Ultra-Early Combination Antiplatelet Therapy with Cilostazol for the Prevention of Branch Atheromatous Disease: A Multicenter Prospective Study

Abstract

Background and purpose: The optimal use of antiplatelet therapy for intracranial branch atheromatous disease (BAD) is not known.

Methods: We conducted a prospective multicenter, single-group trial of 144 consecutive patients diagnosed with probable BAD. All patients were treated within 12 h of symptom onset to prevent clinical progression using dual antiplatelet therapy with cilostazol plus one oral antiplatelet drug (aspirin or clopidogrel). Endpoints of progressive BAD in the dual therapy group at 2 weeks were compared with a matched historical control group of 142 patients treated with single oral antiplatelet therapy using either cilostazol, aspirin, or clopidogrel.

Results: Progressive motor paresis occurred in 14 patients (9.7%) in the aggressive antiplatelet group, compared with 48 (33.8%) in the matched single antiplatelet group. Multivariate logistic regression analysis revealed the following variables to be associated with a better prognosis for BAD: baseline modified Rankin Scale score, dual oral antiplatelet therapy with cilostazol, and dyslipidemia (odds ratios of 0.616, 0.445, and 0.297, respectively). Hypertension was associated with a worse prognosis for BAD (odds ratio of 1.955).

Conclusions: Our trial showed that clinical progression of BAD was significantly reduced with the administration of ultra-early aggressive combination therapy using cilostazol compared to treatment with antiplatelet monotherapy.

Keywords: Branch atheromatous disease; Cilostazol; Dual antiplatelet therapy; Progressive stroke.

© 2016 The Author(s) Published by S. Karger AG, Basel.

Figures

Fig. 1

Single oral antiplatelet administration. a A 73-year-old man presented with left hand weakness during breakfast, and thereafter his hemiparesis progressively deteriorated. At noon, he was admitted to our hospital on foot but with apparent gait disturbance. Admission MRI DWI revealed a high signal intensity in the right LSA territory. MRA (time of flight, TOF) showed no stenosis of the right M1. A diagnosis of probable BAD was made, and monotherapy (clopidogrel 225 mg) and argatroban were started immediately. The next morning, his left hemiparesis progressed to hemiplegia and MRI (DWI) demonstrated an expanded lesion on hospital day 1, with further expansion on day 7. b An 81-year-old man was found to be unable to drive due to right extremity weakness and was taken immediately by his co-workers by car to our hospital. After admission, progression to mild right hemiparesis and dysarthria was observed. Admission MRI (DWI) showed a partial high intensity lesion in the left ventral pons and no basilar artery stenosis on MRA. A diagnosis of probable BAD was made and monotherapy (aspirin 300 mg) and argatroban were administrated immediately; however, he experienced progressive hemiplegia during the first night of admission and MRI (DWI) on hospital day 1 revealed lesion expansion, with further expansion on day 7.

Fig. 2

Single oral antiplatelet administration. Patients in the monotherapy-matched group were treated with one oral antiplatelet drug plus an intravenous drug such as ozagrel, argatroban or edaravone. Therapy was initiated within 1 h from the time of hospital admission and within 12 h of onset. Patients in the aggressive dual antiplatelet group were given cilostazol (200 mg) plus aspirin (ASA, 300 mg) or cilostazol (200 mg) plus clopidogrel (CLP, 225 mg loading reduced to 75 mg after day 3) in addition to the standard intravenous protocol. Overall oral antiplatelet medication was decreased to one drug after 1 week.

Fig. 3

Aggressive dual oral antiplatelet administration. a A 72-year-old women complained of speech difficulty with right hand weakness after lunch, and was admitted to our hospital in the evening on foot with unsteady gait. The neurological examination on admission revealed dysarthria and mild right hemiparesis. MRI (DWI) on admission showed a high intensity in the left LSA territory, with no stenosis of the M1 on MRA (time of flight, TOF). A diagnosis of probable BAD in the left LSA territory was made. Dual antiplatelet medication (cilostazol 200 mg and clopidogrel 225 mg) and argatroban was administrated immediately. On the next day, the dysarthria and right hemiparesis improved, and there was no evidence of lesion expansion on hospital day 1 or day 7 MRI (DWI). She was discharged home on hospital day 14 with no deficits. b A 76-year-old woman complained of speech difficulty and gait disturbance, and was immediately admitted on foot to our hospital. On admission, her neurological examination showed mild dysarthria, mild right hemiparesis, and mild hemidysethesia. MRI (DWI) on admission showed a pale high-intensity lesion throughout the left PPA territory in the pons without basilar artery stenosis on MRA (TOF). A diagnosis of probable BAD in the left PPA territory of the pons was made and dual antiplatelet medication (cilostazol 200 mg and clopidogrel 225 mg) with argatroban was administrated immediately. On hospital day 1, her symptoms improved, and MRI (DWI) showed a spotty high-intensity lesion in the ventral pons. She was discharged home on hospital day 14 with only mild hemidysesthesia.

Fig. 4

a Univariate logistic regression for prognosis of BAD. Univariate logistic regression analysis revealed the following statistically significant prognostic factors for BAD: mRS at baseline; ozagrel and argatroban as intravenous drugs; oral cilostazol and statin medication, and a previous history of hypertension and obesity. b Multivariate logistic regression for the prognosis of BAD. Multivariate logistic regression analysis revealed the following statistically significant prognostic factors for BAD: mRS at baseline; oral cilostazol; a previous history of hypertension, dyslipidemia, and obesity. χ2 test for multivariate model coefficient: p < 0.001. Selection of variables: forward selection method using likelihood ratio. Variables used: baseline mRS, dextran, ozagrel Na, cilostazol, clopidogrel, statin, hypertension, diabetes mellitus, dyslipidemia, smoking, and obesity. Variables seen in univariate analysis: p < 0.2.