The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

Abstract

Background: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients.

Methods: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints.

Finding: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events.

Interpretation: Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis.

Funding: This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Keywords: Atherothrombotic infarction; Cholesterol; Hemorrhagic stroke; Ischemic stroke; Statin.

Supplementary Figs. S1–4

Cox proportional hazards for stroke and TIA (S1), atherothrombotic infarction (S2), lacunar infarction (S3), and intracranial hemorrhage (S4) in pre-defined subgroups. Bars represent the relative risk with a 95%CI. p values for interaction test for heterogeneity of treatment across subgroups. *Hazard ratio was not obtained because of low number of subjects and events. TIA, transient ischemic attack. HDL, high density lipoprotein. LDL, low density lipoprotein. SBP, systolic blood pressure. DBP, diastolic blood pressure. ACA, anterior cerebral artery. MCA, middle cerebral artery. PCA, posterior cerebral artery. VA, vertebral artery. BA, basilar artery. mRS, modified Rankin scale. CDR, clinical dementia rating.

Supplementary Figs. S1–4

Cox proportional hazards for stroke and TIA (S1), atherothrombotic infarction (S2), lacunar infarction (S3), and intracranial hemorrhage (S4) in pre-defined subgroups. Bars represent the relative risk with a 95%CI. p values for interaction test for heterogeneity of treatment across subgroups. *Hazard ratio was not obtained because of low number of subjects and events. TIA, transient ischemic attack. HDL, high density lipoprotein. LDL, low density lipoprotein. SBP, systolic blood pressure. DBP, diastolic blood pressure. ACA, anterior cerebral artery. MCA, middle cerebral artery. PCA, posterior cerebral artery. VA, vertebral artery. BA, basilar artery. mRS, modified Rankin scale. CDR, clinical dementia rating.

Supplementary Figs. S1–4

Cox proportional hazards for stroke and TIA (S1), atherothrombotic infarction (S2), lacunar infarction (S3), and intracranial hemorrhage (S4) in pre-defined subgroups. Bars represent the relative risk with a 95%CI. p values for interaction test for heterogeneity of treatment across subgroups. *Hazard ratio was not obtained because of low number of subjects and events. TIA, transient ischemic attack. HDL, high density lipoprotein. LDL, low density lipoprotein. SBP, systolic blood pressure. DBP, diastolic blood pressure. ACA, anterior cerebral artery. MCA, middle cerebral artery. PCA, posterior cerebral artery. VA, vertebral artery. BA, basilar artery. mRS, modified Rankin scale. CDR, clinical dementia rating.

Supplementary Figs. S1–4

Cox proportional hazards for stroke and TIA (S1), atherothrombotic infarction (S2), lacunar infarction (S3), and intracranial hemorrhage (S4) in pre-defined subgroups. Bars represent the relative risk with a 95%CI. p values for interaction test for heterogeneity of treatment across subgroups. *Hazard ratio was not obtained because of low number of subjects and events. TIA, transient ischemic attack. HDL, high density lipoprotein. LDL, low density lipoprotein. SBP, systolic blood pressure. DBP, diastolic blood pressure. ACA, anterior cerebral artery. MCA, middle cerebral artery. PCA, posterior cerebral artery. VA, vertebral artery. BA, basilar artery. mRS, modified Rankin scale. CDR, clinical dementia rating.

Fig. 1

Trial profile.

Fig. 2

Changes in lipid profile and blood pressure. Changes in the lipid profile and blood pressure were analyzed by mixed-effects model with repeated measurements (MMRM). Open and close circles represent adjusted mean, with standard error expressed by error bars. Levels of total cholesterol (A), low density lipoprotein (LDL) cholesterol (B), and triglyceride (C) were lower in the pravastatin group. Level of high density lipoprotein (HDL) cholesterol was higher in the pravastatin group (D). Systolic blood pressure (E) and diastolic blood pressure (F) were appropriately controlled in the normal ranges in both groups. Mean values (mean ± SE) of total cholesterol during follow-up periods in pravastatin group and control group were 4.75 ± 0.02 vs. 5.32 ± 0.02 mmol/L, LDL cholesterol 2.67 ± 0.02 vs. 3.22 ± 0.02 mmol/L, triglyceride 1.45 ± 0.02 vs. 1.52 ± 0.02 mmol/L, HDL cholesterol 1.44 ± 0.01 vs. 1.40 ± 0.01 mmol/L, systolic blood pressure 134.1 ± 0.38 vs. 134.4 ± 0.38 mm Hg, and diastolic blood pressure 76.8 ± 0.25 vs. 77.4 ± 0.25 mm Hg, respectively.

Fig. 3

Kaplan–Meier curves for the primary and secondary endpoints. Although stroke and TIA similarly occurred in the pravastatin and control groups (A), occurrence of atherothrombotic infarction was less frequent in the pravastatin group (B). Occurrence of lacunar infarction (C), cardioembolic infarction (D), and intracranial hemorrhage (E) was similar between the two groups. Hazard ratios are adjusted for the stratification factors at randomization: i.e., stroke subtype (atherothrombotic infarction vs. others), high blood pressure (≥ 150/90 mm Hg vs. not), and diabetes mellitus (absence vs. presence).

Fig. 4

Changes in stroke-related outcomes. Changes in modified Rankin scale score (A), Barthel index score (B), clinical dementia rating score (C), and mini-mental state examination score (D) were analyzed by mixed-effects model with repeated measurements (MMRM). Open and close circles represent adjusted mean, with standard error expressed by error bar.