Treat Stroke to Target - Treat Stroke to Target

Contribution To Literature:

The Treat Stroke to Target trial showed that aggressive LDL-C reduction with a goal of <70 mg/dl is superior to more modest reduction with LDL-C of 90-110 mg/dl among patients with ASCVD and evidence of ischemic stroke/TIA.

Description:

The goal of the trial was to assess the safety and efficacy of aggressive lipid lowering with statins among patients with established atherosclerotic cardiovascular disease (ASCVD) and evidence of ischemic stroke or transient ischemic attack (TIA).

Study Design

Eligible patients were randomized in a 1:1 fashion to statin therapy with either a goal low-density lipoprotein cholesterol (LDL-C) of <70 mg/dl (n = 40) or 90-110 mg/dl (n = 40). Any statin and dose was permissible. LDL-C titrations could be done after 3 weeks of randomization. Other lipid-lowering therapy including ezetimibe could be utilized if needed as additional therapy.

  • Total number of enrollees 2,873
  • Duration of follow-up: 5.3 years
  • Mean patient age: 67 years
  • Percentage female: 32%
  • Percentage with diabetes: 23%

Inclusion criteria:

  • ≥18 years of age
  •  Ischemic stroke within the past 3 months with a modified Rankin scale score of 0-3
  • TIA within 15 days
  • Evidence of ASCVD that included stenosis of an extracranial or intracranial cerebral artery, ipsilateral or contralateral to the region of imputed brain ischemia; atherosclerotic plaque of the aortic arch measuring ≥4 mm in thickness; or a known history of coronary artery disease 
  • Indication for statin therapy
  • LDL-C of ≤70 mg/dl if on statin, ≤100 mg/dl if not on statin

Other salient features/characteristics:

  • Index event: Ischemic stroke: 86%
  • Prior stroke/TIA: 11%
  • Prior coronary artery disease: 17%
  • Baseline LDL-C: 135 mg/dl
  • Blood pressure: 141/80 mm Hg
  • Hemoglobin A1c: 6.3%
  • Statin only as therapy for lower-target (LDL-C <70 mg/dl) vs. higher-target (LDL-C 90-110 mg/dl): 65.9% vs. 94%
  • Use of ezetimibe: 33.8% vs. 5.8%
  • 30% drug discontinuation at 2.7 years

Principal Findings:

The trial stopped early due to lack of funding. The primary outcome, major adverse cardiac events (cerebral infarction or stroke of undetermined origin, myocardial infarction [MI], unstable angina followed by urgent coronary artery revascularization, TIA treated with urgent carotid revascularization, CV death) for lower-target vs. higher-target LDL-C, was: 85% vs. 10.9% (hazard ratio 0.78, 95% confidence interval 0.61-0.98, p = 0.04)

  • Nonfatal cerebrovascular accident (CVA)/stroke: 5.7% vs. 7.0%
  • CV death: 1.2% vs. 1.7%

Secondary outcomes for lower-target vs. higher-target:

  • MI or urgent revascularization: 1.4% vs. 2.2% (p = 0.12)
  • All-cause mortality: 6.2% vs. 6.5% (p > 0.05)
  • Intracranial hemorrhage: 1.3% vs. 0.9% (p > 0.05)
  • Mean LDL-C at 3.5 years: 65 vs. 96 mg/dl (p < 0.05)
  • Newly diagnosed diabetes mellitus: 7.2% vs. 5.7% (p > 0.05)

Interpretation:

The results of this trial indicate that aggressive LDL-C reduction with a goal of <70 mg/dl is superior to a more modest reduction with LDL-C of 90-110 mg/dl among patients with ASCVD and evidence of ischemic stroke/TIA. This benefit was driven primarily by a numerically greater reduction in nonfatal CVA/stroke events. Rates of intracranial hemorrhage and new-onset diabetes mellitus were numerically higher with more aggressive control, but not statistically significant. Additional use of nonstatin lipid-lowering therapies, primarily ezetimibe, were necessary in about one third of patients in the lower-target arm. Although this trial was stopped prematurely due to loss of funding, these results are still very important and will likely inform future guidelines. These results also mirror similar findings noted among patients with coronary artery disease. It is unclear if more aggressive lowering (<50 mg/dl) would show greater benefit.

The 2018 American College of Cardiology/American Heart Association cholesterol guideline recommends high-intensity statin use among patients with established ASCVD. In addition, among patients with very high risk ASCVD (multiple major ASCVD events [recent acute coronary syndrome, history of MI, history of ischemic stroke, symptomatic peripheral artery disease] or one major ASCVD event + multiple high-risk conditions [age ≥65 years, heterozygous familial cholesterolemia, percutaneous coronary intervention/coronary artery bypass grafting, diabetes mellitus, hypertension, chronic kidney disease, current smoking, LDL-C ≥100 mg/dl despite treatment, history of chronic heart failure]), treating to LDL-C <70 mg/dl should be considered.

References:

Amarenco P, Kim JS, Labreuche J, et al., on behalf of the Treat Stroke to Target Investigators. A Comparison of Two LDL Cholesterol Targets After Ischemic Stroke. N Engl J Med 2019;Nov 18:[Epub ahead of print].

Editorial: Wechsler LR. Statins and Stroke — It’s Complicated. N Engl J Med 2019;Nov 18:[Epub ahead of print].

Presented by Pierre Amarenco at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 18, 2019.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine

Keywords: AHA Annual Scientific Sessions, AHA19, Atherosclerosis, Brain Ischemia, Cerebral Infarction, Cholesterol, LDL, Constriction, Pathologic, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intracranial Hemorrhages, Ischemic Attack, Transient, Myocardial Infarction, Myocardial Revascularization, Plaque, Atherosclerotic, Primary Prevention, Stroke, Vascular Diseases


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