dL) or less than 70 mg/dL. Investigators will use the statin and titrate the dosage to achieve the target assigned by randomization in monotherapy or in combination with ezetimibe or other drugs.

The primary end-point is the occurrence of recurrent non fatal stroke, non fatal MI, and vascular death in each group.

3760 patients will be recruited and followed for eight and a half years maximum.

Detailed Description

The aim of this study is the evaluation of two usual care strategies after stroke or TIA : achieved target LDL-C of 100 mg/dL (+/-10 mg/dL) or less than 70 mg/dL. Investigators will use the statin and titrate the dosage to achieve the target assigned by randomization in monotherapy or in combination with ezetimibe or other drugs.

Inclusion criteria:

• Recent (less than 3 months) ischemic stroke As soon as possible after the event, once the neurologic deficit is stabilized (investigator judgment). These ischemic strokes include TIA with ischemic lesion documented by CT or MRI.
• Or recent TIA (less than 15 days) without documentation of ischemic lesion on CT/MR imaging. Must be limb weakness or aphasia lasting more than 10 min.
• And documented atherosclerotic stenosis in carotid artery (investigator judgment) (based on the results of Duplex echography, CTA, MRA or X ray- angiography), Or in the aortic arch (investigator judgment) (based on TEE or CTA), Or in other brain artery: vertebral, basilar or other intracranial artery (based on CTA, MRA, XRA), Or in coronary arteries (past history of acute coronary syndrome, coronary revascularization or positive coronary angiography)
• And statin treatment is indicated, following ANSM guidelines (French drug agency), age >18 years, rankin score ≤ 4, patient or a legal representative signs consent, patient is affiliated to social security system

Exclusion criteria :

• Ischemic stroke/TIA du to arterial dissection (investigator judgment)
• Cardiac source of embolism (e.g., mitral stenosis, endomyocardial fibrosis) without documented atherosclerotic stenosis : a patient with atrial fibrillation or a past history of recent myocardial infarction or calcified aortic stenosis can be randomized if he otherwise fulfils inclusion criteria
• Symptomatic hemorrhagic stroke : Presence of microbleeds on gradient echo imaging (T2*) is not an exclusion criteria. Hemorrhagic transformation of an ischemic stroke is not an exclusion criteria
• Uncontrolled hypertension (investigator judgment)
• LDL-C <100 mg/dL or patients for whom treatment intensification is impossible
• F/U impossible or bad observance anticipated.
• Co-morbid condition that may interfere with the F/U or with the evaluation of primary endpoint
• Participation to another clinical trial

The primary end-point is:

Recurrent ischemic stroke or stroke of undetermined origin, myocardial infarction, urgent coronary or carotid revascularization following new symptoms requiring hospitalization, and vascular death.

Secondary endpoints:

• Recurrent nonfatal ischemic stroke
• Nonfatal myocardial infarction
• Recurrent ischemic stroke, fatal or non
• Recurrent ischemic stroke or TIA
• Intracranial hemorrhage (intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma)
• All stroke (ischemic or hemorrhagic)
• Any major coronary events (including fatal and nonfatal myocardial infarction)
• Any coronary heart disease end-point (myocardial infarction, hospitalization for acute corornary symptoms, coronary revascularization procedure)
• Any revascularisation procedure (coronary, carotid, or peripheral artery))
• Carotid artery revascularization procedure (urgent following new symptoms or elective)
• Vascular death (ischemic stroke or undetermined stroke, fatal myocardial infarction, other vascular deaths, sudden death, death of undetermined cause, i.e., without other cause documented such as cancer, infection, accident, suicide, etc…)
• All causes deaths
• Primary endpoint plus intracranial hemorrhage
• New onset diabetes

Hypothesis :

• Follow-up of three years
• Risk of primary end-point in the control group (Target LDL <100 mg/dL) : 4% per year (12 % at 36 months)
• 5% Alpha, 80% power, total number of subject is :
• 3068 patients with a RRR 25%
• 20% drop-out: 3760 patients (385 primary EP)

Study specifications Follow-up : eight and a half years Follow-up visit : every 6 months Number of centers (French Stroke Units, under the auspice of the French Neurovascular Society) : 60-100

Ancillary study As an ancillary study, 800 patients (400 in each arm in 4 centers) will participate in the TST-PLUS (Plaque Ultrasound Study), in which they will have three ultrasound examination (baseline, 1 year and 3 years) and baseline blood sampling. The primary endpoint of this substudy will be the rate of occurrence of new carotid plaque, with the hypothesis that Rate of plaque occurrence in the <100 mg/dL group will be 25% after 3 years (45% in EVA when atherosclerosis was present at baseline) RRR of plaque of 25% in the <70 mg/dL group Alpha 5%, power 80%

As an ancillary study, 1000 patients will participate in the TST-PGS (Pharmacogenetics) Study, in which they will have 1 blood sampling either at baseline or during one of the follow-up visits of TST. The aim of this study is to show that the benefit (risk of ischemic stroke, myocardial infarction, and vascular death) observed with a strategy of LDL-C <0.7 g / l compared to a strategy of LDL-C to 1 ± 0.1 g / l is higher in carriers of polymorphism 719Arg of the gene KIF-6 than non-carriers of this polymorphism.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Ischemic Stroke
• Transient Ischemic Attack
• Atherosclerotic Stenosis

Intervention

• Procedure: Target : 100 mg/dL (+/-10 mg/dL)
  Statin +/- other lipid lowering therapy during 3 years, Target : LDL-C =100 mg/dL (+/-10 mg/dL), recording recurrent non fatal stroke, non fatal MI, and vascular death and others endpoints such as new onset diabetes, hemorrhagic strokes.
  Other Name: treat to target
• Procedure: 70 mg/dL
  Statin +/-lipid lowering therapy during eight and a half years maximum, Target : LDL-C concentration of less than 70 mg/dL, recording recurrent of non fatal stroke, non fatal IM, and vascular death and others endpoints such as: new onset diabetes, hemorrhagic strokes.
  Other Name: treat to target

Study Arms

• LDL-C to100 mg/dL (+/-10 mg/dL)

  Target : 100 mg/dL (+/-10 mg/dL):

  Patients recruited in this arm will receive statin +/-other lipid lowering therapy in order to reach a LDL-C concentration of 100 mg/dL(+/-10 mg/dL).

  Intervention: Procedure: Target : 100 mg/dL (+/-10 mg/dL)
• LDL-C < 70 mg/dL
  70 mg/dL: Patients recruited in this arm will receive statin +/-other lipid lowering therapy in order to reach a LDL-C concentration of less than 70 mg/dL.
  Intervention: Procedure: 70 mg/dL

Publications *

• Amarenco P, Kim JS, Labreuche J, Charles H, Giroud M, Lee BC, Lavallee PC, Mahagne MH, Meseguer E, Nighoghossian N, Steg PG, Vicaut E, Bruckert E; Treat Stroke to Target Investigators. Yield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trial. Stroke. 2022 Nov;53(11):3260-3267. doi: 10.1161/STROKEAHA.122.039728. Epub 2022 Sep 26.
• Amarenco P, Kim JS, Labreuche J, Charles H, Giroud M, Lavallee PC, Lee BC, Mahagne MH, Meseguer E, Nighoghossian N, Steg PG, Vicaut E, Bruckert E; Treat Stroke to Target Investigators*. Intracranial Hemorrhage in the TST Trial. Stroke. 2022 Feb;53(2):457-462. doi: 10.1161/STROKEAHA.121.035846. Epub 2021 Dec 29.
• Amarenco P, Kim JS, Labreuche J, Charles H, Giroud M, Lee BC, Lavallee PC, Mahagne MH, Meseguer E, Nighoghossian N, Steg PG, Vicaut E, Bruckert E; Treat Stroke to Target Investigators; Treat Stroke to Target investigators:. Impact of Lower Versus Higher LDL Cholesterol Targets on Cardiovascular Events After Ischemic Stroke in Patients With Diabetes. Diabetes. 2021 Aug;70(8):1807-1815. doi: 10.2337/db21-0302. Epub 2021 May 12.
• Amarenco P, Hobeanu C, Labreuche J, Charles H, Giroud M, Meseguer E, Lavallee PC, Gabriel Steg P, Vicaut E, Bruckert E, Touboul PJ. Carotid Atherosclerosis Evolution When Targeting a Low-Density Lipoprotein Cholesterol Concentration <70 mg/dL After an Ischemic Stroke of Atherosclerotic Origin. Circulation. 2020 Aug 25;142(8):748-757. doi: 10.1161/CIRCULATIONAHA.120.046774. Epub 2020 Jun 29.
• Amarenco P, Kim JS, Labreuche J, Charles H, Giroud M, Lee BC, Mahagne MH, Nighoghossian N, Gabriel Steg P, Vicaut E, Bruckert E; Treat Stroke to Target Investigators. Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol <70 mg/dL During 5 Years After Ischemic Stroke. Stroke. 2020 Apr;51(4):1231-1239. doi: 10.1161/STROKEAHA.119.028718. Epub 2020 Feb 20.
• Amarenco P, Kim JS, Labreuche J, Giroud M, Lee BC, Mahagne MH, Nighoghossian N, Simon T, Steg PG, Touboul PJ, Vicaut E, Yelles N, Bruckert E. Treat stroke to target trial design: First trial comparing two LDL targets in patients with atherothrombotic strokes. Eur Stroke J. 2019 Sep;4(3):271-280. doi: 10.1177/2396987319838100. Epub 2019 Mar 26.
• Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Bejot Y, Cabrejo L, Cha JK, Ducrocq G, Giroud M, Guidoux C, Hobeanu C, Kim YJ, Lapergue B, Lavallee PC, Lee BC, Lee KB, Leys D, Mahagne MH, Meseguer E, Nighoghossian N, Pico F, Samson Y, Sibon I, Steg PG, Sung SM, Touboul PJ, Touze E, Varenne O, Vicaut E, Yelles N, Bruckert E; Treat Stroke to Target Investigators. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med. 2020 Jan 2;382(1):9. doi: 10.1056/NEJMoa1910355. Epub 2019 Nov 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 15, 2019): 2873
• Original Estimated Enrollment (submitted: December 2, 2010): 3760
• Actual Study Completion Date: May 26, 2019
• Actual Primary Completion Date: May 26, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• • Recent (less than 3 months) ischemic stroke
• As soon as possible after the event, once the neurologic deficit is stabilized (investigator judgment)

• These ischemic strokes include TIA with ischemic lesion documented by CT or MRI

  • Or recent TIA (less than 15 days)

• without documentation of ischemic lesion on CT/MR imaging

• Must be limb weakness or aphasia lasting more than 10 min

  • And documented atherosclerotic stenosis

• In carotid artery (investigator judgment) (based on the results of Duplex echography, CTA, MRA or X ray- angiography)
• Or in the aortic arch (investigator judgment) (based on TEE or CTA)
• Or in other brain artery: vertebral, basilar or other intracranial artery (based on CTA, MRA, XRA)

• Or in coronary arteries (past history of acute coronary syndrome, coronary revascularization or positive coronary angiography)

  • And

• Statin treatment is indicated, following ANSM guidelines (French drug agency)
• age >18 years
• rankin score ≤ 4
• patient or a legal representative signs consent
• Patient is affiliated to social security system

Exclusion Criteria:

• • Ischemic stroke/TIA du to
• arterial dissection (investigator judgment)

• Cardiac source of embolism (e.g., mitral stenosis, endomyocardial fibrosis) without documented atherosclerotic stenosis : a patient with atrial fibrillation or a past history of recent myocardial infarction or calcified aortic stenosis can be randomized if he otherwise fulfils inclusion criteria

  • Symptomatic hemorrhagic stroke

• Presence of microbleeds on gradient echo imaging (T2*) is not an exclusion criteria.

• Hemorrhagic transformation of an ischemic stroke is not an exclusion criteria

  • Uncontrolled hypertension (investigator judgment)
  • LDL-C <100 mg/dL or patients for whom treatment intensification is impossible
  • F/U impossible or bad observance anticipated.
  • Co-morbid condition that may interfere with the F/U or with the evaluation of primary endpoint
  • Participation to another clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT01252875
• Other Study ID Numbers: P081244
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Assistance Publique - Hôpitaux de Paris
• Original Responsible Party: Yannick Vacher, Department Clinical Research of developpement
• Current Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Original Study Sponsor: Same as current

Collaborators

• Pfizer
• AstraZeneca
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Pierre Amarenco, MD; Assistance Publique - Hôpitaux de Paris

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: June 2019