Statin and Dual Antiplatelet Therapy to Prevent Early Neurological Deterioration in Branch Atheromatous Disease

Acute Stroke Clinical Trial

— SATBRAD  

Official title:

Early Intensive Medical Therapy for the Prevention of Early Neurological Deterioration in Branch Atheromatous Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04824911
• Other study ID #: 202001386A3
• Status: Recruiting
• Phase: Phase 2
• Start date: March 23, 2021
• Est. completion date: July 30, 2026

Study information

• Verified date: September 2023
• Source: Chang Gung Memorial Hospital
• Contact: Yenchu Huang
• Phone: +88653625642
• Email: yenchu.huang[@]msa.hinet.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Branch atheromatous disease (BAD) has been reported to contribute to small-vessel occlusion and is associated with a higher possibility of early neurological deterioration (END). Because the pathology of BAD is due to atherosclerosis, the investigators postulate that early intensive medical treatment with dual antiplatelet therapy(DAPT) and high-intensity statin may prevent END and recurrent stroke. The investigators hypothesise that intensive medical therapy can prevent END in BAD using aspirin, clopidogrel and high-intensity statin.

Description:

The SATBRAD study is a single-centre, prospective, open-label, single-group trial with a historical control group of BAD patients treated with single antiplatelet therapy and regular statin treatment in Chang Gung Memorial Hospital in Taiwan.

Eligible participants are as follows:

1. have a clinical diagnosis of ischemic stroke;

2. National Institute of Health Stroke Scale (NIHSS) score of 1-8;

3. an ischemic lesion on diffuse-weighted imaging located in the middle cerebral artery(MCA) perforator, Heubner's artery or vertebrobasilar perforator territories;

4. BAD, defined by a visible lesion in three or more axial MRI cuts in the MCA perforator territory or Heubner's artery territories or infarcts that extended from the basal surface of the brainstem.

5. can receive intensive medical treatment within 24 hours of stroke onset.

Participants in the intervention group will receive DAPT and high-intensity statin treatment. DAPT treatment is administered within 24 hours of stroke onset, with aspirin (300 mg loading and 100 mg/day) and clopidogrel (300mg and 75m/day). Participants will take aspirin and clopidogrel for 21 days and then keep aspirin or clopidogrel alone. High-intensity statin is administered, including atorvastatin 40-80mg or rosuvastatin 20 mg for 3 months.

A historical control group of patients receiving single oral antiplatelet medication and regular statin treatment will be drawn from previous prospective observation studies which were executed since Jan. 2011 to Dec. 2020. The total sample sizes are 147 for intervention group and 277 for control group.

The primary endpoint is the composite of END, defined as an increase of ≧2 points of NIHSS within 7 days, and recurrent ischemic stroke within 30 days.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 424
• Est. completion date: July 30, 2026
• Est. primary completion date: February 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of ischemic stroke with National Institute of Health Stroke Scale (NIHSS) score of 1-8

• An ischemic lesion on diffuse-weighted imaging located in the MCA perforator, or Heubner's artery territories or vertebro-basilar perforator territories at brain stem.

• Branch atheromatous disease, defined by a visible lesion in three or more axial MRI cuts in the MCA perforator or Heubner's artery territories or infarcts that extended from the basal surface of the brainstem.

• Ability to randomize within 24 hours of time last known free of new ischemic symptoms.

• Head CT or MRI ruling out hemorrhage or other pathology, such as vascular malformation, tumor, or abscess, that could explain symptoms or contraindicate therapy.

• Ability to tolerate high intensity medical therapy, including aspirin at a dose of 50-325 mg/day, clopidogrel with 300mg loading and 75mg after day 2 and high-intensity statin(either atorvastatin 40-80mg or rosuvastatin 20 mg/day).

• Pre-stroke mRS?1

Exclusion Criteria:

• Age < 20 years.

• In the judgment of the treating physician

• A candidate for thrombolysis, endarterectomy or endovascular intervention.

• Receipt of any intravenous or intra-arterial thrombolysis within 1 week prior to index event.

• Patients with more than 50% stenosis of the relevant arteries on magnetic resonance angiography (MRA), including intra- or extra-cranial internal carotid artery, middle cerebral artery or basilar artery.

• Patients with high risk of cardioembolic source, such as atrial fibrillation, acute myocardial infarction, severe heart failure or valvular heart disease.

• Other determined stroke etiology, such as vasculitis, shock, antiphospholipid antibody syndrome and etc.

• Gastrointestinal bleed or major surgery within 3 months prior to index event.

• History of nontraumatic intracranial hemorrhage.

• Clear indication for anticoagulation during the study period (deep venous thrombosis, pulmonary embolism or hypercoagulable state).

• Qualifying ischemic event induced by angiography or surgery.

• Severe non-cardiovascular comorbidity with life expectancy <3 months.

• Contraindication to clopidogrel, aspirin, atorvastatin or rosuvastatin

• Known allergy to clopidogrel, aspirin atorvastatin or rosuvastatin

• Severe renal (serum creatinine >2 mg/dL) or hepatic insufficiency (INR>1.2; ALT>40 U/L or any resultant complication, such as variceal bleeding, encephalopathy, or jaundice)

• Hemostatic disorder or systemic bleeding in the past 3 months

• Current thrombocytopenia (platelet count <100 x109/L) or leukopenia (<2 x109/L)

• History of drug-induced hematologic or hepatic abnormalities

• Anticipated requirement for long-term (>7 day) non-study antiplatelet drugs (e.g., dipyridamole, ticagrelor, ticlopidine), or NSAIDs.

• Low-density lipoprotein<70mg/dl without prior statin treatment in recent one year or within 2 days after recruitment

Related Conditions & MeSH terms

• Acute Stroke
• Dual Antiplatelet Therapy
• Statin
• Stroke

Intervention

Drug:
• Clopidogrel
300mg loading and 75mg/day from day 2
• Aspirin
Aspirin(100-300mg/day)
• Atorvastatin
Atorvastatin 40-80mg/day
• Rosuvastatin
Rosuvastatin 20 mg/day.

Locations

Country	Name	City	State
Taiwan	Yenchu Huang	Chiayi City

Sponsors (1)

Lead Sponsor	Collaborator
Chang Gung Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (14)

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Chung JW, Cha J, Lee MJ, Yu IW, Park MS, Seo WK, Kim ST, Bang OY. Intensive Statin Treatment in Acute Ischaemic Stroke Patients with Intracranial Atherosclerosis: a High-Resolution Magnetic Resonance Imaging study (STAMINA-MRI Study). J Neurol Neurosurg Psychiatry. 2020 Feb;91(2):204-211. doi: 10.1136/jnnp-2019-320893. Epub 2019 Aug 1. — View Citation

Fang JX, Wang EQ, Wang W, Liu Y, Cheng G. The efficacy and safety of high-dose statins in acute phase of ischemic stroke and transient ischemic attack: a systematic review. Intern Emerg Med. 2017 Aug;12(5):679-687. doi: 10.1007/s11739-017-1650-8. Epub 2017 Mar 16. — View Citation

Gao S, Wang YJ, Xu AD, Li YS, Wang DZ. Chinese ischemic stroke subclassification. Front Neurol. 2011 Feb 15;2:6. doi: 10.3389/fneur.2011.00006. eCollection 2011. — View Citation

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625. Epub 2018 Nov 10. Erratum In: Circulation. 2019 Jun 18;139(25):e1182-e1186. Circulation. 2023 Aug 15;148(7):e5. — View Citation

Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225. doi: 10.1056/NEJMoa1800410. Epub 2018 May 16. — View Citation

Kim D, Park JM, Kang K, Cho YJ, Hong KS, Lee KB, Park TH, Lee SJ, Kim JG, Han MK, Kim BJ, Lee J, Cha JK, Kim DH, Nah HW, Kim DE, Ryu WS, Kim JT, Choi KH, Choi JC, Lee BC, Yu KH, Oh MS, Kim WJ, Kwon JH, Shin DI, Sohn SI, Hong JH, Lee JS, Lee J, Gorelick PB, Bae HJ. Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke. Stroke. 2019 May;50(5):1184-1192. doi: 10.1161/STROKEAHA.119.024786. — View Citation

Kim JS, Yoon Y. Single subcortical infarction associated with parental arterial disease: important yet neglected sub-type of atherothrombotic stroke. Int J Stroke. 2013 Apr;8(3):197-203. doi: 10.1111/j.1747-4949.2012.00816.x. Epub 2012 May 9. — View Citation

Kimura T, Tucker A, Sugimura T, Seki T, Fukuda S, Takeuchi S, Miyata S, Fujita T, Hashizume A, Izumi N, Kawasaki K, Katsuno M, Hashimoto M, Sako K. Ultra-Early Combination Antiplatelet Therapy with Cilostazol for the Prevention of Branch Atheromatous Disease: A Multicenter Prospective Study. Cerebrovasc Dis Extra. 2016;6(3):84-95. doi: 10.1159/000450835. Epub 2016 Oct 12. — View Citation

Petrone L, Nannoni S, Del Bene A, Palumbo V, Inzitari D. Branch Atheromatous Disease: A Clinically Meaningful, Yet Unproven Concept. Cerebrovasc Dis. 2016;41(1-2):87-95. doi: 10.1159/000442577. Epub 2015 Dec 16. — View Citation

Siegler JE, Martin-Schild S. Early Neurological Deterioration (END) after stroke: the END depends on the definition. Int J Stroke. 2011 Jun;6(3):211-2. doi: 10.1111/j.1747-4949.2011.00596.x. — View Citation

Wang C, Yi X, Zhang B, Liao D, Lin J, Chi L. Clopidogrel plus aspirin prevents early neurologic deterioration and improves 6-month outcome in patients with acute large artery atherosclerosis stroke. Clin Appl Thromb Hemost. 2015 Jul;21(5):453-61. doi: 10.1177/1076029614551823. Epub 2014 Sep 23. — View Citation

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013 Jul 4;369(1):11-9. doi: 10.1056/NEJMoa1215340. Epub 2013 Jun 26. — View Citation

Yamamoto Y, Ohara T, Hamanaka M, Hosomi A, Tamura A, Akiguchi I. Characteristics of intracranial branch atheromatous disease and its association with progressive motor deficits. J Neurol Sci. 2011 May 15;304(1-2):78-82. doi: 10.1016/j.jns.2011.02.006. Epub 2011 Mar 13. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The percentage of patients with early neurological deterioration within 7 days and recurrent ischemic stroke within 30 days.	The early neurological deterioration is defined as an increase of 2 points of NIHSS.; The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The maximum possible score is 42, with the minimum score being a 0.	30 days
Secondary	Percentage of patients with favorable functional recovery defined as a mRS ?1	Defined as a mRS ?1. The Modified Rankin Scale (mRS) runs from 0-6, running from perfect health without symptoms(score 0) to death(score 6).	90 days
Secondary	Percentage of patients with new clinical vascular events	ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death	90 days
Secondary	Changes of atherosclerotic plaque	The changes of atherosclerotic plaque was measured by high-resolution MRI initially and 6 months later.	6 months
Secondary	Numbers of moderate to severe bleeding events		90 days
Secondary	Total mortality		90 days