Treat Stroke to Target

Benefit of a Target LDL Cholesterol Less Than 70 mg/dl After an Ischemic Stroke of Atherosclerotic Origin, the Treat Stroke to Target Trial Results

Trial Summarized by: Mohammad-Ali Jazayeri, MD | Reviewed/Approved by: James de Lemos, MD

Evaluation Of Two Secondary Care Strategies After Stroke Or Transient Ischemic Attack (TIA): Achieved Target LDL-C To 100 mg/dL (+/- 10,mg/dl) Or Less Than 70 mg/dL.

The goal of the TST trial was to study in patients with ischemic stroke due to atherosclerotic disease, whether a strategy of intensive lipid lowering to a target LDL <70 mg/dL would reduce the primary endpoint of recurrent non-fatal stroke, myocardial infarction, urgent carotid or coronary revascularization, or vascular death, as compared to a target of 100 mg/dL (+/- 10 mg/dL).

Key Findings

Following an atherosclerotic ischemic stroke, reducing LDL-C to <70 mg/dL compared to 100±10 mg/dL resulted in lower risk for more CV events.

Commentary

Results: Treat Stroke to Target with Pierre Amarenco, MD Principal Investigator Pierre Amarenco, MD provides an overview of the results of the "Treat Stroke to Target" trial, which he presented during Scientific Sessions 2019.

Purpose: To evaluate the reduction in CV events by targeting LDL-C < 70 mg/dl after atherothrombotic ischemic stroke compared to an LDL of 100 ±10 mg/dL.

Trial Design: N=2860. Median 3.5 years follow-up. Open label.  Patients with atherothrombotic ischemic stroke in the past 3 months or TIA in the past 15 days randomized 1:1 to an LDL-C target of < 70 mg/dl compared to an LDL of 100 ±10 mg/dL using statins with or without ezetimibe.

Primary Composite Endpoint: Non-fatal ischemic stroke or MI, new symptoms requiring urgent coronary or carotid revascularization, vascular death

Results: After an atherothrombotic ischemic stroke, targeting LDL-C <70 mg/dL lowered the risk for CV events more than the 100±10 mg/dL target.

  After Median 3.5 Years Primary Composite Endpoint
Mean LDL-C<70 mg/dL 65 mg/dL 121 patients 8.5%
Mean LDL-C 100 ± 10 mg/dL 96 mg/dL 156 patients 10.9%
    HR 0.78 P=0.036

Purpose: Intensive lipid lowering is recommended after atherosclerotic transient ischemic attack (TIA) and stroke, but the optimal target for LDL cholesterol remains uncertain. The goal of the TST trial was to study in patients with ischemic stroke or TIA due to atherosclerotic disease, whether a strategy of intensive lipid lowering to a target LDL <70 mg/dL would reduce the primary endpoint of recurrent non-fatal stroke, myocardial infarction, urgent carotid or coronary revascularization, or vascular death, as compared to a target of 100 mg/dL (+/- 10 mg/dL).

Key Findings: 2860 patients with ischemic stroke in the preceding 3 months or TIA within 15 days with documented atherosclerotic disease were randomized 1:1 to a target LDL of 100+10 mg/dL or less than 70 mg/dL and treated with statins and/or ezetimibe. After a median follow-up of 3.5 years, the groups achieve a mean LDL cholesterol of 96 mg/dL and 65 mg/dL respectively. The primary composite endpoint of ischemic stroke, myocardial infarction, new symptoms requiring urgent revascularization, and vascular death, occurred less in the 70mg/dL target group, as compared to the more liberal LDL goal (121 [8.5%] vs. 156 [10.9%]; adjusted hazard ratio 0.78 [95% CI 0.61-0.98]; P=.036).

Impression: After an ischemic stroke with evidence of atherosclerosis, a target LDL of less than 70 mg/dL reduced the risk of subsequent cardiovascular events, as compared to a target of 100+10 mg/dL, without increasing the risk of hemorrhagic stroke or incident diabetes.

Detailed Results*

Primary Endpoints Results:
Composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and death.

  • Target <70 mg/dL (8.5%) vs. target 100 mg/dL (10.9%); adjusted hazard ratio 0.78 [95% CI 0.61-0.98]; P=.036

Secondary Endpoints Results:
(Target <70 mg/dL [N=1430] vs. target 100 mg/dL [N=1430]):

  • Myocardial infarction or urgent coronary revascularization
    • 20 (1.4%) vs. 31 (2.2%); HR 0.64 (0.37-1.13); P=.12
  • Cerebral infarction or urgent revascularization of carotid or cerebral artery
    • 88 (6.2%) vs. 109 (7.6%); HR 0.81 (0.61-1.07)
  • Cerebral infarction or TIA
    • 120 (8.4%) vs. 139 (9.7%); HR 0.87 (0.68-1.11)
  • Any revascularization procedure (coronary, carotid, or peripheral artery)
    • 94 (6.6%) vs. 99 (6.9%); HR 0.93 (0.70-1.24)
  • Death due to cardiovascular cause
    • 22 (1.5%) vs. 32 (2.2%); HR 0.69 (0.40-1.18)
  • Death due to any cause
    • 88 (6.2%) vs. 93 (6.5%); HR 0.97 (0.73-1.30)
  • Cerebral infarction or intracranial hemorrhage
    • 103 (7.2%) vs. 126 (8.8%); HR 0.82 (0.63-1.07)
  • Intracranial hemorrhage
    • 18 (1.3%) vs. 13 (0.9%); HR 1.38 (0.68-2.82)
  • Newly diagnosed diabetes
    • 103 (7.2%) vs. 82 (5.7%); HR 1.27 (0.95-1.70)
  • Primary outcome or intracranial hemorrhage
    • 133 (9.3%) vs. 165 (11.5%); HR 0.80 (0.63-1.00)

*The trial was originally planned to continue until an accrual of 385 primary endpoints, with follow-up visits conducted every 6 months. The trial was stopped on May 25, 2019 after allocated funds were used, with 277 primary endpoints accrued and a median follow-up 3.5 years (5.3 years in France (61 sites), 2.0 years in Korea (16 sites after joining the trial in late 2015).

Recommended


Related Science

  • Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack. Stroke; a journal of cerebral circulation 2014;45:2160-2236.
  • Sillesen H, Amarenco P, Hennerici MG et al. Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke; a journal of cerebral circulation 2008;39:3297-302.
  • Amarenco P, Goldstein LB, Szarek M et al. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke; a journal of cerebral circulation 2007;38:3198-204.

Background

Trial Design — Randomized, open label trial with parallel assignment to either LDL-C target of <70 mg/dL or a target of 100 mg/dL (+/-10 mg/dL), using statin +/- other lipid lowering therapy?

Trial Population: — 2860 adult (>18 years) patients with recent (<3 months) transient ischemic attack or ischemic stroke of documented atherosclerotic origin; 1430 patients per group to achieve adequate power to detect 25% relative risk reduction in the primary endpoint between the 2 arms.

  • Key inclusion criteria:
    • Adult men & women >18 years of age
    • Ischemic stroke/TIA within 3 months
    • Stroke/TIA assessed with imaging for identification of ischemic lesion (CT/MR)
    • Limb weakness and/or aphasia lasting >10 min
    • Documented atherosclerotic stenosis in carotid arteries, aortic arch, other brain artery, or in coronary arteries using appropriate imaging modalities, AND the following:
      • Statin treatment indicated and no contraindication
      • Rankin score <4
      • Patient or their representative able to provide consent
      • Patient registered in the French social security system
         
  • Key exclusion criteria:
    • Ischemic stroke/TIA due to arterial dissection
    • Cardioembolic mechanism of stroke without documented atherosclerotic stenosis (caveat: patients with atrial fibrillation or a history of recent MI or calcified aortic stenosis can be randomized if otherwise fulfilling inclusion criteria
    • Symptomatic hemorrhagic stroke (caveats: presence of microbleeds on gradient echo imaging (T2*) is not an exclusion criterion; hemorrhagic transformation of ischemic stroke is not an exclusion criterion)
    • Uncontrolled hypertension
    • LDL <100 mg/dL or patients for whom treatment intensification is not possible
    • Follow-up impossible or poor adherence anticipated
    • Co-morbid condition which may interfere with follow-up or evaluation of the primary endpoint
    • Participation in another clinical trial

Primary Endpoint: Composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and death.

Secondary Endpoints:

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

Exploratory Endpoints:

  • Time to deep venous thrombosis and pulmonary embolus
  • Time to atrial fibrillation
  • Time to heart failure hospitalization
  • Time to coronary revascularization
  • Change in high-sensitivity C-reactive protein from baseline to 6 months

Sponsor(s)/Collaborator(s): Assistance Publique - Hôpitaux de Paris (Paris, France); Collaborators: Pfizer, AstraZeneca, Merck Sharp & Dohme Corp.

References

Keywords:
American Heart Association Scientific Sessions; AHA2019; LDL; LDL-C; Cholesterol; Stroke; Transient Ischemic Attack; Statin; Lipid Lowering Therapy

Related clinical topics
Stroke; Ischemic Attack, Transient; Ischemia; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lipid Regulating Agents