Optimal Target Low-density Lipoprotein Cholesterol Level for Small Vessel Occlusion Stroke

Official title

Optimal Target Low-density Lipoprotein Cholesterol Level for Small Vessel Occlusion Stroke (SVO70)

Overview

Lipid-lowering therapy constitutes a cornerstone of secondary prevention in ischemic stroke; however, current stroke guidelines remain deficient in providing optimal target low-density lipoprotein (LDL)-cholesterol levels tailored to the stroke subtypes. Most clinical trials on LDL-cholesterol management have not differentiated between stroke subtypes or have primarily focused on large artery atherosclerosis (LAA) stroke, leaving a gap in evidence for managing LDL-cholesterol in other stroke subtypes, e.g., small vessel occlusion (SVO) stroke. While hypertension is the leading risk factor for SVO strokes, the link between elevated LDL-cholesterol and SVO stroke is also recognized. Establishing optimal LDL-cholesterol targets for SVO stroke would significantly enhance secondary prevention strategies and improve patient outcome. Thus, the investigators aim to compare intensive versus standard lipid-lowering in patients with SVO stroke. SVO70 is a multicenter, prospective, randomized, open, blinded-endpoint clinical trial. Adult participants with objectively confirmed SVO stroke within 180 days of randomization will be included. Exclusion criteria include those with predefined LDL-cholesterol targets for other conditions, statin contraindications, or women who are pregnant, breastfeeding, or planning pregnancy during the study period. Eligible participants will be randomized 1:1 to target LDL-cholesterol \<70 mg/dL (intensive group) or 90-110 mg/dL (standard group). The trial plans to enroll 4,016 participants, with the primary outcome being major adverse cardiovascular events-cardiovascular death, stroke, and acute coronary syndrome-during a follow-up period of at least 4 years. This study would provide valuable information for determining the optimal LDL-cholesterol target for patients with SVO stroke.

Interventions

• Drug Statins and/or Ezetimibe
  Statin ± Ezetimibe to achieve target LDL-cholesterol level
• Drug PCSK9 inhibitor
  The use of PCSK9 inhibitors is permitted to achieve target LDL-cholesterol levels in participants who did not reach the target with statins ± ezetimibe.

Primary outcome measures

• Major adverse cardiovascular event [Time frame: 4 years]

Secondary outcome measures (6)

• Any stroke [Time frame: 4 years]
• Ischemic stroke or transient ischemic attack [Time frame: 4 years]
• Cardiovascular death [Time frame: 4 years]
• Myocardial infarction [Time frame: 4 years]
• Any death [Time frame: 4 years]
• Acute coronary syndrome [Time frame: 4 years]

Eligibility criteria

Inclusion criteria

• Age 19 years or older
• Patients with objectively confirmed small vessel occlusive infarctions in the subcortical or brainstem regions, identified through neuroimaging (MRI or CT)
• Patients with a history of symptomatic ischemic stroke caused by the lesion described in 2), occurring within 180 days prior to enrollment
• Patients or guardians who agree to the study protocol and sign with informed consent

Exclusion criteria

• Patients requiring intensive LDL cholesterol management (LDL-C <70 mg/dL) due to another condition, with LDL cholesterol targets specified in the guidelines for that condition
• Patients contraindicated for statin use (e.g., active liver disease, serum transaminase levels elevated more than three times the normal limit, muscle disorders, hypersensitivity to statins, or taking medications contraindicated for use with statins)
• Women who are pregnant, breastfeeding, or intending to become pregnant during the study period
• Deemed unsuitable for participation in the study for more than four years, as per the investigators' discretion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

South Korea · 46 centers

• Korea University Ansan Hospital — Ansan
• Hallym University Sacred Heart Hospital — Anyang
• Pusan National University Hospital — Busan
• Gyeongsang National University Changwon Hospital — Changwon
• Samsung Changwon Hospital — Changwon
• Chungbuk National University Hospital — Cheongju-si
• Hallym University Chuncheon Sacred Heart Hospital — Chuncheon
• Kangwon National University Hospital — Chuncheon
• … and 38 more centers

Publications

• Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41. doi: 10.1161/01.str.24.1.35. PMID 7678184
• Amarenco P, Benavente O, Goldstein LB, Callahan A 3rd, Sillesen H, Hennerici MG, Gilbert S, Rudolph AE, Simunovic L, Zivin JA, Welch KM; Stroke Prevention by Aggressive Reduction in Cholesterol Levels Investigators. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes. Stroke. 2009 Apr;40(4):1405-9. doi: 10.1161/STROKEAHA.108.534107. Epub PMID 19228842
• Duering M, Biessels GJ, Brodtmann A, Chen C, Cordonnier C, de Leeuw FE, Debette S, Frayne R, Jouvent E, Rost NS, Ter Telgte A, Al-Shahi Salman R, Backes WH, Bae HJ, Brown R, Chabriat H, De Luca A, deCarli C, Dewenter A, Doubal FN, Ewers M, Field TS, Ganesh A, Greenberg S, Helmer KG, Hilal S, Jochems ACC, Jokinen H, Kuijf H, Lam BYK, Lebenberg J, MacIntosh BJ, Maillard P, Mok VCT, Pantoni L, Rudilo PMID 37236211
• Goldstein LB, Amarenco P, Szarek M, Callahan A 3rd, Hennerici M, Sillesen H, Zivin JA, Welch KM; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2008 Jun 10;70(24 Pt 2):2364-70. doi: 10.1212/01.wnl.0000296277.63350.77. Epub 2007 Dec 12. PMID 18077795
• Mok V, Kim JS. Prevention and Management of Cerebral Small Vessel Disease. J Stroke. 2015 May;17(2):111-22. doi: 10.5853/jos.2015.17.2.111. Epub 2015 May 29. PMID 26060798
• Hosomi N, Nagai Y, Kohriyama T, Ohtsuki T, Aoki S, Nezu T, Maruyama H, Sunami N, Yokota C, Kitagawa K, Terayama Y, Takagi M, Ibayashi S, Nakamura M, Origasa H, Fukushima M, Mori E, Minematsu K, Uchiyama S, Shinohara Y, Yamaguchi T, Matsumoto M; J-STARS Collaborators. The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study. EBioMedi PMID 26501105
• Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Wolf ME, Hennerici MG. The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping). Cerebrovasc Dis. 2013;36(1):1-5. doi: 10.1159/000352050. Epub 2013 Jul 30. PMID 23899749
• 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 Cholest PMID 31738483

Identifiers

NCT: NCT06649240 · H-2310-119-1479 · KCT0009043

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗